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insmed Investor Presentation August 2026 We're in . For patients . 1
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2 Forward Looking Statements The forward-looking statements in this presentation are based upon the Company’s current expectations and beliefs, and involve known and unknown risks, uncertainties and other factors, which may cause the Company’s actual results, performance and achievements and the timing of certain events to differ materially from the results, performance, achievements or timings discussed, projected, anticipated or indicated in any forward-looking statements. Such risks, uncertainties and other factors include, among others, the following: failure to continue to successfully commercialize ARIKAYCE® in the U.S., Europe or Japan or failure to successfully commercialize BRINSUPRI® in the U.S. or Europe, or to maintain U.S., European or Japanese approval for ARIKAYCE or U.S. or E.U. approval for BRINSUPRI; our inability to obtain full approval of ARIKAYCE from the FDA, including the risk that we will not successfully or in a timely manner complete the confirmatory post-marketing clinical trial required for full approval of ARIKAYCE, or our failure to obtain regulatory approval to expand ARIKAYCE’s indication to a broader patient population; failure to obtain, or delays in obtaining, regulatory approvals for our product candidates in the U.S., Europe or Japan, for ARIKAYCE outside of the U.S., Europe and Japan, including separate regulatory approval for the Lamira® Nebulizer System in each market and for each usage, or for BRINSUPRI outside of the U.S. and the E.U.; failure to successfully commercialize our product candidates, if approved by applicable regulatory authorities, or to maintain applicable regulatory approvals for such product candidates, if approved; uncertainties or changes in the degree of market acceptance of our marketed products or, if approved, our product candidates, by physicians, patients, third-party payors and others in the healthcare community; our inability to obtain and maintain adequate reimbursement from government or third-party payors for our marketed products or, if approved, our product candidates, or acceptable prices for our marketed products or, if approved, our product candidates; inaccuracies in our estimates of the size of the potential markets for our marketed products and our product candidates or in data we have used to identify physicians, expected rates of patient uptake, duration of expected treatment, or expected patient adherence or discontinuation rates; failure of third parties on which we are dependent to manufacture sufficient quantities of our marketed products and our product candidates for commercial or clinical needs, as applicable, to conduct our clinical trials, or to comply with our agreements or laws and regulations that impact our business; risks and uncertainties associated with, and the perceived benefits of, our senior secured loan with certain funds managed by Pharmakon Advisors, LP and our royalty financing with OrbiMed Royalty & Credit Opportunities IV, LP, including our ability to maintain compliance with the covenants in the agreements for the senior secured loan and royalty financing and the impact of the restrictions on our operations under these agreements; our inability to create or maintain an effective direct sales and marketing infrastructure or to partner with third parties that offer such an infrastructure for distribution of our marketed products or any of our product candidates that are approved in the future; failure to successfully conduct future clinical trials for our marketed products or our product candidates and our potential inability to enroll or retain sufficient patients to conduct and complete the trials or generate data necessary for regulatory approval of our product candidates or to permit the use of ARIKAYCE in the broader population of patients with MAC lung disease, among other things; development of unexpected safety or efficacy concerns related to our marketed products or our product candidates; risks that our clinical studies will be delayed, that serious side effects will be identified during drug development, or that any protocol amendments submitted will be rejected; failure to successfully predict the time and cost of development, regulatory approval and commercialization for novel gene therapy products; risk that interim, topline or preliminary data from our clinical trials that we announce or publish from time to time may change as more patient data become available or may be interpreted differently if additional data are disclosed, or that blinded data will not be predictive of unblinded data; risk that our competitors may obtain orphan drug exclusivity for a product that is essentially the same as a product we are developing for a particular indication; our inability to attract and retain key personnel or to effectively manage our growth; our inability to successfully integrate our acquisitions and appropriately manage the amount of management’s time and attention devoted to integration activities; risks that our acquired technologies, products and product candidates will not be commercially successful; inability to adapt to our highly competitive and changing environment; inability to access, upgrade or expand our technology systems or difficulties in updating our existing technology or developing or implementing new technology; risk that we are unable to maintain our significant customers; risk that healthcare legislation or other government action materially adversely affects our business; business or economic disruptions due to catastrophes or other events, including natural disasters or public health crises; risk that our current and potential future use of AI and machine learning may not be successful; deterioration in general economic conditions in the U.S., Europe, Japan and globally, including the effect of prolonged periods of inflation, affecting us, our suppliers, third-party service providers and potential partners; risk that we could become involved in costly intellectual property disputes, be unable to adequately protect our intellectual property rights or prevent disclosure of our trade secrets and other proprietary information, and incur costs associated with litigation or other proceedings related to such matters; restrictions or other obligations imposed on us by agreements related to our marketed products or our product candidates, including our license agreements with PARI and AstraZeneca AB, and failure to comply with our obligations under such agreements; the cost and potential reputational damage resulting from litigation to which we are or may become a party, including product liability claims; risk that our operations are subject to a material disruption in the event of a cybersecurity attack or issue; changes in laws and regulations applicable to our business, including any pricing reform and laws that impact our ability to utilize certain third parties in the research, development or manufacture of our product candidates, and failure to comply with such laws and regulations; our history of operating losses, and the possibility that we never achieve or maintain profitability; goodwill impairment charges affecting our results of operations and financial condition; inability to repay our existing indebtedness and uncertainties with respect to our ability to access future capital; and delays in the execution of plans to build out an additional third- party manufacturing facility approved by the appropriate regulatory authorities and unexpected expenses associated with those plans. MAC / MACLD: Mycobacterium avium complex lung disease | FDA: Food & Drug Administration | AI: artificial intelligence
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3 Additional Disclaimers Please be aware that TPIP, INS1201, INS1202, INS1148, and INS1033 are investigational products that have not been approved for sale or found safe or effective by the FDA or any regulatory authority. In addition, ARIKAYCE has not been approved for the treatment of all patients with MAC lung disease and brensocatib has not been approved for the treatment of patients with non-cystic fibrosis bronchiectasis outside the U.S. and the E.U. This presentation is not promotion or advertisement of ARIKAYCE, BRINSUPRI, TPIP, INS1201, INS1202, INS1148, or INS1033. Insmed, ARIKAYCE and BRINSUPRI are registered trademarks of Insmed Incorporated. All other trademarks are property of their respective owner(s). Certain information contained in this presentation relates to or is based on studies, publications, surveys and other data obtained from third-party sources, as well as our own internal estimates and research. While we believe the information in these third-party sources to be reliable as of the date of this presentation, we have not independently verified any such information or the underlying assumptions relied on in such third-party sources. In addition, while we believe our internal research is reliable, such research has not been verified by any independent source. TPIP: treprostinil palmitil inhalation powder | MAC / MACLD: Mycobacterium avium complex lung disease | FDA: Food & Drug Administration
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4 Respiratory Immunology & Inflammation Neuro & Other Rare Research & Business Development Three Therapeutic Areas, One Goal: Develop First- and Best-in-Class* Therapies * “Best-in-disease/best-in-class" indicates a profile that could be considered more attractive than other treatment options for a particular disease. Head-to-head clinical trials are not anticipated.
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5 First-in-Class and Potentially Best-in-Class* Assets Across Each Phase of Development Pre-Clinical Phase 1 Phase 2 Phase 3 Commercial INS1201, Gene Therapy: Duchenne Muscular Dystrophy (DMD) INS1202, Gene Therapy: Amyotrophic Lateral Sclerosis (ALS) INS1203, Gene Therapy: Stargardt Disease INS1033, DPP1 Inhibitor: Rheumatoid Arthritis (RA) INS1033, DPP1 Inhibitor: Ulcerative Colitis (UC) MAC / MACLD: Mycobacterium avium complex lung disease | TPIP: treprostinil palmitil inhalation powder | SCF248 mAb: stem cell factor 248 monoclonal antibody | DPP1: dipeptidyl peptidase 1 inhibitor | I&I: Immunology & Inflammation Therapeutic Area | N&OR: Neuro & Other Rare Therapeutic Area | U.S.: United States | UK: United Kingdom | * “Best-in-disease/best-in-class" indicates a profile that could be considered more attractive than other treatment options for a particular disease. Head-to-head clinical trials are not anticipated. | ** Brensocatib is approved in the U.S., Europe, and the UK. Brensocatib remains under review by regulatory authorities in Japan RESPI RATO RYI& IN & OR Respiratory Immunology & Inflammation Neuro & Other Rare BRINSUPRI® (Brensocatib)**: Non-Cystic Fibrosis Bronchiectasis (NCFB) ARIKAYCE® (Amikacin Liposome Inhalation Suspension): Refractory MAC Lung Disease Amikacin Liposome Inhalation Suspension: MAC Lung Disease TPIP: Pulmonary Hypertension Interstitial Lung Disease (PH-ILD) TPIP: Pulmonary Arterial Hypertension (PAH) TPIP: Progressive Pulmonary Fibrosis (PPF) TPIP: Idiopathic Pulmonary Fibrosis (IPF) INS1148, SCF248 mAb: Progressive Pulmonary Fibrosis (PPF) INS1148, SCF248 mAb: Idiopathic Pulmonary Fibrosis (IPF) INS1033: DPP1 Inhibitor: Chronic Obstructive Pulmonary Disease (COPD)
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6 Second-Quarter Performance Supports Updated Full-Year Guidance for BRINSUPRI Revenue $1.25B to $1.4B † $450M to $470M ‡ Gross-to-Net Mid-20%s to High-20%s Low-20%s to Mid-20%s B: billion | M: million | † BRINSUPRI guidance does not contemplate meaningful revenue contribution from a potential Japanese approval in the second-half of 2026 | ‡ ARIKAYCE guidance does not contemplate contribution from a potential label expansion approval in the U.S. and Japan in 2026 G U I D A N C E G U I D A N C E Full-Year 2026 Previously “Greater than $1B” Previously “Mid-20%s to Low-30%s” Unchanged Unchanged
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7 Peak Revenue Estimate Raised to $14B+ for Three Lead Assets Across Their Respective Indications* B: billion | NCFB / Bronchiectasis: non-cystic fibrosis bronchiectasis | TPIP: treprostinil palmitil inhalation powder | PAH: pulmonary arterial hypertension | PH-ILD: pulmonary hypertension due to interstitial lung disease | PPF: progressive pulmonary fibrosis | IPF: idiopathic pulmonary fibrosis | MAC / MACLD: Mycobacterium avium complex lung disease | COPD: chronic obstructive pulmonary disease | FDA: Food and Drug Administration | * Assumes approval in listed indications by applicable regulatory authorities | † Updated estimate reflects expected growth of the currently addressable NCFB market, driven by earlier and more consistent diagnosis and exacerbation tracking due to increased awareness among physicians and patients. This estimate does not include contributions from the potentially meaningful opportunity of NCFB patients from the comorbid COPD and asthma populations | Note: TPIP is an investigational product that has not been approved for sale or found safe or effective by the FDA or any regulatory authority TPIP Prior Bronchiectasis PAH, PH-ILD, PPF, IPF All MACLD Bronchiectasis† All MACLD PAH & PH-ILD Only $5B+ $7B+ $2B+ $6B+ $1B+ $1B+ $14B+ Updated (Investigational Product) Total Peak Revenue Estimate*
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8 Respiratory T H E R A P E U T I C A R E A
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10 BRINSUPRI Approved by the FDA • Approved in 10 mg and 25 mg tablet form for adults and adolescents 12+ years with NCFB • Indication label has no requirement on number of documented pulmonary exacerbations • 25 mg dose label includes details on statistically significant benefits on FEV1 • Label reflective of the safety profile observed during clinical development Label Offers Physicians Flexibility to Prescribe Either Dose of BRINSUPRI to Patients FDA approval received August 12, 2025 | NCFB / Bronchiectasis: non-cystic fibrosis bronchiectasis | FEV1: forced expiratory volume in 1 second (a key measure of lung function) | mg: milligram
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11 Strong Second-Quarter Revenue Results Increase Confidence to Raise Full-Year 2026 Guidance M: million | B: billion | Q: quarter | † Unaudited revenues for three months ended June 30, 2026 $309.2M Q2 2026 RESULTS GUIDANCE Full-Year 2026 Revenues $1.25 $1.4B Global Net Revenues† to
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12 145 208 309 70 149 200 280 37 71 103 136 29 89 139 131 21 65 86 125 15 62 103 137 7 29 55 79 0 50 100 150 200 250 300 350 BRINSUPRI WINREVAIR OHTUVAYRE DUPIXENT FASENRA REZDIFFRA TEZSPIRE Third Full-Quarter Revenues Continue to Outperform Analogs, Enabled by Operational Excellence U.S.: United States | † Launch-aligned revenues compare each product based on quarters since launch (1 st quarter post-launch, 2nd quarter post-launch, etc.), regardless of calendar quarter or year. All reported revenues are in millions of U.S. dollars. | ‡ Includes the launch-aligned revenues for analog launches in each launch’s fourth full quarter on the market | Note: unaudited BRINSUPRI revenues for the first and second quarters of 2026 | Note: Numbered footnotes referenced on this slide can be found in the appendix of this presentation titled "Launch Analog F ootnotes“ | Note: Product revenues are reported in U.S. dollars and sourced from financial filings and earnings disclosures as described in more detail in the footnotes. Revenues have not been adjusted for inflation and reflect reported values as of the date of public disclosure. Launch-Aligned Revenues by Quarter† 2nd Full Quarter1st Full Quarter 3rd Full Quarter 4th Full Quarter 3rd full quarter BRINSUPRI revenues exceeded 4th full quarter revenues of analog launches‡ ®1 ®4 ®5 2 3 6 7
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13 Strategic Collaborations and Future Studies Aim to Expand Long-Term Evidence European Multi-centre Bronchiectasis Audit and Research Collaboration (EMBARC) 3-year open-label study Up to 3,000 patients Across six countries ► Assess long-term disease modification potential with sustained 25 mg brensocatib treatment ► Evaluate whether earlier brensocatib initiation further slows disease progression Study Goals: v Ongoing plans to demonstrate long-term evidence through Phase 4 and real-world studies in the U.S. that reinforce BRINSUPRI's leadership in NCFB EMBARC: European Multi-centre Bronchiectasis Audit and Research Collaboration (European bronchiectasis registry) | mg: milligram | U.S.: United States | NCFB: non-cystic fibrosis bronchiectasis
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14 Brensocatib in Bronchiectasis Opportunity Could Potentially Reach >1M Patients* TAM: total addressable market | U.S.: United States | *Pending regulatory approval for bronchiectasis indication in specified regions | NCFB / Bronchiectasis: non-cystic fibrosis bronchiectasis | M: million | K: thousand | † EU5 comprised of France, Germany, Italy, Spain and the United Kingdom (UK) | ‡ Includes misdiagnosed, miscoded, and undiagnosed NCFB patients | Note: COPD and asthma patients may be comorbid with bronchiectasis and not all patients with bronchiectasis have comorbid asthma or COPD | Note: Numbered prevalence footnotes referenced on this slide can be found in the appendix of this presentation titl ed “Epidemiological Footnotes” U.S. TAM EU5† TAM Japan TAM Diagnosed with Bronchiectasis1 0.8M2.4M 2.1MUndiagnosed‡ Bronchiectasis2 Asthma or COPD3 150K500K 600K 17M32M 27M
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16 Executing Commercially While Preparing for Label Expansion in the U.S. & Japan* U.S.: United States | Int’l: international | M: million | sNDA: supplemental new drug application | FDA: Food and Drug Administration | PMDA: Pharmaceuticals and Medical Devices Agency | H: half | MACLD: Mycobacterium avium complex lung disease | * if expanded label for ARIKAYCE is approved in the U.S. and Japan | † Unaudited revenues for three months ended June 30, 2026; Growth is vs. same prior year period Preparing for Potential Label Expansion Q2 2026 Revenue† U.S. $70.2M +2.2% Int’l $46.1M +19.1% Worldwide $116.3M +8.3% ✓ Filed sNDA with FDA in July in newly diagnosed MACLD patients • Intend to submit data to PMDA in 2H:26 to support potential Japanese label expansion • Demonstrated clinical evidence and an experienced commercial team position ARIKAYCE for launch success* ► U.S. label expansion would extend ARIKAYCE treatment to all MACLD patients, if approved
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17 ARIKAYCE Has Potential to Be the Best-in-MACLD Treatment U.S.: United States | TAM: total addressable market | MAC / MACLD: Mycobacterium avium complex lung disease; Refractory MAC patients included in all MACLD TAM estimates | K: thousand | * If approved | † EU5 comprised of France, Germany, Italy, Spain and the United Kingdom (UK) | Note: Numbered prevalence footnotes referenced on this slide can be found in the appendix of this presentation titled “Epidemiologi cal Footnotes” 125-145K Refractory MAC4 95-115K 14KMACLD4 15-18K12-17K 1.4K We anticipate marketing ARIKAYCE in newly diagnosed MACLD patients at same price and dosage as currently available ARIKAYCE, if approved * U.S. TAM EU5† TAM Japan TAM
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18 MAC / MACLD: Mycobacterium avium complex lung disease | AZI: Azithromycin | ETH: Ethambutol | EOT: end of treatment | QD: once-daily | U.S.: United States | DCC: durable culture conversion | * A predefined sequential testing approach was applied to control the overall type I error rate (α=0.05) | 1 ARIKAYCE (590 mg) + macrolide-based background regimen consisting of AZI (250 mg) and ETH (15 mg/kg) | 2 Empty liposome control placebo + macrolide-based background regimen consisting of AZI and ETH | 3 Respiratory Symptom Score (RSS) ranges from 0 to 100, with positive change indicating improvement | Culture conversion was defined as no MAC growth on agar and broth media in all sputum cultures at 2 consecutive visits (8 total samples). Durable culture conversion defined as no MAC growth (culture negative) at Months 11, 12, 13, and 15 Key Secondary Endpoint (DCC) 425 adults with new occurrence of MAC lung infection who have not received antibiotics (randomized) ARIKAYCE Arm1 ARIKAYCE + AZI + ETH | QD Comparator Arm2 Placebo + AZI + ETH | QD Primary Endpoint (RSS) Month 13 Month 15 active : placebo Screening 1:1 One Month Off Treatment Three Months Off Treatment Off Treatment Months 1-12 Baseline EOT ENCORE Primary Endpoint • Change from baseline in Respiratory Symptom Score (RSS)3 at Month 13 (one month off treatment) Multiplicity-Controlled Secondary Endpoints* • Proportion of patients achieving culture conversion by Month 13 (one month off treatment) • Proportion of patients achieving durable culture conversion by Month 15 (three months off treatment) • Proportion of patients achieving culture conversion by Months 12 and Month 6 • Change from baseline fatigue symptom score at Month 13 (PROMIS Fatigue T-score) Other Secondary & Exploratory Endpoints • Change from baseline in RSS at Month 15 • Proportion of participants meeting the meaningful within- patient change (MWPC) threshold as reflected in the change in RSS computed from baseline to Month 13 • Time to culture conversion ARIKAYCE Phase 3b in MACLD:
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19 RSS Improvement ✓ Statistically significant at Month 13* ✓ Strengthening of improvement at Month 15^ ✓ Greater proportion of clinically meaningful RSS responders at Month 13 Culture Conversion ✓ Statistically significant greater conversion by Months 6, 12, 13 and 15* ✓ Earlier, greater, and more durable conversion Results Show That Early Treatment With ARIKAYCE + Multidrug Therapy Can Significantly Improve Outcomes for MACLD Patients Treatment with ARIKAYCE1 vs. Comparator2 showed… Safety & Tolerability ✓ >90% completion in both study arms ✓ No new or unexpected safety signals observed AZI: Azithromycin | ETH: Ethambutol | 1 ARIKAYCE (590 mg) + macrolide-based background regimen consisting of AZI (250 mg) and ETH (15 mg/kg) | 2 Empty liposome control placebo + macrolide-based background regimen consisting of AZI and ETH | MAC / MACLD: Mycobacterium avium complex lung disease | RSS: Respiratory Symptom Score | * statistically significant | ^ not multiplicity controlled; nominally statistically significant
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20 Treprostinil Palmitil Inhalation Powder (TPIP) TPIP: treprostinil palmitil inhalation powder | FDA: Food and Drug Administration | Note: TPIP is an investigational product that has not been approved for sale or found safe or effective by the FDA or any regulatory authority
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21 Investigational Once-Daily Prostanoid With the Potential to Deliver Best-in-Class† Efficacy With Enhanced Tolerability TPIP: treprostinil palmitil inhalation powder | PAH: pulmonary arterial hypertension | PH-ILD: pulmonary hypertension due to interstitial lung disease | * Analysis based on safety and tolerability data from the Phase 2a PH-ILD published May 2024, and the Phase 2b PAH study published June 2025 | ** No head-to-head or convenience studies have been conducted or planned | † “Best-in-disease/best- in-class" indicates a profile that could be considered more attractive than other treatment options for a particular disease. Head-to-head clinical trials are not anticipated. Potential Advantages of TPIP Efficacy* • Inhaled therapy delivered directly to the lung tissue • Slow-release properties enable high, consistent treprostinil levels in lungs • Flexibility to titrate up to patient max tolerated dose in pursuit of optimal therapeutic benefit Safety* • Potential for reduced systemic side effects due to lower peak exposure • Inert pro-drug formula may improve tolerability − Shown preclinically to reduce cough vs. active drug of the same dose Convenience** • Administered once daily vs. the 4-times per day of other approved inhaled treprostinils − 1-2 breaths per day (even for 1,280 µg dose) • Less frequent dosing may improve patient adherence to therapy
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22 Four TPIP Indications Represent Substantial Commercial Opportunities TPIP: treprostinil palmitil inhalation powder | TAM: total addressable market | IPF: idiopathic pulmonary fibrosis | PPF: progressive pulmonary fibrosis | PH-ILD: pulmonary hypertension due to interstitial lung disease | PAH: pulmonary arterial hypertension | U.S.: United States | K: thousand | DPI: dry powder inhalation | † EU5 comprised of France, Germany, Italy, Spain and the United Kingdom (UK) | ‡ Wholesale acquisition cost (WAC) as of March 12, 2024 | Note: IPF and PPF estimates do not account for overlap with PH-ILD; estimated that ~10% of IPF and PPF patients may overlap with PH-ILD | Note: Numbered prevalence footnotes referenced on this slide can be found in the appendix of this presentation titled “Epidem iological Footnotes” 15K35K 40KPAH5 PH-ILD6 20K50K 65K TPIP U.S. TAM EU5† TAM Japan TAM ~$300K U.S. Pricing Benchmark TYVASO DPI® List Price‡ PPF7 IPF8 20K145K 90K 20K125K 75K
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23 Expansive Registrational Program Across Four Indications Progressing on Track TPIP: treprostinil palmitil inhalation powder | TRE: treprostinil | PAH: pulmonary arterial hypertension | PH-ILD: pulmonary hypertension due to interstitial lung disease | PPF: progressive pulmonary fibrosis | IPF: idiopathic pulmonary fibrosis | µg: micrograms | Note: Initiation indicates that trial sites are open and ready to screen patients for enrollment PH-ILD IPFPPF PAH TPIP PALM-ILD study actively enrolling PALM-PAH study actively enrolling Phase 3 study initiation expected 2H:26 Phase 3 study initiation expected 1H:27 • TPIP's broad dosing range could provide physicians with the flexibility to optimize the balance between efficacy and tolerability • The flexibility to quickly & safely dose TPIP to higher levels than other inhaled TRE therapies could meaningfully differentiate it within the class All Phase 3 studies permit titration to patient maximum tolerated dose (up to 1,280 µg) ► The ability to continue to dose patients higher on inhaled therapy could delay their need to switch to parenteral options
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24 • Change in baseline exercise capacity (6MWD) at peak exposure (1-3 hours post-dose) • Time to clinical worsening2 • Time to first major morbidity or mortality3 • Change in baseline cardiac stress (NT-proBNP concentration) • Change in baseline 6MWD at trough exposure (pre-dose) at Week 22 • Mean change from baseline in living with pulmonary fibrosis (L-PF) total symptom domain score • Pharmacokinetics PALM-ILD (Week 24) • ILD exacerbations • Change from baseline in Quality of Life (QoL) • Change from baseline lung function (FVC, FEV1) • Respiratory imaging Primary Endpoint Secondary Endpoints Exploratory Endpoints TPIP Phase 3 in PH-ILD: PALM-ILD NCT07179380 Trial summary 4 weeks TPIP 80-1,280 µg inhalation capsules once daily Placebo inhalation capsules once daily Screening Treatment period 24 weeks Baseline End of Study 30 days Follow-up For participants that have not entered the OLE study1 Expect ~344 patients randomized Steady-state period 4-week initial titration to the individual max tolerated dose active : placebo 1:1 End of Treatment Primary Analysis Dose increases allowed up to Week 16 TPIP: treprostinil palmitil inhalation powder | PH-ILD: pulmonary hypertension due to interstitial lung disease (ILD) | 6MWD: 6-minute walk distance | OLE: open-label extension | NT-proBNP: N-terminal pro-B-type natriuretic peptide | FVC: forced vital capacity | FEV1: forced expiratory volume in 1 second (a key measure of lung function) | WHO: World Health Organization | NYHA: New York Heart Association | 1 Participants enrolled in the OLE study will remain on-treatment until Week 104, followed by a 4-week follow-up | 2 Clinical worsening is defined as one of the following: (1) hospitalization due to cardiopulmonary indication related to PH-ILD, (2) deterioration of PH-ILD, including a decrease of 15% or more in 6MWD and/or signs and symptoms of worsened right heart failure or WHO/NYHA functional class, (3) lung transplantation (except pre-planned prior to study), (4) death from any cause. All events will be adjudicated by an independent blinded committee. | 3 Morbidity or mortality defined as one of the following: (1) hospitalization due to cardiopulmonary indication related to the worsening of PH-ILD, (2) lung transplantation (except pre-planned prior to study), (3) death from any cause. Measured at Week 24 unless otherwise specified
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25 • Change in baseline exercise capacity (6MWD) at peak exposure (1-3 hours post-dose) • Proportion of patients with baseline WHO FC improvement • Change in baseline 6MWD at trough exposure (pre-dose) at Week 22 • Change in baseline cardiac stress (NT-proBNP concentration) • Change in baseline PAH-SYMPACT domain scores • Time to clinical worsening2 PALM-PAH (Week 24) • Change from baseline in Quality of Life (QoL) • Plasma concentrations of treprostinil palmitil and treprostinil over time • Safety & tolerability3 Primary Endpoint Secondary Endpoints Exploratory Endpoints TPIP: treprostinil palmitil inhalation powder | PAH: pulmonary arterial hypertension | 6MWD: 6-minute walk distance | OLE: open-label extension | NT-proBNP: N-terminal pro-B-type natriuretic peptide | WHO: World Health Organization | NYHA: New York Heart Association | FC: functional class | 1 Participants enrolled in the OLE study will remain on-treatment until Week 104, followed by a 4-week follow-up | 2 Clinical worsening is defined as one of the following: (1) death from any cause,(2) hospitalization for worsening of PAH (≥24 hours), (3) need for atrial septostomy, (4) worsening-related listing for lung and/or heart-lung transplant, (5) need to initiate parenteral therapy with an approved PAH therapy, or (6) deterioration of PAH (defined as a combination of the following changes from baseline: a decrease in 6MWD of ≥15%, confirmed by 2 tests ≥4 hours but not >2 weeks apart, and signs/symptoms of worsened right heart failure or worsened WHO/NYHA FC). All events will be adjudicated by an independent blinded committee. | 3 including AEs, laboratory assessments, vital signs, and 12- lead electrocardiogram 4 weeks TPIP 80-1,280 µg inhalation capsules once daily Placebo inhalation capsules once daily Screening Treatment period 24 weeks Baseline End of Study 30 days Follow-up For participants that have not entered the OLE study1 Expect ~344 patients randomized Steady-state period 4-week initial titration to the individual max tolerated dose active : placebo 1:1 End of Treatment Primary Analysis Dose increases allowed up to Week 16 Participants on background sotatercept capped at ~20% of sample size (stratification factor) Measured at Week 24 unless otherwise specified TPIP Phase 3 in PAH: PALM-PAH NCT07481981 Trial summary
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26 s Positive OLE Study Results in PAH Reinforce TPIP’s Potential to Become the Prostanoid of Choice Phase 2b Study Results 6MWD Improvement2 (meters) PVR Reduction1 NT-proBNP Reduction3 ~35% * +35.5 ^ ~60% ^ 12-Month Data from Ongoing OLE Study‡ 6MWD Improvement4 (meters) WHO FC I or II Achievement6 NT-proBNP Reduction5 +55 † ~60% † REVEAL Lite 2.0: Refined Low Risk Status Achievement7 ~80% ~65% Results Evaluated Against the Lead-in Study Baseline and Measured ~24 Hours After Dose for Applicable Measures (Not Placebo-Adjusted) Placebo-Adjusted Efficacy Results Measured at Week 16 (~24 Hours After Dose) TPIP: treprostinil palmitil inhalation powder | PAH: pulmonary arterial hypertension | PVR: pulmonary vascular resistance | 6 MWD: 6-minute walk distance | NT-proBNP: N-terminal pro-B-type natriuretic peptide, a biomarker for cardiac stress (concentration levels) | WHO: World Health Organization | FC: functional class | OLE: open -label extension | The REVEAL Lite 2.0 risk calculator is a simplified, non-invasive medical tool used to estimate the mortality and disease progression risk for adult patients with PAH | * Highly statistically significant | ^ Nominally statistically significant; not adjusted for mu ltiplicity | † Metric measured ~24 hours after prior dose was administered and evaluated against the Phase 2b lead -in study pre- randomization baseline value | ‡ Includes all OLE patients in both the “Continued TPIP” and “Placebo Crossed” treatment group s | Note: Numbered footnotes referenced on this slide can be found in the appendix of this presentation
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27 PAH: pulmonary arterial hypertension | FDA: Food and Drug Administration | TPIP: treprostinil palmitil inhalation powder | * Nominal p-value not adjusted for multiplicity | † Covariate-adjusted estimate of location shift. Analysis performed using a rank ANCOVA model, adjusting for treatment group, baseline 6-minute walk distance (6MWD), and randomization stratification factors | 1 Measured ~24 hours after dose FDA Grants Treprostinil Palmitil Orphan Drug Designation in PAH Potential Clinical Superiority Major Contribution to Patient Care Once-daily therapy with: ✓continuity of parenteral treatment ✓localization of inhaled therapy TPIP Profile Efficacy Placebo-Adjusted Improvement in 6MWD † at Week 161 * Nominally statistically significant in Phase 2 +35.5 meters * vs. same drugs already approved for PAH
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28 RCT: randomized clinical trial | PAH: pulmonary arterial hypertension | TPIP: treprostinil palmitil inhalation powder | 6MWD: 6-minute walk distance | OLE: open-label extension | NYHA: New York Heart Association | FC: functional class | NT-proBNP: N- terminal pro-B-type natriuretic peptide | Ph: phase | PVR: pulmonary vascular resistance | WHO: World Health Organization | m: meters | pg/mL: picograms per milliliter | FDA: Food and Drug Administration | * Baseline is the measurement at Visit 1 of SOTERIA or the last measure from the parent study before rollover | **Phase 2 PULSAR data for PVR is included because it represents the largest reduction in PVR achieved by sotatercept in a published randomized placebo-controlled clinical trial | Note: A lead-in study may also be referred to as a parent study in different OLE designs | Note: Cross-trial comparisons are inherently limited and should be interpreted with caution. Differences in study design, patient populations, and prespecified statistical analysis plans may affect comparability. | Note: Numbered footnotes referenced on this slide can be found in the appendix of this presentation titled “TPIP Footnotes” | Note: TYVASO and WINREVAIR are trademarks of their respective owners TPIP’s Profile Could Represent a Compelling Option in the Evolving PAH Treatment Landscape RCT (16 weeks) OLE (12 months) RCT (12 weeks) OLE (12 months) RCT (24 weeks) OLE (SOTERIA) (12 months)13 Phase 2b (Lead-in) Continued Treatment Placebo Crossed X Phase 3 TRIUMPH (Lead-in) Continued Treatment Placebo Crossed X Ph2 PULSAR** or Ph3 STELLAR (Lead-ins)13 Continued Treatment Placebo Crossed PVR -35%1 N/A N/A X N/A N/A N/A X -34%** (0.7 mg dose)14 N/A N/A 6MWD (meters) +35.52 +55.74 vs. lead-in baseline +54.14 vs. lead-in baseline X +209 +3810 vs. lead-in baseline +2510 vs. lead-in baseline X +4115 -1.716 vs. OLE baseline* +4716 vs. OLE baseline* NT-proBNP (pg/mL) -60%3 -60%5 vs. lead-in baseline -60%5 vs. lead-in baseline X -18711 N/A N/A X -44217 -3318 vs. OLE baseline* -82718 vs. OLE baseline* Functional Class 30% of patients on treatment improved WHO FC8 ~80% of OLE patients achieved FC I or II6 X No difference in NYHA FC between groups12 N/A N/A X 29% of patients on treatment improved WHO FC19 ≥80% of OLE patients achieved FC I or II20 TPIP Investigational product that has not been approved for sale or found safe or effective by the FDA or any regulatory authority
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29 INS1148
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30 INS1148: Potential First-in-Class Therapy for Respiratory and I&I Diseases c-Kit: critical receptor tyrosine kinase protein on cell surfaces; binding site to SCF to trigger growth signals | IL: interleukin; cell signaling cytokines | TGFβ: transforming growth factor-beta; cytokine regulating cell growth, differentiation and tissue homeostasis | PPF: progressive pulmonary fibrosis | IPF: idiopathic pulmonary fibrosis | * Humanized monoclonal antibody | 1SCF is the only known ligand for the c-Kit receptor with two known splice variants: SCF220 and SCF248. SCF220 is ubiquitously expressed and exerts its biological function as a transmembrane dimer that binds to c-Kit to signal homeostatic & tissue healing pathways | 2 Cytokines with the ability to promote inflammation, tissue remodeling, and fibrosis when upregulated | SCF: stem cell factor | I&I: immunological & inflammatory | ILC2: Group 2 innate lymphoid cells that produce different cytokines to direct immune responses INS1148* is designed to selectively target SCF248, a specific isoform of SCF (c-Kit receptor ligand1) ✓ Inhibits upstream SCF248/c-Kit signaling associated with inflammatory diseases ✓ Preserves homeostatic & tissue healing pathways associated with SCF2201 Plan to initiate Phase 2 programs in PPF and IPF Inflammatory Mediators SCF248/c-Kit Signaling Pathway Upstream Inflammatory SCF248 Signaling Secreted Cytokines2 (IL-4, IL-9, IL-13, IL-25, TGFβ, etc.) Immune Cells with SCF248 c-Kit Receptors (Mast Cells, ILC2, Eosinophils, etc.) When INS1148 is not present When INS1148 is present ✓ SCF248 Signaling Inhibited ✓ SCF220 Signaling Preserved1 Return to Quiescent Tissue INS1148 (Y) Selectively Binds SCF248 ( ) Fibroblasts (Nearby Quiescent Tissue) Myofibroblasts Expressing SCF248 ( )
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31 Respiratory Therapeutic Area Portfolio & Pipeline NCFB / Bronchiectasis: non-cystic fibrosis bronchiectasis | MAC / MACLD: Mycobacterium avium complex lung disease | TPIP: treprostinil palmitil inhalation powder | PH-ILD: pulmonary hypertension due to interstitial lung disease | PAH: pulmonary arterial hypertension | PPF: progressive pulmonary fibrosis | IPF: idiopathic pulmonary fibrosis | COPD: chronic obstructive pulmonary disease | FDA: Food and Drug Administration | PMDA: Pharmaceuticals and Medical Devices Agency | U.S.: United States | H: half | Ph: phase | * Brensocatib is approved in the U.S., Europe, and UK. Brensocatib remains under review by regulatory authorities in Japan | Initiation indicates that trial sites are open and ready to screen participants for enrollment BRINSUPRI® (brensocatib) Bronchiectasis* Pre-Clinical Ph1 Ph2 Ph 3 Commercial TPIP PH-ILD PAH PPF IPF INS1148 PPF IPF ARIKAYCE® Refractory MAC MAC Lung Disease DPP1 Inhibitors INS1033: COPD Anticipated Catalysts 2H:26 | 2H:26 | 2H:26 | PALM-PPF: Ph3 trial initiation 1H:27 | PALM-IPF: Ph3 trial initiation BRINSUPRI: Japanese regulatory decision* ARIKAYCE: Review ENCORE data with PMDA
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32 Immunology & Inflammation T H E R A P E U T I C A R E A
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33 Immunology & Inflammation Therapeutic Area Pipeline Pre-Clinical Ph1 Ph2 Ph 3 Commercial DPP1 Inhibitors INS1033: RA INS1033: UC RA: rheumatoid arthritis | UC: ulcerative colitis | Q: quarter | Ph: phase | Initiation indicates that trial sites are open and ready to screen participants for enrollment Anticipated Catalysts Q3:26 | RA: Ph1 study initiation in healthy volunteers
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34 Neuro & Other Rare T H E R A P E U T I C A R E A
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35 The IDMC will meet after the completion of the 30-day safety period for the last participant in Cohorts 1 and Cohort 3 for a safety review before initiating to Cohort 2 and Cohort 4 IDMC: Independent Data Monitoring Committee | ddPCR: droplet digital polymerase chain reaction | DNA: deoxyribonucleic acid | DMD: Duchenne muscular dystrophy Primary Endpoint • Safety and tolerability (up to Week 96) Secondary Endpoints • Muscle dystrophin levels (DNA and protein expression) measured by ddPCR and quantitative protein analysis (Week 16 & 48) Exploratory Endpoints • Multiple age-appropriate functional and developmental outcomes ASCEND INS1201 Phase 1 in DMD: ASCEND NCT06817382 Trial summary Cohort 2 3 - <5 years old Higher Dose (3 patients) Cohort 4 2 years old Higher Dose (3 patients) Screening Key Trial Information • Patients must be ambulatory at time of screening • Single dose via intrathecal administration Cohort 3 2 years old Lower Dose (3 patients) Cohort 1 3 - <5 years old Lower Dose (3 patients) Expect ~12 patients
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36 INS1202 Phase 1 in ALS: ARMOR NCT07290062 Trial summary The IDMC will meet after the completion of the 30-day safety period required between dosing the last participant at a given dose level and the first participant at the subsequent dose level within the same ALS subtype Primary Endpoint • Safety and tolerability (up to Week 48) Secondary Endpoints • Recommended Phase 2 dose (RP2D) (up to Week 48) Exploratory Endpoints • Viral vector shedding following the intrathecal administration of INS1202 by ddPCR ARMOR Cohort 3 High Dose Sporadic & SOD1 (5 patients each) Screening Key Trial Information • Cohort enrollment will be staggered, with a 30-day safety observation between the first 3 participants in a cohort regardless of ALS subpopulation • ALS subtypes in Cohorts 2 and 3 can enroll in parallel contingent upon full enrolment of the prior cohort • Single dose via intrathecal administration Cohort 2 Medium Dose Sporadic & SOD1 (5 patients each) Cohort 1 Low Dose Sporadic ONLY (3 patients) Expect ~23 patients IDMC: Independent Data Monitoring Committee | ddPCR: droplet digital polymerase chain reaction | ALS: amyotrophic lateral sclerosis | SOD1: superoxide dismutase 1 gene
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37 Anticipated Catalysts ’26/’27 | ASCEND DMD updates ’26/’27 | ARMOR ALS updates 2027 | IND for Stargardt filing Neuro & Other Rare Therapeutic Area Pipeline Gene Therapy INS1201: DMD INS1202: ALS* INS1203: Stargardt Pre-Clinical Ph1 Ph2 Ph 3 Commercial DMD: Duchenne muscular dystrophy | ALS: amyotrophic lateral sclerosis | IND: investigational new drug application | H: half | Ph: phase | * Studying both SOD1 (superoxide dismutase 1 gene) and sporadic ALS
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38 Research Engine PRE-CLINICAL PROGRAMS & BUSINESS DEVELOPMENT
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39 Multi-Dimensional Early-Stage Research Portfolio Number of Active Pre-Clinical Programs % of Overall Spend on Pre-Clinical Programs Estimated Number of INDs Filed Per Year >30 <20% 1-2 IND: investigational new drug application Gene Therapy Other Research De-Immunized Therapeutic Proteins Synthetic Rescue
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40 Pre-Clinical Research Programs and Business Development Expected to Fuel Future Waves of Growth Our Approach Low upfront costs to acquire technologies Intrathecally Delivered Gene Therapy Deimmunized Protein Engineering Using AI End-Joining Gene Therapy Our Pre-Clinical Platforms Synthetic Rescue Low ongoing expense Pre-clinical Programs <20% Other Expenditures IND: investigational new drug application | AI: artificial intelligence | RNA: ribonucleic acid
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41 Our Culture Is Our Greatest Strength In a recent survey* >90% of employees who responded said they felt: Proud to work at Insmed Inspired by what we do Confident in Insmed’s future Driven to do their best work * The 2025 annual Insmed Pulse Survey included 92% participation across the organization Accolades that span the globe
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42 Appendix
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43 Strong, Long-Dated Patent Exclusivity U.S.: United States | a Based on U.S. Patent Application No.18/024,040 and ex-U.S. counterpart applications issuing as patents. Additionally, given the complexity of drug product (liposomal inhalation with specific nebulizer), required bioequivalence testing could be difficult and lead to few generic entrants.| b Based on potential patent term extension (PTE) in the U.S. and U.S. Application No. 16/975,292, which has been allowed, issuing in the U.S. | c Based on European SPC (supplementary protection certificate) and Japan PTE being capped at 5 years | d Based on U.S. Application No. 18/513,377 and ex-U.S. counterparts issuing as a patent BRINSUPRI ARIKAYCE TPIP Current Exclusivity Potential Exclusivity Current Exclusivity Potential Exclusivity Current Exclusivity Potential Exclusivity 2034 2041d 2034 2041d 2034 2041d 2040 2040+b 2039 2040+c 2035 2040c 2035 2041a 2035 2041a 2035 2041a U.S. EUJapan
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44 Manufacturing Country of Origin BrensocatibARIKAYCE TPIP API Drug Product Spain Canada API Drug Product Taiwan U.S. API Drug Product UK To come online Canada China1 API: active pharmaceutical ingredient | U.S.: United States | UK: United Kingdom | 1 Amikacin sulfate starting materials are fermented and synthesized in China and the API is then finished at ACS Dobfar in Italy Project underway to establish brensocatib secondary source manufacturing in the U.S.
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45 Brensocatib Phase 3 in Bronchiectasis: NCT04594369 Trial summary Adults Stratification • Sputum Pseudomonas aeruginosa culture status at screening (positive or negative) • Number of exacerbations in the prior 12 months (2 or ≥3) • Geographic region (Europe, Japan, North America, or ROW) Primary Endpoint • Annualized rate of adjudicated pulmonary exacerbations* over 52 weeks Secondary Endpoints (Hierarchical) • Time to first pulmonary exacerbation • Proportion of patients who remained exacerbation- free • Change from baseline in post-bronchodilator FEV1 at week 52 • Annualized rate of severe exacerbations • Change from baseline in QoL-B Respiratory Symptom Domain score at week 52 ASPEN NCFB / Bronchiectasis: non-cystic fibrosis bronchiectasis | FEV1: forced expiratory volume in 1 second (a key measure of lung function) | QoL-B: Quality of Life-Bronchiectasis Questionnaire | ROW: rest of world | * Defined as the presence of ≥3 of the following symptoms for at least 48 hours, resulting in a physician’s decision to prescribe systemic antibiotics: (1) increased cough, (2) increased sputum production or change in sputum consistency, (3) increased sputum purulence, (4) increased breathlessness and/or decreased exercise tolerance, (5) fatigue and/or malaise, or (6) hemoptysis Adults (1,680) 4 weeks Screening Baseline End of Trial Week 52 End of Study Week 56 6 weeks Brensocatib 10 mg once daily Brensocatib 25 mg once daily Placebo once daily Off Treatment 1,721 patients randomized 1:1:1 2:2:1 Adolescents (41) Treatment period 52 weeks RESPIRATORY | Brensocatib (Bronchiectasis)
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46 Phase 3 ASPEN Study a Clear Win: Primary Endpoint Achieved Statistical Significance on Both Doses NCFB / Bronchiectasis: non-cystic fibrosis bronchiectasis | PE: pulmonary exacerbation | FEV1: forced expiratory volume in 1 second (a key measure of lung function) | QoL-B: Quality of Life-Bronchiectasis Questionnaire | mg: milligram | * statistically significant | ^ nominally significant p-value Brensocatib 10 mg compared to placebo Brensocatib 25 mg compared to placebo Primary Endpoint Reduction in annualized rate of PEs 21.1% p = 0.0019* 19.4% p = 0.0046* Secondary Endpoints Prolongation of time to first PE 18.7% p = 0.0100* 17.5% p = 0.0182* Increase in odds of remaining exacerbation free over 52 weeks 41.2% p = 0.0059* 40.0% p = 0.0074* Change from baseline in post-bronchodilator FEV1 at week 52 11 mL p = 0.3841 38 mL p = 0.0054* Reduction in annualized rate of severe PEs 25.8% p = 0.1277 26.0% p = 0.1025 Change from baseline in the QoL-B Respiratory Score at week 52 2.0 points p = 0.0594 3.8 points p = 0.0004^ RESPIRATORY | Brensocatib (Bronchiectasis)
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47 ASPEN: Annualized Rate of Adjudicated Pulmonary Exacerbations Over 52 Weeks ITT: intention-to-treat | NCFB / Bronchiectasis: non-cystic fibrosis bronchiectasis | mg: milligram | n: number of patients | a Exacerbations were adjudicated events in the ITT analysis set analyzed using a negative binomial model | b P value is statistically significant when adjusted for multiplicity control 1.015 1.036 1.286 0 0.5 1 1.5 Brensocatib 10 mg Brensocatib 25 mg Placebo Annualized rate of exacerbationsa 21.1% Risk reduction 19.4% Risk reduction Brensocatib 10 mg n=583 Brensocatib 25 mg n=575 Rate ratio vs. placebo (95% CI) 0.789 (0.680–0.916) 0.806 (0.694–0.936) P-value 0.0019b 0.0046b Primary endpoint Risk Reduction Consistent Across Nearly All Pre-specified Subgroups RESPIRATORY | Brensocatib (Bronchiectasis)
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48 ARIKAYCE Phase 3 Programs to Potentially Expand MAC Indication NCT04677543 & NCT04677569 Trial summaries ENCORE Primary Endpoint • Change from baseline respiratory symptom score at Month 13 (one month off treatment) Select Secondary Endpoints • Proportion of patients achieving culture conversion at Months 6, 12, and 13 • Proportion of patients achieving durable culture conversion at Month 15 (three months off treatment) ARISE Primary Endpoint • Demonstrate reliability, validity and responsiveness of the patient reported outcome (PRO) / symptom scores (at Baseline / Baseline to Month 7) Select Secondary Endpoints • Demonstrate effect of ARIKAYCE on culture conversion / time to first culture conversion (Month 7) • Recurrence of MAC relapse or new infection (Month 7) MAC / MACLD: Mycobacterium avium complex lung disease | AZI: Azithromycin | ETH: Ethambutol | PMR: post marketing requirement Key Endpoints Double-Blind Registration PMR Trial Culture Negativity Endpoint Months 1-6 ARIKAYCE + AZI + ETH Off Treatment 425 Adults enrolled with new MAC lung disease randomized Psychometric Validation Study Month 7 Placebo + AZI + ETH 99 Adults enrolled with new MAC lung disease randomized ENCORE ARISE Screening Months 1-12 ARIKAYCE + AZI + ETH Placebo + AZI + ETH Key Endpoints Off Treatment Month 13 Month 15 1:1 1:1 active : placebo active : placebo RESPIRATORY | ARIKAYCE
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49 ARISE: QoL-B Respiratory Score Changes* Show Clear Separation When PGI-S Category Improved vs. No Change or Decline QoL-B: Quality of Life-Bronchiectasis Respiratory Domain questionnaire | PGI-S: Patient Global Impression of Severity | MAC: Mycobacterium avium complex | * Includes patient data from both the treatment and control arm of the ARISE study Estimated Meaningful Score Difference Region is +12.2 to +16.7 points Estimated Meaningful Score Difference for QoL-B Resp. in MAC patients is +14.8 points RESPIRATORY | ARIKAYCE (Refractory MAC)
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50 QoL-B Respiratory Domain ALIS+AZI+ETH N=48 ELC+AZI+ETH N=51 Difference # of Participants Evaluated for Change from Baseline to Month 7 43 48 # of Missing Change from Baseline to Month 7 Value 5 3 Change in PRO Score from Baseline to Month 7 (LS-Mean) 12.24 7.76 4.48 (95% Confidence Interval) (7.96, 16.53) (3.76, 11.77) (-0.97, 9.93) p-value 0.1073 ARISE: Comparison Between Treatment Arms Shows Clear Favorable Trend for ARIKAYCE Arm MAC / MACLD: Mycobacterium avium complex lung disease | ALIS: amikacin liposome inhalation suspension | AZI: azithromycin | ELC: empty liposome control | ETH: ethambutol | LS: least-squares | QoL-B: Quality of Life-Bronchiectasis Respiratory Domain questionnaire | PRO: patient-reported outcome | MAC: Mycobacterium avium complex | ITT: intention-to-treat | N: number of patients ITT analysis with multiple imputation for missing data ANCOVA model includes change from baseline as response variable and treatment, baseline Resp Score, and history of MAC lung infection as independent variables. RESPIRATORY | ARIKAYCE (Refractory MAC)
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51 -50 -45 -40 -35 -30 -25 -20 -15 -10 -5 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 0 10 20 30 40 50 60 70 80 90 100 Cumulative Percentage ELC+AZI+ETH (N=51) ALIS+AZI+ETH (N=48) Median change among patients responding 'somewhat better' on PGI-S (median= 14.8) Worsening Improvement Change from Baseline to Month 7 in QoL-B Respiratory Symptom score (9 Items) ARISE: QoL-B Respiratory Score Changes from Baseline to Month 7 Show Clear Separation for ARIKAYCE Group CDF: cumulative distribution function | ALIS: amikacin liposome inhalation suspension | AZI: azithromycin | ELC: empty liposome control | ETH: ethambutol | QoL-B: Quality of Life-Bronchiectasis Respiratory Domain questionnaire | MAC / MACLD: Mycobacterium avium complex lung disease | N/n: number of patients Estimated Meaningful Score Difference for QoL-B Resp. in MAC patients is +14.8 points Estimated Meaningful Score Difference Region is +12.2 to +16.7 points 43.8% of patients in ARIKAYCE arm achieved >14.8-point improvement 33.3% of patients in control arm achieved >14.8-point improvement RESPIRATORY | ARIKAYCE (Refractory MAC)
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52 ARISE: Significantly* Higher, More Persistent Culture Conversion in ARIKAYCE Arm ALIS: amikacin liposome inhalation suspension | AZI: azithromycin | ELC: empty liposome control | ETH: ethambutol | MAC / MACLD: Mycobacterium avium complex lung disease | * “Nominally statistically significant” because no hierarchical testing or adjustment for multiplicity was conducted in ARISE 80.6% 78.8% 63.9% 47.1% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% Month 6 Month 7 Percentage of Patients Achieving Culture Conversion, Months 6 and 7 ALIS+AZI+ETH ELC+AZI+ETH Difference at Month 7 Nominally Statistically Significant* (p-value = 0.0010) Proportions estimated by Standardized Logistic Regression with treatment group and History of MAC Lung Infection as factors in the model with multiple imputation for missing data. RESPIRATORY | ARIKAYCE (Refractory MAC)
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53 ARISE: For Those Who Achieved Culture Conversion, Patients in ARIKAYCE Arm Converted Faster ALIS: amikacin liposome inhalation suspension | AZI: azithromycin | ELC: empty liposome control | ETH: ethambutol | MAC: Mycobacterium avium complex 74% 47% 0% 10% 20% 30% 40% 50% 60% 70% 80% ALIS+AZI+ETH ELC+AZI+ETH Percentage of Patients with Two Consecutive Negative Cultures by Month 2, Of Those Who Converted By Month 6 ~74% of converters on ARIKAYCE achieved clinical conversion at the first possible time point (Month 2) vs. ~47% for the control arm RESPIRATORY | ARIKAYCE (Refractory MAC)
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54 ALIS+AZI+ETH (N=48) Culture Converted by Month 6 Not Culture Converted by Month 6 Difference Change in QoL-B Resp. Score (Baseline to Month 7) +15.74 +3.53 +12.21 (95% Confidence Interval) (+11.45, +20.03) (-5.34, +12.41) (+2.33, +22.08) p-value 0.0167 Culture Converted by Month 7 Not Culture Converted by Month 7 Difference Change in QoL-B Resp. Score (Baseline to Month 7) +14.89 +4.50 +10.39 (95% Confidence Interval) (+10.47, +19.31) (-4.40, +13.40) (+0.42, +20.37) p-value 0.0416 ARISE: Correlation Shown Between Culture Conversion and QoL-B Respiratory Score Changes in ARIKAYCE Arm ALIS: amikacin liposome inhalation suspension | AZI: azithromycin | ETH: ethambutol | LS: least-squares | QoL-B: Quality of Life-Bronchiectasis Respiratory Domain questionnaire | MAC: Mycobacterium avium complex ANCOVA model includes change from baseline as the response variable and baseline Resp Score, and culture conversion status as independent variables using observed data. RESPIRATORY | ARIKAYCE (Refractory MAC)
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55 ALIS+AZI+ETH N=48 ELC+AZI+ETH N=51 Total N=99 Study completion (%) 44 (91.7) 48 (94.1) 92 (92.9) Treatment completion with all 3 drugs (%) 35 (72.9) 47 (92.2) 82 (82.8) Early ALIS/ELC discontinuation (%) 11 (22.9) 4 (7.8) 15 (15.2) Any TEAE (%) 44 (91.7) 41 (80.4) 85 (85.9) Dysphonia (%) 20 (41.7) 2 (3.9) 22 (22.2) Cough (%) 13 (27.1) 4 (7.8) 17 (17.2) Diarrhea (%) 13 (27.1) 13 (25.5) 26 (26.3) COVID-19 (%) 6 (12.5) 5 (9.8) 11 (11.1) # Participants with Serious TEAE (%) 7 (14.6) 3 (5.9) 10 (10.1) ARISE: No New or Unexpected Safety Signals in ARISE ALIS: amikacin liposome inhalation suspension | AZI: azithromycin | ELC: empty liposome control | ETH: ethambutol | TEAE: treatment-emergent adverse event | MAC: Mycobacterium avium complex | N: number of patients All serious TEAEs unrelated to ARIKAYCE RESPIRATORY | ARIKAYCE (Refractory MAC)
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56 ARIKAYCE Arm1 N=213 Comparator Arm2 N=212 Total N=425 Age: Median at Screening, Years 68.0 69.0 68.0 ≥65, % (n) 67.1% (143) 70.3% (149) 68.7% (292) Sex: Female, % (n) 80.3% (171) 78.3% (166) 79.3% (337) Geographic Region: % (n)* North America 24.4% (52) 25.5% (54) 24.9% (106) Japan 20.2% (43) 19.3% (41) 19.8% (84) Europe 26.8% (57) 25.9% (55) 26.4% (112) Rest of the World 28.6% (61) 29.2% (62) 28.9% (123) Race: % (n) White 62.9% (134) 62.7% (133) 62.8% (267) Asian 32.4% (69) 35.4% (75) 33.9% (144) Other 4.7% (10) 1.9% (4) 3.3% (14) History of MAC Lung Infection3: Initial,% (n)* 82.2% (175) 82.5% (175) 82.4% (350) Mean Baseline† Respiratory Symptom Score4 (RSS), Points 63.91 61.52 62.72 Mean Baseline PROMIS Fatigue T-Score, Points 55.23 54.88 55.05 Baseline Characteristics Were Well-Balanced Across Arms MAC / MACLD: Mycobacterium avium complex lung disease | AZI: Azithromycin | ETH: Ethambutol | N/n: number of patients | 1 ARIKAYCE (590 mg) + macrolide-based background regimen consisting of AZI (250 mg) and ETH (15 mg/kg) | 2 Empty liposome control placebo + macrolide-based background regimen consisting of AZI and ETH | 3 Initial diagnosis defined as a patient being diagnosed with MAC lung infection for the first time. Subsequent diagnosis defined as a previously infected MAC patient being reinfected with the disease (new infection). A reinfected patient is not the same as a refractory patient, who did not culture convert on initial therapy and must add or switch therapies to treat the same infection | 4 RSS ranges from 0 to 100, with positive change indicating improvement | † Baseline value is the last non-missing value prior to the first dose of ARIKAYCE or empty liposomal control placebo | * randomization stratification factors RESPIRATORY | ARIKAYCE (MACLD)
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57 MAC / MACLD: Mycobacterium avium complex lung disease | AZI: Azithromycin | ETH: Ethambutol | RSS: Respiratory Symptom Score | LS: least-squares | SE: standard error | CI: confidence interval | SAP: statistical analysis plan | N: number of patients | 1 RSS ranges from 0 to 100, with positive change indicating improvement | 2 ARIKAYCE (590 mg) + macrolide-based background regimen consisting of AZI (250 mg) and ETH (15 mg/kg) | 3 Empty liposome control placebo + macrolide-based background regimen consisting of AZI and ETH | 4 LS mean changes from baseline RSS to Month 15 for the ARIKAYCE and Comparator arms were 16.63 points and 11.83 points, respectively | † ANCOVA (analysis of covariance) model includes change from baseline as the dependent variable and treatment, baseline RSS, history of MAC lung infection (initial or subsequent), and region as independent variables. Multiple imputations are applied to impute the missing RSS scores in the analysis using ANCOVA according to the type of incurrent events and the assumptions of mission data mechanism described in the SAP | * statistically significant | ^ nominal not adjusted for multiplicity control Symptom benefit at Month 15 expands to a 4.80-point difference4,†, favoring the ARIKAYCE arm (p=0.0015^) Exploratory Endpoint RSS: Statistically Significant Improvement in RSS1 Observed With ARIKAYCE at Month 13 PRIMARY ENDPOINT 17.77 14.66 0 5 10 15 20 ALIS Arm Comparator Arm LS Mean Change From Baseline RSS to Month 13† ARIKAYCE Arm2 N=213 Comparator Arm3 N=212 3.11 points, p=0.0299* 95% CI [0.30, 5.92] SE (1.01) SE (1.01) Change From Baseline RSS to Month 15 RESPIRATORY | ARIKAYCE (MACLD)
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58 Responder Analysis: ARIKAYCE Arm Showed Higher Rates of Clinically Meaningful Improvement in RSS1 at Month 13 Meaningful Within-Patient Change in RSS Secondary Endpoint Separation observed between arms consistently favored ARIKAYCE across a range of possible RSS improvement thresholds that could be determined clinically meaningful by the FDA CDF (%) 16.67 — ARIKAYCE Arm2 — Comparator Arm3 8.0% Difference at lower threshold favoring ARIKAYCE arm p=0.0570^ 8.2% Difference at higher threshold favoring ARIKAYCE arm p=0.0390^ Predicted Change in RSS (Points) I M P R O V E M E N T D E T E R I O R A T I O N Estimated Range of Meaningful Within-Patient RSS Improvement† 20.83 MAC / MACLD: Mycobacterium avium complex lung disease | AZI: Azithromycin | ETH: Ethambutol | RSS: Respiratory Symptom Score | CDF: covariate-adjusted cumulative distribution function | FDA: Food and Drug Administration | MWPC: meaningful within-patient change | 1 RSS ranges from 0 to 100, with positive change indicating improvement | 2 ARIKAYCE (590 mg) + macrolide-based background regimen consisting of AZI (250 mg) and ETH (15 mg/kg) | 3 Empty liposome control placebo + macrolide-based background regimen consisting of AZI and ETH | Note: 53.4% of ARIKAYCE arm participants achieved the 16.67 MWPC in RSS threshold (vs. 45.4% in the Comparator arm) and 43.5% of ARIKAYCE arm participants achieved the 20.83 MWPC in RSS threshold (vs. 35.5% in the Comparator arm); using the standardized logistic regression (SLR); analysis includes treatment group, baseline, region, and history of MAC lung infection (initial or subsequent) as factors in model | ^ nominal not adjusted for multiplicity control | † Estimated threshold range established using data (prior to unblinding) from the Phase 3 ARISE and ENCORE studies RESPIRATORY | ARIKAYCE (MACLD)
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59 MAC / MACLD: Mycobacterium avium complex lung disease | AZI: Azithromycin | ETH: Ethambutol | SAP: statistical analysis plan | SE: standard error | N: number of patients | 1 Conversion by Month 13 was defined as negative MAC cultures at Month 12 and Month 13 after applying adjustment rules as specified in the SAP | 2 ARIKAYCE (590 mg) + macrolide-based background regimen consisting of AZI (250 mg) and ETH (15 mg/kg) | 3 Empty liposome control placebo + macrolide-based background regimen consisting of AZI and ETH | † standardized logistic regression (SLR); analysis includes treatment group, region, and history of MAC lung infection (initial or subsequent) as factors in model. Multiple imputations are applied to impute the missing culture conversion results in the analysis using SLR model according to the type of incurrent events and the assumptions of missing data mechanism as described in the SAP | * statistically significant 82.4% 55.6% 0 20 40 60 80 100 26.8%-points, p<0.0001* 95% CI [18.3%, 35.3%] Rate of Culture Conversion (%) by Month 13† ARIKAYCE Arm2 N=213 Comparator Arm3 N=212 Culture Conversion: Statistically Significant Greater Proportion of ARIKAYCE Patients Achieved Culture Conversion1 by Month 13 SECONDARY ENDPOINT SE (2.7%) SE (3.4%) RESPIRATORY | ARIKAYCE (MACLD)
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60 MAC / MACLD: Mycobacterium avium complex lung disease | AZI: Azithromycin | ETH: Ethambutol | SAP: statistical analysis plan | SE: standard error | N: number of patients | 1 Durable converters at Month 15 are participants who achieved and maintained negative MAC cultures by Months 11, 12, 13 and 15 after applying adjustment rules as specified in the SAP | 2 ARIKAYCE (590 mg) + macrolide-based background regimen consisting of AZI (250 mg) and ETH (15 mg/kg) | 3 Empty liposome control placebo + macrolide-based background regimen consisting of AZI and ETH | † standardized logistic regression (SLR); analysis includes treatment group, region, and history of MAC lung infection (initial or subsequent) as factors in model. Multiple imputations are applied to impute the missing culture conversion results in the analysis using SLR model according to the type of incurrent events and the assumptions of missing data mechanism as described in the SAP | * statistically significant 76.2% 47.6% 0 20 40 60 80 100 28.6%-points, p<0.0001* 95% CI [19.7%, 37.5%] Rate of Durable Culture Conversion (%) by Month 15† ARIKAYCE Arm2 N=213 Comparator Arm3 N=212 Statistically Significant Greater Proportion of ARIKAYCE Patients Achieved Durable Culture Conversion1 by Month 15 KEY SECONDARY ENDPOINT SE (3.0%) SE (3.4%) RESPIRATORY | ARIKAYCE (MACLD)
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61 Earlier and Greater Culture Conversion1 Rates Were Achieved in ARIKAYCE Arm at Every Measured Timepoint 71.5 80.7 84.0 84.3 87.8 88.9 86.5 86.9 88.0 84.0 84.7 82.4 76.2 43.6 53.1 56.4 53.8 57.0 60.5 60.8 64.0 63.4 59.8 61.3 55.6 47.6 0 20 40 60 80 100 2 3 4 5 6 7 8 9 10 11 12 13 15 ARIKAYCE Arm Comparator Arm Proportion of Patients with Culture Conversion, ±SE (%)† Month ARIKAYCE Arm3 Comparator Arm4 MAC / MACLD: Mycobacterium avium complex lung disease | AZI: Azithromycin | ETH: Ethambutol | SE: standard error | SAP: statistical analysis plan | EOT: end of treatment | DCC: durable culture conversion | 1Culture conversion rate at each visit from Month 2 to Month 13 is displayed as the second month of 2 consecutive negative cultures after applying adjustment rules as specified in the SAP | 2 Durable converters at Month 15 are participants who achieved and maintained negative MAC cultures by Months 11, 12, 13 and 15 after applying adjustment rules as specified in the SAP | 3 ARIKAYCE (590 mg) + macrolide-based background regimen consisting of AZI (250 mg) and ETH (15 mg/kg) | 4 Empty liposome control placebo + macrolide-based background regimen consisting of AZI and ETH | † standardized logistic regression (SLR); analysis includes treatment group, region, and history of MAC lung infection (initial or subsequent) as factors in model. Multiple imputations are applied to impute the missing culture conversion results in the analysis using SLR model according to the type of incurrent events and the assumptions of missing data mechanism as described in the SAP | ‡ ARIKAYCE arm achieved median time to culture conversion at Month 2 vs. Month 3 for the active comparator arm (Hazard Ratio of 2.03, suggesting that patients treated with ARIKAYCE were roughly twice as likely to achieve culture conversion (nominal p<0.0001, not adjusted for multiplicity control) Time to Culture Conversion Exploratory Endpoint ARIKAYCE patients were roughly twice as likely to achieve earlier culture conversion vs. active comparator patients‡ (EOT) (DCC)2 RESPIRATORY | ARIKAYCE (MACLD)
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62 Safety: No New or Unexpected Safety Signals Observed ARIKAYCE Arm1 N=213 Comparator Arm2 N=212 DISPOSITION % n % n Study Completion** 90.6% 193 93.4% 198 ARIKAYCE/Comparator Treatment Completion 81.7% 174 88.2% 187 ARIKAYCE/Comparator Discontinuation 18.3% 39 11.8% 25 SAFETY TEAES 98.1% 209 97.2% 206 Serious 14.1% 30 11.3% 24 Severe 15.0% 32 10.4% 22 Leading to ARIKAYCE/Comparator Discontinuation 14.6% 31 8.5% 18 Leading to Death 0.5% 1 0.5% 1 Most Common TEAEs Reported* Dysphonia 58.7% 125 8.5% 18 Cough 32.9% 70 14.6% 31 Fatigue 17.4% 37 11.3% 24 Dyspnea 16.4% 35 5.7% 12 Nausea 15.5% 33 12.7% 27 Headache 12.7% 27 11.8% 25 MAC / MACLD: Mycobacterium avium complex lung disease | AZI: Azithromycin | ETH: Ethambutol | 1 ARIKAYCE (590 mg) + macrolide-based background regimen consisting of AZI (250 mg) and ETH (15 mg/kg) | 2 Empty liposome control placebo + macrolide-based background regimen consisting of AZI and ETH | N/n: number of patients | TEAE: treatment-emergent adverse event | * TEAEs that occurred in ≥10% of the ARIKAYCE arm and were elevated compared to the Comparator arm | ** Patients may discontinue one or more of the treatments in the study, but not discontinue the entire study Tolerability profile of ARIKAYCE + multidrug therapy was consistent with known profiles of these therapies >90% completion observed for both study arms** No deaths were considered ARIKAYCE- or placebo-related RESPIRATORY | ARIKAYCE (MACLD)
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63 TPIP showed substantially lower Cmax and longer half-life Supports the potential for improved tolerability, efficacy and convenience • Safety profile was generally well tolerated, AEs were mild and consistent with inhaled prostanoid • Tolerability was improved with an up-titration approach • Findings suggest TPIP may be safely dosed at nominal doses far in excess of TYVASO® • PK supports development of TPIP with once daily dosing • TPIP showed substantially lower Cmax and longer half- life than that of TYVASO® • Future studies would use an up-titration dosing schedule to the maximum individual tolerated dose exceeding 600 µg once daily TPIP Phase 1 Study: Key Takeaways TPIP: treprostinil palmitil inhalation powder | AE: adverse event | Cmax: highest concentration of a drug in blood, fluid, or target organ after dosing | PK: pharmacokinetics RESPIRATORY | TPIP
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64 TPIP Phase 2a in PH-ILD Primary Endpoints Secondary Endpoints • Pharmacokinetics • Safety and tolerability • Oxygenation at exercise Exploratory Endpoints • Improvement in 6-Minute Walk Distance (6MWD) • Improvement in biomarkers of cardiac stress (NT-proBNP) • Improvement in lung function and pulmonary vascular volume (FRI) • Improvements in Quality of Life (CAMPHOR questionnaire) • Clinical worsening* TPIP: treprostinil palmitil inhalation powder | PH-ILD: pulmonary hypertension due to interstitial lung disease | 6MWD: 6-minute walk distance | NT-proBNP: N-terminal pro-B-type natriuretic peptide | FRI: functional respiratory imaging | * Clinical worsening is defined as one of the following: (1) Hospitalization due to a cardiopulmonary indication, (2) Lung transplantation, (3) Death from any cause, or (4) Decrease in 6MWD of at least 15% from baseline (at 2 consecutive visits at least 24 hours apart), directly related to disease NCT05176951 Trial summary PH-ILD Trial4 weeks TPIP 80-640 µg inhalation capsules once daily* Placebo inhalation capsules once daily Screening Treatment period 16 weeks Baseline End of Treatment Primary Analysis End of Study 4 weeks Follow-up 39 patients randomized active : placebo Steady-state period 3-week titration period; last dose increase at week 5 visit 3:1 RESPIRATORY | TPIP (PH-ILD)
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65 PH-ILD Phase 2 Study Met Primary Objective of Safety and Tolerability, With Lower Rates of Treatment Discontinuation and SAEs vs. Placebo TEAE: treatment emergent adverse event | SAE: serious adverse event | TPIP: treprostinil palmitil inhalation powder | PH-ILD: pulmonary hypertension due to interstitial lung disease | N/n: number of patients | 1 Based on investigator’s evaluation | 2 All events of cough were mild, and none led to treatment discontinuation. | 3 Includes any death that occurred on or after the first dose date. All deaths in the trial were related to disease progression or comorbid causes and none were attributed to TPIP. TPIP (N=29) Placebo (N=10) Dose Titration % Patients Titrated to Maximum 640 µg Dose of TPIP or Placebo (n) % Patients Titrated to at least 480 µg Dose of TPIP or Placebo (n) 79.3% (23) 89.6% (26) 100.0% (10) 100.0% (10) % Patients with Any TEAE (n) 93.1% (27) 90.0% (9) % Patients with Study Drug Related1 TEAE (n) % Patients with Study Drug Related Cough2 (n) 55.2% (16) 37.9% (11) 40.0% (4) 0.0% (0) % Patients with TEAE Leading to Treatment Discontinuation (n) 13.8% (4) 30.0% (3) % Patients with Any SAE (n) 20.7% (6) 40.0% (4) % Patients with Study Drug Related1 SAE (n) 0.0% (0) 0.0% (0) % Patient Deaths3 (n) 6.9% (2) 20.0% (2) Trial was randomized 3:1 TPIP vs. placebo RESPIRATORY | TPIP (PH-ILD)
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66 PH-ILD Phase 2 Exploratory Efficacy Endpoints Support Advancement Into Phase 3 PH-ILD: pulmonary hypertension due to interstitial lung disease | TPIP: treprostinil palmitil inhalation powder | 6MWD: 6-minute walk distance | N/n: number of patients | pg/mL: picograms per milliliter | 1 Calculation based on Hodges-Lehmann Estimate Location Shift | 2 Calculation based on geometric mean | 3 Calculation based on Fisher's Exact Test | 4 Two placebo patients each experienced two events, but this analysis counted only one event per subject Trial was randomized 3:1 TPIP vs. placebo TPIP (N=29) Placebo (N=10) Week 16 n Week 16 n 6-Minute Walk Distance (6MWD) Treatment effect (TPIP vs. placebo) at Week 161 (m) Confidence interval P-value 30 [-49.0, 171.0] 0.3484 29 N/A 10 NT-proBNP concentrations (pg/mL)2 (Baseline concentrations) Geometric mean ratio to Baseline (Geometric SD) 197.50 (242.90) 0.81 (3.36) 24 382.59 (338.43) 1.13 (1.50) 7 % Patients with Clinical Worsening Event (n) P-value (TPIP vs. placebo)3 10.3% (3) 0.0164 29 50.0% (5)4 10 % Patients hospitalized due to cardiopulmonary indication (n) 0.0% (0) 29 30.0% (3) 10 % Patients with decrease in 6MWD ≥ 15% from Baseline (n) 3.4% (1) 29 20.0% (2) 10 % Patients who died from any cause (n) 6.9% (2) 29 20.0% (2) 10 RESPIRATORY | TPIP (PH-ILD)
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67 TPIP: Change From Baseline in Small and Large Blood Vessels SD: standard deviation | TPIP: treprostinil palmitil inhalation powder | BV5A: volume of pulmonary arteries smaller than 5 mm2 in cross-sectional area | BV10A: volume of pulmonary arteries larger than 10 mm2 in cross- sectional area | PH-ILD: pulmonary hypertension due to interstitial lung disease | n: number of patients | a Effect size was calculated as a percentage of the treatment effect divided by the placebo arm baseline mean. There was a consistent increase of blood volume in small arteries observed with TPIP vs. placebo Baseline, mean (SD) Change from baseline, % Effect size,a % P valueTPIP (n=9) Placebo (n=5) TPIP (n=9) Placebo (n=5) BV5A (mL) volume of pulmonary arteries <5 mm2 19.5 (7.3) 33.6 (21.1) +14.0 –7.5 +13.0 0.24 BV5A PR (%) volume of small arteries (<5 mm2) as a fraction of total pulmonary vessel volume 24.1 (5.0) 27.6 (8.2) +8.4 –5.5 +13.7 0.02 BV5A PRA (%) volume of small arteries (<5 mm2) as a fraction of total pulmonary artery volume 44.4 (8.1) 47.1 (13.2) +8.0 –3.8 +13.6 0.05 BV10A (mL) volume of pulmonary arteries >10 mm2 11.9 (6.5) 15.8 (6.4) –7.1 +16.3 –25.7 0.14 BV10A PR (%) volume of large arteries (>10 mm2) as a fraction of total pulmonary vessel volume 14.0 (4.3) 14.6 (5.2) –10.8 +16.4 –23.2 0.08 BV10A PRA (%) volume of large arteries (>10 mm2) as a fraction of total pulmonary artery volume 25.7 (7.0) 25.0 (8.5) –12.0 +18.7 –24.8 0.07 BV5A:BV10A RATIO 2.0 (1.1) 2.6 (2.5) +31.4 –10.5 +49.4 0.17 Lung imaging results from the Phase 2 PH-ILD study RESPIRATORY | TPIP (PH-ILD)
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68 TPIP: Change From Baseline in High Attenuation Abnormality Scorea A numerical decrease from baseline in the HAA score observed with TPIP and slight increase with placebo HAA: high-attenuation abnormality | SD: standard deviation | TPIP: treprostinil palmitil inhalation powder PH-ILD: pulmonary hypertension due to interstitial lung disease | N/n: number of patients | a A deep-learning algorithm was trained to distinguish between patches of voxels from scans of subjects with IPF and healthy subjects using automatically extracted high-attenuation textural features, excluding segmented blood vessels and airway walls, and to output a probability that a given patch is "fibrotic.” The algorithm is applied to overlapping patches, calculating the attenuation probability for a given voxel as an average probability of all the patches which cover that voxel. The HAA score is that volume of high-attenuation voxels with a greater than 50% chance of being "fibrotic.“ | b The HAA score is expressed as a percentage of total lung volume. | c Effect size was calculated as a percentage of the treatment effect divided by the placebo arm baseline mean. Change from baseline, mean (SD) Effect size,c % P valueTPIP (n=9) Placebo (n=5) HAA score,b % –0.7 (2.7) 0.3 (1.8) –10.5 0.54 Lung imaging results from the Phase 2 PH-ILD study RESPIRATORY | TPIP (PH-ILD)
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69 Color indicates vessel size. Small vessels with cross-sectional area (CSA) <5 mm2 are colored in red (●), vessels with CSA 5-10 mm2 – in yellow (●), and CSA >10 mm2 – in blue (●). Parameters indicated as BV5 and BV10 represent the total volume of vessels with CSA <5 mm2 and >10 mm2, respectively. Note the increase of small vessels colored in red (●) in patients treated with TPIP at week 16, compared with placebo. TPIP: FRI in Representative Patients Treated With TPIP (A) vs. Placebo (B) • TPIP treatment resulted in a significant increase in the fraction of blood volume in small arteries and a directional improvement in small-to-large artery volume ratio versus placebo • Results suggestive of small vessel vasodilation and improved pulmonary arteriole recruitment • A numerical decrease in HAA score was observed with TPIP • Limitations included the small sample size, which may limit the generalizability of the results and may increase the risk of random variation • Further evaluation of FRI in a larger trial may provide additional insights and support the strength and potential increased generalizability of these findings FRI: functional respiratory imaging | CSA: cross-sectional area | BV5A: volume of pulmonary arteries smaller than 5 mm2 in cross-sectional area | BV10A: volume of pulmonary arteries larger than 10 mm2 in cross- sectional area | TPIP: treprostinil palmitil inhalation powder | HAA: high-attenuation abnormality | PH-ILD: pulmonary hypertension due to interstitial lung disease TPIP Change from baseline, mL (%) BV5A:BV10A RATIO +0.45 (+29.7%) Placebo Change from baseline, mL (%) BV5A:BV10A RATIO -0.11 (-8%) TPIP (A) Placebo (B) Lung imaging results from the Phase 2 PH-ILD study RESPIRATORY | TPIP (PH-ILD)
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70 • Change from baseline in pulmonary vascular resistance (PVR)* • Change from baseline in exercise capacity (6MWD)* • Change from baseline in biomarkers of cardiac stress (NT-proBNP)* • Pharmacokinetics PAH Trial (Week 16) • Proportion of patients that improved WHO Functional Class • Change from baseline Cardiac Index (CI)* • Change from baseline in Quality of Life (CAMPHOR questionnaire) Primary Endpoint Secondary Endpoints Exploratory Endpoints 4 weeks TPIP 80-640 µg inhalation capsules once daily Placebo inhalation capsules once daily Screening Treatment period 16 weeks Baseline End of Study 4 weeks Follow-up 102 patients randomized Steady-state period 3-week titration period; last dose increase at Week 5 visit active : placebo 2:1 End of Treatment Primary Analysis TPIP Phase 2b in PAH NCT05147805 Trial summary TPIP: treprostinil palmitil inhalation powder | PAH: pulmonary arterial hypertension | PVR: pulmonary vascular resistance | 6MWD: 6-minute walk distance | NT-proBNP: N-terminal pro-B-type natriuretic peptide | WHO: World Health Organization | CI: Cardiac Index | * measured approximately 24 hours after prior dose RESPIRATORY | TPIP (PAH)
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71 TPIP: treprostinil palmitil inhalation powder | PAH: pulmonary arterial hypertension | BMI: body mass index | WHO: World Health Organization | N/n: number of patients | PVR: pulmonary vascular resistance | 6MWD: 6-minute walk distance | * stratification factor | ** All patients were on at least one stable background medication TPIP (N=69) Placebo (N=33) Total (N=102) Age: Mean, years (SD) Age < 65 years, % (n) 48.1 (15.00) 75.4 (52) 46.9 (15.22) 87.9 (29) 47.7 (15.00) 79.4 (81) Sex: Female, % (n) 84.1 (58) 78.8 (26) 82.4 (84) BMI: Mean, kg/m2 (SD) 26.746 (4.8690) 27.050 (4.8296) 26.844 (4.8344) Geographic Region, % (n) USA Europe Japan Rest of the World 13.0 (9) 37.7 (26) 11.6 (8) 37.7(26) 9.1 (3) 33.3 (11) 6.1 (2) 51.5 (17) 11.8 (12) 36.3 (37) 9.8 (10) 42.2 (43) WHO Functional Class*, % (n) Class II Class III 65.2 (45) 34.8 (24) 66.7 (22) 33.3 (11) 65.7 (67) 34.3 (35) Number of Baseline PAH Medications*, % (n) 0 or 1** 2 23.2 (16) 76.8 (53) 12.1 (4) 87.9 (29) 19.6 (20) 80.4 (82) PAH Subtype, % (n) Idiopathic Heritable Connective Tissue Disease-Associated Congenital Heart Disease-Related 72.5 (50) 4.3 (3) 21.7 (15) 1.4 (1) 69.7 (23) 6.1 (2) 21.2 (7) 3.0 (1) 71.6 (73) 4.9 (5) 21.6 (22) 2.0 (2) Pulmonary Vascular Resistance Mean PVR, Wood Units (SD) Mean PVR, dyn.s.cm-5 (SD) 9.588 (5.0072) 751.33 (401.421) 11.069 (5.9400) 856.83 (464.290) 10.067 (5.3427) 785.46 (423.376) 6-Minute Walk Distance Mean 6MWD, meters (SD) 348.48 (79.791) 371.06 (60.571) 355.78 (74.576) Baseline Characteristics Reasonably Well-Balanced Across Study Arms RESPIRATORY | TPIP (PAH)
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72 TPIP: treprostinil palmitil inhalation powder | OLE: open-label extension | N/n: number of patients | * Dose level achieved at end of dosing interval (Week 5 visit) TPIP (N=69) Placebo (N=33) Total (N=102) Dose Titration, % (n)* Titrated to at least 480 μg Titrated to max dose of 640 μg 84.1 (58) 75.4 (52) 84.8 (28) 81.8 (27) Participants Completed the Study, % (n) Completed Discontinued Reason for Discontinuation: Adverse Event Physician Decision Withdrawal of Subject 89.9 (62) 10.1 (7) 5.8 (4) 1.4 (1) 2.9 (2) 100.0 (33) 0 0 0 0 93.1 (95) 6.9 (7) 3.9 (4) 1.0 (1) 2.0 (2) TPIP Generally Well-Tolerated With a Low Discontinuation Rate 75% 90% Reached study max dose of 640 μg Completed the 16-week study TPIP Participants 95% of the 95 patients that completed the trial have enrolled in the OLE study OLE patients may titrate up to a max daily dose of 1,280 μg RESPIRATORY | TPIP (PAH)
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73 n: number of patients | TPIP: treprostinil palmitil inhalation powder | PVR: pulmonary vascular resistance | LS: least-squares | WHO: World Health Organization | * statistically significant at Week 16 | † Analysis performed using an ANCOVA model, adjusting for treatment group, baseline pulmonary vascular resistance (PVR), and randomization stratification factors. The model was applied to log-transformed PVR values, which were then back-transformed to the original scale. TPIP (N=69) Placebo (N=33) Week 16 n Week 16 n Primary Endpoint Pulmonary Vascular Resistance PVR at Baseline: Mean PVR, Wood Units (SD) PVR at Week 16: Mean PVR, Wood Units LS Mean Ratio to Baseline† Placebo-Adjusted Mean Ratio to Baseline PVR†: Ratio of LS Mean Ratio to Baseline [95% Confidence Interval] P-value 9.588 (5.0072) 6.218 0.63 0.65 [0.54, 0.79] <0.001 69 62 69 11.069 (5.9400) 10.019 0.97 33 33 33 PVR: Highly Statistically Significant Primary Endpoint Achieved With Once-Daily Therapy (P<0.001*) Results showcase strong treatment effect when evaluated ~24 hours after prior dose was administered 35% Placebo-Adjusted Reduction in PVR† at Week 16 * RESPIRATORY | TPIP (PAH)
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74 TPIP (N=69) Placebo (N=33) Week 16 n Week 16 n Secondary Endpoint 6-Minute Walk Distance 6MWD at Baseline (m): Mean (SD) 6MWD at Week 16 (m): Mean (SD) Absolute Change from Baseline 6MWD (m): Mean (SD) Median Placebo-Adjusted Improvement from Baseline 6MWD† (m): [95% Confidence Interval] P-value* 348.48 (79.791) 405.13 (98.497) 49.71 (66.197) 41.50 35.49 [11.23, 60.73] 0.003 69 61 61 69 371.06 (60.571) 382.61 (91.148) 11.55 (65.167) 20.50 33 33 33 Exercise Capacity: TPIP Showed a Clear Improvement in 6MWD (P=0.003*) n: number of patients | TPIP: treprostinil palmitil inhalation powder | 6MWD: 6-minute walk distance | * Nominal p-value not adjusted for multiplicity | † Covariate-adjusted estimate of location shift. Analysis performed using a rank ANCOVA model, adjusting for treatment group, baseline 6-minute walk distance (6MWD), and randomization stratification factors Placebo-Adjusted Improvement in 6MWD † at Week 16 All Efficacy Endpoints Measured ~24 Hours After Dose +35.5 meters RESPIRATORY | TPIP (PAH)
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75 TPIP: treprostinil palmitil inhalation powder | NT-proBNP: N-terminal pro-B-type natriuretic peptide | LS: least-squares | n: number of patients | pg/mL: picograms per milliliter | * Nominal p-value not adjusted for multiplicity | † Analysis performed using a repeated measures mixed model, adjusting for treatment group, baseline NT-proBNP, randomization stratification factors, visit and treatment-by-visit interaction. The model was applied to log-transformed NT-proBNP values, which were then back-transformed to the original scale. TPIP (N=69) Placebo (N=33) Week 16 n Week 16 n Secondary Endpoint NT-proBNP Concentration Concentration at Baseline (pg/mL): Mean Concentration at Week 16 (pg/mL): Mean LS Mean Ratio to Baseline† (pg/mL) Placebo-Adjusted Mean Ratio to Baseline NT-proBNP†: Ratio of LS Mean Ratio to Baseline [95% Confidence Interval] P-value* 785.58 342.40 0.48 0.40 [0.27, 0.59] <0.001 69 62 67 798.91 1180.14 1.22 33 33 33 Cardiac Stress: TPIP Showed a Meaningful Reduction in NT-proBNP (P<0.001*) Placebo-Adjusted Reduction in NT-proBNP Concentrations† at Week 16 All Efficacy Endpoints Measured ~24 Hours After Dose 60% RESPIRATORY | TPIP (PAH)
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76 Represents at Least One Functional Class Improvement 30% TPIP 15% Placebo vs. FC Improvement Week 16 vs. Baseline n: number of patients | TPIP: treprostinil palmitil inhalation powder | PAH: pulmonary arterial hypertension | FC: functional class | * Includes at least one functional class improvement achieved at Week 16 | ** Nominal p-value not adjusted for multiplicity † Analysis performed using Cochran-Mantel-Haenszel (CMH) test, stratified by randomization factors. TPIP (N=69) Placebo (N=33) Week 16 n Week 16 n Exploratory Endpoint WHO Functional Class Shift, % FC Improvement* at Week 16: FC II Improvement to FC I FC III Improvement to FC II or FC I: Improvement to FC II Improvement to FC I Odds Ratio for TPIP vs. Placebo†: [95% Confidence Interval] P-value** 30.4 13.0 17.4 15.9 1.4 2.566 [0.834, 7.890] 0.098 21 9 12 11 1 15.2 6.1 9.1 9.1 0 5 2 3 3 0 WHO Functional Class: More Patients on TPIP Achieved an Improvement in Functional Class RESPIRATORY | TPIP (PAH)
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77 TPIP: treprostinil palmitil inhalation powder | LS: least-squares | CI: cardiac index | PAH: pulmonary arterial hypertension | n: number of patients | † Analysis performed using an ANCOVA model, adjusting for treatment group, baseline cardiac index, and randomization stratification factors. The model was applied to log-transformed cardiac index values, which were then back-transformed to the original scale. | * Nominal p-value not adjusted for multiplicity Cardiac Index: TPIP Showed an Increase Compared to Placebo (P=0.006*) TPIP (N=69) Placebo (N=33) Week 16 n Week 16 n Exploratory Endpoint Cardiac Index, L/min/m2 Cardiac Index at Baseline: Mean Cardiac Index at Week 16: Mean LS Mean Ratio to Baseline† Placebo-Adjusted Mean Ratio to Baseline Cardiac Index†: Ratio of LS Mean Ratio to Baseline [95% Confidence Interval] P-value* 2.641 3.070 1.12 1.15 [1.04, 1.27] 0.006 69 62 69 2.691 2.777 0.98 33 33 33 Increase in CI Achieved vs. Placebo at Week 16 15% TPIP Cardiac Index RESPIRATORY | TPIP (PAH)
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78 TPIP: treprostinil palmitil inhalation powder | TEAE: treatment-emergent adverse event | PAH: pulmonary arterial hypertension | n: number of patients | * TEAEs that occurred in >5% of the treatment group and were elevated compared to placebo group Safety: Most Common TPIP TEAEs Were Consistent With Known Profile of Inhaled Treprostinil TPIP (N=69) Placebo (N=33) Week 16 n Week 16 n Safety TEAEs, % Any TEAE Serious TEAE Severe TEAE TEAE Leading to Treatment Discontinuation Death 88.4 7.2 5.8 5.8 0 61 5 4 4 0 75.8 3.0 3.0 0 0 25 1 1 0 0 Most Common TEAEs Reported, %* Cough Headache Fatigue Chest Discomfort Flushing Upper Respiratory Tract Infection Non-Cardiac Chest Pain 40.6 31.9 10.1 8.7 8.7 7.2 5.8 28 22 7 6 6 5 4 21.2 15.2 3.0 0 3.0 3.0 3.0 7 5 1 0 1 1 1 Cough Severity, % Cough: Mild Moderate Cough Leading to Treatment Discontinuation (Moderate) 40.6 34.8 5.8 1.4 28 24 4 1 21.2 18.2 3.0 0 7 6 1 0 All cough incidences were reported as mild or moderate >85% of cough incidences were reported as mild TPIP Incidence of Cough RESPIRATORY | TPIP (PAH)
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79 Open-Label Extension Intended to Evaluate TPIP’s Long-Term Safety & Tolerability Over 24 Months • Safety and tolerability (frequency & severity of TEAEs) • Change from baseline in exercise capacity (6MWD)* • Change from baseline in biomarkers of cardiac stress (NT-proBNP)* • Proportion of patients that improved WHO Functional Class vs. baseline • Change from baseline REVEAL Lite 2.0 Score** Key OLE Study Endpoints • Proportion of patients who achieve a REVEAL Lite 2.0 Low Risk status • Proportion of patients with improvement in the REVEAL Lite 2.0 Risk status Primary Endpoint Secondary Endpoints Exploratory Endpoints OLE: open-label extension | PAH: pulmonary arterial hypertension | TPIP: treprostinil palmitil inhalation powder | TEAE: treatme nt-emergent adverse event | 6MWD: 6 -minute walk distance | WHO: World Health Organization | NT -proBNP: N-terminal pro- B-type natriuretic peptide | PVR: pulmonary vascular resistance | * Measured approximately 24 hours after prior dose was admini stered | ** A simplified, non-invasive medical tool used to estimate the mortality and disease progression risk for adult patients with PAH | *** Double-dummy titration was used to maintain blinding and permit patients who received TPIP in the lead-in studies (“TPIP Continued”) to receive their achieved dose of TPIP at the start of the OLE. Patients who received placebo in the lead-in study (“Placebo Crossed”) or had delayed rollover underwent titration starting at 80 µg once daily up 640 µg or high est tolerated dose. After Week 3, most patients maintained a stable TPIP dose. Investigators are permitted to titrate up to 1 ,280 µg to optimize treatment benefit after Week 3 of the study. | † Lead -in studies include the Phase 2b study (NCT05147805), which contributed 90 patients, and the Phase 2a 24-hour PVR study (NCT04791514), which contributed 1 patient (study was discontinued). Pre-randomization baseline values are not available for the single PVR study participant. | ‡ OLE study outcomes were evaluated against the Phase 2b lead-in study pre-randomization baseline values for relevant measurements | ^ Patients located in Japan will remain in the OLE for 84 months in accordance with Japan -specific protocol 4 weeks24 months Day 1 of OLE End of OLE^ 16 weeks Follow-upLead-in Studies† 3-week titration period*** Month 24 of OLE Baseline‡ Month 12 of OLE TPIP 80-1,280 µg inhalation capsules once daily Open -Label Treatment Period *** 91 patients enrolled in the OLE RESPIRATORY | TPIP (PAH) NCT05649748
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80 Baseline† Characteristics Were Comparable Across Groups Continued TPIP1 N=60 Placebo Crossed2 N=31 Total N=91 Age: Mean, years 47.9 47.6 47.8 Sex: Male, % (n) 13.3% (8) 19.4% (6) 15.4% (14) Geographic Region: % (n) United States 10.0% (6) 9.7% (3) 9.9% (9) Europe 36.7% (22) 35.5% (11) 36.3% (33) Rest of World 53.3% (32) 54.8% (17) 53.8% (49) PAH Subtype (Idiopathic)*: % (n) 66.7% (40) 67.7% (21) 67.0% (61) PAH Medications*: % (n) 1 23.3% (14) 9.7% (3) 18.7% (17) 2 75.0% (45) 90.3% (28) 80.2% (73) 6MWD*: Mean (SD), meters 355.1 (79.00) 369.5 (61.73) 360.1 (73.48) NT-proBNP*: Mean (SD), pg/mL 787.5 (1,193.2) 795.8 (1,042.1) 790.4 (1,137.5) WHO Functional Class*: % (n) Class II 61.7% (37) 67.7% (21) 63.7% (58) Class III 36.7% (22) 32.3% (10) 35.2% (32) REVEAL Lite 2.0 Status*: % (n) Low (Score ≤5) 51.7% (31) 58.1% (18) 53.8% (49) Refined Low (Score ≤4) 35.0% (21) 51.6% (16) 40.7% (37) Intermediate (Score 6-7) 25.0% (15) 22.6% (7) 24.2% (22) High (Score ≥8) 21.7% (13) 19.4% (6) 20.9% (19) PAH: pulmonary arterial hypertension | 6MWD: 6-minute walk distance | NT-proBNP: N-terminal pro-B-type natriuretic peptide | WHO: World Health Organization | REVEAL Lite 2.0 risk calculator is a simplified, non- invasive medical tool used to estimate the mortality and disease progression risk for adult patients with PAH | N/n: number of patients | pg/mL: picograms per milliliter | 1 Includes all rollover patients randomized to TPIP in the Phase 2b study (NCT05147805) and 1 participant from Phase 2a 24-hour PVR study (NCT04791514) | 2 Includes all rollover patients randomized to placebo in Phase 2b study | * Single participant from the Phase 2a 24-hour PVR study had missing baseline data | † All baseline characteristics presented reflect values from both lead-in studies unless otherwise noted | Note: WHO Functional Class and number of baseline medications were stratification factors in the Phase 2b lead-in study’s prespecified statistical analysis plan (SAP) | Note: All patients were on at least one background PAH medication RESPIRATORY | TPIP (PAH)
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81 TPIP Was Generally Safe and Well-Tolerated; No Newly Identified Safety Signals Through Month 12 SAFETY Total (N=91) % n Any TEAE 89.0% 81 ≤640 µg Max Dose Achieved 86.1% 62 >640 µg Max Dose Achieved** 89.5% 17** Serious 18.7% 17 ≤640 µg Max Dose Achieved 20.8% 15 >640 µg Max Dose Achieved** 10.5% 2** Study Drug Related 1.1% 1† Leading to Death 4.4% 4‡ Severe 16.5% 15 Leading to Study Discontinuation*** 7.7% 7 Leading to Dose Reduction 11.0% 10 Study Drug Related 35.2% 32 TPIP: treprostinil palmitil inhalation powder | TEAE: treatment-emergent adverse event | SAE: serious adverse event | OLE: open-label extension | PAH: pulmonary arterial hypertension | * TEAEs reported in ≥5% of patients | ** Includes patients whose max tolerated dose exceeded 640µg and whose adverse event occurred at a dose level that exceeded 640µg | ***All patients who discontinued treatment also discontinued study | † Patient from the Phase 2b lead-in study was hospitalized with orthostatic hypotension and subsequently discharged after precautionary workup was completed (patient discontinued their anti-hypertensive agent). Primary investigator assessed this event as study drug related | ‡ Location of participant deaths: 1 Argentina (myocardial infarction), 2 Philippines (acute respiratory failure, hypovolemic shock), 1 United States (single patient from the Phase 2a 24-hour PVR study died of acute respiratory distress syndrome in the setting of pneumonia during titration period after being off TPIP therapy for ~18 months) | Note: TEAEs reported in this table are only those that emerged during the OLE, not during the lead-in studies MOST COMMON TEAEs*, % (n) Headache 28.6% (26) Dizziness 6.6% (6) Cough 15.4% (14) Epistaxis 6.6% (6) Nasopharyngitis 14.3% (13) Nausea 6.6% (6) Diarrhea 11.0% (10) Anemia 5.5% (5) Upper Respiratory Tract Infection 9.9% (9) Influenza 5.5% (5) Bronchitis 7.7% (7) Pneumonia 5.5% (5) ✓ 19 patients (21%) achieved >640 µg dose ✓ No deaths or study drug related SAEs; No TEAEs led to study discontinuation** ✓ Only 1 cough TEAE was reported** >640 µg Max Dose Achieved by Month 12 None of the 4 deaths were considered study drug related All TEAEs of cough were classified as mild or moderate, with >85% being mild RESPIRATORY | TPIP (PAH)
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82 0 20 40 60 80 Change from 202 Baseline in 6MWD (m)+/- SE 202 Baseline 203 Day 1 203 Month 6 203 Month 12 Visit Placebo-crossed Continued TPIP Mean-Placebo-crossed Mean-Continued TPIP Median-Placebo-crossed Median-Continued TPIP Patients that Continued on TPIP Showed Sustained Improvement in 6MWD Over 12 Months Change from Baseline* 6MWD† (SE), meters Lead-in Study Baseline* Week 16 Ph2b Study / Day 1 OLE Study‡ Month 6 OLE Study Month 12 OLE Study +55.7 Continued TPIP meters +54.1 Placebo Crossed meters Mean Improvement from Baseline* 6MWD at Month 12 Patients who crossed from placebo to TPIP achieved 6MWD improvement outcomes nearly in-line with those of continuing TPIP patients at Month 12 TPIP: treprostinil palmitil inhalation powder | 6MWD: 6-minute walk distance, measured approximately 24 hours after prior dose was administered | OLE: open-label extension | SE: standard error | Ph: phase | * Phase 2b lead-in study pre-randomization baseline values. Phase 2a 24-hour PVR study single patient data were not included in change from baseline analysis as no baseline was available. | † Last observation carried forward (LOCF) is used to impute the missing values at each visit | ‡ Day 1 OLE values are the same as the Phase 2b lead-in study Week 16 values for patients who rolled over into the OLE study within 7 days of completion. Continued TPIP Placebo Crossed Median - Continued TPIP Median - Placebo Crossed Mean - Placebo CrossedMean - Continued TPIP Phase 2b Study RESPIRATORY | TPIP (PAH)
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83 0. 0 0. 5 1. 0 1. 5 wi t h Geomet r i c St andar d Er r or Geomet r i c Mean Rat i o t o 202 Basel i ne 202 Basel i ne 203 Day 1 203 Mont h 6 203 Mont h 12 Vi si t Pl acebo- cr ossedCont i nued TPI PAnal ysi s Tr eat ment Patients that Continued on TPIP Showed Sustained Reduction in NT-proBNP Over 12 Months Geometric Mean Ratio to Baseline* NT-proBNP Concentration† (SE) Mean Reduction from Baseline* NT-proBNP Concentration at Month 12 TPIP: treprostinil palmitil inhalation powder | NT-proBNP: N-terminal pro-B-type natriuretic peptide, measured approximately 24 hours after prior dose was administered | OLE: open-label extension | SE: standard error | Ph: phase | * OLE study outcomes were evaluated against the Phase 2b lead-in study pre-randomization baseline value for relevant measurements | † Last observation carried forward (LOCF) is used to impute the missing value at each visit | ‡ Day 1 values are the same as the Phase 2b lead-in study Week 16 values for patients who rolled over into the OLE within 7 days of completion. | Note: Phase 2a 24-hour PVR study single patient data were not included in change from baseline analysis as no baseline was available Patients from both groups achieved an ~60% mean reduction in NT-proBNP levels by Month 6 and maintained these levels at Month 12 Continued TPIP Placebo Crossed ~60% Continued TPIP ~60% Placebo Crossed Phase 2b Study Lead-in Study Baseline* Week 16 Ph2b Study / Day 1 OLE Study‡ Month 6 OLE Study Month 12 OLE Study RESPIRATORY | TPIP (PAH)
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84 0% 25% 50% 75% 100% Lead-in Study Baseline* Month 6 OLE Study Month 12 OLE Study Both Groups Showed Meaningful Improvement in WHO Functional Class (FC) by Month 12 Continued TPIP (N=60) Placebo Crossed (N=31) Proportion of Patients† ~80% of all patients achieved FC I or II Functional Class by Month 12 >25% of all patients achieved FC I − FC I indicates no limits on physical activity TPIP: treprostinil palmitil inhalation powder | WHO: World Health Organization | FC: functional class | W: week | Ph: phase | N: number of patients | OLE: open-label extension | *OLE study outcomes were evaluated against the Phase 2b lead-in study pre-randomization baseline value for relevant measurements | † Figure proportions are based on the number of patients in the full analysis set within that treatment group including patients with missing data | ‡ Day 1 values are the same as the Phase 2b lead-in study Week 16 values for patients who rolled over into the OLE within 7 days of completion. | Note: Phase 2a 24-hour PVR single patient did not have baseline data for WHO Functional Class Phase 2b Study Lead-in Study Baseline* Month 6 OLE Study Month 12 OLE Study Phase 2b Study W16 Ph2b / Day 1 OLE‡ W16 Ph2b / Day 1 OLE‡ 50% of patients in the Continued TPIP group and 42% of the Placebo Crossed group improved by at least one FC category by Month 12 RESPIRATORY | TPIP (PAH)
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85 Scoring Components† REVEAL Lite 2.0 Score: Simplified, Non-Invasive, Validated Tool to Estimate the Mortality Risk of PAH Patients Scoring1,2 Points Estimated Mortality Risk Estimated Morbidity Risk3 High Risk ≥ 8 >10% at 1 year Intermediate Risk 6 – 7 ~5-10% at 1 year Low Risk ≤ 5 ~1-5% at 1 year ~12% at 1 year Refined Low Risk4 ≤ 4 <5% at 1 & 3 years ~7% at 1 year A 1-point improvement from baseline REVEAL score is associated with a ~23% reduction in risk of death and ~21% reduction in clinical worsening (morbidity)1,2,3 PAH: pulmonary arterial hypertension | NT-proBNP: N-terminal pro-B-type natriuretic peptide (BNP); a biomarker of cardiac stress | WHO: World Health Organization | NYHA: New York Heart Association | 1 Benza RL, Boucly, A., Farber, HW, et al, “Change in REVEAL Lite 2 risk score predicts outcomes in patients with pulmonary arterial hypertension in PATENT study.” Journal of Heart and Lung Transplantation, 2022, 41(3), 412-420 | 2 Benza RL, Gomberg-Maitland M, Elliott, CG et al, “Development and validation of an abridged version of the REVEAL Lite 2.0 Risk Score Calculator, REVEAL Lite 2, for use in patients with pulmonary arterial hypertension. Chest 2021; 159 (1); 337-346 | 3 Morbidity, or clinical worsening, is defined by any of the following: lung transplantation, hospitalization for PAH, initiation of long-term oxygen therapy, 15% decrease in 6-minute walking distance (6MWD) from baseline with a worsening of NYHA Functional Class, or the addition of a new PAH medication. | 4 Fauvel, C., Correa Jaque, P, Liu Y, Lee SW, et al, “Refining the definition for “Low Risk” in Pulmonary Arterial Hypertension – Time to reduce morbidity and mortality.” JACC: Heart failure, 2026 | † A minimum of three scoring components (variables) are required to generate a score where at least two are most predictive variables (denoted by *) NYHA / WHO Functional Class* 6-Minute Walk Distance Test* Renal Insufficiency Heart Rate Systolic Blood Pressure BNP / NT-proBNP Concentration* RESPIRATORY | TPIP (PAH)
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86 3. 0 3. 5 4. 0 4. 5 5. 0 5. 5 6. 0 +/ - St andar d Er r or Mean REVEAL Li t e 2. 0 Scor e ( LOCF) 202 Basel i ne 203 Day 1 203 Mont h 6 203 Mont h 12 Vi si t Pl acebo- cr ossedCont i nued TPI PAnal ysi s Tr eat ment Both Groups Showed Clinically Meaningful Improvement in Mean REVEAL Lite 2.0 Score by Month 12Mean REVEAL Lite 2.0 Score (SE)† ~65%** of all patients achieved Refined Low Risk status by Month 12 REVEAL Score Improvement by Month 12 TPIP: treprostinil palmitil inhalation powder | PAH: pulmonary arterial hypertension | OLE: open-label extension | SE: standard error | Ph: phase | * Phase 2b lead-in study pre-randomization baseline | ** Percentage is based on responder analysis where the denominator is the full analysis set within that treatment group | † Last observation carried forward (LOCF) is used to impute the missing value at each visit | ‡ Day 1 values are the same as the Phase 2b lead-in study Week 16 values for patients who rolled over into the OLE within 7 days of completion. | Note: The REVEAL Lite 2.0 (or REVEAL Lite 2) risk calculator is a simplified, non- invasive medical tool used to estimate the mortality and disease progression risk for adult patients with PAH. The score can be calculated if at least two of the most predictive variables and at least three variables in total are available. | Note: Phase 2a 24-hour PVR study single patient did not have baseline REVEAL data but did have Day 1 OLE observed data and LOCF imputed data for Month 6 and Month 12 Refined Low Risk Status Low Risk Status Intermediate Risk Status (>5 to <8) Phase 2b Study Continued TPIP Placebo Crossed Lead-in Study Baseline* Week 16 Ph2b Study / Day 1 OLE Study‡ Month 6 OLE Study Month 12 OLE Study Continued TPIP Placebo Crossed 2.0points 1.4 points RESPIRATORY | TPIP (PAH)
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87 TPIP Has the Potential for Clear Differentiation in PH-ILD and PAH TPIP Inhaled (dry powder) Once daily Yes Ph2 Data Support Ph3 Advancement Ph2 Data Support Ph3 Advancement Remodulin® IV or subcutaneous Continuous Yes Yes No data TYVASO® & Yutrepia® Inhaled (nebulized and/or dry powder) 4-times per day No Yes Yes Orenitram® & Uptravi® Oral 2- or 3-times per day No Yes No data Method of administration Dosing frequency Favorable tolerability for dose expansion† Efficacy in PAH (WHO Group 1) Efficacy in PH-ILD (WHO Group 3) Potential Differentiators Approved Treprostinil Therapies*** Convenience* Safety & Efficacy** Favorable safety profile & higher dosing may lead to improved outcomes TPIP: treprostinil palmitil inhalation powder | PAH: pulmonary arterial hypertension | PH-ILD: pulmonary hypertension due to interstitial lung disease | Ph: phase | * No head-to-head or convenience studies have been conducted or planned | ** Analysis based on safety and tolerability data from the Phase 2 PH -ILD study disclosed on May 6, 2024, and the Phase 2 PAH study disclosed on June 10, 2025 | † Based on most recent publicly available data | *** Yutrepia® is approved for PAH & PH-ILD. TYVASO ® is approved in PAH & PH-ILD. All other listed products are approved in PAH. TYVASO: nebulized and dry- powder. Yutrepia: dry powder. Orenitram: 2-3 times per day. Uptravi: 2-times per day RESPIRATORY | TPIP (PAH)
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88 Epidemiological Footnotes (1 of 3) 1. Internal analysis of published BE epidemiology, including internal market research and US patient level claims data analysis: a) Weycker, et al. Prevalence and incidence of NCFBE among US adults in 2013. Chronic Respiratory Disease. 2017 b) BE Patient Level Claims Data Analysis. Source: swoop/ipm.ai c) Trinity Epidemiology Assessment; 2020 (for Japan epi) d) Ringausen et al 2019 Growth (Germany) e) Aliberti 2016; quality standards for the management of bronchiectasis in Italy f) Snell et al. United Kingdom; 2019 g) Internal Insmed NCFBE market sizing EU5 report 2. Internal analysis and estimations based on internal market research and US patient level claims data analysis: a) Insmed Analysis 2022: Potential Undiagnosed or Misdiagnosed (with COPD, Asthma) BE patients in US estimated based on Medical Experts driven insights, applied to Patient Level Claims Data -using advanced analytics / statistical methods Potential Undiagnosed or Co-morbid (with COPD) BE patients in US derived based on internal Insmed meta- analysis of 16 epi studies that look at BE prevalence in COPD patients; Ex-US estimates are based on extrapolation of US focused claims and epi data analysis 3. Internal analysis and estimations based on published epidemiology studies: a) National Health Interview Survey (NHIS) Data (2021) b) Alshabanat A, Zafari Z, Albanyan O, Dairi M, FitzGerald JM (2015) Asthma and COPD Overlap Syndrome (ACOS): A Systematic Review and Meta Analysis. PLoS ONE 10(9): e0136065. doi:10.1371/ journal.pone.0136065 c) OECD/European Union (2016), “Asthma and COPD prevalence”, in Health at a Glance: Europe 2016: State of Health in the EU Cycle, OECD Publishing, Paris. d) Hosseini, M., Almasi-Hashiani, A., Sepidarkish, M. et al. Global prevalence of asthma-COPD overlap (ACO) in the general population: a systematic review and meta- analysis. Respir Res 20, 229 (2019). https://doi.org/10.1186/s12931-019-1198-4 e) Blanco I, Diego I, Bueno P, et al. Geographic distribution of COPD prevalence in the world displayed by Geographic Information System maps. Eur Respir J 2019; 54: 1900610 [https://doi.org/ 10.1183/13993003.00610-2019]. f) R. de Marco et al. Eur Respir J 2012; 39:883-892. DOI: 10.1183/09031936.000611. g) Iwanaga T, Tohda Y. [Epidemiology of asthma in Japan]. Nihon Rinsho. 2016 Oct;74(10):1603-1608. Japanese. PMID: 30551268 h) Massoth L, Anderson C, McKinney KA. Asthma and Chronic Rhinosinusitis: Diagnosis and Medical Management. Med Sci (Basel). 2019 Mar 27;7(4):53. doi: 10.3390/medsci7040053. PMID: 30934800; PMCID: PMC6524348. i) Hashimoto S, Yoshida Y, Makita N, Sorimachi R, Sugaya S, Arita Y, Hayashi N, Tashiro N, Ichinose M. Real-World Evidence on the Diagnostic and Clinical Characteristics of Asthma in Japanese Patients with COPD: The ACO Japan Cohort Study. Int J Chron Obstruct Pulmon Dis. 2023;18:37-46 j) Awad MT, Sankari A. Asthma and COPD Overlap. [Updated 2023 Jun 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK592422/ k) https://www.cdc.gov/asthma/most_recent_national_asthma_data.htm l) https://www.cdc.gov/copd/php/case-reporting/national-trends-in-copd.html m) Minakata Y, Ichinose M. [Epidemiology of COPD in Japan]. Nihon Rinsho. 2011 Oct;69(10):1721-6. Japanese. PMID: 22073563
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89 Epidemiological Footnotes (2 of 3) 4. Internal analysis of published NTM epidemiology, including internal market research and US patient level claims data analysis: a) Jennifer Adjemian, Kenneth N Olivier, Amy E Seitz, Steven M Holland, D Rebecca Prevots: Prevalence of nontuberculous mycobacterial lung disease in U.S. Medicare beneficiaries Am J Respir Crit Care Med. 2012 Apr 15; 185(8):881-6 DOI: 10.1164/rccm.201111-2016OC b) Jennifer Adjemian, D Rebecca Prevots, Jack Gallagher, Kylee Heap, Renu Gupta, David Griffith: Lack of adherence to evidence-based treatment guidelines for nontuberculous mycobacterial lung disease Ann Am Thorac Soc. 2014 Jan; 11(1): 9–16 DOI: 10.1513/AnnalsATS.201304-085OC c) Sara E. Strollo , Jennifer Adjemian, Michael K. Adjemian, and D. Rebecca Prevots: The Burden of Pulmonary Nontuberculous Mycobacterial Disease in the United States Ann Am Thorac Soc Vol 12, No 10, pp 1458–1464, Oct 2015 DOI: 10.1513/AnnalsATS.201503-173OC d) https://www.kff.org/medicare/state-indicator/total-medicare-beneficiaries/?currentTimeframe=0&sortModel=%7B%22colId%22:%22Location%22,%22sort%22:%22asc%22%7D e) Felix C. Ringshausen, Dirk Wagner, Andrés de Roux, Roland Diel, David Hohmann, Lennart Hickstein, Tobias Welte, Jessica Rademacher: Prevalence of Nontuberculous Mycobacterial Pulmonary Disease, Germany, 2009–2014 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 22, No. 6, June 2016 DOI: http://dx.doi.org/10.3201/eid2206.151642 f) Jonathan E Moore, Michelle E Kruijshaar, L Peter Ormerod, Francis Drobniewski , Ibrahim Abubakar: Increasing reports of non-tuberculous mycobacteria in England, Wales and Northern Ireland, 1995-2006 BMC Public Health 2010, 10:612 http://www.biomedcentral.com/1471-2458/10/612 g) Hoefsloot, Van Ingen et al, The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples, AN NTM-NET collaborative study; 2013, European Respiratory Journal 2013 42: 1604-1613; DOI: 10.1183/09031936.00149212 h) Kozo Morimoto , Kazuro Iwai , Kazuhiro Uchimura , Masao Okumura , Takashi Yoshiyama , Kozo Yoshimori, Hideo Ogata , Atsuyuki Kurashima , Akihiko Gemma, and Shoji Kudoh: A Steady Increase in Nontuberculous Mycobacteriosis Mortality and Estimated Prevalence in Japan Ann Am Thorac Soc Vol 11, No 1, pp 1–8, Jan 2014, DOI: 10.1513/AnnalsATS.201303-067OC 5. Internal assessment of published epidemiology and US patient level claims data analysis, including: a) Kirson, N. Y., Birnbaum, H. G., Ivanova, J. I., Waldman, T., Joish, V., & Williamson, T. (2011). Prevalence of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension in the United States. Current Medical Research and Opinion, 27(9), 1763–1768. https://doi.org/10.1185/03007995.2011.604310 b) 2019 National Audit of Pulmonary Hypertension Great Britain; Humbert M et al, “Pulmonary arterial hypertension in France: results from a national registry”, Feb 2006 c) Ling Y, Johnson MK, Kiely DG, Condliffe R, Elliot CA, Gibbs JS, Howard LS, Pepke-Zaba J, Sheares KK, Corris PA, Fisher AJ, Lordan JL, Gaine S, Coghlan JG, Wort SJ, Gatzoulis MA, Peacock AJ. Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland. Am J Respir Crit Care Med. 2012 Oct 15;186(8):790-6. doi: 10.1164/rccm.201203-0383OC. Epub 2012 Jul 12. PMID: 22798320. d) Escribano-Subias P, Blanco I, López-Meseguer M, Lopez-Guarch CJ, Roman A, Morales P, Castillo-Palma MJ, Segovia J, Gómez-Sanchez MA, Barberà JA; REHAP investigators. Survival in pulmonary hypertension in Spain: insights from the Spanish registry. Eur Respir J. 2012 Sep;40(3):596-603. doi: 10.1183/09031936.00101211. Epub 2012 Feb 23. PMID: 22362843. e) Hoeper MM, Huscher D, Pittrow D. Incidence and prevalence of pulmonary arterial hypertension in Germany. Int J Cardiol. 2016 Jan 15;203:612-3. doi: 10.1016/j.ijcard.2015.11.001. Epub 2015 Nov 9. PMID: 26580339. f) Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Simonneau G. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006 May 1;173(9):1023-30. doi: 10.1164/rccm.200510-1668OC. Epub 2006 Feb 2. PMID: 16456139. g) Secondary research: Japan’s Intractable Disease Database 2021
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90 Epidemiological Footnotes (3 of 3) 6. Internal assessment of published epidemiology, including: a) Andersen, C. U., Mellemkjær, S., Hilberg, O., Nielsen-Kudsk, J. E., Simonsen, U., & Bendstrup, E. (2012). Pulmonary hypertension in interstitial lung disease: prevalence, prognosis and 6 min walk test. Respiratory medicine, 106(6), 875-882. b) Ryu, Jay H., et al. "Pulmonary hypertension in patients with interstitial lung diseases." Mayo Clinic Proceedings. Vol. 82. No. 3. Elsevier, 2007 c) Duchemann et al., “Prevalence and incidence of interstitial lung diseases in a multi-ethnic county of Greater Paris.” European Respiratory Journal, 2017 d) Diagnosed prevalence for PH-LHD, CTEPH and PH-Idiopathic sourced from “Patient-Based Forecast Model Pulmonary Hypertension”, Datamonitor, September 2023. 7. Internal assessment of published epidemiology, including: a) Singer et al, “Claims-based Prevalence of Disease Progression among Patients with Fibrosing Interstitial Lung Disease Other than Idiopathic Pulmonary Fibrosis in the United States”, Annals of American Thoracis Society 2022 Jul;19(7):1112-1121. doi: 10.1513/AnnalsATS.202102-222OC b) EU and JPN PPF prevalence estimated based on (1:1.2) ratio given lack of robust sources on EU5/JPN 8. Internal assessment of published epidemiology, including: a) Perez et al, “Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: a population-based study”, Chest 2010 Jan;137(1):129-37. doi: 10.1378/chest.09-1002 b) Agabiti et al, “Idiopathic Pulmonary Fibrosis (IPF) incidence and prevalence in Italy”, Sarcoidosis Vasc Diffuse Lung Dis 2014 Oct 20;31(3):191-7 c) Kreuter et al, “Epidemiology, healthcare utilization, and related costs among patients with IPF: results from a German claims database analysis”, 2022 Mar 19;23(1):62. doi: 10.1186/s12931-022-01976-0 d) Navaratnam et al, “The rising incidence of idiopathic pulmonary fibrosis in the U.K”, Thorax, 2011 Jun;66(6):462-7. doi: 10.1136/thx.2010.148031 e) Harari et al, “Epidemiology of idiopathic pulmonary fibrosis: a population-based study in primary care”, Intern Emerg Med, 2020 Apr;15(3):437-445. doi: 10.1007/s11739-019-02195-0. Epub 2019 Sep 20 f) Secondary Research: Japan’s Intractable database, 2025
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91 TPIP Footnotes (1 of 3): 1. Insmed Phase 2b Study of TPIP in PAH; Placebo-Adjusted Reduction from Baseline PVR at Week 16; Analysis performed using an ANCOVA model, adjusting for treatment group, baseline pulmonary vascular resistance (PVR), and randomization stratification factors. The model was applied to log-transformed PVR values, which were then back-transformed to the original scale; statistically significant, p<0.001; Measurements were taken at ~24 hours post dose (“at trough”); Topline results presented June 2025. 2. Insmed Phase 2b Study of TPIP in PAH; Placebo-Adjusted Improvement from Baseline 6MWD at Week 16; Covariate-adjusted estimate of location shift. Analysis performed using a rank ANCOVA model, adjusting for treatment group, baseline 6-minute walk distance (6MWD), and randomization stratification factors; Nominally statistically significant, not adjusted for multiplicity, p=0.003; Measurements were taken at ~24 hours post dose (“at trough”); Topline results presented June 2025. 3. Insmed Phase 2b Study of TPIP in PAH; Placebo-Adjusted Mean Ratio to baseline NT-proBNP of 0.40; Analysis performed using a repeated measures mixed model, adjusting for treatment group, baseline NT-proBNP, randomization stratification factors, visit and treatment-by-visit interaction. The model was applied to log-transformed NT-proBNP values, which were then back- transformed to the original scale; nominally statistically significant, not adjusted for multiplicity, p<0.001; Measurements were taken at ~24 hours post dose (“at trough”); Topline results presented June 2025. 4. Insmed OLE Study of TPIP in PAH (12-Month Analysis); Patients in the TPIP Continued group showed a mean improvement from baseline 6MWD of 55.7 meters at Month 12. Patients in the Placebo Crossed group showed a mean improvement from baseline 6MWD of 54.1 meters; Measurements were taken at ~24-hours post dose (“at trough”); The baseline values used in this OLE are from the Phase 2b study (pre-randomization values). The Phase 2a 24-hour PVR study single patient data were not included in this change from baseline analysis as no baseline data were available; Last observation carried forward (LOCF) is used to impute the missing values at each visit; Results presented July 2026. 5. Insmed OLE Study of TPIP in PAH (12-Month Analysis); Patients in the TPIP Continued group showed a mean improvement from baseline NT-proBNP concentration of 60% at Month 12. Patients in the Placebo Crossed group showed a mean reduction from baseline NT-proBNP concentration of 60%; Measurements were taken at ~24 hours post dose (“at trough”); The baseline values used in this OLE are from the Phase 2b study (pre-randomization values). The Phase 2a 24-hour PVR study single patient data were not included in this change from baseline analysis as no baseline data were available; Last observation carried forward (LOCF) is used to impute the missing values at each visit; Results presented July 2026. 6. Insmed OLE Study of TPIP in PAH (12-Month Analysis); ~80% of patients in the TPIP Continued group and the Placebo Crossed group achieved WHO Functional Class I or II at Month 12; Results presented July 2026. 7. Insmed OLE Study of TPIP in PAH (12-Month Analysis); ~65% of patients in the TPIP Continued group and the Placebo Crossed group achieved Refined Low Risk status (REVEAL Lite 2.0 Score of ≤4) at Month 12; Percentage is based on responder analysis where the denominator is the full analysis set within that treatment group; When calculating the mean REVEAL Lite 2.0 score, last observation carried forward (LOCF) methodology was used to impute the missing values at each visit. The Phase 2b lead-in study (pre-randomization values) was used as the baseline. The Phase 2a 24-hour PVR study single patient did not have baseline REVEAL data but did have Day 1 OLE observed data. LOCF was used to impute data for Month 6 and Month 12 for this patient; Results presented July 2026. 8. Insmed Phase 2b Study of TPIP in PAH; 30.4% of patients on TPIP improved WHO Functional Class by at least 1 category (vs. baseline) at Week 16 compared to 15% of patients on placebo; Topline results presented June 2025.
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92 9. Phase 3 TRIUMPH study; Hodges-Lehmann (H-L) median treatment difference in change from baseline 6MWD at 12 weeks measured at peak drug exposure (p<0.001); McLaughlin, V, Benza, R, Rubin, L. et al. Addition of Inhaled Treprostinil to Oral Therapy for Pulmonary Arterial Hypertension: A Randomized Controlled Clinical Trial. JACC. 2010 May | URL: https://doi.org/10.1016/j.jacc.2010.01.027 10. TRIUMPH OLE Study; Median changes in 6MWD at 6, 12, 18, and 24 months were 28, 31, 32, and 18 meters, respectively, for all participants, inclusive of the significant attrition in median change in walk distance for those patients who initially received the placebo; Benza RL, Seeger W, McLaughlin VV, et al. Long-term effects of inhaled treprostinil in patients with pulmonary arterial hypertension: the Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension (TRIUMPH) study open-label extension. J Heart Lung Transplant. 2011 | URL: https://www.tyvasohcp.com/pah/efficacy-safety/triumph-extension-study/ 11. Phase 3 TRIUMPH study; Hodges-Lehmann (H-L) between-treatment median difference in change from baseline NT-proBNP concentration measured at 12 weeks (p=0.0014) (ancillary endpoint); McLaughlin, V, Benza, R, Rubin, L. et al. Addition of Inhaled Treprostinil to Oral Therapy for Pulmonary Arterial Hypertension: A Randomized Controlled Clinical Trial. JACC. 2010 May | URL: https://doi.org/10.1016/j.jacc.2010.01.027 12. Phase 3 TRIUMPH study; NYHA Functional Class was a prespecified secondary endpoint but did not differ significantly between treatment and placebo at 12 weeks; McLaughlin, V, Benza, R, Rubin, L. et al. Addition of Inhaled Treprostinil to Oral Therapy for Pulmonary Arterial Hypertension: A Randomized Controlled Clinical Trial. JACC. 2010 May | URL: https://doi.org/10.1016/j.jacc.2010.01.027 13. SOTERIA OLE participants included eligible adults with PAH on stable background therapy who completed a prior sotatercept study (Phase 2 or Phase 3) without early discontinuation were enrolled. Participants received subcutaneous sotatercept (≤0.7 mg dose once every 21 days). This differs from the design of the OLE studies conducted for TYVASO and TPIP where OLE participants originated from the same lead-in (parent) study | Note on TPIP OLE: A single participant was enrolled in the OLE study from the Phase 2a 24-hour PVR study along with 90 participants from the Phase 2b study 14. Phase 2 PULSAR study; The greater degree of reduction in pulmonary vascular resistance as compared with placebo was seen at both dose levels of sotatercept, with the higher dose (0.7 mg dose) resulting in a 34% reduction from baseline. Least-squares mean difference as compared with placebo -239.5 dyn.sec.cm-5 (baseline 755.9 dyn.sec.cm-5 for high dose); Humbert, M., McLaughlin, V., Gibbs, J. S. R., Gomberg-Maitland, M., Hoeper, M. M., Preston, I. R., Souza, R., Waxman, A., Escribano Subias, P., Feldman, J., Meyer, G., Montani, D., Olsson, K. M., Manimaran, S., Barnes, J., Linde, P. G., de Oliveira Pena, J., & Badesch, D. B. (2021). Sotatercept for the treatment of pulmonary arterial hypertension. New England Journal of Medicine | URL: https://doi.org/10.1056/NEJMoa2024277 15. Phase 3 STELLAR study; Table 2. Change from Baseline at Week 24 in Primary and Secondary Efficacy End Points (Intention-to-Treat Population); The Hodges–Lehmann (H-L) estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (p<0.001); Hoeper, M. M., Badesch, D. B., Ghofrani, H. A., et al. (2023). Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. New England Journal of Medicine 2023 | URL: https://doi.org/10.1056/NEJMoa2213558 TPIP Footnotes (2 of 3):
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93 16. SOTERIA OLE study; Supplementary Table 5. Change from Baseline at Week 24 and Year 1; Mean change from baseline defined as measurement at Visit 1 of SOTERIA or the last measure from the parent study before rollover in 6MWD; Interim results of SOTERIA; Preston, I. R., Badesch, D. B., Ghofrani, H.-A., Hoeper, M. M., Channick, R. N., Chin, K. M., Humbert, M., Jing, Z.-C., Lang, I. M., McLaughlin, V. V., Simonneau, G., Souza, R., Tapson, V. F., Torres, F., White, R. J., Beaufils, B., Kim, J. B., & Rubin, L. J. (2025). A long-term follow-up study of sotatercept for treatment of pulmonary arterial hypertension: Interim results of SOTERIA. European Respiratory Journal, 2025 July | URL: https://doi.org/10.1183/13993003.01435-2024 17. Phase 3 STELLAR study; Table 2. Change from Baseline at Week 24 in Primary and Secondary Efficacy End Points (Intention-to-Treat Population); The Hodges–Lehmann (H-L) estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in NT-proBNP concentration was -441.6 pg/mL; Hoeper, M. M., Badesch, D. B., Ghofrani, H. A., et al. (2023). Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. New England Journal of Medicine 2023 | URL: https://doi.org/10.1056/NEJMoa2213558 18. SOTERIA OLE study; Supplementary Table 5. Change from Baseline at Week 24 and Year 1; Mean change from baseline defined as measurement at Visit 1 of SOTERIA or the last measure from the parent study before rollover in NT-proBNP; Interim results of SOTERIA; Preston, I. R., Badesch, D. B., Ghofrani, H.A., Hoeper, M. M., Channick, R. N., Chin, K. M., Humbert, M., Jing, Z.C., Lang, I. M., McLaughlin, V. V., Simonneau, G., Souza, R., Tapson, V. F., Torres, F., White, R. J., Beaufils, B., Kim, J. B., & Rubin, L. J. (2025). A long-term follow-up study of sotatercept for treatment of pulmonary arterial hypertension: Interim results of SOTERIA. European Respiratory Journal, 2025 July | URL: https://doi.org/10.1183/13993003.01435- 2024 19. Phase 3 STELLAR study; Table 2. Change from Baseline at Week 24 in Primary and Secondary Efficacy End Points (Intention-to-Treat Population); Percentage of patients with improvement from baseline WHO Functional Class 29.4% for sotatercept arm and 13.8% for placebo arm; Hoeper, M. M., Badesch, D. B., Ghofrani, H. A., et al. (2023). Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. New England Journal of Medicine 2023 | URL: https://doi.org/10.1056/NEJMoa2213558 20. SOTERIA OLE study; Supplementary Table 5. Percent of patients in the Continued Sotatercept and Placebo-Crossed groups that achieved WHO-FC II/I by Year 1; Interim results of SOTERIA; Preston, I. R., Badesch, D. B., Ghofrani, H.-A., Hoeper, M. M., Channick, R. N., Chin, K. M., Humbert, M., Jing, Z.-C., Lang, I. M., McLaughlin, V. V., Simonneau, G., Souza, R., Tapson, V. F., Torres, F., White, R. J., Beaufils, B., Kim, J. B., & Rubin, L. J. (2025). A long-term follow-up study of sotatercept for treatment of pulmonary arterial hypertension: Interim results of SOTERIA. European Respiratory Journal, 2025 July | URL: https://doi.org/10.1183/13993003.01435-2024 TPIP Footnotes (3 of 3):
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94 Launch Analog Footnotes (1 of 3) 1. BRINSUPRI | Launched in Q3 2025; Q4 2025 represents the first full quarter of sales a) BRINSUPRI generated US$144.6 million in net product sales during the fourth quarter of 2025 (Insmed Incorporated, 2026). Insmed Incorporated. Insmed Reports Fourth-Quarter and Full-Year 2025 Financial Results and Provides Business Update. February 19, 2026. https://investor.insmed.com/2026-02-19-Insmed-Reports-Fourth-Quarter-and-Full-Year-2025- Financial-Results-and-Provides-Business-Update b) BRINSUPRI generated US$207.9 million in net product sales during the first quarter of 2026 (Insmed Incorporated, 2026). Insmed Incorporated. (2026, May 7). Insmed reports first- quarter 2026 financial results and provides business update. https://investor.insmed.com/2026-05-07-Insmed-Reports-First-Quarter-2026-Financial-Results-and-Provides-Business- Update c) BRINSUPRI generated US$309.2 million in net product sales during the second quarter of 2026 (Insmed Incorporated, 2026). Insmed Incorporated. (2026, August 6). Insmed reports second-quarter 2026 financial results and provides business update. 2. WINREVAIR | Launched in Q2 2024 a) WINREVAIR generated US$70 million in sales during the second quarter of 2024 (Merck & Co., Inc., 2024). Merck & Co., Inc. (2024, July 30). Merck announces second-quarter 2024 financial results. https://www.merck.com/news/merck-announces-second-quarter-2024-financial-results/ b) WINREVAIR generated US$149 million in sales during the third quarter of 2024 (Merck & Co., Inc., 2024). Merck & Co., Inc. (2024, October 31). Merck announces third-quarter 2024 financial results. https://www.merck.com/news/merck-announces-third-quarter-2024-financial-results/ c) WINREVAIR generated US$200 million in sales during the fourth quarter of 2024 (Merck & Co., Inc., 2025). Merck & Co., Inc. (2025, February 4). Merck announces fourth-quarter and full-year 2024 financial results. https://www.merck.com/news/merck-announces-fourth-quarter-and-full-year-2024-financial-results/ d) WINREVAIR generated US$280 million in sales during the first quarter of 2025 (Merck & Co., Inc., 2025). Merck & Co., Inc. (2025, April 24). Merck announces first-quarter 2025 financial results. https://www.merck.com/news/merck-announces-first-quarter-2025-financial-results/ 3. OHTUVAYRE | Launched in Q3 2024; Q4 2024 represents the first full quarter of sales a) Ohtuvayre generated US$36.6 million in net product sales during the fourth quarter of 2024 (Verona Pharma plc, 2025). Verona Pharma plc. (2025, February 27). Verona Pharma reports fourth quarter and full year 2024 financial results and provides corporate update. https://www.veronapharma.com/news/verona-pharma-reports-fourth-quarter-and-full-year- 2024-financial-results-and-provides-corporate-update/ b) Ohtuvayre generated US$71.3 million in net product sales during the first quarter of 2025 (Verona Pharma plc, 2025). Verona Pharma plc. (2025, April 29). Verona Pharma reports first quarter 2025 financial results and provides corporate update. https://www.veronapharma.com/news/verona-pharma-reports-first-quarter-2025-financial-results-and-provides-corporate- update/ c) Ohtuvayre generated US$102.9 million in net product sales during the second quarter of 2025 (Verona Pharma plc, 2025). Verona Pharma plc. (2025, August 6). Quarterly report (Form 10-Q) for the quarter ended June 30, 2025. U.S. Securities and Exchange Commission. https://www.sec.gov/Archives/edgar/data/1657312/000165731225000026/vrna- 20250630.htm d) Ohtuvayre generated US$136 million in net sales during the third quarter of 2025 (Ligand Pharmaceuticals Incorporated, 2025). Ligand Pharmaceuticals Incorporated. (2025, November 6). Third quarter 2025 financial results [PDF]. https://s206.q4cdn.com/221775662/files/doc_financials/2025/q3/Q3_2025_Earnings_Release_Slides.pdf | Note: Third-quarter 2025 Ohtuvayre sales were sourced from Ligand disclosure of Verona-reported net sales; Ligand is eligible to receive low single-digit royalties on global Ohtuvayre net sales pursuant to its license agreement with Verona Pharma.
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95 Launch Analog Footnotes (2 of 3) 4. DUPIXENT | Launched in Q2 2017 a) Dupixent collaboration revenue was US$28.6 million during the second quarter of 2017 (Regeneron Pharmaceuticals, Inc., 2017). Regeneron Pharmaceuticals, Inc. (2017, August 3). Quarterly report (Form 10-Q) for the quarterly period ended June 30, 2017. U.S. Securities and Exchange Commission. https://www.sec.gov/Archives/edgar/data/872589/000153217617000027/regn-063017x10q.htm b) Dupixent collaboration revenue was US$89 million in the third quarter of 2017, with sales occurring almost exclusively in the United States (Regeneron Pharmaceuticals, Inc., 2017). Regeneron Pharmaceuticals, Inc. (2017, November 8). Regeneron reports third quarter 2017 financial and operating results. https://investor.regeneron.com/news-releases/news- release-details/regeneron-reports-third-quarter-2017-financial-and-operating c) Dupixent collaboration revenue was US$138.9 million during the fourth quarter of 2017 (Regeneron Pharmaceuticals, Inc., 2018). Regeneron Pharmaceuticals. Form 10-K, fiscal year ended December 31, 2017, filed February 8, 2018. U.S. SEC EDGAR. https://investor.regeneron.com/sec-filings/sec-filings/sec-filing/10-k/0001532176-18-000013 d) Dupixent collaboration revenue was US$131.4 million during the first quarter of 2018 (Regeneron Pharmaceuticals, Inc., 2018). Regeneron Pharmaceuticals, Inc. (2018, May 3). Regeneron reports first quarter 2018 financial and operating results. https://investor.regeneron.com/news-releases/news-release-details/regeneron-reports-first-quarter-2018-financial- and-operating 5. FASENRA | Launched in Q4 2017; Q1 2018 represents the first full quarter of sales a) Fasenra generated US$21 million in product sales during the first quarter of 2018 (AstraZeneca PLC, 2018). AstraZeneca PLC. (2018, May 18). Q1 2018 results announcement [PDF]. https://www.astrazeneca.com/content/dam/az/PDF/2018/Q1-2018/Q1%202018%20Results%20announcement.pdf b) Fasenra generated US$65 million in product sales during the second quarter of 2018 (AstraZeneca PLC, 2018). H1 2018 Results Announcement. July 26, 2018. https://www.astrazeneca.com/content/dam/az/PDF/2018/h1-2018/H1%202018%20Results%20announcement.pdf c) Fasenra generated US$86 million in product sales during the first nine months of 2018 (AstraZeneca PLC, 2018). Year-to-Date and Q3 2018 Results Announcement. November 8, 2018. https://www.astrazeneca.com/content/dam/az/PDF/2018/Q3/Year-To-Date_and_Q3_2018_Results_announcement.pdf d) Fasenra generated US$125 million in product sales during the fourth quarter of 2018 (AstraZeneca PLC, 2019). AstraZeneca PLC. Full-Year 2018 Results Announcement. February 14, 2019. https://www.astrazeneca.com/content/dam/az/PDF/2018/full-year/Full-Year_2018_Results_announcement.pdf 6. REZDIFFRA | Launched in Q2 2024 a) Rezdiffra generated US$14.6 million in net sales during the second quarter of 2024 (Madrigal Pharmaceuticals, Inc., 2024). Madrigal Pharmaceuticals, Inc. (2024, August 7). Madrigal Pharmaceuticals reports second quarter 2024 financial results and provides business update. https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal- pharmaceuticals-reports-second-quarter-2024-financial b) Rezdiffra generated US$62.2 million in net sales during the third quarter of 2024 (Madrigal Pharmaceuticals, Inc., 2024). Madrigal Pharmaceuticals, Inc. (2024, November 7). Madrigal Pharmaceuticals reports third quarter 2024 financial results and provides business update. https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal- pharmaceuticals-reports-third-quarter-2024-financial c) Rezdiffra generated US$103.3 million in net sales during the fourth quarter of 2024 (Madrigal Pharmaceuticals, Inc., 2025). Madrigal Pharmaceuticals, Inc. (2025, February 27). Madrigal Pharmaceuticals reports fourth quarter and full year 2024 financial results and provides business update. https://ir.madrigalpharma.com/news-releases/news-release- details/madrigal-pharmaceuticals-reports-fourth-quarter-and-full-year-2024 d) Rezdiffra generated US$137.3 million in net sales during the first quarter of 2025 (Madrigal Pharmaceuticals, Inc., 2025). Madrigal Pharmaceuticals, Inc. First Quarter 2025 Financial Results. May 8, 2025. Rezdiffra net sales of $137.3M. https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-pharmaceuticals-reports-first-quarter-2025-financial
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96 Launch Analog Footnotes (3 of 3) 7. TEZSPIRE | Launched in Q1 2022 a) TEZSPIRE generated US$7 million in sales during the first quarter of 2022 (Amgen Inc., 2022). Amgen reports first quarter 2022 financial results. https://investors.amgen.com/news- releases/news-release-details/amgen-reports-first-quarter-2022-financial-results b) TEZSPIRE generated US$29 million in sales during the second quarter of 2022 (Amgen Inc., 2022). Amgen reports second quarter 2022 financial results. https://www.amgen.com/newsroom/press-releases/2022/08/amgen-reports-second-quarter-2022-financial-results c) TEZSPIRE generated US$55 million in sales during the third quarter of 2022 (Amgen Inc., 2022). Amgen reports third quarter 2022 financial results. https://www.amgen.com/newsroom/press-releases/2022/11/amgen-reports-third-quarter-2022-financial-results d) TEZSPIRE generated US$79 million in sales during the fourth quarter of 2022 (Amgen Inc., 2023). Amgen reports fourth quarter and full year 2022 financial results. https://investors.amgen.com/news-releases/news-release-details/amgen-reports-fourth-quarter-and-full-year-2022-financial-results
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