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Sionna Therapeutics Positive Phase 1 Data for NBD1 Stabilizers SION-719 & SION-451 June 4, 2025
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2 Disclaimers and forward-looking statements This presentation contains forward-looking statements of Sionna Therapeutics, Inc. (“Sionna”, “the Company”, “we”, “us”, or “our”) that involve substantial risks and uncertainties. All statements other than historical factual information are forward-looking statements, including without limitation statements regarding the initiation, timing, progress, and results of our research and development programs, preclinical studies, and clinical trials and studies, including the timing of the planned initiation of a Phase 2a proof-of-concept trial and a Phase 1 healthy volunteer combination trial and the expected timing of topline data from these trials; our ability to replicate positive results from earlier preclinical studies or clinical trials conducted by us or third parties in current or future clinical trials; our ability to develop and advance our current and future product candidates and programs; our ability to demonstrate that our product candidates are safe and effective for their proposed indication and our expectations around their beneficial characteristics and therapeutic effects; our ability to advance our current and future product candidates through applicable regulatory approval processes, including the timing of investigational new drug application submissions; the implementation of our business model and strategic plans; our estimates regarding the market opportunity of our product candidates; our ability to rely on third-party manufacturers and successfully manufacture our product candidates for preclinical use, for clinical trials and on a larger scale for commercial use, if approved; our ability to maintain, expand and protect our intellectual property; our ability to enter into future license agreements and collaborations; general economic, industry, and market conditions, including rising interest rates and inflation; our ability to attract and retain key scientific and management personnel; our ability to compete effectively with existing competitors and new market entrants; and our expectations regarding our pipeline, operating plan, use of capital and capital requirements, expenses and other financial results, including our cash runway projection. In some cases, you can identify forward-looking statements because they contain words such as “may,” “will,” “shall,” “should,” “expects,” “plans,” “anticipates,” “could,” “intends,” “target,” “projects,” “contemplates,” “believes,” “estimates,” “predicts,” “potential,” or “continue” or the negative of these words or other similar terms or expressions that concern our expectations, strategy, plans or intentions, although not all forward-looking statements are accompanied by such words. Forward-looking statements are based on assumptions and assessments made by our management in light of their experience and perceptions of historical trends, current conditions, expected future developments and other factors they believe to be appropriate, and speak only as of the date of this presentation. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause our actual results, performance or other events to be materially different from any future results, performance or other events expressed or implied by the forward-looking statements. Given these uncertainties, you should not place undue reliance on forward-looking statements. Our actual future results, performance or other events may be materially different from what we expect. Except as required by law, we assume no obligation to update these forward-looking statements, or to update the reasons actual results could differ materially from those anticipated in these forward-looking statements, even if new information becomes available in the future. Factors that could cause actual results to differ from those predicted in our forward-looking statements include, among other things: the initiation, timing, progress, and results of our planned and future clinical trials, including our ongoing drug-drug interaction study and planned clinical trials of SION-719 and SION-451; our ability to replicate positive results from earlier preclinical studies or clinical trials conducted by us or third parties in current or future clinical trials; our ability to demonstrate that our NBD1 stabilizers, complementary CFTR modulators, and any potential future product candidates are safe and effective for their proposed indications and our expectations around their beneficial characteristics and therapeutic effects; our ability to advance our current programs and any potential future product candidates through applicable regulatory approval processes, including timing of Investigational New Drug applications and final U.S. Food and Drug Administration approval, if any, of our current and any future product candidates; our estimates of the number of patients that we will enroll and our ability to initiate, recruit and enroll patients in and conduct and successfully complete our clinical trials at the pace we project; the implementation of our business model and strategic plans; our ability to rely on third-party manufacturers; the size and growth potential of the cystic fibrosis market for our programs and our ability to serve those markets; our ability to realize the benefits of collaborations for the development and commercialization of our programs or any other potential future product candidates; our ability to maintain, expand and protect our intellectual property; developments relating to our competitors and our industry; existing regulations and regulatory developments in the United States and other jurisdictions; general economic, industry, and market conditions, including potential tariffs implications, supply chain disruptions, rising interest rates and inflation; our ability to attract, hire, and retain our key personnel and additional qualified personnel; and those risks and uncertainties identified in our filings with the Securities and Exchange Commission, including our Annual Report on Form 10-K, filed on March 20, 2025, as well as any subsequent filings with the SEC. These risks are not exhaustive. New risk factors emerge from time to time, and it is not possible for our management to predict all risk factors, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in, or implied by, any forward-looking statements. Market data and industry information used throughout this presentation are based on management’s knowledge of the industry and the good faith estimates of management. We also relied, to the extent available, upon management’s review of independent industry surveys and publications and other publicly available information prepared by a number of third-party sources. All of the market data and industry information used in this presentation involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. Although we believe that these sources are reliable as of their respective dates, we cannot guarantee the accuracy or completeness of this information, and we have not independently verified this information. Projections, assumptions and estimates of our future performance and the future performance of the industry in which we operate are necessarily subject to a high degree of uncertainty and risk due to a variety of factors. These and other factors could cause results to differ materially from those expressed in our estimates and beliefs and in the estimates prepared by independent parties. The trademarks included herein are the property of the owners thereof and are used for reference purposes only. Such use should not be construed as an endorsement of such products. This presentation discusses product candidates that are investigational only and have not yet been approved for marketing by the U.S. Food and Drug Administration. No representation is made as to the safety or effectiveness of these product candidates for the use for which such product candidates are being studied.
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Sionna Overview & Today’s Announcement
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FRANCHISE DRIVES STRATEGIC OPTIONALITY PREDICTIVE ASSAY / BIOMARKERS* NBD1, A CRITICAL CF TARGET 4 Sionna’s novel approach focused on stabilizing NBD1 has the potential to revolutionize the current CF treatment paradigm HIGH UNMET NEED IN LARGE MARKET Despite current treatments, >2/3rd of patients do not have normal CFTR function Today’s market is >$11B1, expected to be $15B by 20292 We believe NBD1 has the potential to deliver full CFTR function, and none of the approved CFTR modulators directly stabilize NBD1 Industry standard CFHBE assay and sweat chloride biomarker have been highly predictive of clinical outcomes for approved CFTR modulators Robust clinical stage pipeline of NBD1 stabilizers and complementary modulators provides multiple potential paths to transform the standard of care for CF patients 1. VRTX 4Q24 earnings call; 2. 2024 Wall Street research estimates; *Source: Preclinical assays conducted by Sionna; results observed from our preclinical studies may not necessarily be predictive of clinical outcomes, and actual outcomes may differ; CF – Cystic fibrosis; NBD1 - Nucleotide Binding Domain 1 of CFTR; CFTR - CF transmembrane conductance regulator; CFHBE – CF Human Bronchial Epithelial primary cells
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Cell Membrane TMD2 TMD1 ICL4 NBD1 NBD2 F508del Mutation SION-2222 SION-2851 SION-109 SION-719 SION-451 SION-3067 5 We believe stabilizing NBD1 is central to unlocking meaningful improvements in clinical outcomes for CF patients CFTR Structure ~90% of people with CF have a F508del mutation; F508del resides within the NBD1 domain of CFTR F508del severely destabilizes CFTR, preventing its normal folding, trafficking, and function We believe stabilizing NBD1 is the key to normalizing CFTR function None of the approved CFTR modulators directly stabilize NBD1 The Importance of NBD1 TMD – Transmembrane Domain 1 and 2 of CFTR; ICL4 – Intracellular Loop 4 of CFTR
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Highlights from today’s announcement 6 Both NBD1 stabilizers SION-719 and SION-451 exceeded our desired PK targets, were generally well-tolerated, and will be advanced to the next phases of development Positive NBD1 Phase 1 Results SION-719 to advance as add-on to SOC in Phase 2a proof-of-concept trial, based on high potency at low doses SION-451 to advance as anchor in proprietary dual combinations, based on higher exposure achieved NBD1 Portfolio Strategy SION-719 IND cleared and DDI study ongoing; Phase 2a proof-of-concept in CF patients to be initiated 2H25 SION-451 Phase 1 healthy volunteer dual combination trial to be initiated 2H25 Well-positioned to execute with cash runway into 2028 Next Development Phase IND – Investigational New Drug; DDI – Drug to drug interaction; PK – pharmacokinetic SOC – standard of care
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PROGRAM / MECHANISM PRECLINICAL PHASE 1 PHASE 1 COMBO PHASE 2 UPCOMING MILESTONES Initiate Ph 1 HV dual combo 2H25, TLD mid-26 Initiate Ph 1 HV dual combo 2H25, TLD mid-26 *Licensed compounds from AbbVie; Clinical trials conducted by AbbVie; Galicaftor and Navocaftor completed Ph 2 combination trials POC – proof of concept; HV – healthy volunteer; TLD – topline data; Ph – phase 7 PROGRAM / MECHANISM PRECLINICAL PHASE 1 PHASE 2 UPCOMING MILESTONES Complete DDI; Initiate Ph 2a POC 2H25, TLD mid-26 SION-719 NBD1 Galicaftor* SION-2222 TMD1 SION-451 NBD1 SION-109 ICL4 SION-451 NBD1 ADD-ON TO STANDARD OF CARE NBD1 Stabilizer + SOC PROPRIETARY DUAL COMBINATIONS NBD1 Stabilizer + Complementary Modulator PROGRAM / MECHANISM PRECLINICAL PHASE 1 PHASE 2 SION-2851 TMD1 Navocaftor* SION-3067 Potentiator Lifecycle Development Sionna has a robust and differentiated pipeline, with several near-term clinical milestones
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NBD1 Programs Phase 1 Data: SION-719 & SION-451
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SION-719 and SION-451: Phase 1 trial summary 9 Phase 1 clinical trials of SION-451 and SION-719 • Evaluating the safety, tolerability, and PK profiles of single and multiple ascending doses of SION-719 and SION-451 in healthy volunteers • 3:1 randomized, double-blind, placebo-controlled studies in Australia • SAD/MAD parts dosed as oral suspension (fasted unless noted); MAD dosing duration of 10 days • FE/BE Part C evaluated the effect of food on PK and bioequivalence of a tablet formulation compared to oral suspension SION-451 • 110 total subjects dosed: • SAD: 25mg (fed), 75mg (fasted & fed), 150mg, 300mg, 450mg • MAD (BID): 25mg (fed), 75mg, 150mg, 225mg, 300mg • FE/BE Part C: doses in add-on to SOC and dual combo ranges SION-719 • 100 total subjects dosed: • SAD: 20mg (fasted & fed), 40mg, 80mg, 160mg • MAD (BID): 20mg, 40mg, 80mg, 120mg, 160mg • FE/BE Part C: doses in add-on to SOC and dual combo ranges SAD – single ascending dose; MAD – multiple ascending dose; FE – Food Effect; BE – BioEquivalence; BID – twice a day
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SION-719 exceeded target exposures predicted by our CFHBE assay, and is an attractive add-on to SOC given high potency at lower doses 10 MAD PK Summary Day 10 Through 36 Hours Post-administration PK observations in the SAD portion of the trial were generally consistent with the MAD findings shown Add-on target coverage at all doses studied; dual combination coverage at ≥40mg BID Part C data support use of the tablet in future studies and indicate SION-719 can be dosed in fed or fasted state 0.1 1.0 10.0 100.0 1000.0 0 6 12 18 24 30 36 Mean SION-719 Concentration (ng/mL) Semi-log scale Time (hrs) 20mg BID 40 mg BID 80mg BID 120mg BID 160 mg BID ‘Dual Combo’ Cave target for clinically meaningful benefit ‘Add-on’ Cave target for clinically meaningful benefit Each solid line shows mean concentration data from a dosing cohort on Day 10 High potency and synergy with SOC support lower dose SION-719 for Phase 2a POC trial
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SION-719 Phase 1 data suggest favorable tolerability profile 11 Placebo BID 20 mg BID 40 mg BID 80 mg BID 120 mg BID 160 mg BID MAD Total Study Participants (n)* (n=10) (n=6) (n=6) (n=6) (n=6) (n=6) (n=40) Any TEAE, n (%) 4 (40) 2 (33) 4 (67) 6 (100) 5 (83) 3 (50) 24 (60) Mild (Grade 1) 3 (30) 2 (33) 3 (50) 5 (83) 2 (33) 3 (50) 18 (45) Moderate (Grade 2) 1 (10) - 2 (33) 1 (17) 3 (50) 1 (17) 8 (20) Severe (Grade 3) - - - - - - - Life-threatening (Grade 4) - - - - - - - Leading to treatment discontinuation - - - - - - - Serious TEAEs, n (%) - - - - - - - Most frequent TEAEs (≥2 subjects), n (%) Headache - - 4 (67) 1 (17) 2 (33) 2 (33) 9 (23) Diarrhea 1 (10) 1 (17) - - - 2 (33) 4 (10) Nausea 1 (10) - 1 (17) - - 1 (17) 3 (8) Catheter site phlebitis - - - - 2 (33) - 2 (5) Pruritus 1 (10) - - - - 1 (17) 2 (5) * Safety Population; includes participants who received all or part of at least 1 dose of SION-719 or placebo SAE – Serious adverse event; TEAE – Treatment emergent adverse event after first dose of drug; LFT – liver function test ECG – electrocardiogram SION-719 MAD Safety Summary SION-719 SAD, MAD, and FE/BE Safety Highlights • No SAEs; Most TEAEs were mild to moderate (Grade 1 or Grade 2) • No TEAEs led to discontinuation of drug and no dose-limiting TEAEs observed • No TEAEs related to LFTs in treated subjects • No clinically meaningful trends in other safety parameters, vital signs or ECG parameters
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0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 2.25 2.50 Mean CFHBE CFTR-dependent current compared to ETI at its Emax ELX/TEZ/IVA VX440/TEZ/IVA, VX152/TEZ/IVA SION-2222 + SION-3067 TEZ/IVA LUM/IVA IVA F/F IVA G551D F508del homozygous LUM G551D/F508del Minimum target for clinically meaningful improvement to SOC 12 SION-719’s potency at low doses enables a potentially differentiated profile when added to SOC Wild-type range is the average FSK response +/- standard error of the mean across a panel of 8 non-CFHBE primary cell donors Potential of SION-719 as an add-on to SOC* Phase 1 PK data indicate potential for clinically meaningful benefit, including to wild-type levels, as add-on to SOC based on CFHBE target zone Minimum CFHBE target represents at least 10 mmol/L SwCl and ~3 ppFEV1 improvement Wild-type levels of CFTR function *Source: Preclinical assays conducted by Sionna and SION-719 Phase 1 PK; results observed from our preclinical studies may not necessarily be predictive of clinical outcomes, and actual outcomes may differ Gating mutation – G551D CFTR; ELX – elexacaftor; IVA – ivacaftor; LUM – lumacaftor; TEZ – tezacaftor; Trikafta – ELX/TEZ/IVA; SwCl – Sweat Chloride; ppFEV - Percent Predicted Forced Expiratory Volume SION-719 + ELX/TEZ/IVA Potential zone based on ‘719 clinical exposures
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SION-451 is an ideal anchor for dual combinations given level of exposures achieved in target concentration zones as predicted by our CFHBE assay 13PK observations in the SAD portion of the trial were generally consistent with the MAD findings shown 0.1 1.0 10.0 100.0 1000.0 10000.0 0 6 12 18 24 30 36 Mean SION-451 Concentration (ng/mL) Semi-log scale Time (hrs) 25mg BID Fed 75mg BID 150mg BID 225mg BID 300mg BID ‘Dual Combo’ Cave target for clinically meaningful benefit ‘Add-on’ Cave target for clinically meaningful benefit Each solid line shows mean concentration data from a dosing cohort on Day 10 MAD PK Summary Day 10 Through 36 Hours Post-administration Dual combination target coverage at ≥75 mg BID; add-on target coverage at all doses studied Part C data support use of the tablet in future studies and indicate SION-451 can be dosed in fed or fasted state High exposures support evaluating SION-451 upper dose range in Ph 1 HV dual combination
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SION-451 Phase 1 data suggests favorable tolerability profile 141. Subject was in isolated dose cohort of SION-451 (150mg BID) that was impacted by an outbreak of respiratory infection Placebo BID 25 mg BID 75 mg BID 150 mg BID 225 mg BID 300 mg BID MAD Total Study Participants (n)* (n=9) (n=6) (n=5) (n=6) (n=6) (n=6) (n=38) Any TEAE, n (%) 5 (56) 2 (33) 3 (60) 3 (50) 4 (67) 2 (33) 19 (50) Mild (Grade 1) 4 (44) 2 (33) 2 (40) 1 (17) 4 (67) - 13 (34) Moderate (Grade 2) 1 (11) - 1 (20) 1 (17) - 2 (33) 5 (13) Severe (Grade 3) - - - 1 (17) - - 1 (3) Life-threatening (Grade 4) - - - - - - - Leading to treatment discontinuation - - - - - - - Serious TEAEs, n (%) - - - - - - - Most frequent TEAEs (≥2 subjects), n (%) Headache 3 (33) 1 (17) - - 2 (33) 1 (17) 7 (18) Influenza - - - 2 (33) - - 2 (5) Upper Respiratory Tract Infection 1 (11) - - 1 (17) - - 2 (5) * Safety Population; includes participants who received all or part of at least 1 dose of SION-451 or placebo • No SAEs; Most TEAEs were mild to moderate (Grade 1 or Grade 2) • No TEAEs led to discontinuation of drug and no dose-limiting TEAEs observed • 1 Grade 1 TEAE related to LFTs observed in a treated subject who tested positive for influenza 1; no TEAEs related to LFTs in other cohorts • Same subject had transient Grade 3 neutropenia at same time as influenza • No clinically meaningful trends in other safety parameters, vital signs or ECG parameters SION-451 MAD Safety Summary SION-451 SAD, MAD, and FE/BE Safety Highlights
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0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 2.25 2.50 15 SION-451 in a dual combination has the potential to provide a superior treatment option for people living with CF *Source: Preclinical assays conducted by Sionna and SION-451, SION-2222 and SION-109 Phase 1 PK; results observed from our preclinical studies may not necessarily be predictive of clinical outcomes, and actual outcomes may differ Mean CFHBE CFTR-dependent current compared to ETI at its Emax ELX/TEZ/IVA VX440/TEZ/IVA, VX152/TEZ/IVA SION-2222 + SION-3067 TEZ/IVA LUM/IVA IVA F/F IVA G551D F508del homozygous LUM G551D/F508del Minimum target for clinically meaningful improvement to SOC Wild-type range is the average FSK response +/- standard error of the mean across a panel of 8 non-CFHBE primary cell donors Wild-type levels of CFTR function Potential of SION-451 in dual combination* SION-451 + SION-2222 SION-451 + SION-109 Potential zone based on ‘451 clinical exposuresPotential zone based on ‘451 clinical exposures Phase 1 PK data indicate potential for clinically meaningful benefit, including to wild-type levels, in a dual combination based on CFHBE target zone Minimum CFHBE target represents at least 10 mmol/L SwCl and ~3 ppFEV1 improvement
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Clinical Strategy
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Sionna’s development strategy is data-driven with multiple near-term milestones 17 2025 2026 Add-On to SOCDual Combination Ph 1 Trial SION-719 Ph 2a POC Trial SION-719 + SOCDDI Study Ph 1 Trial SION-451 Ph 1 Healthy Volunteer Dual Combo SION-451 + SION-2222 Ph 1 Healthy Volunteer Dual Combo SION-451 + SION-109 Dual combination selection & planned Ph 2b initiation NBD1 NBD1 NBD1 NBD1 TMD1 NBD1 ICL4
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18 Phase 2a Proof-of-Concept trial in patients with CF: Evaluating low-dose SION-719 added to Trikafta® Phase 2a Endpoints Primary: Safety Secondary: Sweat Chloride, PK Study powered for ≥10 mmol/L SwCl change Study Population Adult CF subjects homozygous for F508del on stable dose of physician-prescribed Trikafta Screening 28 Day Trikafta Run-In 14 Day SION-719 + Trikafta Placebo + Trikafta 14 Day Safety Follow-up 28 Day Placebo + Trikafta SION-719 + Trikafta 14 Day NBD1 Washout 28 Day Objectives are to demonstrate that NBD1 is mechanistically unique from, and synergistic with the components of Trikafta, and that adding a low dose of NBD1 to Trikafta is associated with improved CFTR function n = ~8 n = ~8 Trikafta is a registered trademark of Vertex Pharmaceuticals Incorporated
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19 Clinical Drug-Drug Interaction (DDI) study in healthy subjects: Evaluating the potential to dose SION-719 with standard dose Trikafta Clinical Pharmacology Single Midazolam Dose Steady state Objective is to evaluate the potential effect of low dose SION-719 on CYP3A4 substrate to confirm SION-719 can be combined with the standard dose of Trikafta SION-719 BID Dosing Steady state SION-719 + Midazolam Steady state Midazolam is a sensitive CYP3A4 substrate, used as a probe to test the potential effect of SION-719 on CYP3A4 substrates (e.g., components of Trikafta)
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20 Healthy volunteer Phase 1 dual combination trial: Evaluating safety, tolerability, and PK of SION-451-based dual combos Ph 1 Dual Combo SION-451 + SION-2222 SION-451 + SION-109 14 Day n =12 9 active/ 3 placebo Objective is to evaluate different doses of SION-451 in combination with SION-2222 and with SION-109 in healthy volunteers and select the NBD1-based dual combination to advance to Phase 2b trial in patients with CF n =12 9 active/ 3 placebo Safety/ tolerability and PK will determine next dose(s) SION-451 + SION-2222 SION-451 + SION-109 14 Day Sequential cohorts, doses selected based on data Randomized, double-blind, placebo controlled Combo Doses #2Combo Doses #1
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Unmet Need & Opportunity
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22 Significant commercial opportunity exists for our NBD1-led franchise to provide a potentially transformative treatment for CF , if approved ~106K patients with CF across 94 countries1 ~90% patients have at least one F508del-CFTR mutation2 >$11B worldwide revenues of CFTR modulators today7 ~33k U.S. ~35k EU4 + UK ~38k ROW 1. CFF estimates 2023, 2023 CFF Registry data, 2022 ECFS Registry 2. Taylor-Cousar 2019; 3. Konstan, NACFC poster 2022 4. Vertex 2Q23 Earnings Call Transcript; 5. Vertex 2Q24 Earnings Presentation; 6. Sploletini 2022 JCF; Ibrahim 2023 Front Pha rmacol 7. VRTX 4Q24 earnings call; 8. 2024 Wall Street research estimates; * as measured by sweat chloride EU4 – FR, GE, IT, ES; ROW – Rest of World >2/3 of patients on SOC do not have normal CFTR function3* >20% of eligible patients are currently not on CFTR modulators5 Non-responders or patients with tolerability challenges have limited or no alternatives6 >6,000 patients have discontinued use of approved CFTR modulators4 $15B opportunity by 20298
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Despite advancements in treatment, the unmet need remains high, as many CF patients on treatment do not achieve normal CFTR function 1. Konstan, NACFC poster 2022; 2. Zemanick, JCF 2024; 3. Vertex press release, Feb 5th 2024 * Observational study of 3,131 CF patients from the CFF Registry showing sweat chloride levels pre- and post- treatment of a CFTR modulator 23 Normal sweat chloride <30 mmol/L n = number of participants Bold lines are SC means CHEC-SC Study; All Patients Pre- and Post- Modulator1* Abnormal sweat chloride ≥30 mmol/L Kalydeco (I) Orkambi (LI) Symdeko (TI) Trikafta (ETI) Standard of Care Prescribed CFTR Modulator SwCl (mmol/L) >2/3rd of patients on Trikafta do not have normal CFTR function1,2 as measured by sweat chloride <30mmol/L ~69% of Alyftrek patients in two Phase 3 clinical trials conducted by Vertex did not achieve normal CFTR function3
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Closing
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25 We intend to transform the treatment of CF and are well-positioned given our deep portfolio, strong clinical execution, and cash runway into 2028 $219M Upsized IPO in 1Q25 Funds Sionna into 2028 Pioneering a First-in- Class NBD1 Portfolio with Pipeline of Combination Assets Proven Execution with Multiple Ph 1 Trials Multiple Upcoming Clinical Milestones Positive Ph 1 data support advancing both NBD1s while maintaining timelines and cash runway