Good morning, everyone. I'm Amita Gupta from Biotech Research at TD Cowen. It's my pleasure here today to introduce Spero Therapeutics. With us today, we have Sath Shukla, President and CEO of Spero. For the audience, we'll have a round of Q&A at the end of the presentation, but then with that, yeah, I'll take it away. Fantastic! Thanks, Amita. A pleasure to be here today and to discuss the Spero story with you all. A reminder that today's discussion will contain the usual forward-looking statements. Spero was founded in 2013, and now, as we enter our second decade, we consider ourselves leaders in the rare and infectious disease space. Our portfolio focus is listed on the left side of this slide. We focus on a late-stage development pipeline with a special focus on oral small molecule drugs. These drugs have strong IP protection and QIDP and/or Fast Track designations. And most importantly, we progress a portfolio where we feel that it is laser-focused on high unmet need and a addressable patient population that can then translate into a strong economic opportunity. On the right side of this slide is the focus of our wholly-owned lead asset, SPR720. SPR720 is a potential novel oral therapy for first-line patients suffering from nontuberculous mycobacterial disease or NTM. This is a rare infectious lung disease with approximately a quarter million patients in major developed markets worldwide. There are currently no approved first-line therapies, and therapies that are in later stages of development are still focused on inhaled therapies, not oral. Finally, we are expecting proof of concept data on this asset in the second half of this year. The way we progress SPR720 and all our assets is through world-class partnerships that we'll cover in a moment, that have yielded us a cash runway into late 2025. This slide is a snapshot of where we stand today on our portfolio. SPR720, wholly owned and licensed from Vertex, and progressing in NTM-PD with a phase IIa data readout in the second half of this year. Our other assets, Tebipenem HBr, is currently enrolling a phase III study that with a data readout and target commercialization by 2026. It's expected to complete enrollment in the second half of 2025, and it's progressing by funding from our partners at GSK, who are also the leading shareholders in the company. SPR206, our next-generation polymyxin, is an IV asset that has recently been cleared on an IND for a phase II study. This asset usually progresses on only non-dilutive funding, either from our partnerships with Pfizer, who own European rights, Everest Medicines, who own certain China rights, or funding from government agencies such as BARDA and NIAID. So one thing to call out about this page is that in our history, we've had the benefit of partnerships, scrutiny, and evaluation of our assets by a variety of partners, ranging from large pharma to government agencies, and that's something we take pride in. Moving to 720, our lead asset. NTM is a chronic, debilitating disease, with a five-year mortality rate of 35%. This slide lays out the landscape for the disease. On the left side are the pathogens that cause this disease. They are widespread. For many people today, when you took a shower, you probably inhaled some NTM bacteria. But for most of us, our systems clear it, and it does not take root. However, from patients who suffer from any lung issues or certain immunocompromised situations, the exposure to these pathogens basically leads to the development of this disease. The symptoms are listed on the right, and these are really, painful symptoms for lifestyle considerations and health considerations for patients who are unfortunate enough to get these infections. And in addition to these symptoms, lung damage begins to take place over time. So if this disease is left untreated in the earliest stages, it has the potential, beyond its symptoms, to progress to life-threatening situations. So patients need an effective oral therapy early on, in their disease journey, and that is the value proposition for SPR720. This slide lays out the patient journey again, but, with a focus on current SOC. So towards the right side of the slide, are following diagnoses, usually by pulmonologists. Depending on whether you have the non-cavitary form of the disease or cavitary form, where your lungs unfortunately start developing cavities. The guidance-based SOC, nothing approved, but off-label TB drugs are usually combinations of macrolides, such as azithromycin or clarithromycin, along with ethambutol and rifampin for non-cavitary, and there's IV amikacin that's added on for the cavitary form. These therapies suffer from both a lack of efficacy for many patients and also suffer from significant tolerability issues for many patients. So on the efficacy side, only about 2/3 of patients see their sputum convert from positive to negative on these therapies 1/3 of patients do not. And even for the patients who see that conversion, recurrence happens on 50% of those patients. In addition to that lack of efficacy, a whole Pandora's box of tolerability issues is listed on the right: hepatotoxicity, optic neuritis, peripheral neuropathy, GI intolerability, QT prolongation. Really, the patients that we bring in to see our R&D teams talk about their disease journey, and when they go to physicians, they're told the good news is that there are therapies out there for NTM. The bad news is that they are often worse in their tolerability profile than the disease, which in turn forces prescribers and patients to settle into the watchful waiting mode, which does not preclude the progression of lung disease or the damage to those, to the lungs. So the unmet medical need here is for better tolerability and effectiveness, fewer DDI, and a shorter therapy duration. This, we talked about the 250,000 or thereabouts patients for NTM. The vast majority of them are first-line, and SPR720 is being developed for those treatment-naive and treatment-experienced non-refractory patients. On the left side of the slide, you'll see the geographic landscape, U.S. at approximately 95,000 patients, Japan with an even higher prevalence, showing real potential for ex-U.S. possibilities. And on the right side, this inverted pyramid, again, showcases why the current landscape for first-line patients is fairly unpromising. Because once diagnosed, because of tolerability and efficacy considerations, only 50% of the patients are actually treated with the guideline-based therapies we discussed earlier. And roughly 18 months later, only 11% continue. And it's not because all of these patients have seen that culture conversion. It's because going back to that, safety and tolerability and efficacy issues that drive this outcome. So SPR720, if approved, aims to be the principal foundation for first-line standard of care for these patients. So what— So why is it well-positioned for addressing that high unmet need for patients? Starting with efficacy, what we have seen in data that we'll cover shortly, in vitro and in vivo data, it's shown potency against multiple NTM pathogens, including M. avium complex and M. abscessus. These two pathogens drive roughly 80%-90% of NTM infections. The drug has a novel MOA, which in turn translates to, so far, no evidence of cross-resistance with marketed antibiotics and low propensity for selection of resistance. And for people who follow the space, MDR considerations are a real barrier for development. By focusing on a novel MOA here, we feel that we bypass those challenges. We have data today that support the potential for efficacy, macrophage penetration, the drug getting to where it needs to get to, and safety and tolerability. It can be administered with and without food, and as mentioned earlier, it has very good exclusivity and IP protection. Talking about the MOA. So it's an oral small molecule gyrase B inhibitor. Many people are familiar with gyrase A inhibitor in fluoroquinolones, but because of this novelty, this is not exploited by current antibiotics. No cross-resistance, low propensity for selection of resistance. It basically targets bacterial DNA replication, penetrates lung macrophages from what we have seen in hollow fiber models, and differentiated advantages in vitro and in vivo that we'll cover in just a moment. Speaking of the data that we have so far, this slide lays out in vitro comparisons for SPR719, the active moiety for SPR720, to amikacin. Amikacin is the foundation for inhaled Arikayce, which is Insmed's therapy in development in NTM. The comparison here is on minimum inhibitory concentration 90 measures, so essentially, the degree of drug required to reduce bacterial burden by 90%. So a lower number is better. And across the chart, what we see is very good data for SPR719, and those numbers are significantly lower than what you would see from amikacin. This in vitro data gave us promising, promising outlook for continued development that we continue to see in vivo data. So this is a standard murine chronic infection model. It is in log terms, so a decline from 6- 4 represents a 99% reduction in lung burden. The black bars are untreated subjects. The blue bars are different doses of SPR720, and the green bars show either the current macrolides as standalone or in combination with SPR720. So what you see here is a dose response on the blue bars. So, SPR720 as a monotherapy showed good activity against these pathogens and comparable to clarithromycin, a leading macrolide on top of clarithromycin and ethambutol, which is the very right side of the bar chart, you saw a four-log reduction in lung burden. So these in vivo data, again, supported the in vivo data we have seen on the potential efficacy and potency of this drug. This was accompanied by a SAD/MAD study in 96 healthy volunteers, to evaluate the favorability of to evaluate a safety and tolerability profile. And, the top line there was that we found it to be generally well-tolerated, within the predicted therapeutic exposures of 500 mg-1,000 mg. The data showed no SAEs. The only AEs we saw were mild GI, which are very common in these types of oral therapies. Only one discontinuation at well above predicted therapeutic levels. A grade 2 enzyme elevation that was asymptomatic, monitorable, and reversible. And as this was a patient study with no control on patient lifestyle during the time of dosing and their follow-on, that discontinuation was deemed to be non-drug related. These data, the in vitro, in vivo, and safety data, have informed the phase IIa study we are running currently, with the expected data readout in the second half of this year. The treatment population is treatment-naive, treatment-experienced, but non-refractory patients suffering from MAC, again, the leading cause of NTM. Approximately up to 35 patients, 56 days of dosing. A short study, as there's no SOC component to it, with five treatment arms: placebo, 500 mg, and 1,000 mg. 27 patients are randomized and blinded, along with two small open-label sub-studies for more PK data. The endpoints for this is first to evaluate the primary endpoint of microbiological response, the change from baseline for these patients. We have seen that this drug kills bugs. We have seen it being well-tolerated in healthy volunteers, and now we want to see, does it kill bugs in patients, and is it well-tolerated? For the microbiological eradication piece, the comparison to placebo will be essentially divergence from that placebo lines for the patients who are on drug. In addition, we expect to get some supporting secondary endpoint data as well. Continued safety and tolerability, as we discussed earlier, because that's such a large feature for the treatment path that we want to travel. How patients feel and function, which will become much more relevant for follow-on studies, including the registrational studies, where the PRO per FDA guidance will be the primary endpoint, and plasma PK. This study, we started it in late 2022. We have informed our stakeholders that patients have been getting enrolled and dosed and is on track for that second half of this year data readout. That study provides a large subset of what we expect to be a fairly comprehensive data set in the second half of 2024. But there are some additional data that are forthcoming as well. This slide, the first three items, the microbiological response, the patient-reported outcomes that will inform the primary endpoints in later trials, PK, and safety and tolerability, are things that we will see in the phase IIa study. But in addition, we are also doing a BAL study and a co-administration study with azithromycin and ethambutol in healthy volunteers for additional PK data. So this is, again, a...w hat we feel to be a very robust data set that will inform us in designing our next studies going forward, as well as the data package we would go take with us to the FDA for guidance for those next studies. So just for conclusion, this slide lays out why we are so excited about SPR720, because on a variety of measures, it really offers promise and potential. Starting with that novel MOA, which then translates into low propensity for resistance, activity in macrolide-resistant MAC, and activity in MAC that is very potent from the in vitro data we have seen so far, the oral administration, and the evidence of any food effect. So what that takes us to, from what we know today, is that this seems to be the only asset where we can really check off these relevant boxes, that for the assets that are in development today. But go to the first slide. Changing gears to our other asset in late-stage development, tebipenem HBr. So, tebipenem came to us from our partners, Meiji Seika, in Japan, where it has been approved in a granular form for treatment of pediatric pneumonia, since 2009. So in that indication, in Japan, millions of patients treated, a safe, well-tolerated, and effective therapy. Spero's innovation here was to convert it into a tablet form for complicated urinary tract infections. cUTI sees an incidence of millions of patients in the U.S. alone every year, and right now, that treatment pathway ends up with many patients suffering from those complicated infections and ending up in the hospital, which takes up 7-10 days of being on an IV, being subjected to that treatment and also therapies and development for cUTI are also subjected to being under the DRG reimbursement considerations. The innovation here was to think about an oral carbapenem, keep it outside the hospital, treat patients in community centers, and so enable patients to either avoid hospitalization or leave the hospital sooner. So that's where tebipenem HBr, we believe, fits in. Potentially differentiated oral therapy, a oral carbapenem, if approved. A robust IP through 2038, broad prescriber base from data that we have collected in the past, QIDP designation, and that phase III has started enrollment, as we announced at the end of last year, with a first patient, first dose that triggered several of the significant economics associated with this asset that I'll cover in just a moment. Tebipenem is in a global commercial partnership. GSK, our leading shareholders, have the commercial rights worldwide, excluding Japan and certain Asian territories, which are held by our partners, Meiji Seika. And this partnership has provided robust financial terms that have not only strengthened our balance sheet to date but provide potentially significant upside economics going forward as well. This slide lays out some details for our agreement with GSK. Spero is responsible for execution and costs of tebipenem Phase III in the U.S. GSK are responsible for ex-U.S. development. GSK take on the submission of an NDA and commercialization, assuming positive data. And the financial terms, to date, Spero has disclosed receipt of $105 million and has disclosed that we have qualified for another $95 million on development milestones coming up over the next two years to pay for development and this Phase III. So out of potentially $600 million in milestones, $200 million have either been received or been qualified for to take this asset through that Phase III development. On development milestones, should an NDA be filed by GSK upon positive data, Spero receives another $25 million, and GSK have communicated publicly that they are targeting 2025 for NDA submission, with potential commercialization in 2026. If that does turn out to be the case, then upon first sale, Spero receives another up to $150 million on that first sale. We say up to, as there's a U.S. and an ex-U.S. component on it, as it's a worldwide partnership. Then up to $225 million in sales-related milestones. If the drug reaches certain revenue benchmarks at the earlier levels of sales, $200, $300, $400 million, the economics are sales milestone related, so $25 million increments, according to the company. At higher sales numbers, these sales milestones die off, but royalty numbers take their place. Royalties start off at low single-digit figures but rise to low double-digit figures as sales reach a billion and above. So $600 million in milestones, plus royalties up to double digits, are the financials, transactions and components of this agreement. The Phase III I mentioned earlier, this slide lays out the details. So patients with a diagnosis of complicated urinary tract infections or acute pyelonephritis, large trial, almost 2,650 patients, 7-10 days of dosing, two treatment arms, tebipenem and imipenem. And the primary endpoints of this will be the overall response, test of cure in micro-ITT population. The analysis, as tends to be for any of these non-inferiority studies, would be an assessment based on a 10% NI margin. What we also disclosed was in 2023, the alignment with the FDA on a special protocol assessment. What the FDA indicated then was that positive and persuasive results from this trial, along with the work that we have done in the past, could be sufficient for the approval of tebipenem as a treatment for cUTI and AP in a limited use indication. Quick time check. Okay, great. Moving on to SPR206. So as I mentioned earlier, we recently disclosed good news on this asset, IND clearance for a Phase II HABP study. This is a innovative investigational next-generation polymyxin for treatment of resistant Gram-negative pathogens. Right now, polymyxins are used very frequently for these types of treatments, but standard polymyxins also have nephrotoxicity issues. They will kill the infection, but they also unfortunately kill kidney cells. The value proposition here is, again, that safe and tolerable and effective therapy. The current studies that have informed this to-be-initiated phase II study are preclinical data, SAD/MAD studies, a BAL study, and a renal impairment study that provided both dosing information and exposure information. And the next step indeed is to start that phase II HABP study upon continued accruing of non-dilutive funding. This is an asset where Spero currently owns U.S. rights, but its European rights are held by our partners, Pfizer, who are also shareholders in the company, and by Everest Medicines in China. So, funding for this asset historically has come from those partnerships, along with government entities such as BARDA and NIAID. On a portfolio basis, that is a summary of where we stand today. Really promising assets with near-term data on our leading asset, a balance sheet that is de-risked until late 2025, and a lot of upside from our perspective. I'll conclude that as the formal part of this discussion and happy to take questions. Real quick on the- Mm-hmm. 720 trial that we're going to see at the end of this year. You, you mentioned that you started enrolling in 2022, was it? mmmmh So if you just quickly kind of do that, and then what was the rationale for you had the two groups, with the thought process and what you're expecting to see there? Yeah. Let's take it back to the slide. Yeah, so started enrolling, as you said, in late 2025. And, a small patient population because, again, there's no SOC component to it. So we expect the therapeutic range for, dosing to be between 500 mg and 1,000mg. That's what we saw in our SAD/MAD studies, and that will basically inform our dosing decisions as we go forward. What in particular struck your curiosity? So 35 patients, 55 days of dosing. So have they all been dosed at this point? Yeah, we haven't disclosed patient dosing numbers, but we have disclosed that, yes, patients have been getting enrolled and dosed. So we have seen dosing on patients, and those data, of course, are getting collected as they generate. Other questions? Your expectations a bit of that data read out, and what are the different scenarios, and how you would think about the next steps in those different scenarios? Thanks for asking. As historically, development in the space focused on microbiological eradication. Recently, it's moved more to PROs. What we want to see in stages is first standalone activity. Is this efficacious against MAC, against placebo? Going forward, we expect the future to be combo, whichever form that takes, and that's why in NTM, given that high patient unmet need, we are actually very usually very excited to see development for many assets, because for MDR reasons, the future will be combo. For us, as we collect this subset of data, the microbiological data, the patient-reported outcomes, that will inform the PRO along with the PK data. We then expect to be able to go and give much more greater clarity on what registrational trials will look like. But what we have disclosed is that co-administration study that can serve as a leading indicator to you of SPR720, azithromycin, and ethambutol. Got it. That's very helpful. For the complicated UTI trial, the Phase III one, data in next year's second half of 2025, can we expect any interim data look anytime this year or, For which data? For tebipenem phase III. For tebipenem. We haven't guided to releasing of interim data, so far, the patient uptake on the study is expected to be quite fast. So given that we are targeting 2,650 patients, with a target NDA submission in the middle of next year, we will certainly be evaluating patient enrollment and uptake, but we have not guided to disclosure of that interim data in between. Do you have one, or are you not guiding to even the opportunity to even have that? No, usually, when you have these interim data, you disclose them. But, for us, we haven't said one way or another. Got it. Can you discuss the competitive landscape in this space? I saw that there was FDA approval of another drug for complicated UTI last week, I think, in late February. So how does tebipenem differentiate over there? Yeah. So, historically, approvals have been on the uncomplicated side of urinary tract infections. In fact, that was one of the reasons that GSK partnership made so much sense for both GSK and for us. They're developing gepotidacin for example for the treatment of uncomplicated urinary tract infection and there have been therapies in UTI.Oral therapies as well for first-line. What has been missing so far are the carbapenems in later stages for complicated urinary tract infection and to the best of our knowledge we are the only oral carbapenem,so that combination of oral and really strong efficacious therapy we feel that we stand pretty alone in this. Super helpful. Looks like the next 12-24 months are going to be very clinical-