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spk05: Q1 earnings conference call and webcast. At this time, all participants are in a listen-only mode. After the speaker presentation, there will be a question and answer session. To ask a question during the session, you'll need to press star 1 on your telephone keypad. If you require any further assistance, please press star then 0. I would now like to hand the conference over to your speaker today, Mike Gray. Thank you and please go ahead, sir.
spk01: Okay, thank you. And good morning, everyone, and welcome to Amara's first quarter 2021 conference call. I'd like to remind everyone that various statements we make during this conference call about the company's future expectations, plans, and prospects constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual events or results could differ materially from those expressed or implied by these forward-looking statements as a result of various important factors. including those set forth in the risk factors section of our most recent quarterly report on Form 10-Q that we filed with the SEC this morning, as well as any other filings that we make with the SEC. Any forward-looking statements made on this call represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so, even if our views change. Therefore, you should not rely on these forward-looking statements as representing our views as of any date subsequent to today. With that, I'll now turn the call over to Amara's President and CEO, Rahul Bilal. I'll return following Rahul's discussion to review our first quarter financial results, and we'll then open the call for questions. Rahul?
spk02: Thanks, Mike. Good morning, everyone, and thank you for joining this morning's call. The start of 2021 has been a productive period for Amara and marks the beginning of a data-rich year for both our sickle cell and beta thalassemia clinical programs. We have made substantial enrollment progress in our Phase IIb clinical trials for patients with sickle cell disease and beta thalassemia, which are designed to test higher doses of IMR 687. We are now conducting these studies at 75 clinical trial sites across 20 countries and have fully enrolled the transfusion-dependent beta thalassemia arm of the FORTE trial. closing new screening activities for that subgroup. We remain on track to complete the protocol-driven interim analyses from the ARDIN and FORTE trials and expect to report interim data in the second half of 2021 for both these programs. We also expect to report data from the primary analyses for both these studies in the first half of 2022 and data from the final analysis in the second half of 2022. This progress is a testament to the entire company across every function, and I'm appreciative and excited by this momentum. Importantly, following the recommendation of independent data monitoring committees, we have opened the higher-dose treatment arms in both Phase IIb clinical trials and are currently testing IMR687 at daily doses of up to 400 mg. With the high dose open in both trials, three out of every four patients are being randomized to an active treatment arm, with the high-dose being enriched in a two-high-dose, one-low-dose, one-placebo schema, which is a two-to-one-to-one randomization. Both interim readouts in the second half of 2021 will have patients from the high-dose arm. In addition to our progress in the Phase 2B clinical trials, we reported top-line data from our Phase 2A clinical trial of IMR687 in sickle cell disease. in which IMR687 was well-tolerated and in which we saw promising reductions in the rate of vaso-occlusive crises, or VOCs, with variable changes in HBF and F-cells. We also reported preliminary data from our Phase IIa open-label extension trial, which showed that IMR687 at doses of 200 mg was well-tolerated and in which increases in fetal hemoglobin and F-cells were observed. We plan to present comprehensive VOC data from the larger 93-patient phase 2A parent study, as well as additional data from the ongoing open-label extension trial at the European Hematology Association, or IHA, 2021 virtual congress in June. We've also been working to explore the therapeutic potential of IMR687 in additional indications. We're pleased to have successfully completed preclinical studies of IMR687 in heart failure with preserved ejection fraction, or HFPAF, and have submitted an abstract to an upcoming cardiovascular meeting later in 2021. We continue to formulate a protocol for a proof-of-concept study with our clinical advisory board, which is made up of leading cardiologists. Lastly, in March, we launched the second annual Real Impact Grants Program, to support local community-based organizations serving patients and families affected by rare blood disorders. 2020 marked an incredibly difficult time for those living with sickle cell disease and beta thalassemia, and many of these challenges remain as we move through 2021. We expect to increase grant funding under the Real Impact program from 125,000 in 2020 to up to 150,000 in 2021 across three key areas. including social determinants of health, including COVID-19 relief, virtual support program, and community-based organization, or CBO, capacity. We continue to strive to put our patients first, and the Real Impact Grant Program is a key embodiment of our core mission. We expect awards to be made in June, and we look forward to supporting the 2021 recipients in their ongoing commitment to the patient community. I would now like to spend a few minutes with further details on our core programs before turning the call back to Mike to review financial results. I'll begin with an overview of recent progress from our Phase IIb clinical trials of IMR687, including the ARDENT trial in adult patients with sickle cell disease and the FORTE trial in adult patients with beta thalassemia. We continue to expand the global footprint for our ARDENT and FORTE studies. with 35 and 40 active clinical centers, respectively, and across 20 countries with additional near-term activation of centers. This clinical operations effort has resulted in accelerated enrollment in both the ARDIT and FORTE trials, and we now have fully enrolled the transfusion-dependent beta-thalassemia arm of the FORTE trial, having randomized over 60 patients in this arm. As mentioned earlier, we remain on track to complete the respective protocol-driven interim analyses for these Phase IIb trials in the second half of 2021, and I'm pleased to reaffirm this guidance from earlier this year. With increasing enrollment, we now expect data from the primary analysis from each of these trials in the first half of 2022 and data from the final analysis from each of these trials in the second half of 2022. This is a significant accomplishment. and demonstrates our team's ability to effectively conduct these studies in the backdrop of a global pandemic. And I'd like to take this opportunity to thank them for their tireless commitment to these studies. During the first quarter, separate independent data monitoring committees for the ARDEN and FORTE trials recommended opening of the higher-dose IMR687 treatment arm in each of these studies following review of available safety and tolerability data. These additional arms were pre-specified in the two protocols, and enrollment is proceeding in each study at the IMR687 higher dose, which is once daily dosing of 300 mg or 400 mg based on patient weight, IMR687 lower dose, which is once daily dose of 200 mg or 300 mg based on patient weight, or placebo. As a reference point, Our recently completed Phase 2A clinical trial in sickle cell disease started as low as 50 mg per day and escalated sequentially to 100 mg or 200 mg per day over 16 to 24 weeks. Dosing in the Phase 2B clinical trials is substantially higher, both at the starting dose and through the treatment period, starting as high as 400 mg on day one and without a dose titration. As a reminder... The ARDENT Phase IIb trial will enroll approximately 99 adult patients with sickle cell disease and is a double-blind, randomized trial where patients will be stratified by use of hydroxyurea as well as by region. The planned primary efficacy objective is to evaluate the proportion of patients with fetal hemoglobin response defined as an increase of HPF of 3% or greater from baseline to week 24 versus placebo. and the trial is powered for statistical significance for this endpoint. Patients will continue on treatment through 52 weeks to provide data for planned secondary and additional endpoints, including the key secondary endpoint evaluating IMR687 versus placebo on annualized VOCs. Other secondary endpoints include time till first VOC, HBF-associated biomarkers, indices of red cell hemolysis, white blood cell adhesion, and quality of life measures. The fourth day trial will evaluate safety and tolerability of IMR687 in approximately 60 transfusion-dependent patients and approximately 60 non-transfusion-dependent patients. For transfusion-dependent patients, we plan to evaluate the effects of IMR687 versus placebo on transfusion burden, pre-transfusion hemoglobin, and the change in iron load as a result of transfusion during the trial and in comparison to historical rates in the 12 weeks prior to study start. The Forte trial will also examine additional exploratory endpoints as well as safety and PK endpoints. Safety and tolerability of IMR687 will be assessed after 24 weeks of dosing. I'll next turn very briefly to our Phase IIa clinical trial. We disclosed top-line results in January, in which IMR687 was well-tolerated and in which promising reductions in the rates of vaso-occlusive crises and variable changes in certain biomarkers, including HPF and F cells, were observed. We look forward to presenting comprehensive VOC data from this completed 93-patient placebo-controlled Phase IIa clinical trial at EHA next month, as VOCs remain an important clinical outcome for this program. I'll now turn to our Phase IIa open-label extension trial, or OLE trial, for which we reported new data in March. We believe this new data helped reestablish HBF and EFSA activity from treatment with 200 mg of IMR687 after seeing variable results from these biomarkers in the Phase IIa trial. As a reminder, the four-year OLE trial allows patients from the Phase IIa program to enroll in a long-term safety, and tolerability study of IMR 687 following completion of the Phase II-A trial. The OLE trial was initially designed so patients were administered a daily dose of 100 mg of IMR 687, and in the second quarter of 2020, a protocol amendment increased the daily dose to 200 mg. A preliminary review of 24 patients enrolled in the OLE program as of December 31, 2020, demonstrate that IMR687 was well tolerated and had a safety profile similar to that observed in the Phase 2A clinical trial. Approximately 12 of these patients had evaluable PD biomarker data for at least four months of treatment on the OLE trial. Biomarker results demonstrated absolute increases in both HBF and F cells after four months of treatment. In addition to this four-month data, In March, we also provided an update on two case narratives that we most recently reported at the American Society of Hematology Annual Meeting, December 2020. Both patients continued to see increased HPF from baseline of greater or equal to 4.5% and increases from baseline in F cell measurements. Falling in line with our higher dose arm in the Phase IIb studies, A separate safety review committee has approved dose escalation in the OLE trial to a minimum daily dose of 300 mg, with certain patients being eligible for a daily dose of 400 mg based upon their weight. This same weight gate-driven approach is employed in both of our Phase IIb programs and is an efficient way to maximize exposure and maintain safety. We have submitted a revised protocol to the FDA and MHRA and expect to start transitioning patients to higher doses of IMR-687 in mid-2021 on the OLE study. We also expect to present additional data from the OLE, including eight-month PD biomarker and VOC data at the upcoming EHA Congress. In conclusion, we believe that the first quarter marked another productive period for AMARA in both enrollment gains and the important transition to administering higher doses of IMR 687. We look forward to updating on our further progress, including multiple data readouts planned in 2021. Thank you, and I will now turn the call back to Mike to review our financial results.
spk01: Mike? Thank you, Raul. Our first quarter 2021 results can be found in the press release that we issued this morning, which I'll summarize now. More details are also included in the 10-Q that we filed with the SEC also earlier this morning. R&D expenses were $7.1 million for the first quarter of 2021 as compared to $5.8 million for the first quarter of 2020. The increase of $1.3 million was primarily related to our development efforts of IMR 687, as well as increased personnel-related and other R&D operating costs. General and administrative expenses were $3.2 million for the first quarter of 2021 as compared to $1.6 million for the first quarter of 2020. The increase of $1.6 million was primarily due to increased personnel related and other G&A operating costs as a result of operating as a public company. Net loss attributable to common stockholders was $10.3 million or 58 cents per share for the first quarter of 2021. as compared to $15.1 million or $4.31 per share for the first quarter of 2020. The first quarter of 2020 net loss attributable to common stockholders included a $7.9 million charge associated with the accretion of Series B convertible stock. We ended the first quarter with cash, cash equivalents and investments of $75.6 million, and we expect that this will be sufficient to fund our planned operations into mid-2022. And that concludes our prepared remarks. Could you please open the line for questions? Thank you. Brandi, we're ready for questions if you could open the line.
spk05: Certainly. At this time, if you would like to ask a question, please press star, then the number 1 on your telephone keypad. Your first question comes from the line of Yagel Nushimotis with Citigroup.
spk03: Hi, Rahul and Mike. Thanks very much for taking the questions. I had a few on the interim analysis for ARDENT and FORTE. First, Rahul, I thought I heard you say that the interim analysis will include patients that have enrolled on the higher dose arms, so could you confirm that? Second, what aspect of the protocol triggers the timing of the interim analysis for ARDENT and FORTE? And finally, what, in your view, would constitute a positive outcome for the interim analysis for both of these trials? Next.
spk02: Thanks, Chagall. I appreciate the questions. Number one, yes, I can confirm for both interim analyses for the ARDIT and FORTE trial that they will include higher doses and the higher dose arm of IMR687. And number two, the pre-specified protocol-driven analysis for those trials to report are the following. 33 patients randomized at 24 weeks for the sickle cell ARDENT trial, and approximately 30 patients for the beta-thal trial, the FORTE trial. And then finally, I think your question was in reference to what do we see as positive outcomes. They're slightly different. For the beta-thalsemia trial, we'll be looking at a combination. This is our first trial in patients, so we'll be looking at a combination of safety and efficacy specifically for the transfusion-dependent subgroup. We'll be looking for reduced transfusion burden as long as, in addition to looking for pre-transfusion hemoglobin and safety. For the non-transfusion patients, we'll be looking at PD biomarkers, specifically fetal hemoglobin and hemoglobin. And what constitutes success for me is seeing that higher doses of IMR687 in that trial are well-tolerated in a beta-thalassemia patient population, as well as starting to see some of those improvements in transfusion burden in the transfusion-dependent patients, as well as some improvements in biomarkers in the non-transfusion-dependent patients. So that's the beta thalassemia study. Sickle cell study is slightly different. It's our second trial in sickle cell, and it is a powered study. So for those interim analyses, the 33 patients at 24 weeks, we'll be looking specifically at the efficacy endpoint of fetal hemoglobin as well as F cells and making sure that we understand that the response rate in those 33 patients is is trending positive vis-a-vis placebo. I can't give you a number in terms of what I would say is a successful outcome, but certainly we'd like to see improved response rate in those patients on active, and hopefully we see some of the dose-dependent improvements because there are two arms that are active in the sickle cell trial, low dose and high dose versus placebo. So it would be nice to see a dose-dependent improvement in response as well as fetal hemoglobin response in the active versus placebo arms.
spk03: Okay, great. That's super helpful. I actually had a question on the additional indications for IMR 687. Could you just summarize quickly the conclusions from the preclinical heart failure studies and what specifically about the mechanism for 687 suggests an opportunity in HEF-PEF but not in HEF-REF? Or is HEF-REF just a potential avenue that you would consider down the road when you have more information?
spk02: Yeah, sure. So we've run three preclinical studies in the heart failure with preserved EF phenotype. Two of them are preventative. They have an insult of an agent that creates the HFPEF phenotype through an angiotensin II and aldosterone II treated mouse model. Those two are preventative models, so you treat the mouse with a caustic agent and ultimately on top at imr 687 and imr 687 has been protective of those specifically in three areas the first one in hypertrophy the second one in fibrosis and the third one in inflammation so it works in a multimodal approach in a preventative model then we took it one step further into a therapeutic model we treated dbdb mice that had generated the phenotype after 20 weeks of eating and getting bigger, and those mice have phenotype for HFPEF. Then you treat those mice who have the phenotype in a treatment approach for eight weeks with IMR 687, and we saw the similar reductions in cardiac hypertrophy, reductions in inflammation, and reductions in fibrosis. Across all three models, The key takeaway finding is we see a reduction in NT-proBNP as a biomarker of cardiac stress. And as you asked the question about mechanistically why that could be relevant, PD-9 uniquely works in the neprilysin cyclic GMP pathway, and so it is uniquely configured for HEF-PEF versus HEF-REF. And specifically, we found preclinically that PD-9 is overexpressed in a number of models in HEF-PEF. And our three models showed an increase in PD-9 expression when that phenotype developed, and we were able to reduce that PD-9 expression with our PD-9 inhibitor. there's a mechanistic, direct mechanistic relevance of PD9 overexpression in the HEF-PEF model. And so that's why we believe it's uniquely positioned for this indication versus HEF-REF. And we will be, as I said in the call, we'll be presenting that whole package in the fall of 2021 at a cardiovascular meeting.
spk03: Got it. Thank you, Rahul.
spk02: Thanks, you guys.
spk05: Your next question comes from the line of Matthew Adjarrison with Morgan Stanley.
spk00: Hi, good morning, everyone. This is Kostas Ohn for Matthew. A question from us on sickle cell disease. You have commented that your preclinical work suggested that the driver of the 687 efficacy is the time that the PK remains above IC90. We are wondering whether you have validated this in the Phase IIa data and how your expectations would change in case other PK parameters, such as the Cmax or AUC, turn out to be the efficacy drivers. Thank you.
spk02: Thank you. So a couple answers to that question. Appreciate you asking it. We will be presenting some additional data at EHA that look at exposure response. and help start determining that concept around time above the IC90 or trough levels in addition to looking at Cmax and AUC. So that data is in front of us and certainly we'll be presenting part of that at EHA. Number two, the advantage of going up on dose up to 400 milligrams is you check the box across a number of these different PK parameters. Number one, you increase AUC exposure by going up to 400 milligram. You certainly increase Cmax, and you increase trough levels past the IC90 for 24 hours. And so part of the reason that we like going up on dose, and this is not just for the Phase IIb program but for the open-label extension, is we get to see the advantages of those PK parameters play out across the exposure response curve. And so as you think about the Phase IIb data coming in the interim analyses, we'll be doing additional work on the PK side of things, specifically for beta thalassemia, to help us understand and continue to realize the potential of higher dose treatment, including AUC, C24, as you noted,
spk00: and CMAX. Thank you very much for looking forward to the data. Thank you.
spk05: Your next question comes from the line of Joseph Schwartz with SVB LeeRank.
spk04: Hi, thanks very much. My first question is similar to Yigal's first question when he asked about the interim analysis and what that entails. I was hoping you could do the same and walk us through what the primary analysis will entail. Is that a new look? I only recall interim and final analyses before, but maybe I missed something. And so in addition to what primary entails, will you be able to make any course corrections based on what you're seeing in each of these analyses? And are regulatory agencies OK with you unblinding at each of these looks and keeping the trial intact.
spk02: Yeah, it's a good question. Let me walk you through. So we've always had a primary, an interim, a primary, and a final, Joe, and that's in part due to the fact that the The studies are quite long, as you know. Let me walk you through both studies, both sickle and beta-thalassemia, to give you at least a snapshot of what we expect to see and report out. The interim analysis, as we've guided to in the second half of this year, will look at 33 patients at 24 weeks, and I really look at that as a check the box on exposure, safety tolerability, and initial understanding of PD biomarker. The primary analysis, which is the statistically powered time point, which is 99 patients at 24 weeks, will be a rigorous and statistically powered analysis of HBF in 99 patients and looking for that response of 3% or greater. It will also step down in a hierarchical fashion to to look at annualized VOCs at that primary analysis. as well as looking at time till first VOC and then a litany of other secondary and exploratory biomarkers that will be done in a hierarchical fashion to maintain power and preserve alpha. And as you know, the study is a 52-week treatment paradigm. So patients will be read out at week 24, but those 99 patients, or the ones that continue, will go through a 52-treatment paradigm. And so that 52-week period will be part of the final analysis. And, of course, we'll look at annualized VOC. The primary analysis, as we've guided, will be in the first half of 2022. That final analysis, which will look at the 52-week time point, specifically focused on VOCs, will be in the second half of 2022. The beta thalassemia program is slightly different. It's shorter in length. It's a nine-month treatment paradigm and a six-month primary. And so for the interim analysis, we'll be, again, looking at a subset of patients, 30 patients at 24 weeks in the second half of this year. In the first half of 2022, we'll be looking at 60 patients in the TDT arm and a subset of those in the NTDT arm at 24 weeks. And in the second half of 2022, we will be looking at that nine-month or 36-week time point in beta thalassemia. So just taking a step back, that will be the full 120 patients in both the NTD and TD subgroup in those final analyses. And so the difference overall between primary and final in beta thalassemia is 24 weeks versus 36 weeks. The difference in sickle between primary and final is 24 weeks versus 52 weeks, and I've already delineated the timeframes for that.
spk04: Does that help? That makes a lot of sense. Absolutely. Thank you. It's helpful to have that laid out again. And then in your queue, it highlights that you're planning to perform a STATMAD study looking at what appears to be up to twice the doses that are being studied currently. Can you talk about that decision? Is that based on anything that you've seen so far from response exposure analyses?
spk02: Yeah, sure. So, you know, when we opened up the higher dose arms for the Phase IIb studies for both beta thalassemia in January, and sickle cell in March, we opened those dose arms and wanted to see how higher doses were doing and if they were well tolerated. Those doses are proceeding. We believe, obviously, we're blinded. We believe that the safety signal from those higher doses points to tolerability. And so part of the rationale to start a SAD-MD study is continue to explore higher doses beyond 400 milligrams, as you noted, And so certainly we believe that this SAD-MD study will allow us to potentially expand the dose range for IMR687, and we just wanted to have that optionality as we had previously. and are going through the Phase IIb programs. Will we implement higher doses of IMR687 potentially? That is data dependent on that SAD-MD study, but we wanted to make sure that we had an opportunity to do that, which is why we started the study now versus later.
spk04: Very helpful. Thanks again for taking my question.
spk02: Thanks, Joe.
spk05: And there are no further questions at this time. I would now like to turn the call back over to the speakers for any closing remarks.
spk02: Thank you, everyone. Well, I appreciate you joining us this morning. We look forward to future updates. It is a data-rich year, and we're excited to have you forward in enrollment to have that data later this year, and see you at EHA. Thank you.
spk05: This concludes today's conference call you may now disconnect.
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