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spk01: Ladies and gentlemen, thank you for standing by, and welcome to the EMARA Inc. Q4 and 2021 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 will need to press star 1 on your telephone. If you require any further assistance, please press star then 0. I would now like to hand the conference over to your speaker, Mr. Mike Gray, Chief Financial and Chief Operating Officer for EMARA. Please go ahead, sir.
spk00: Okay. Thank you, Cherie. Good morning, everyone, and welcome to EMARA's fourth quarter 2021 conference call. I'm joined this morning by EMARA's President and CEO, Rahul Bilal, and our Chief Medical Officer, Ken Addy. Before we begin, 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 factor section of our most recent annual report on Form 10-K, that we filed with the SEC this morning, as well as other filings that we may 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. Okay, with that, I'll turn the call over to Amara's President and CEO, Rahul Bilal, who will provide an overview of our fourth quarter and key recent accomplishments, as well as for our expectations around interim analyses from each of our ARDN and FORTE Phase 2B clinical trials in sickle cell disease and beta thalassemia, respectively. I'll then return following Rahul's discussion to review our 2021 financial results, and we'll then open the call for any questions. Rahul?
spk03: Thank you, Mike. Good morning, everyone, and thank you for joining today's call. The fourth quarter and the start of 2022 have enabled important pipeline expansion for AMARA, including the clearance by the FDA of our IND for tovinetrine in heart failure with preserved rejection fraction, or HEPPES, as well as introduction of IMR261, an oral, clinic-ready activator of Nrv2. I'll spend some time on each one of these exciting new programs today, would like to begin this morning's call with a review of our key Phase IIb sickle cell disease and beta thalassemia programs, including a review of timing and descriptions of the important interim readouts in our ARTED and FORTE clinical trials, both of which are on track for expected release the first week of April. I'll begin with our sickle cell disease program for IMR667, which is also known as Tevinitri. In 2021, We, number one, reported data from our completed Phase IIa trials to Finitreen, demonstrating reductions in annualized rate of VOCs. Number two, successfully completed enrollment of the ARDENT Phase IIb trial. And number three, had important regulatory interactions with the FDA, resulting in a change of the primary efficacy endpoint of the ARDENT trial to annualized rate of VOCs. All these advancements are an encouraging setup to what we believe will be an important 2022 for this development program. First, I will discuss the decision to change the primary efficacy endpoint in our sickle cell ARDENT Phase IIb clinical trial of tevinitrine. Following our presentation of positive Phase IIa VOC data at the European Hematology Association meeting in June 2021, we engaged the FDA on several topics, including getting feedback on a draft statistical analysis plan for the ARDENT trial. In reviewing the draft plan, the FDA recommended in November that we change the primary endpoint of the trial to be annualized rate of VOCs, and we agreed with the FDA's written recommendation, knowing we had a study already configured for VOC endpoints and seeing encouraging VOC benefits at low doses to Vinodrine. The prior primary endpoint, HBF response, will continue to be evaluated as a key secondary endpoint, along with other key secondary endpoints, including time of first VOC. The endpoint revisions did not affect the conduct of the trial or operational aspects of the study. As part of its recommendation, the FDA suggested further engagement on the potential of the current program for regulatory decision-making, and we look forward to these future interactions following the Phase IIb interim analysis. The basis for the Phase IIb interim readout from the ARDENT trial is when all ongoing subjects have completed assessments through at least week 24 and will rely on an intent-to-treat analysis population. Since this is a fixed-sequence approach, the interim efficacy readout will be for our primary which is a comparison of the annualized VOC rate between the high-dose treated group versus placebo. The high-dose group is once daily dose of 300 or 400 milligrams based on a weight gain. We expect this efficacy readout to consist of approximately 80 patients in those two groups. Additionally, because we are spending a small amount of alpha to review efficacy results, we will generate and report a p-value for this VOC analysis. We also plan to report safety data for all 115 patients enrolled in the ARDENT trial, which includes the high-dose, low-dose, and placebo arms. We are limiting our data review in this interim analysis to the primary efficacy endpoint and safety data to minimize alpha spend, thereby preserving the vast majority of alpha for the final analysis. which is expected in the second half of 2022. In summary, this interim data will be a robust look at an approvable DOC endpoint. The statistical analysis plan has been reviewed by the FDA twice, and the study is powered at 80 to 85 percent to show a 35 to 40 percent difference between the high-dose and placebo arms. It is an important data set for the company and provides a launching pad for potential Phase III planning, as well as for regulatory interactions in the coming months. We expect the interim Phase IIb ARDN data to build on existing VOC results we presented at medical meetings in 2021. Most recently, we reported 12-month data from the ongoing Phase IIa Open Label Extension, or OLE, clinical trial of tivinitrine. which was presented at the American Society of Hematology, or ASH, annual meeting in December. The OLE data showed patients who were on tovinitrine in the completed Phase IIa trial maintained a reduced annualized rate of VOCs while on the OLE trial. In addition, a 38% reduction in median annualized VOC rate was observed in patients that received placebo in the Phase IIa trial and switch to tivinitrine as part of the OLE trial. We are encouraged by the durable VOC benefit observed in the Phase IIa OLE trial through 12 months and the consistent VOC benefit across studies and time points. Recall that the VOC data that has been presented to date has been for subjects treated with daily doses of up to 200 milligram of tivinitrine. PKPD modeling suggests that higher doses of tivinitrine as administered in our current Phase IIb studies, may further reduce VOC reach, which is why we're optimistic about the upcoming Phase IIb high-dose interim readout. I'll turn now to our Phase IIb program in beta thalassemia. We also expect to report interim data from our Forte Phase IIb clinical trial of tivinitrine in beta thalassemia patients in the first week of April, alongside our interim Phase IIb sickle cell date. During the fourth quarter of 2021, we reported the first interim clinical data from the transfusion-dependent cohort of the Phase IIb clinical trial. This marked an important milestone for MARA and patients seeking oral therapies for this disease. We observed a positive trend for transfusion burden reduction at the higher dose of tivinitrine as compared to placebo, and we are hopeful that this signal will strengthen with more patient data at our upcoming TDT interim analysis. We're also pleased that the interim data demonstrated a favorable and tolerability profile at once daily doses of tibinitrine up to 400 mg. In the first week of April, we expect to report additional data on transfusion burden from the transfusion-dependent cohort of the Phase IIb trial and the first clinical data from the non-transfusion-dependent cohort of this trial. The efficacy data set will consist of approximately 50 transfusion-dependent patients at 24 weeks and approximately 30 non-transfusion-dependent patients at 24 weeks for a total of approximately 80 patients. It will include safety and biomarker data, and we are looking forward to this near-term readout. Turning to our heart failure program, we're very excited about taminotriene's potential in heart failure with preserved ejection fraction, or FPF. We have made significant progress in the last year and have transformed this program from a promising preclinical effort to a Phase II proof-of-concept study with clearance from the FDA to proceed with the study. We have also built a leading internal development team and an external KOL team to support our development efforts, including recently adding Peter Ponikowski from Wroclaw, Medical University in Poland to the executive committee. Our excitement for the HFPEF program comes from the results of in-vivo studies of telinitrine in different models of HFPEF, which were presented at the AHA scientific sessions in November 2021. Furthermore, our clinical approach focuses on identifying HFPEF patients with high PD-9 expression, creating a targeted approach in this highly prevalent disease. We also believe we have the best-in-class PD-9 inhibitor for evaluation in this patient population, with in vitro data demonstrating superior potency and selectivity when compared to other available PD-9 inhibitors. To briefly cover the study design, the SPIN Phase II clinical trial will be a randomized, double-blind, placebo-controlled study in which we expect to enroll approximately 170 patients randomized on a one-to-one basis to receive either placebo or a twice-daily dose of either 300 mg or 400 mg of tivinitrine, depending on a weight gain. Patients will be dosed for 16 weeks, and the primary study endpoint will be the change in plasma NT-proBNP, a clinically relevant biomarker of cardiac stress. Secondary endpoints include safety and tolerability and quality of lifespan quality of life measures such as Kansas City Cardiomyopathy Questionnaire, KCCQ, and New York Heart Association NYHA classification. We will also look at exploratory endpoints such as clinical composite scores, six-minute walk tests, and evaluation of cardiac structure and function. Additional details on the SPIN trial will be available on clinicaltrials.gov and we look forward to dosing the first subject in our Phase II program, which is anticipated to occur in the second quarter of 2022. Finally, our head of the HEF-PEF program is a seasoned cardiologist with deep connections among key opinion leaders. In Q4 of 2021, we appointed Tony Bransford, MD, as Vice President of Clinical Development to work with Ken Addy and lead clinical development of Tevinitrine as a treatment for HEF-PEF. A cardiologist, Tony comes to Amara with 15 years of clinical development experience within global pharmaceuticals, biotech, and CROs. Tony has accumulated extensive experience in the cardiovascular therapeutic area, including, for example, as Senior Medical Director within the Global Clinical Development Program at Novartis, where she was the clinical lead for the HFAP program conducting the Paramount and Paragon trials. We're delighted to have Tony on board. In addition, to our internal HFF team, we have also established a leading external executive committee to oversee the SPIN trial, which is chaired by Deepak Gupta of Vanderbilt University Medical Center and includes Maggie Redfield of the Mayo Clinic, Sanjeev Shah of Northwestern, Thomas Wang of UT Southwestern, and now Peter Ponikowski. from Watsop University in Poland. We are very excited about the development of tivititrine in HFPEF, and we look forward to updating you on our progress. In addition to the progress we've made with tivititrine, in the fourth quarter of 2021, we announced the addition of IMR261, an activator of nuclear factor erythroid II-related factor II, or NFR2, to our pipeline. We recently showed preclinical data at an oral presentation on IMR261 at the ASH annual meeting in December 2021. In preclinical sickle cell models, IMR261 was observed to activate expression of HBF and reduce VOCs. In a preclinical beta-thal model, IMR261 increased hemoglobin and enabled red blood cell maturation. We've initiated work on drug product manufacturing for IMR261 and we are exploring potential clinical development paths, which could include treating iron disorders. We look forward to providing further updates on IMR261 later this year. In conclusion, we believe the fourth quarter and beginning of 2022 have been productive periods for MARA. We are fast approaching key interim analyses and readouts for our ARDENT and FORTE Phase IIb clinical trials, We've expanded the Tovinatrine opportunity into HFPEF and are developing a clinic-ready pipeline with the addition of IMR261. We look forward to updating on our further progress, beginning with expected data readouts from the ARDENT and FORTE trials in the first week of April. Thank you, and I will turn the call back to Mike to review our financial results.
spk00: Okay, thanks, Rahul. Our full 2021 financial 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-K that we filed with the SEC earlier this morning. R&D expenses were $38.4 million for the year ended December 31, 2021, as compared to $32.2 million for the year ended December 31, 2020. The increase of $6.3 million was primarily related to the conduct of clinical trials and manufacturing of clinical materials related to our ongoing development of Tobinitrine, as well as increased personnel-related and other R&D operating costs. G&A expenses were $13 million for 2021, as compared to $9.5 million for 2020. The increase of $3.5 million was primarily due to increased costs associated with certain insurance premiums, as well as increases in personnel-related and other G&A operating costs as a result of operating as a public company for the full year in 2021. Net loss attributable to common stockholders was $51.4 million or $2.37 per share for 2021 as compared to a net loss of $49.2 million or $3.53 per share for 2020. Cash, cash equivalents and investments were $90.3 million as of December 31st, 2021, as compared to $88.2 million as of December 31st, 2020. We currently expect that full-year 2020 R&D expenses will range between $60 and $65 million, and that our full-year 2022 G&A expenses will range between $13 and $15 million. We expect that our cash, cash equivalents and investments as of December 31st, 2021, will be sufficient to fund our planned operations substantially through the first quarter of 2023 for approximately one year from our reporting of interim data from our ARD and Forte Phase 2B clinical trials in the coming weeks. That concludes our prepared remarks. Cherie, if you wouldn't mind, could you please open the line for questions? Thank you.
spk01: My pleasure. As a reminder, to ask a question, you will need to press star 1 on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question will come from Edon Notomovich with Citigroup. Please go ahead.
spk04: Edon Notomovich Hi. Thank you for taking the question. As you noted, Virgil, the FDA cited potential for regulatory decision-making following the interim look for SBP. So I'm just wondering, is there any potential that you could file for an accelerated approval if the results of the STD interim are sufficiently promising? Thanks.
spk03: Thanks, Yagal. I appreciate the question. Nice to hear from you. So the FDA interaction around the VOC endpoint is slightly different than the accelerated approval pathway because the annualized rate of VOC is an approvable endpoint. So as opposed to taking the accelerated approval pathway with a post-marketing commitment, we could be in a position to talk to the FDA about an approvable endpoint and getting full approval on the drug. I would just cite the experience with chrysalizumab versus global blood therapeutics. With chrysalizumab, they got a full approval on their monoclonal antibody to P-selectin versus oxbrita, which got an accelerated approval pathway with hemoglobin. So we would be taking the approach that with a regulatory endpoint that is approvable, we would not need to use the accelerated approval pathway. Now, that being said, because this is a Phase II study, we are hoping that it's something more than a Phase II study. It could always be postmarking commitments that the FDA may consider, but that would always be a discussion with them in the future.
spk04: Got it. Okay, thanks. And just operationally, can you just clarify for the interim so everyone understands, is the P value threshold going to be the 0.05, or is it something more stringent at the interim?
spk03: Yeah, it's a great question. I'll turn it over to our chief medical officer, Ken, to give a perspective on alpha spend and P values. Ken?
spk02: Yeah, thanks, Raul, and thanks for the question. Yeah. As is typically done, in order to perform the analysis at the interim, we have to spend some alpha. However, these data mature as the study reaches its completion at 52 weeks, so we would want to preserve as much alpha as possible for the final analysis when all patients have completed the study. Therefore, as you guessed, at the interim analysis, there will be a very small alpha spend, and that means that we will provide a nominal P value, which we hope will be below or around 0.05, but that would not be sufficient to declare victory for the study at the interim analysis. That would be a much smaller P value, which is the amount of alpha spent.
spk04: Okay. I got it. Yeah. And then for Rahul, for the beta cell interim, can you talk about what you're looking to see with respect to the decrease in transfusion burden from baseline? And is that something that you're going to be attaching key values to, or is that going to be more of a descriptive statement?
spk03: Yeah, it's a good question. So the analysis for beta thalassemia is a per-procol analysis. That's our patient population, and we are signal finding, to your point. So in general, if you look across the beta thalassemia landscape, when you look at a reduction in transfusion burden, and remember, from a beta thalassemia perspective, unlike sickle, you're comparing to historical transfusion burden. So we're looking for a difference. compared to a historical rate, both looking at the placebo arm on study versus 12 weeks prior to study, and the high-dose arm and low-dose arm, 12 weeks on study and 12 weeks prior to study. In general, and looking at what's been approved in terms of Reblazol, we'd like to see anywhere from a 20% to 30% reduction in transfusion burden in the transfusion-dependent thalassemia patients, and that is a difference between arms, so between high dose, for example, and placebo. That would be for the transfusion-dependent analysis. As you know, for the non-transfusion-dependent analysis, you're not really measuring transfusion burden in the same way, so we would certainly be looking for biomarker signals in the fetal hemoglobin and hemoglobin contacts And those numbers, we haven't put a number on it, but generally speaking, you'd want to see something that looked greater than 30% in the high-dose versus placebo of patients above 1 gram per deciliter or above 3% for fetal hemoglobin. And again, it's signal finding. It's our first study in beta-thal, so those aren't hard numbers, but that's generally where we are in terms of evaluating this data set.
spk04: Okay, thanks. And if I could just throw in one more on HFPEF. You mentioned the PD9 high expression. What percent of the HFPEF populations do you believe are falling to that high PD9 expression bucket?
spk03: Yeah, it's a good question. So there has been quite a bit of triangulation at our executive committee on exactly what constitutes high PD9 expression. But roughly, roughly, we think it's about a third of HFPEF patients. give or take, and so if HEF-PEF is anywhere from 3 to 3.5 million, you're looking at patients that are enriched for PD-9 in that million to sub-million category. So there are a lot of patients we think that have increased PD-9 expression, and of course we're using an exclusion-inclusion criteria to help target for those.
spk04: Great, thank you.
spk01: Thank you. Our next question will come from Joseph Swartz with SVB Securities. Please go ahead.
spk05: Hi. Thanks very much, and congrats on all the progress. A couple questions on the interim analysis for the ARDENT study. Did you discuss with the FDA how looking at annualized VOC rate instead of HBF at the interim analysis can be done in a manner that won't risk on blinding or biasing the final analysis? Did you discuss, you know, to the extent to which each of these endpoints is objective or subjective and any of those considerations? And then I have a follow-up.
spk03: Sure, that's a great question. I'll turn it to Ken Addy to give some perspective on that first question. Ken? Yeah, thanks.
spk02: Yeah, it's a good question. I think the FDA was transparent in those questions. factors in our statistical analysis plan that were of interest and of concern to them. So they actually pass along, first of all, the recommendation to make annualized rate of VOCs our primary endpoint, and then suggestions on how to preserve alpha by, you know, what other data can be looked at. So for example, even for our safety data, we're being very careful not to become unblinded to any individual patient's randomization assignment. And the same holds true for efficacy. Everything will be based on group changes, medians for the group. Even when we describe the medians, we don't look at all the descriptive stats to be sure not to be unblinded at any point. So I think we're in alignment with FDA on the approach to the interim analysis. That's helpful. Thank you.
spk05: Just to confirm, will you not be looking at the lower doses in the trial? And what's the reasoning for that?
spk02: I think that is correct. At this interim analysis, we won't report data for the low dose except for safety data. And again, this is in the effort to preserve alpha. And so each analysis, if you will, requires an alpha spend. And we really are trying to preserve as much of the 0.05 alpha for the final analysis as possible.
spk05: Okay, great. And maybe one more. Could you give us an update on the proportion of patients in ARDENT that have been eligible to roll over into extension trial phases and how many have elected to do that?
spk03: So it's a good question. We're in the process of getting our open label extension study started for that program, so we don't have a number to date. But I will say that the interest level has been extremely high across almost all of our sites to get their patients onto this open label extension. And I think it's worth noting that that open label extension, as of right now, is designed for patients to roll over to the high-dose arm of the Phase IIb study. So the 300-slash-400-milligram arm, as currently noted as the high-dose arm in the Phase IIb ARTEN study, is the dose that patients would roll over to. In other words, a placebo patient would go from placebo to 300 or 400. A low-dose patient would go from 200 to 300. to the high-dose arm of 300 to 400, and obviously the high-dose patients from the ARDENT Phase IIb would roll over to that same dose in the open-label extension. So I think the OLE will be really important for us to get long-term safety data and hopefully see continued VOC benefit. I also think it is indicative of our confidence level that the high-dose 300 slash 400 is well-tolerated and will be well-tolerated.
spk05: Great. Thanks for all the comments.
spk03: Thanks, Joe.
spk01: I'm showing no further questions in the queue at this time. I will now turn the call back over to management for any closing remarks.
spk03: Thank you very much. I appreciate everyone's time this morning. We're excited by the momentum and start into 2022 and look forward to these upcoming data readouts for the ARDEN and Forte trials in the coming weeks. Everyone stay safe and healthy and look forward to talking again soon. Have a good morning. Thank you.
spk01: Ladies and gentlemen, this concludes today's conference call. Thank you for your participation.
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