This conference call transcript was computer generated and almost certianly contains errors. This transcript is provided for information purposes only.EarningsCall, LLC makes no representation about the accuracy of the aforementioned transcript, and you are cautioned not to place undue reliance on the information provided by the transcript.
spk00: 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 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. With that, I'll now turn the call over to Amara's President and CEO, Rahul Blal, who will provide an overview of our third quarter and key recent accomplishments. I'll then return following Rahul's discussion to review our third quarter financial results, and we'll then open the call for any questions. Rahul?
spk02: Thank you, Mike. Good morning, everyone, and thank you for joining today's call. The third quarter and recent weeks have been productive periods for AMARA, and specifically on IMR687, which we'll also refer to in its generic name, to Vinotrin. We are pleased to have made substantial progress in our ongoing Phase IIb trials, and we expect to report interim data from both our ARTID trial in sickle cell disease and FORTE trial in beta-valcemia this quarter. Furthermore, we have taken concrete steps to expand our development pipeline by continuing to work with tuvinitrine in heart failure with preserved ejection fraction, or HFPS, and announcing a new clinic-ready program in IMR261, an oral nerve 2 activator. Beginning with sickle cell disease, and as we reported earlier this quarter, we have completed patient enrollment in our ongoing ARDENT Phase 2B clinical trial of tuvinitrine. We expect to report data from an interim analysis of this trial in approximately one-third of patients at 24 weeks during this quarter. The interim analysis will have a focus on safety dose and PD biomarkers, specifically HBF and F cells. In addition to this readout, we expect the primary analysis dataset in the first quarter of 2022. The primary analysis will focus on HBF and F cells as well as the effect of tivinitrine on the rate of vaso-occlusive crises, or VOCs, at 24 weeks. The ARDN study has been a global effort, as we have enrolled approximately 115 subjects from across the world, including Europe, U.S., Middle East, and Africa. Our team has worked tirelessly on the conduct of this trial and are pleased to have important data readouts in the coming months. In addition to the ARDN trial readout this quarter, We look forward to reporting updated 12-month safety and VOC data from our Phase IIa Open Label Extension, or OLE, trial of tavinitrine in adults with sickle cell disease at the American Society of Hematology annual meeting to be held December 11th through the 14th of this year. As a refresher, we reported final results from the Phase IIa parent trial, as well as eight-month data from the OLE in June at the European Hematology Hematology Association Annual Congress. The parent study results indicate a well-tolerated safety profile, lower VOC rates, improved patient-reported severity score, and variable biomarker results, including with respect to HPF. Importantly, VOC results for all 93 subjects enrolled in the Phase II trial demonstrated a 40 percent lower mean annualized VOC rate in the pooled-to-vinitrine-treated groups versus the pooled placebo groups. In addition, data from the parent study demonstrated a significant increase in the median time to first VOC, as well as reduced rate of annualized VOC-related hospitalizations in each case when pooled tovinetrine groups were compared to pooled placebo groups. We're also encouraged to see patients in the OLE clinical trial continue to benefit from lower annualized VOC rates. We believe that these continued VOC benefits in the OLE trial further support the findings from the 93-patient Phase 2A study. Lastly, in addition to the positive VOC data in the OLE study, we're also pleased that 36%, or 4 of 11 patients in the OLE trial, had absolute HPF increases of more than 3% at the 8-month time point, while receiving 200 mg of tovinetrine. We believe that higher doses of tivinitrine have the potential to show even more robust HPF increases. Remember that the ARDENT Phase IIb trial is currently dosing at up to 400 milligram daily and is powered to show an HPF response rate of 35% in tivinitrine versus 5% on placebo at 24 weeks. We expect higher doses may further improve on that signal, which is why we're looking forward to reporting the interim data from the ARDENT trial later this quarter. Turning to our Forte Phase 2B clinical trial in beta thalassemia, we also reached full enrollment in the transfusion-dependent or TDT cohort, while also seeing continued enrollment in the non-transfusion-dependent or NTDT cohort. We expect interim data from the TDT cohort this quarter, in which we plan to evaluate safety, transfusion burden, and PD biomarkers in approximately 30 patients at 24 weeks on stage. Furthermore, we plan to conduct additional readouts for the full TDT cohort at 24 weeks in the first quarter of 2022, looking at similar data points at the interim analysis. In addition to this important upcoming clinical data, we plan to present preclinical data in beta thalassemia at the upcoming ASH annual meeting in December, and we are looking forward to providing both of these updates in the coming weeks. We are also selectively expanding our indication footprint to areas where PD9 overexpression is implicated in serious diseases with high unmet needs. To that end, we expanded our internal team and developed a protocol for a phase two proof of concept study in heart failure, the preserved rejection fraction, or HEPPF, with the help of our experienced cardiology clinical advisory board. We also expect to interact with the FDA Division of Cardiology and Nephrology this quarter So collectively, we've made substantial progress in enabling the HF-PEF program with an eye towards the clinic in 2022. Yesterday, we announced an oral presentation at the American Heart Association Scientific Sessions, which is scheduled to take place later this week. Our abstract includes data in three preclinical mouse models of HF-PEF, in which selective inhibition of PD-9 with taminitrine was shown to reduce the median size of cardiomyocytes and lower plasma B-type and atrial natriuretic peptide levels. In addition, markers of renal dysfunction, including blood urea nitrogen and urine albumin to creatinine ratio, were lower in mice treated with tovinutrine compared to vehicle-treated mice in all models. Importantly, tovinutrine did not significantly change heart rate or blood pressure. In summary, alongside independent literature on the potential value of PD9 inhibition of half-death, as well as our own internally generated data, we believe tovinitrine may be a promising treatment option for patients with half-death. To lead clinical development of tovinitrine as a treatment for half-death, I'm also pleased to announce that Amara has appointed Tony Bransford, MD, as Vice President of Clinical Development. A seasoned cardiologist, Toni comes to Amara with 15 years of clinical development expertise within global pharmaceuticals, biotech, and clinical research organizations. Toni comes to Amara from Kaleido, where she led clinical research programs for multiple projects and oversaw translation of discovery programs. Prior to her roles at Amara and Kaleido, Tony accumulated deep experience in the cardiovascular therapeutic area, including at Novartis, where she was a clinical lead for the HF-PATH program, conducting the Paramount and Paragon trials, was also responsible for leading regulatory authority interactions. We're delighted to have Dr. Bansford join our team to lead our HF-PATH development efforts, working closely with our Chief Medical Officer, Ken Addy. In addition to the progress we've made with Suvinitrine, We are excited to announce IMR261 as a new asset in our development pipeline. Briefly, IMR261 is a clinic-ready oral activator of nuclear factor erythroid 2-related factor 2, or Nrf2. In vitro and in vivo studies show that Nrf2 coordinates the expression of antioxidant genes in response to oxidative stress, regulates inflammation, inhibits the NSKB pathway, and reactivates fetal hemoglobin, or HBF. IMR261 was formerly known as CXA10 and was previously evaluated by Complexa Inc. in Phase II clinical trials for focal segmental glomular sclerosis, FSGS, and pulmonary arterial hypertension, PAH. Independent medical literature suggests that Nrf2 activation could be relevant in a number of red blood cell diseases and disorders of hemoglobin, And as a proof of principle, there's substantial preclinical data in sickle cell models with dimethylfumarate, a known Nrf2 activator. Amara ran its own preclinical sickle cell disease models and found IMR261 significantly increased HBF and F cells, improved hemolytic markers, and decreased VOCs. In a preclinical beta thalassemia model, IMR261 increased hemoglobin, and enabled red blood cell maturation. The IMR261 data and submitted abstract was selected for an oral presentation at the upcoming ASH meeting, and Dr. Betty Pace, a leader in sickle cell research with DMF and Nrf2, is an author on this abstract. Since IMR261 is a clinic-ready asset, we've initiated work toward drug product manufacturing as we explore potential clinical development paths. We look forward to providing updates on IMR 261 in 2022. In conclusion, we believe that the third quarter and first part of the fourth quarter have been productive periods for AMARA on our core programs, expanding our indication opportunities, and developing a clinic-ready pipeline. We look forward to updating you on our further progress, including expected data readouts beginning later this quarter and in the first quarter of 2022. Thank you and I'll turn the call back to Mike to review our financial results.
spk00: Mike. Thanks Rahul. Our third 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 10Q that we filed with the SEC earlier this morning. Research and development expenses were $10.4 million for the third quarter of 2021 as compared to $9.5 million for the third quarter of 2020. The increase of $900,000 was primarily related to the development, manufacturing of clinical materials, clinical research and oversight of the company's clinical trials, and investigator fees related to the development of divinitrine, as well as increased personnel related and other R&D operating costs. General administrative expenses were $3.3 million for the third quarter of 2021 as compared to $3 million for the third quarter of 2020. The increase of $300,000 was primarily due to increased personnel-related and other G&A operating costs. Net loss attributable to common stockholders was $13.6 million, or $0.55 per share, for the third quarter of 2021, as compared to a net loss of $12.4 million, or $0.72 per share, for the third quarter of 2020. Cash equivalents and investments were $102.8 million as of September 30th, 2021, as compared to $88.2 million as of December 31st, 2020. We believe this capital provides AMARA with sufficient funds to enable us to fund our plant operations into the first quarter of 2023. And that concludes our prepared remarks. Operator, could you please open the line for questions?
spk04: As a reminder to ask a question, you would need to press star, then the number one on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Your first question comes from the line of Yagal Notramovitz with Citi.
spk05: Hi, this is Carly on for Yagal. Thanks for taking our questions. We had two questions. First, on the Nrf2 activator that you licensed, will you consider indications in kidney disease, or are you focused on hemoglobin disorders? And then second, on the Phase IIb study in sickle cell, you mentioned some of the details on the powering on BL hemoglobin. Just curious what you can say about the powering on annualized VOC rate, and relatedly, are you stratifying patients based on the number of VOCs patients had in the year prior to the study. Thanks so much.
spk02: Thank you. I'll take the first one and then hand it to our Chief Medical Officer, Ken, for the second question. So I think, as you know, a Nrf2 activation is implicated in a number of different diseases, including renal diseases. Our focus right now is rare cell disorders, rare blood cell disorders, including hemoglobinopathy. So our first shot at the disease indication is really in that sphere. We are looking at associated and affiliated areas beyond sickle cell and beta-thal, but for right now, our data is the strongest in those two indications. I'll just note that unlike renal diseases and PAH, which leverage Nrv2's antioxidant mechanism, The Nrv2 activators in sickle cell disease are actually specifically designed to induce and reactivate fetal hemoglobin. And so we like the specific mechanism around Nrv2 translocation to the nucleus, which actually creates the ability to reactivate fetal hemoglobin. So there are some mechanistic advantages to going into red cell disorders over some of the kidney indications that have been previously tried with this asset and certainly Turn it over to Ken to give you some color on the powering of the study, both the primary and secretaries.
spk01: Yeah, thanks, Raul. This is Ken Addy. We have powered the study primarily for the primary endpoint, which was an increase in hemoglobin F response rate for an increase of 3% or more from baseline. We haven't separately done power calculations for each of the secondary endpoints, although we have now made annualized rate of VOCs the key secondary endpoint. And based on our results from the Phase IIa study, we feel that we will probably be powered to show a difference similar to what we saw in the Phase IIa study with the number of patients in the Phase IIb study. That study had several stratification factors, the current study, but it did not include the baseline VOC rate or the historical VOC rate. In order to get into the study, subjects had to have had initially one to 12 VOCs in the prior year. We revised the protocol to specify a minimum of two VOCs in the previous year. And so in our analysis plan, statistical analysis plan, which we have finalized, We will be looking at both subjects with 1 to 12 POCs in the prior year, as well as 2 to 12 as a sensitivity analysis.
spk05: Okay, great. Thanks very much.
spk01: Thanks.
spk04: Our next question comes from the line of Joseph Schwartz with SVV Lyric.
spk06: Hi, I'm Drew Reed, dialing in for Joe. Thank you for taking our questions. First, I guess I was wondering, you know, what could we expect to see when you present your 12-month VOC data from your ongoing phase 2a OLE study that's presented at ASH? You know, how many patients' worth of data should we expect? And are there any differences we should expect from what you've presented so far from your OLE study?
spk02: Sure. So, I think, thanks for the question, first of all. So I think our 12-month data for the LLE study will have kind of two nuances that the eight-month data did not. As you guys know, we have been doing annualized rates of VOCs. So a patient that has been on a study for eight months, for example, is annualized out to 12 months. And so if a patient has two VOCs in six months, they're annualized out to have four VOCs over the period of one year. Nice part about the data that we're going to present at ASH is now that we're looking at the 12-month endpoint, the annualization effort is minimal in the sense that most patients will have over 320 days on study. That will be approximately 20 patients. And so when we look at those VOC rates, we'll be, I think, comfortable in understanding what the yearly VOC rate is for those patients as opposed to annualizing out data that was eight months and shorter. So I think that's going to be an advantage of that data set. And then maybe just to finish that point, we'll obviously be showing what we've shown throughout the eight-month data set at EHA, which is HBF and F-cells, as well as these incremental views on VOCs.
spk01: I'll just add that we have safety data for all 26 subjects enrolled as of September 30th. And as Raul mentioned, one-year data for approximately 20 subjects.
spk06: Okay, great. Thank you. And then our next question is on 261, IMR 261. How did you decide on advancing IMR 261, and what are some challenges or gating factors you envision to getting this agent into the clinics?
spk02: Yes, so we have followed the Nrf2 literature for quite some time. And as you guys may or may not know, there is actually quite a bit of detailed literature from Dr. Pace's lab at Augusta University on dinethyl fumarate and its ability to reactivate fetal hemoglobin, reduce NS-kappa B activation around those pathways, as well as B and antioxidant in general. And so as we looked at programs that were available and ready for the clinic, we were lucky enough to stumble upon a program that had Phase II data that was safe and well-tolerated, that certainly did not have success in kidney indications, as we mentioned, and PAH, that had a unique perspective vis-a-vis dosing and regimen for a sickle cell study in the future. To be specific, Those patients in the PAH and FSGS trials were dosed at a very low dose. They were not titrated up for a long time. And that company was able to complete a study prior to handing the acid over to us that showed you could increase the dose by two to four fold. And so we're starting from a much higher dose perspective. We are starting from a mechanism that is at least preclinically well-defined. And if you look at our ASH presentation, the fetal hemoglobin induction or reactivation is extremely robust. As an example, in the CD34 cells that many companies use to approximate fetal hemoglobin induction, we're seeing a seven-fold increase and a dose-dependent increase in fetal hemoglobin as an example. Furthermore, in the TALS models, not only did we look at fetal hemoglobin induction, which was near threefold, we also looked at the reduction in VOC crises, as shown by the TNF-alpha data. And so not only are we confirmed that the drug is active in a number of sickle cell models, we've done the same in beta thalassemia. Then you add the existing literature for DMF that shows that this is, in fact, happening across the class. and you get pretty excited about 261 as a clinic-ready asset for sickle cell disease. You also noted the point about challenges. So anytime you receive a clinical asset from another company, drug product is certainly one of those in terms of expiry dates, in terms of getting drug substance to ultimately make drug product. So we've started that work on the drug substance, drug product side already. And as we've done that, we are in the process of evaluating a number of clinical paths to market for 261. Since it already had an IND for FSGS and PAH, we would foresee starting a clinical study in patients right away. And we'll certainly update external markets in 2022 about our path forward.
spk06: Okay. Thank you very much.
spk01: Thanks.
spk04: As a reminder, to ask a question, you would 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. Your next question comes from the line of Matthew Harrison with Morgan Stanley.
spk03: Good morning, everyone. This is Costa Son for Matthew. I congratulate on the progress. Two questions from us on 261. Can you talk a little bit about the doses you tested in mice and how these doses translate in humans and what the safety profile looks like under these doses in humans, given you have available data? And secondly, how fast do you think the development pathway could potentially be, given all the available data you have from Complexa? Thank you.
spk02: Yeah, Costas, good to hear from you, and thanks for the questions. So when we tested IMR261 in our preclinical models, I had referenced from the previous question about the study that Complexa did prior to handing the acid over to us. To be brief, they studied doses as high as 300 mg BID in the clinic in healthy volunteers, 600 mg total daily. And so we modeled that high dose that they tested as the dose in our preclinical models. So the doses for the TALENDS model, to be specific, are 37.5 mg per kg BID for a total of 75 mg per kg daily. That, if you look at the human equivalent dose, is right around the 300 mg BID. So we started with clinical data and we downscaled to mice, so we knew getting out of the preclinical, before we even started the preclinical experiments, that we could hit the dose in the clinic. So that is an advantage of getting a clinic-ready asset in this case. You talked a little bit about safety. We've gone through the data, and at the doses that we just mentioned, the 300 mg DID, the healthy volunteer data, nausea, headache, and vomiting, were the most commonly associated AEs, and overall the drug was well tolerated with food. And so as you think about triangulating dose efficacy in preclinical models and obviously safety, we have, I think, done a good job of finding a dose forward for the clinic. Of course, drug product and drug substance remain a challenge for us in terms of getting that to the next stage and actually making the drug.
spk03: Thank you. And just on clarification, do you mean that you will be testing the 300 milligram BID in clinic, or you haven't disclosed the dose yet?
spk02: We haven't disclosed any doses. I think your question was, do we feel comfortable with the preclinical data that it could translate to clinical doses of efficacy? I think the answer is yes, but as I said, we're still working through the clinical path forward, both on dose and ultimately indications.
spk03: Perfect. Thank you very much. And if you could touch on the potential scenarios around the development pathway, how accelerated can it be potentially given the available data from Complexa? Thank you.
spk02: Yeah. So, again, I think we are in the process of detailing a clinical development path forward, and we'll certainly update you over time so we're not commenting on on the timelines for that at this point, but I think maybe three organizing principles for us. Number one, we're a clinical stage company that knows how to do clinical trials. Number two, we really wanted a clinic-ready asset that could be put into the clinic near term. And number three, certainly we understand the rare red cell disorders and hemoglobinopathies quite well. So there's lots of different approaches that we're gonna take to evaluating the best and fastest path forward, but the fact that the drug has been tested in over 100 patients, the fact that there are two INDs open on this drug, and the fact that they've tested higher doses that could potentially be used by us, all sets up for a rapid path to clinic.
spk03: Very helpful, thank you.
spk02: Thanks for the questions, Carlos.
spk04: At this time, there are no further questions. Oh, now let's just turn the call back over to management.
spk02: Thank you very much and appreciate your time today. Thank you for joining this morning's call. We're excited about the momentum that we have as a company from a variety of different angles that we've already talked about and look forward to the upcoming data readouts. Everyone's Stay healthy and safe and speak safe.
spk04: This concludes today's conference call. Thank you for participating. You may now disconnect.
Disclaimer