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spk01: Good day. Thank you for standing by, and welcome to the EMARA Inc. Q2 Earnings Conference Call and Webcast. At this time, all participants are in the listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during this session, you will need to press star 1 on your telephone. If you require any further assistance, please press star 0. I would now like to hand the conference over to your speaker today. Mike Gray, thank you. Please go ahead.
spk03: Thanks, Kalandra. Good morning, everyone, and welcome to Amara's second quarter 2021 conference call. I'm joined this morning by Amara'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 that 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 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 second quarter and key recent accomplishments. I'll then return following Rahul's discussion to review our second quarter financial results, and we'll then open the call for questions. Rahul?
spk06: Thank you, Mike. Good morning, everyone, and thank you for joining today's call. The second quarter and recent weeks have been a productive period for Amara, and specifically IMR 687. We are pleased to have moved the ball downfield and have made substantial progress in our ongoing Phase IIb trials. First, in sickle cell disease, we have made key progress in our ongoing ARDENT Phase IIb clinical trial. We have seen accelerated study enrollment in the ARDENT trial and, as announced yesterday, we have completed patient enrollment. This is an important accomplishment for Mara. And I want to thank our team for its dedication and commitment to this trial, most of which has been conducted in the backdrop of the COVID-19 pandemic. The ARDEN study has been a global effort as we enrolled subjects from across the world, including the US, Europe, Middle East, and even Africa. As a result, faster enrollment across several countries, we are refining our prior guidance and now expect to report data from the primary analysis from this trial in the first quarter of 2022. As part of that primary analysis, we expect to examine safety, PD biomarkers, including fetal hemoglobin or HBF, NF cells, as well as the effect of IMR687 on vaso-occlusive crises or VOCs in approximately 99 patients at 24 weeks. We also expect to report data from an interim analysis of approximately one-third of patients enrolled in this trial at 24 weeks during the fourth quarter of 2021 with a focus on safety dose and PD biomarkers, including HBF and F cells. We view this interim readout as a check-in ahead of the full study results in Q1 2022. We have worked tirelessly on the conduct of the ARDN trial and are very pleased to have important data readouts in the coming months. We also recently presented final data from the 93-patient Phase IIa Placebo-Control Clinical Trial and its Open Label Extension, or OLE, trial of IMR687 in adults with sickle cell disease at the 2021 European Hematology Association, or EHA, Annual Congress, which was held virtually in June. We held a webcast to review these data in June, and that webcast and EHA presentation are both available within the events and presentations of the investors section of our website. We view the Phase IIa results presented at EHA as an important proof of concept for relevant clinical outcomes with IMR687 treatment. It strengthens our expectations that the Phase IIb study at substantially higher dose levels could achieve its primary endpoint, which is an HPF response rate defined as an absolute HPF increase of at least 3% in 35% of subjects on IMR687 versus 5% on placebo. In addition, we expect to demonstrate clinical outcome improvements in the key secondary endpoint of annualized VOC rate, similar to what was seen in the Phase IIa study. At the end of the day, if we can replicate the lower rates of VOCs seen in the Phase IIa and OLE studies, the Phase IIb will be a success. IMR 687 will have a clear path to Phase III and have a competitive commercial profile if approved. As a refresher, the final results from the Phase IIa trial indicate a well-tolerated safety profile, lower VOC rates, improved patient-reported pain severity scores, and variable biomarker results, including with respect to HBF. VOC results for all 93 subjects enrolled demonstrate a 40% lower mean annualized VOC rate in the pooled IMR687 treated groups versus the pooled placebo groups. In addition, a significant increase in median time to first VOC of 169 days for the IMR687 treated groups versus 87 days for the placebo groups was observed. Regarding the annualized rate of VOC-related hospitalizations, the rate was 0.84 hospitalizations per year in the IMR687 treated groups compared with 1.36 per year in the placebo group. In patients taking background hydroxyurea, the mean annualized VOC rate was substantially lower in patients on IMR687 plus HU versus placebo plus HU. We are also encouraged to see patients in the separate OLE clinical trial continuing to benefit from lower annualized VOC rates. This is based on interim data from 18 patients treated for approximately eight months and is a distinct data set from the Phase IIa study. Patients who were on active treatment in the parent maintained similar low VOC rates on IMR687 in the OLE clinical trial. For patients who were previously in the placebo groups in the parent Phase IIa study, there was a 39% decrease in the mean annualized VOC rate when they switched to IMR687 in the OLE study, with patients serving as their own control. The continued VOC benefits in this trial further support the findings from the 93-patient Phase IIa study. Finally, we believe that the VOC improvement point points to a multimodal mechanism of action of IMR687 in sickle cell disease, which potentially works across several categories, red blood cells, reduced activation and adhesion of white blood cells and other cell types, reduced inflammation, and vasodilation. Importantly, IMR687 was well-tolerated as a monotherapy as well as in combination with HU, in each of the Phase IIa and OLE clinical trials, opening the opportunity for both combination therapy alongside monotherapy use. In addition to positive VOC data, we are also pleased that 36% or four of 11 patients in the OLE clinical trial had absolute HPF increases of more than 3% at the eight-month time point while receiving a 200-milligram dose of IMR687. We believe that higher doses of IMR687 have the potential to show even more robust HBF increases. Remember, ARDIN Phase 2B clinical trial is currently dosing up to 400 milligram daily, and it's powered to show an HBF response rate of 35% on IMR687 versus 5% on placebo at 24 weeks. So, with 200 milligram in the OLE, and a 36 percent HPF response rate. We are already in the right ballpark and expect higher doses to further improve on that signal. Turning to our FORTE Phase 2B clinical trial in beta-thalassemia, we've also seen accelerated enrollment in this trial, having reached full enrollment in the transfusion-dependent, or TDT, cohort while also seeing increased enrollment in the non-transfusion dependent or NTDT cohort where we have enrolled approximately half of the study patients. We expect to report interim data from the TDT cohort in the fourth quarter of 2021 in which we plan to evaluate safety, transfusion burden, and PD biomarkers in approximately 30 patients at 24 weeks on the study. Furthermore, faster enrollment rates now allow an additional readout of the full TDT cohort at 24 weeks in the first quarter of 2022, looking at similar data points as the interim analysis. We are also selectively expanding our indication footprint to areas where PD-9 overexpression is implicated in serious disease with high unmet medical needs. To that end, We're developing a protocol for a phase two proof of concept study in heart failure with preserved ejection fraction, or HFPEF, with help from our experienced cardiology clinical advisory board. And we expect to interact with the FDA cardiorenal division in late 2021. We've submitted our recent preclinical work in HFPEF to our cardiology-focused medical meeting and hope to present these data later this year. We've been interested in HFPEF as an indication for some time now and think that PD-9 is an enriched and attractive target that may help treat this debilitating disease. Hence, we are excited to begin working on this indication in a meaningful way in the coming months with an eye toward the clinic. During the second quarter, we also announced the grant recipients for our second annual Real Impact Community Support Initiative. This program, which includes grant funding to support nonprofit, community-based organizations serving patients and families impacted by sickle cell disease and beta thalassemia, awarded 30 grants to CBOs in 16 states, totaling $150,000. The grant funding was increased by $25,000 from 2020, the program's inaugural year. We are proud of the positive effects the Real Impact program has had on the health and lives of patients. their families, and their local communities to date. Expanding the program for its second year reflects our continued commitment to foster innovative ideas and let local community organizations further accomplish their goals of supporting people affected by sickle cell disease and beta thalassemia. We also mark key highlights on the corporate front, including the appointment of Laura Williams, MD, MPH to our Board of Directors. Laura brings 25 years of early to late stage drug development experience across multiple therapeutic areas. And in addition to her significant experience leading clinical trials and guiding products through commercializations, she is a strong advocate for the community, making her an outstanding addition to our board. Also in July, we closed a $50 million public financing, which provides Amara the important capital to continue to fund IMR 687, and extends our capital runway through the end of 2022. Lastly, in June, United States Adopted Names Council, or USAN, formally adopted Tovinitrine as a generic name for IMR 687. You may see IMR 687 referred to as Tovinitrine in our future communications. In conclusion, we believe that the second quarter and first part of the three productive periods for AMARA both in terms of presenting encouraging VOC data and making significant progress in our ongoing Phase 2B clinical trials. We look forward to updating you on further progress, including on multiple data readouts planned in the beginning in the fourth quarter of 2021 and the first quarter of 2022. Thank you, and I will now turn the call back to Mike to review financial results.
spk03: Thanks, Rahul. Our second 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. R&D expenses were $10.1 million for the second quarter of 2021 as compared to $7.9 million for the second quarter of 2020. The increase of $2.2 million 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 IMR 687. G&A expenses were $3.1 million for the second quarter of 2021 as compared to $2.4 million for the second quarter of 2020. The increase of $700,000 was primarily due to increased personnel related and other GNA operating costs as a result of operating as a public company. Net loss attributable to common stockholders was $13.2 million or 74 cents per share for the second quarter of 2021 as compared to a net loss of $10.2 million or 59 cents per share for the second quarter of 2020. We ended the first quarter, sorry, the second quarter with cash, cash equivalents and investments of $66.8 million. We believe that our cash, cash equivalents and investments as of June 30, 2021, as well as the approximately $47 million in net proceeds from our July 2021 public offering of shares of common stock will enable us to fund our operating expenses and capital expenditure requirements through the end of 2022. That concludes our prepared remarks. Operator, could you please open the line for questions? Thank you.
spk01: If you would like to ask a question at this time, simply press star, then the number one on your telephone keypad. We will pause for just a moment to compile the Q&A roster. And your first question comes from the line of Yaigel Nokomotovich from Citi.
spk00: Hi, this is Carly . Thanks for taking our questions and congrats on completing enrollment in the sickle cell trial. We had a couple questions on the VOC data that you've reported so far. So I guess first, what biomarker data are you collecting in the Phase IIb trial that could help support IMR 687's effect on VOCs? And then secondly, I think you mentioned that you plan to report VOC data as part of the primary analysis in the first quarter of next year. Just wanted to get your thoughts on if you anticipate 24 weeks will be enough time to see an impact on VOCs or if we should really be waiting for sort of the 52-week data to better understand the effect on VOCs in a larger cohort of patients. Thank you.
spk06: Thank you very much, Carly, for the questions. I'm going to turn it over to our Chief Medical Officer, Ken Addy, to cover those responses.
spk05: Hi. Good morning. Thanks. Maybe I'll take your second question first. When we say that we're going to do an interim analysis with subjects at 24 weeks, it's actually when that particular subject, whether it's a third of the patients or all the patients, has reached 24 weeks. That means all of the other subjects have somewhere between 24 and 52 weeks. So they actually will be a large number of subjects with substantially more than 24 weeks of treatment. And then what you do in the VOC analyses is annualize it. So we will use all data available. So if someone was treated with nine months, we annualize it based on the nine months. Some patients might even be at 12 months already. So I think it'll be a pretty good approximation, but obviously you're correct. When everyone reaches 52 weeks, that'll be the most accurate reflection of the one-year VOC rates. To your first question, we are... measuring many of the same biomarkers that we've been looking at pre-clinically and in clinical trials previously. This includes markers of hemolysis, markers of adhesion, markers of inflammation, and even of cardiac stress. So we still have all of those biomarkers being measured in this study. Of course, it's blinded right now. And so those results are not available just yet. But the primary biomarkers, of course, that we look at are related to hemoglobin F and total hemoglobin and the red blood cells that contain hemoglobin F or F cells. Those will be the primary biomarkers that we look at.
spk00: OK. That's very helpful. Thank you so much. Thank you.
spk06: Thanks.
spk01: And your next question comes from the line of Matthew Harrison from Morgan Stanley.
spk02: Good morning, everyone. This is for Matthew. Two questions from us on 687. The first one is around competition, given that several small molecules for sickle cell disease are currently progressing in development. And these molecules include HBF in users or hemoglobin modifiers. We are wondering how are you thinking about the competition and what, in your view, would differentiate 687 versus competitors? Thank you. And then I have a follow-up.
spk06: Great. Thank you. I'll start and then I'll obviously turn it over to Ken to add some additional commentary. First of all, we're excited by the development in Sickle Cell. It's great to see lots of different companies approaching this landscape. Our fundamental view for IMR 687 is that unlike other competitors, the drug works in a multimodal way in that it potentially works on red cells, white cells, inflammation, and even vasodilation. And the aggregation of all those different mechanisms allows us to differentiate ourselves on VOCs. And at the end of the day, When you look at the approved products, both from hydroxyurea and Adacvio, our Phase IIa results in the 93-patient study squarely hit approximately the same type of VOC reductions that those two products saw. Hydroxyurea is in the mid-40s. Adacvio is in the mid-40s in terms of reduction in annualized VOC rates. 2A results, the mean change was around 40%, and we've seen the same type of results in the OLEs. So just taking a step back, when you look at a target product profile for the company, I think differentiating on VOCs by taking all the advantages of the mechanism into that readout is ultimately, for us, what makes us competitive. Anything else, Ken?
spk05: No, I just think that some of the other molecules are quite focused on red blood cells and hemoglobin changes. And I think that being the case, they might see very nice results there, but maybe not as robust results in terms of VOCs. So we are certainly focused now on the ability of our drug to reduce not only the number of painful crises, but the number of hospitalizations and the severity of the pain crisis as well.
spk02: Thank you. Very helpful. And a follow up. We are hearing that the in-person physician visits for sickle cell patients remains significantly below the pre-pandemic levels, mostly because the vaccination In this sickle cell disease population, the vaccination rate is lower than the total population. We are wondering if this has or potentially can have any impact on the sampling of PK PD measurements from the sickle cell disease patients in your study. Thank you.
spk05: I think that's a good question. I could say that we've seen a turning point in many countries. that they're making sure that patients are coming in for all office visits, well visits, as well as clinic visits for studies. So we've been averaging something like 10 new patients a week for the last few weeks. That's a really robust recruitment rate, in part due to bringing more sites on board, but I think there's also some enthusiasm about getting a drug like this and trying it out in patients. So we haven't seen too many missed visits. We've simplified our PK collection based on some of our PK modeling. We decided we didn't need to have them stay overnight for PK sampling, so that's being done in a one-day visit. So I think our PK data is going to be pretty robust. We've also are in the middle of an extensive PK study in Healthy Volunteers. So we have a lot of PK and PD data coming in.
spk02: Thank you very much. Very helpful. Thank you. Thanks, Jose.
spk01: Your next question comes from the line of Joseph Swartz.
spk04: Good morning. Thanks very much. Your last comments on PK are a good segue to one of my questions, which is basically, you know, have you done any response exposure analyses for the Phase IIa and found data that supports the hypothesis that higher doses of IMR687 can produce better responses, better increases in HBF or decreases in VOCs, and are there any implications on the Phase IIb trial where some higher doses are being evaluated?
spk05: Yeah, hi. Thanks for that question. We have indeed done those analyses, not in the formal way that we hope to do it when we have a bit more data from these new studies, but I'll give you an example of what we've looked at. So for the subjects In the phase 2a study where we were able to do full PK evaluation at the end of the study, we compared the annualized VOC rate versus the area under the curve for their PK profile. And we saw a nice negative correlation, so that's what we want, right? So as the exposure increases, we see fewer and fewer VOCs. You know, that didn't have a very high R or P value, but that trend was there, and really at the higher exposures, and we're talking about only 200 milligrams per day, we saw fairly low VOC rates, you know, less than two per year. So as we go up now to 300 and 400 milligrams in our Phase IIb trials, we know that we're going to be approximately doubling the AUC in some patients that will extend that curve out to, again, really low VOC level. That relationship was even stronger for hemoglobin F and for F cells in particular. So the absolute change in F cell percentage increased with increasing exposure. And there we had an R of 0.43 and a P of 0.043. So that was saying that we're going to see this 10, 15, 20% increase in F cells at our current dose levels, even at 200. And then as we go to 300 and 400, we could see that go even dramatically higher. So, you know, we're going to start seeing subjects with 40, 50% of their red cells as F cells and maybe even more. And that, in turn, will drive up the hemoglobin F percentage.
spk04: Interesting. And then how much of the reduction in VOCs was explained by HPF factors versus other things? Have you looked at those correlations also?
spk05: We would have to say that it would not be fully explained by hemoglobin F or the change in F cells. We did look at it. or any specific other biomarkers. We saw some directional improvement in adhesion molecules and in reticulocytes, et cetera. But no single biomarker seemed to be driving this. And that's why we're going to take the data at face value and say it's a combination of these factors right now. Sure, it would be great to have a single surrogate marker for when VOCs go down, but I'm not sure we're going to get there. But as we go up on the dose, I think these signals will get stronger.
spk04: Right. It's probably a complex multi-factor equation. Yeah. Maybe another question on the Phase IIa versus B trials. Can you tell us how were the VOCs in Phase IIa adjudicated, and will it differ in any way in the Phase IIb? sickle cell trial, and how extensively distributed are the sites in Phase 2b, and is your ClinOps organized to ensure the highest quality conducted results?
spk05: So I would say in the Phase 2a trial that our collection of the VOCs was refined over the course of the study to reflect some feedback from the FDA. I don't think it changed the behavior of the sites in the UK and the US. They know how to recognize VOCs, sequestration, priapism, acute chest syndrome, you know, the need for analgesia, and all the other parameters that you look at to characterize a VOC as a VOC. We've done most of that adjudicating through the safety review committees which include investigators and outside experts as well as our own internal review of the data. We now have two MDs that are reviewing the VOC data coming in on our side as well as two MDs at the CRO. So I think the VOCs are being carefully looked at, not with an independent adjudication committee if that's your question. We are capturing VOCs on a unique case report form for VOCs and of course we capture even more information if they're hospitalized with the serious adverse event information. I think going forward that we're going to continue to have careful Mostly to make sure that we have a standard way of characterizing the BOCs. As far as the study and where it's being conducted, we are in 10 to 15 countries and over 40 sites. So it is a challenge, but I would say the sites are performing extremely well. Like I said, we're not having missed visits or labs. The physicians are really... responding to our queries quite rapidly and quite concertedly. They're making an effort to not only recruit patients but keep them in the study when logistical challenges come up. So we're really noticing that. So we have our own group of trial managers and the group at PRA-ICOM that are now quite experienced at it. Just to give you an example, we're trying to collect and send some of these biomarker data from Africa to Europe. And that's a challenge sometimes in terms of the transport of the samples. So we've done a number of creative things to make sure the samples arrive in good condition and can still be analyzed in a timely manner. So these things are being looked at carefully throughout the study.
spk04: That's really helpful, Keller. Thanks for all the insights.
spk01: Again, if you would like to ask a question, simply press star, then the number 1. And there are no further questions at this time. Mr. Gray?
spk06: Thank you very much, Operator. Again, we wanted to thank you for joining today's call. We're excited by our momentum going into the fall and look forward to upcoming data readouts across our programs later this year. Stay safe and healthy and speak soon. Thanks again.
spk01: This does conclude today's conference call. Thank you for your participation. You may now disconnect.
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