Enliven Therapeutics, Inc.
Q3 2021 Earnings Call Transcript

Published: 9 Nov 2021

[Operator:]

Good day, and thank you for standing by. Welcome to the IMARA Inc. Q3 Earnings Conference Call and Webcast. At this time, all participants are in a listen-only mode. After the speaker presentation, there will be question-and-answer session. I would now like to hand the conference over to your speaker today, Mike Gray. Please go ahead.

[Mike Gray:]

Thank you, Operator. Good morning, everyone, and welcome to IMARA’s third quarter 2021 conference call. I’m joined this morning by IMARA’s President and CEO, Rahul Ballal. Before we begin, I’d like to remind everyone that various statements we made 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 IMARA’s President and CEO, Rahul Ballal, 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?

[Rahul Ballal:]

Thank you, Mike. Good morning, everyone, and thank you for joining today’s call. The third quarter and recent weeks have been a productive period for IMARA and specifically on IMR-687, which we'll also refer to in this generic game tovinontrine. We are pleased to have made substantial progress in our ongoing Phase 2b trial and we expect to report interim data from both our Ardent trial and sickle cell disease, the Forte trial in beta-thalassemia this quarter. Furthermore, we have taken concrete steps to expand our development pipeline by continuing to work with tovinontrine in heart failure with preserved Ejection Fraction or HFpEF. And announcing a new clinic-ready program in IMR-261 an Oral Nrf2 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 tovinontrine. We expect to report data from an interim analysis of this trial in approximately one-third of patients at 24 weeks during this quarter. Interim analysis will 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 tovinontrine on the rate of vaso-occlusive crises or VOCs at 24 weeks. The Ardent 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 Ardent trial readout this quarter, we look forward to reporting updated 12 months safety and VOC data from our Phase 2a open label extension or OLE trial of tovinontrine in adult with sickle cell disease at the American Society of Hematology annual meeting to be held December 11 to 14 this year. As a refresher, we reported final results from the Phase 2a parent trial, as well as 8-month data from the OLE in June at the European 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 HbF. Importantly, VOC results for all 93 subjects enrolled in the Phase 2 trial demonstrated a 40% lower meaning annualized VOC rate in the pooled tovinontrine treated groups versus the pooled placebo groups. In addition, data from the parent study demonstrated a significant increase in the median time 2 for VOC, as well as reduced rate of annualized VOC related hospitalizations. In each case, when pooled tovinontrine groups were compared to pooled placebo groups. They're also encouraged to see patients in the OLE clinical trial continuing 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 patients Phase 2a study. Lastly, in addition to the positive VOC data and OLE study, we’re also pleased that 36% or 4 of 11 patients in the OLE trial had absolute HbF increases of more than 3% at the 8-month time point or receiving 200 milligram of tovinontrine. We believe that higher doses of tovinontrine have the potential to show even more robust Hbf increases. Remember that the Ardent Phase 2b trial is currently dosing at up to 400 milligram boe, and is power to show an HbF response rate 35% in tovinontrine 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 interim data from the Ardent trial later this quarter. Turning to our Forte Phase 2b clinical trial and beta thalassemia. We also reach for enrollment in the transfusion dependent or TDT cohort. Also seeing continued enrollment in the non-transfusion dependent or NTDT cohort. We expect interim data from the TDT cohort this quarter, which we plan to evaluate safety, transfusion burden and PD biomarkers in approximately 30 patients at 24 weeks. 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 December, we're looking forward to providing both of these updates in the coming days. We are also selectively expanding our indication footprint to areas where PDE9 over expressions implicated in serious diseases with high unmet needs. To that end, we expanded our internal team and developed a protocol for a Phase 2 proof-of-concept study in heart failure with preserved Ejection Fraction or HFpEF with the help of our experienced cardiology clinical advisory board. We also expect to interact with the FDA division of cardiology nephrology this quarter, so collectively, we've made substantial progress in enabling the HFpEF program with an eye towards the clinic in 2022. Yesterday, we announced an oral presentation of the American Heart Association Scientific Sessions, which is scheduled to take place later this week. Our abstract includes data in 3 preclinical mouse models with HFpEF in which selective inhibition of PDE9 with tovinontrine was shown to reduce the median size of cardiomyocytes and lower plasma B-type in atrial natriuretic peptide levels. In addition, markers or renal dysfunction, including blood urea nitrogen and urine albumin-to-creatinine ratio were lower in mice treated with tovinontrine compared with vehicle treated mice in all models. Importantly, tovinontrine did not significantly change heart rate, or blood pressure. In summary, alongside independent literature on the potential value of PDE9 inhibition of HFpEF as well as our own internally generated data, we believe tovinontrine maybe a promising treatment option for patients with HFpEF. To lead clinical development of tovinontrine as a treatment for HFpEF, I'm also pleased to announce that IMARA has appointed Toni Bransford, M.D. as Vice President of Clinical Development. A seasoned cardiologist, Toni comes to IMARA with 15 years of clinical development expertise within global pharmaceuticals, biotech and clinical research organizations. Toni comes to IMARA from Kaleido, where she led clinical research programs for multiple projects and oversaw translation of discovery programs. Prior to her roles at IMARA and Kaleido, Toni accumulated deep experience in the cardiovascular therapeutic area, including at Novartis, where she was a clinical lead for the HFpEF program, conducting the PARAMOUNT and PARAGON trials was also responsible for leading regulatory authority interactions. We're delighted to have Dr. Bransford join our team to lead our HFpEF development efforts, working closely with our Chief Medical Officer, Ken Attie. In addition to the progress we've made with tovinontrine, we are excited to announce IMR-261 as a new asset in our development pipeline. Briefly, IMR-261 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 NF-kB pathway and reactivates fetal hemoglobin, or HbF. IMR-261 was formerly known as CXA-10, that was previously evaluated by Complexa, Inc. in Phase 2 clinical trials through focal segmental glomerulosclerosis FSGS and pulmonary arterial hypertension PAH. Independent medical literature suggests that Nrf2 activation irrelevant 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 dimethyl fumarate, a known Nrf2 activator. IMARA ran its own preclinical sickle cell disease models and sound IMR-261 significantly increased HbF and F-cells improved hemolytic markers and decreased VOCs. In a preclinical beta thalassemia model IMR-261 increased hemoglobin in enabled red blood cell maturation. The IMR-261 data is submitted aspect was selected for an oral presentation at the upcoming ASH meeting. And Dr. Betty Pace, a leader in sickle cell research with EMF and Nrf2 is an author on this abstract. Since IMR-261 is a clinic-ready asset we’ve initiated work toward drug product manufacturing. As we explore potential clinical development tasks. We look forward to providing updates at IMR-261 in 2022. In conclusion, we believe that the third quarter and first part of the fourth quarter have in production periods for IMARA on our core programs, expanding our indication opportunities and developing a clinic ready pipeline. We look forward to updating you on a further progress, including expected data readouts beginning later this quarter, and in the first quarter of 2020. Thank you. And I'll turn the call back to Mike to review our financial results. Mike?

[Mike Gray:]

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 10-Q to be 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 in 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 tovinontrine, 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, cash equivalents and investments were $102.8 million as of September 30, 2021, as compared to $88.2 million as of December 31, 2020. We believe this capital provides IMARA with sufficient funds to enable us to fund our planned operations into the first quarter of 2023. And that concludes our prepared remarks. Operator, could you please open the line for questions?

[Operator:]

Your first question comes from the line of Yigal Nochomovitz with Citi.

[Carly Kenselaar:]

Hi, this is Carly on for Yigal. Thanks for taking our questions. We had two questions. First on the Nrf2 activator that you sensed, will you consider indications in kidney disease or are you focused on hemoglobin disorders? And then second on the Phase 2b study in sickle cell, you mentioned some of the details on the powering on fetal 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.

[Rahul Ballal:]

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, Nrf2 activation is implicated in a number of different diseases, including our renal diseases. Our focus right now is rare cell disorders, red blood cell disorders, including hemoglobinopathies. So our first shot at disease indication is really in that sphere. We are looking at associated and affiliated areas beyond sickle cell and data cell before right now our data is the strongest in those two indications. I'll just note that unlike renal diseases and PAH which leverage Nrf2’s anti-oxidant mechanism, the Nrf2 activators in sickle cell disease are actually specifically designed to induce and reactivate fetal hemoglobin. And so we like the specific mechanism around Nrf2 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 secondary.

[Ken Attie:]

Thanks, Rahul. This is Ken Attie. We have powering 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 our calculations for each of the secondary endpoints. Although we have now made analyzed rate of VOCs the key secondary endpoint and based on our results from the Phase 2a study, we feel that we will probably be powered to show a difference similar to what we saw in the Phase 2a study with the number of patients for the Phase 2b study. That study was 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 initially 1 to 12 VOCs in the prior year. We revised the protocol to specify a minimum of 2 VOCs in the previous year. And so in our analysis plan -̄- fiscal analysis plan which we have finalized we will be looking at both subjects with 1 to 12 VOCs in the prior year as well as 2 to 12 as a sensitivity analysis.

[Operator:]

Your next question comes from the line of Joseph Schwartz with SVB Leerink.

[Unidentified Analyst:]

Hi, I'm dialing in for Joe. Thank you for taking our question. First, I guess I was wondering, what could we expect to see when you present your 12-month VOC data from your ongoing Phase 3 OLE study as presented at ASH. Now, how many patients with data should we expect in? Are there any differences we should expect that’s from what you've presented so far from your OLE study?

[Rahul Ballal:]

Sure. So I think, thanks for the question, first of all. So I think our 12-month data for the OLE study will have kind of two nuances of the 8 month data deny. As you guys know, we have been doing annualized rates of VOC. So patient that has been on the study for 8 months, for example, its annualized out 12 months, since the patient has 2 VOCs in 6 months, their annualized out to have 4 VOCs over the period of one year. The 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 of most patients will have over 320 days on study. That will be approximately 20 patients. So when we look at those VOC rates will be, I think comfortable in understanding what the yearly VOC rate is for those patients as opposed to annualizing out data that was 8 months and shorter. So I think that's going to be an advantage of that data set. And then maybe just finish that point. But obviously we showing what we shown throughout the 8-month data set at EHA, which is HbF and F-cells as well as these incremental views on VOCs.

[Mike Gray:]

So just then we have safety data for all 26 additional rolls as a September 30 and as Rahul mentioned one year data for approximately 2027.

[Unidentified Analyst:]

And then our next question is IMR-261. How did you decide on advancing IMR-261 and where some challenges are getting factors envision, do envision ticketing this agent into the clinic?

[Rahul Ballal:]

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 dimethyl fumarate and its ability to reactivate fetal hemoglobin, reduce NF-kB activation around those pathways, as well as be an 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 2 data that was safe and well tolerated. That certainly did not have success in any indications as we mentioned, 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 dose 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 asset over to us, that showed you could increase the dose by 2 to 4-fold. And so we're starting from a much higher dose perspective. We are starting from a mechanism that is to at least preclinically well defined. And if you look at our ASH presentation, the fetal hemoglobin induction or reactivation is extremely robust. As example the CD34 cells that many companies use to approximate fetal hemoglobin induction we're seeing a 7-fold increase in a dose dependent increase in fetal hemoglobin as an sample. Furthermore, in the models, not only did we look at the fetal hemoglobin induction, which was near 3-fold, 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 DMS, 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 notice that 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 drugs substance to ultimately make drug products. So we've started that work on the drug substance from product side already. And has we've done that we are in the process of evaluating a number of clinical paths, the margin for 261. Since it already had an IND for FSGS and PAH, we would force the starting a clinical study in patients right away. And we'll certainly update external markets in 2022, about our path forward.

[Operator:]

Your next question comes from the line of Matthew Harrison with Morgan Stanley.

[Costa Sean:]

Good morning, everyone. This is Costa Sean for Matthew. Congrats on the progress. 2 questions from us on 261. Can you talk a little bit about doses you test it in May and how these doses translate in humans? And what the safety profile looks like under these doses in humans even 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.

[Rahul Ballal:]

Yes, Costa, it's good to hear from you and thanks for the questions. So when we tested IMR-261 in our preclinical models, made reference from the previous question about the study that Complexa did prior to handing the asset over to us. To be brief, they study doses as high as 300 mg BID in the clinic, in healthy volunteers 600 mg total daily. And so we models that high dose that they tested as the dose in our preclinical models. So the doses for the talent model to be specific, are 37.5 mg per kg BID for total 75 mg per kg daily, that if you look at the human equivalent dose is right around 300 mg BID. So we started with clinical data and we downscale 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 BID, the healthy volunteer data, nausea, headache and vomiting are 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, got 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.

[Costa Sean:]

And just on clarification, do you mean that you will be testing the 300 milligram BID in clinic? Or you haven't disclosed that those yet?

[Rahul Ballal:]

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 paths forward both of those, and ultimately indication.

[Costa Sean:]

And if you could touch on the potential scenarios around the development pathway, our accelerated can it be potentially given the available data from Complexa?

[Rahul Ballal:]

So again, I think we are in the process of detailing our clinical development path forward. And we'll certainly update you, we are not commenting on the timelines for that at this point. But I think maybe 3 organizing principles for us. Number 1, we're a clinical stage company that knows how to do clinical trials. Number 2, we really wanted a clinic-ready asset that could be put into the near-term. And number 3, certainly understand the red cell, rare red cell disorders and hemoglobinopathies quite well. So there's lots of different approaches that we're going to take to evaluating the best and fastest path forward. But the fact that the drug has been tested over 100 patients. The fact that there are 2 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 rapid path to clinic.

[Operator:]

At this time, there are no further questions. I would now like to turn the call back over to management.

[Rahul Ballal:]

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 at the company from a variety of different angles that we've already talked about and look forward to the upcoming data readouts. Everyone stay healthy and safe and speak safe.

[Operator:]

This concludes today's conference call. Thank you for participating. You may now disconnect.