Enliven Therapeutics, Inc.
Q4 2021 Earnings Call Transcript

Published: 15 Mar 2022

[Operator:]

Ladies and gentlemen, thank you for standing by, and welcome to the Imara 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, one on your telephone. If you require any further assistance, please press star then zero. I would now like to hand the conference over to your speaker, Mr. Mike Gray, Chief Financial and Chief Operating Officer for Imara. Please go ahead, sir.

[Mike Gray:]

Okay, thank you Cirie and good morning everyone, and welcome to Imara’s fourth quarter 2021 conference call. I’m joined this morning by Imara’s President and CEO, Rahul Ballal, and our Chief Medical Officer, Ken Attie. 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 Factors 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. With that, I’ll turn the call over to Imara’s President and CEO, Rahul Ballal 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 Ardent and Forte Phase IIb 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 will 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 fourth quarter and the start of 2022 have enabled important pipeline expansion for Imara, including the clearance by the FDA of our IND for tovinontrine in heart failure with preserved ejection fraction, of HFpEF, as well as introduction of IMR-261, an oral clinic-ready activator of Nrf2. I’ll spend some time on each one of these exciting new programs, but 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 Ardent 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 IMR-687, which is also known as tovinontrine. In 2021, we, number one, reported data from our completed Phase IIa trial in tovinontrine 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 end point of the Ardent trial to annualize rate of VOCs. All these advancements are an encouraging set-up to what we believe will be an important 2022 for this development program. First, I will discuss the decision to change the primary efficacy end point in our sickle cell Ardent Phase IIb clinical trial of tovinontrine. 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 end point 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 end points and seeing encouraging VOC benefits at low doses of tovinontrine. The prior primary end point, HPF response, will continue to be evaluated as key secondary end point along with other key secondary end points, including time of first VOC. The end point revisions did not affect the conduct of the trial or operational aspects of the study. As part of this 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 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 end point, 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 mg or 400 mg based on weight gate. 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 end point 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 VOC end point, the statistical analysis plan has been reviewed by the FDA twice, and the study is powered at 80% to 85% to show a 35% to 40% 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 Ardent 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 tovinontrine, which was presented at the American Society of Hematology or ASH annual meeting in December. The OLE data showed patients who were on tovinontrine 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 switched to tovinontrine 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 benefits 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 mg of tovinontrine. PKPD modeling suggests that higher doses of tovinontrine 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 tovinontrine in beta thalassemia patients in the first week of April alongside our interim Phase IIb sickle cell data. 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 Imara and patients seeking oral therapies for this disease. We observed a positive trend for transfusion burden reduction at the higher dose of tovinontrine as compared to placebo and we are hopeful that this signal will strengthen with more patient data at our upcoming TDT interim analysis. We are also pleased that the interim data demonstrated a favorable tolerability profile at once daily doses of tovinontrine 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 tovinontrine’s potential in heart failure with preserved ejection fraction, of HFpEF. 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 Piotr Ponikowski from Wrocław Medical University in Poland to the executive committee. Our excitement for the HFpEF program comes from the results of in vivo studies of tovinontrine 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 PDE9 expression, creating a targeted approach in this highly prevalent disease. We also believe we have the best-in-class PDE9 inhibitor for evaluation in this patient population with in vitro data demonstrating superior potency and selectivity when compared to other available PDE9 inhibitors. To briefly cover the study design, the Spin Phase II clinical trial will be a randomized double blind placebo control 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 or tovinontrine, depending on a weight gate. Patients will be dosed for 16 weeks and the primary study end point will be the change in plasma NTproBNP, a clinically relevant biomarker of cardiac stress. Secondary end points include safety and tolerability and quality of life measures, such as Kansas City Cardiomyopathy Questionnaire - KCCQ, and New York Heart Association - NYHA classification. We will also look at exploratory end points 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 HFpEF program is a seasoned cardiologist with deep connections among key opinion leaders. In Q4 of 2021, we appointed Toni Bransford MD of Vice President of Clinical Development to work with Ken Attie and lead clinical development of tovinontrine as a treatment for HFpEF. A cardiologist, Toni comes to Imara with 15 years of clinical development experience within global pharmaceuticals, biotech, and CROs. Toni 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 HFpEF program conducting the Paramount and Paragon trials. We’re delighted to have Toni on board. In addition to our internal HFpEF team, we have also established a leading external executive committee to oversee the Spin trial, which is chaired by Deepak Gupta of Vanderbilt University and Medical Center and includes Maggie Redfield of the Mayo Clinic, Sanjiv Shah of Northwestern, Thomas Wang of UT Southwestern, and now Piotr Ponikowski from Wrocław University in Poland. We are very excited about the development of tovinontrine in HFpEF and we look forward to updating you on our progress. In addition the progress we have made with tovinontrine, in the fourth quarter of 2021 we announced the addition of IMR-261, an activator of nuclear factor erythroid 2–related factor 2, or Nrf2 to our pipeline. We recently showed preclinical data at an oral presentation of IMR-261 at the ASH annual meeting in December 2021. In preclinical sickle cell models, IMR-261 was observed to activate expression of HPF and reduce VOCs. In a preclinical data down model, IMR-261 increased hemoglobin and enabled red blood cell maturation. We have initiated work on drug product manufacturing for IMR-261 and we are exploring potential clinical development paths which could include treating iron disorders. We look forward to providing further updates on IMR-261 later this year. In conclusion, we believe the fourth quarter and beginning of 2022 have been productive periods for Imara. We are fast approaching key interim analyses and readouts for our Ardent and Forte Phase IIb clinical trials. We have expanded the tovinontrine opportunity into HFpEF and are developing a clinic-ready pipeline with the addition of IMR-261. We look forward to updating you 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.

[Mike Gray:]

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 tovinontrine, 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 31, 2021 as compared to $88.2 million as of December 31, 2020. We currently expect that full year 2020 R&D expenses will range between $60 million and $65 million and that our full year 2022 G&A expenses will range between $13 million and $15 million. We expect that our cash, cash equivalents and investments as of December 31, 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 Ardent and Forte Phase IIb clinical trials in the coming weeks. That concludes our prepared remarks. Cirie, if you wouldn’t mind, could you please open the line for questions? Thank you.

[Operator:]

Our first question will come from Yigal Nochomovitz from Citigroup. Please go ahead.

[Yigal Nochomovitz:]

Hi, thank you for taking the questions. As you noted, Rahul, the FDA cited potential for regulatory decision making following the interim look for STD , so I’m just wondering is there any potential you could file for accelerated approval if the results of the STD interim are sufficiently promising? Thanks.

[Rahul Ballal:]

Thanks Yigal, appreciate the question. Nice to hear from you. The FDA interaction around the VOC end point is slightly different than the accelerated approval pathway because the annualized rate of VOC is an approvable end point, 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 end point and getting full approval on the drug. I would just cite the experience with crizanlizumab versus global blood therapeutics. With crizanlizumab, they got a full approval on their monoclonal antibody to P-selectin versus Oxbryta, which got an accelerated approval pathway with hemoglobin, so we would be taking the approach that with a regulatory end point that is approvable, we would not need to use the accelerated approval pathway. Now that being said, because this is a Phase II study and we are hoping that it’s something more than a Phase II study, there could always be post-marketing commitments that the FDA may consider, but that would always be a discussion with them in the future.

[Yigal Nochomovitz:]

Got it, okay. Thanks. 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?

[Rahul Ballal:]

Yes, that’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?

[Ken Attie:]

Yes, thanks Rahul, and thanks for the question. Yes, 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 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.

[Yigal Nochomovitz:]

Okay, I got it. Then Rahul, for the beta cell interim, can you talk about what you’re looking to see with respect to decrease in transfusion burden from baseline, and is that something that you’re going to be attaching P-values to or is that going to be more of a descriptive statement?

[Rahul Ballal:]

Yes, it’s a good question. The analysis for beta thalassemia is analysis of 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 reblizal , 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 context, 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 one gram per deciliter or above 3% for fetal hemoglobin. 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.

[Yigal Nochomovitz:]

Okay, thanks. If I could just throw in one more on HFpEF, you mentioned the PDE9 at high expression. What percent of the HFpEF population do you believe fall into that high PDE9 expression bucket?

[Rahul Ballal:]

Yes, it’s a good question. There has been quite a bit of triangulation at our executive committee on exactly what constitutes high PDE9 expression, but roughly we think it’s about a third of HFpEF patients give or take, and so if HFpEF is anywhere from 3 million to 3.5 million, you’re looking at patients that are enrich for PDE9 in that million to sub-million category, so there are a lot of patients we think that are--have increased PDE9 expression, and of course we’re using an exclusion-inclusion criteria to help target for those.

[Yigal Nochomovitz:]

Great, thank you.

[Operator:]

Thank you. Our next question will come from Joseph Schwartz with SVB Securities. Please go ahead.

[Joseph Schwartz:]

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 un-blinding or biasing the final analysis? Did you discuss the extent to which each of these end points is objective or subjective and any of those considerations? Then I have a follow-up.

[Rahul Ballal:]

Sure, that’s a great question. I’ll turn it to Ken Attie to give some perspective on that first question. Ken?

[Ken Attie:]

Yes, thanks. It’s a good question. I think the FDA was transparent in those factors in our statistical analysis plan that were of interest and of concern to them, so they actually passed along, first of all, the recommendation to make annualized rate of VOCs our primary end point and then suggestions on how to preserve alpha by what other data can be looked at. For example, even for our safety data, we’re being very careful not to become un-blinded 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 un-blinded at any point. I think we’re in alignment with FDA on the approach to the interim analysis.

[Joseph Schwartz:]

That’s helpful, thank you. Then just to confirm, will you not be looking at the lower doses in the trial, and what’s the reasoning for that?

[Ken Attie:]

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 an 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.

[Joseph Schwartz:]

Okay, great. 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?

[Rahul Ballal:]

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. 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 300/400 mg arm that’s currently noted as the high dose arm in the Phase IIb Ardent study is the dose that patients would roll over to; in other words, the placebo patients 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 patients from the Ardent Phase IIb would roll over to that same dose in the open label extension. 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 300/400 is well tolerated and will be well tolerated.

[Joseph Schwartz:]

Great, thanks for all the color.

[Rahul Ballal:]

Thanks Joe.

[Operator:]

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.

[Rahul Ballal:]

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 Ardent 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.

[Operator:]

Ladies and gentlemen, this concludes today’s conference call. Thank you for your participation. You may now disconnect.