Enliven Therapeutics Inc (ELVN) 2020 Q4 法說會逐字稿

Ladies and gentlemen, thank you for standing by, and welcome to the IMARA Inc. Fourth Quarter Earnings Conference Call and Webcast. (Operator Instructions) I would now like to hand the conference over to your speaker today, Mr. Mike Gray. Thank you. Please go ahead, sir.

Okay. Thank you. Good morning, everyone, and welcome to IMARA's Fourth Quarter 2020 Conference Call. 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 will be filed with the SEC this morning as well as any other filings that we 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. I'll return following Rahul's discussion to review our financial results, and we'll then open the call for any questions. Rahul?

Thank you, Mike. Good morning, everyone, and thank you for joining. 2020 was a productive year for IMARA, and we made progress in building our business and accomplishing several of our key objectives. This momentum is carried into the early part of 2021 and we are looking forward to a robust year of data readouts in both our sickle cell and beta-thalassemia programs. The start of 2020 is highlighted by our initial public offering in March, in which we raised gross proceeds of $86.5 million.

Throughout the course of 2020 and into the early months of 2021, we've continued to build the organization, including expanding our leadership and broader development teams with key hires during the last several months, including Lyn Hopkinson as our SVP of Regulatory; and Ken Attie as our Chief Medical Officer. Lyn joined us from Vertex Pharmaceuticals where she served as Global Head of Regulatory Strategy for the Cystic Fibrosis Program as well as Head of North American Regulatory Strategy for several clinical development candidates, including the CRISPR/CAS9 program with sickle cell disease and beta-thalassemia.

Ken joined IMARA in January and brings more than 30 years of experience within academia and biotech, most recently at Acceleron Pharma, where he led Global Clinical Development efforts that led to recent FDA and EMA approvals of luspatercept, known as REBLOZYL, which is a new treatment for patients with rare anemias, including beta thalassemia. We've also expanded the company's headcount, particularly in key development areas, such as clinical, regulatory, quality and technical operations.

Collectively, this organizational growth has enabled our continued advancement of IMR-687, including initiation of our Ardent Phase IIb clinical trial in sickle cell disease, and our Forte Phase IIb clinical trial in beta thalassemia. The Forte trial reached an important milestone earlier in 2021. Data Monitoring Committee approved opening the higher dose arm. Patients will receive doses of IMR-687 up to 400 milligrams. We anticipate that the Drug Monitoring Committee will meet later in March to evaluate opening the higher dose arm in the Ardent sickle cell trial. Both the Ardent and Forte Phase IIb studies, we continue to expect reporting interim data in the second half of 2021.

We also completed our Phase IIa clinical trial of IMR-687 sickle cell disease and reported topline results from that trial in January. We are continuing to study a subset of these Phase IIa patients in an open-label extension or OLE clinical trial. We increased enrollment in the OLE trial from 2 patients in June of 2020 to 24 patients at the end of 2020. And last August, we presented case narratives of the first 2 patients in the OLE trial that completed at least 6 months of IMR-687 treatment. Today, we disclosed updated data for these 2 patients as well as a broader group of patients from the OLE trial in each case demonstrating absolute increases in HbF and F-cells compared to baseline when patients were on a higher dose of 200 milligrams.

We believe these results start to show how higher doses of IMR-687 could confer additional benefit to patients. We also held what we believe to be an important Type C meeting with the FDA in December of 2020 regarding our planned pediatric study in sickle cell disease, during which the agency expressed alignment with the overall clinical trial design and indicated the study could be submitted with the adult study data in the same NDA. We believe that this is an important step forward as the pediatric population represents a significant portion of the overall sickle cell population. In addition, in 2020, we expanded the potential of IMR-687 through completion of preclinical studies in heart failure with preserved ejection fraction models, and we are currently developing a phase II protocol for potential clinical development investigation.

Lastly, we also expanded our advocacy and patient community efforts, highlighted by our 2020 launch of the Real Impact Grants initiative to support local community-based organizations, serving patients and families affected by rare blood disorders. We plan to continue to expand our advocacy efforts including the Real Impact Grants program in 2021. We believe that our organizational build and clinical trial execution in 2020 will result in important clinical data, including the new early data that we will discuss this morning being released during 2021.

I would now like to spend a few minutes with further details on our core programs before turning the call back to Mike to review financial results. I'll begin with our Phase IIa trial in OLE. In January 2021, we disclosed topline results of this program. As a reminder, in the second quarter of 2019, we amended the trial protocol for the monotherapy substudy to create population A1, which was comprised of patients who either received placebo or IMR-687 at a once-daily dose of 100 milligrams through 4 weeks and then 200-milligram for an additional 20 weeks. At the same time, we amended the trial protocol for the combination substudy to create population B1, which was comprised of patients who received either placebo or IMR-687 once-daily at 50-milligram in addition to standard of care hydroxyurea or HU with escalation after 4 weeks, 200-milligram of IMR-687 for an additional 20 weeks.

None of the patients enrolled in Pop A1 or B1 were included as part of the second interim analysis, which we previously reported in August 2019. Overall, the Phase IIa demonstrated that IMR-687 was well tolerated as a monotherapy and in combination with HU at all dose levels. A 30% lower rate of vaso-occlusive crises or sickle cell pain crises as part of the safety analysis was observed in the population A group when compared to placebo. Furthermore, the rate of VOC related hospitalizations was lower in the population A1 group when compared to placebo. There were no meaningful differences in VOCs or VOC-related hospitalizations between the population B1 group and placebo. Biomarker results for population A1 showed minimal changes in F-cells, HbF levels and total Hb from baseline through week-24. Biomarker results in population B1 treated patients showed an overall increase in F-cells and HbF levels from baseline of week-24, while Hb levels do not meaningfully change.

I'll now move to the open-label extension study. This is data that we released today. We believe that this new data reestablishes HbF and F-cell activity treatment with 200 milligrams of IMR-687 after seeing variable results for these biomarkers in the Phase IIa trial. As a reminder, the 4-year OLE trial allows patients from the Phase IIa program to enroll in a long-term safety and tolerability study of IMR-687, following completion of the Phase IIa. The OLE trial was initially designed for patients who were administered a daily dose of 100-milligram of 687. And in the second quarter of 2020, a protocol amendment increased the daily dose to 200-milligram. Patients from the combination sub-study continue to receive the same dose of HU that they received while they're on the Phase IIa and throughout the duration of the OLE trial.

Based on the tolerability profile of IMR-687 observed thus far, the Safety Review Committee has approved a dose escalation in the OLE trial to a minimum daily dose of 300 milligram, up from 200 milligram, with certain patients being eligible for a daily dose of 400 milligrams based on their weight. This weight-based approach is similar to our ongoing Ardent Phase IIb clinical trial for sickle cell disease. The Safety Review Committee approved these dose adjustments, contingent upon the independent Data Monitoring Committee opening up the higher dose arm in the Ardent Phase IIb trial in sickle cell. We expect the Ardent Phase IIb DMC to make a decision on opening this higher dose in March 2021, paving the way for the OLE dose adjustment via protocol amendment.

In the OLE, we conducted a preliminary review of 24 patients as of December 31, 2020. Overall, data from the 24 patients enrolled in the OLE trial demonstrate that IMR-687 was well tolerated and had a safety profile similar to that observed in the Phase IIa clinical trial. As of December 31, 2020, approximately 12 of these patients had evaluable PD biomarker data for at least 4 months of treatment on the OLE trial. We organized the patients with evaluable PD biomarkers into 2 subgroups: the first subgroup, which are treatment-interrupted patients was comprised of approximately 8 patients who initiated treatment on the OLE trial after a substantial break from the Phase IIa, specifically more than 12 weeks after completing treatment; second subgroup, which are direct rollover patients, is comprised of approximately 4 patients who initiated treatment on the OLE trial right after the Phase IIa specifically within 12 weeks of completing treatment.

Biomarker results demonstrated absolute increases in both HbF and F-cells after 4 months of treatment in both the treatment-interrupted subgroup and the direct rollover subgroup. Specifically, there was a mean absolute increase of the HbF of 1.7% in the treatment-interrupted subgroup and a mean absolute increase of F-cells of 5.9%. In the direct rollover subgroup, there is a mean absolute increase of HbF of 2.3% and a mean absolute increase in F-cells of 10.2%. There were minimal changes in total Hb in both subgroups. Patients in the treatment-interrupted subgroup also demonstrated improvements in markers of hemolysis after 4 months of treatment, whereas the direct rollover subgroup showed variable changes in these measures.

Further details on biomarker results from the OLE trial are described in our annual report on Form 10-K, which we filed this morning with the SEC. Looking ahead, we are in the process of analyzing outcomes with respect to VOCs from the OLE trial and expect to report this information at future medical meetings.

I'll briefly now provide an update on 2 case narratives that we previously reported in the third quarter of 2020 as well as at the American Society of Hematology Annual Meeting in December of 2020. Both patients in these case narratives have continued to see absolute increases in HbF from baseline of greater or equal to 4.5% as well as absolute increases in F-cell measurements. Patient 1 is part of the Pop A monotherapy substudy of the Phase IIa trial and enrolled in the OLE as a direct rollover patient. As of December 31, 2020, patient 1 had been on the OLE trial for approximately 18 months and on IMR-687 for approximately 24 months and has shown in continued increase in levels of HbF with an absolute increase over baseline of 4.8% after 18 months of the OLE trial. Furthermore, this patient has seen increased F-cells compared to baseline as well as improvements in several SCD disease biomarkers.

In addition, a comparison of VOC data for the 24-month period that the patient has been on IMR-687, that 6 months on the Phase IIa and 18 months on the OLE versus data from a retrospective review of the patient's medical records for the 24 months prior to initiation of IMR-687 indicate additional VOC episodes. In the 24-month period on IMR-687, the patient-reported 20 VOCs as compared to 50 reported -- 55 reported VOCs in the 24-month period prior to IMR-687 administration, a 64% reduction in the rate of VOCs.

Patient 2 was part of the HU combination sub-study in the Phase IIa trial, was randomized to the placebo dose group and, therefore, never received IMR-687 during the Phase IIa. The patient started the OLE trial 14 months after completing the Phase IIa trial and is a treatment-interrupted patient. The patient has remained on stable dose of HU during this interim period and while on the OLE trial. As of December 31, 2020, we had data on this patient through 8 months of treatment, reflecting the most recent OLE visit. Patient #2 has shown a sustained increase in levels of HbF, with an absolute increase over baseline of 4.5% after 8 months on the OLE trial and an increase over baseline in F-cells; however, this patient has also showed increasing variability of their SCD biomarkers versus the original case narrative. In addition, a comparison of VOC data for patient #2 for the 8-month OLE trial period versus data from a retrospective review of the patient's medical records for the 8-month period prior to the initiation of the OLE trial, indicates potential benefits of IMR-687 being administered in combination with HU. In the 8-month period on IMR-687, a patient had a 69% reduction in the rate of reported VOCs, 16 to 5 events as compared to the 8-month period prior to IMR-687, and while on HU alone.

We caution that the case narratives reflect data from only 2 patients at specified intervals in the OLE trial and reported VOC comparisons involve retrospective reviews of the patients medical records. As a result, we cannot assure you that future data on these patients will continue to be favorable or that data on other patients in the OLE trial will demonstrate potential benefit of IMR-687.

I would now like to turn to our 2 Phase IIb clinical trials of IMR-687, including our Ardent trial in adult patients with sickle cell disease and Forte trial in adult patients with beta thalassemia. We expended significant effort last year in initiating these trials, and we continue to expect to report interim data in the second half of 2021. We continue to expand the global footprint for both studies with 22 and 36 active clinical centers for Ardent and Forte, respectively, across multiple countries and with continued near-term activation of the digital centers. The Ardent Phase IIb trial will enroll approximately 99 patients with sickle cell disease, that is a double-blind, randomized trial, where patients will be stratified by use of hydroxyurea as well as by region. We are utilizing weight-based dosing to maximize exposures across a wide range of patient weights with the initial lower dose being administered at either 200 or 300 milligram.

We currently anticipate that the Data Monitoring Committee will make a decision later this month whether to open the higher dose arm of the study, which would provide for doses of up to 400-milligram for 52 weeks. Recall that we utilized doses of 50 to 200 milligrams in our Phase IIa clinical trial in a titrated manner through 24 weeks. So this Phase IIb trial being run at both higher doses and longer duration of treatment with IMR-687. The planned primary efficacy objective is to evaluate the proportion of patients with fetal hemoglobin response, defined as an increase of HbF 3% or greater from baseline to week 24 versus placebo, and the trial is powered for statistical significance at this endpoint.

Patients will continue on treatment for 52 weeks to provide data for planned secondary and additional endpoints, including the evaluation of IMR-687 versus placebo on VOCs, HbF associated biomarkers, indices of red cell hemolysis, white blood cell adhesion markers and quality of life measures. The Forte trial is a randomized, double-blind, placebo-controlled Phase IIb trial in adult patients of beta thalassemia. The trial will evaluate the safety and tolerability of IMR-687 in approximately 60 transfusion-dependent patients and approximately 60 non-transfusion patients. For transfusion-dependent patients, we plan to evaluate the effects of IMR-687 versus placebo on transfusion burden and the change in iron load as a result of transfusion during the trial and in comparison to the historical rate in the 12 weeks prior to initiation.

The Forte trial will also examine additional exploratory efficacy endpoints as well as safety and PK endpoints. Like our Ardent Phase IIb trial for sickle cell, we plan to utilize weight-based dosing with potential doses as high as 400 milligrams per day. I'm pleased to announce that the independent Data Monitoring Committee recently opened the higher dose arm for this trial, providing for doses of up to 400 milligrams, and we have already enrolled several patients since this group was opened. Safety and tolerability of IMR-687 will be assessed after 24 weeks of dosing. We currently anticipate initiating our pediatric clinical program of IMR-687 on sickle cell disease in the first half of 2021. We expect to conduct a Phase I/II clinical trial in adolescents between 12 to 17 years old comprised of the single ascending dose phase followed by a 36-week multiple dose expansion phase.

In December of 2020, we held a Type C meeting with the FDA during which the agency expressed alignment with this overall clinical trial design and indicated the study could be submitted with the adult study data in the same NDA, view this as an important advancement for the Pediatric Development Program. In summary, we believe the fourth quarter marked another productive period for IMARA. We look forward to updating you on our further progress, multiple data readouts planned in 2021. Thank you.

And I will now turn the call back to Mike to review our financial results. Mike?

Okay. Thanks, Rahul. Our fourth quarter and year-end 2020 results can be found in the press release that we issued this morning, and I'll summarize those now. More details are also included in the 10-K that we filed with the SEC also earlier this morning.

R&D expenses were $32.2 million for 2020 as compared to $19 million for 2019. The increase was primarily related to the development and manufacturing of clinical materials, clinical research and oversight of our clinical trials and investigator fees related to the development of IMR-687 as well as increased personnel-related and other R&D operating costs.

G&A expenses were $9.5 million for 2020 as compared to $5.1 million for 2019. The increase was primarily due to increased personnel-related and other G&A costs as a result of operating as a public company. Net loss attributed to common stockholders was $49.2 million or $3.53 per share for 2020 as compared to a net loss of $23.5 million or $33.40 per share for 2019. We ended 2020 with cash, cash equivalents and investments of $88.2 million, and we expect that this will be sufficient to fund our planned operations into mid-2022.

That concludes our prepared remarks. We'd like to open the line for questions. Operator?

(Operator Instructions) Your first question comes from the line of Matthew Harrison from Morgan Stanley.

I guess, two for me. First one, as you think about the 2 patients where you gave sort of the patient histories and all the information, how would you think about those as being typical or atypical patients we might see in the Phase IIb? And I guess what I'm really asking is, do you think the doses that they were receiving because of the weight-based dosing and other factors represent something that you're going to see in Phase IIb? Or do you think people could get even higher doses on average than them? And then secondly, could you maybe just talk about how pace of enrollment and other factors are going on in Phase IIb?

Thanks, Matt, for asking the question. So in terms of the 2 patients, if you look at their overall weights and where they would be, if you were to put them in the Phase IIb, both of them would be at the higher doses. Of course, depending on where they're randomized to, they would ultimately be in doses that would be in the 300-milligram range. So from a mg per kg exposure, I would expect those patients very equivalent to go up in dose on the Phase IIb. In addition, again, these patients are on (inaudible) trial so these are monitored much more carefully in the Phase IIb to get data from them every month. So there's kind of additional data points on these patients that you get, obviously, in Phase IIb of higher dose.

To answer your second question, the approach that we took for the Phase IIb studies, both in Ardent and Forte have paid off for us. And what I mean by that is we have decided that it was important to go broad in terms of the number of countries, so approximately 14 to 15 countries in each of those studies and wide in terms of the number of sites. Approximately 50 sites ultimately will be activated for those 2 studies, respectively. And what we've seen is in areas where COVID is not as prevalent as example, Israel, for example, we've seen increased enrollment in those areas. And in areas where COVID is prevalent, case in point of Italy, we've continued to see delays.

And so I would say what's nice about our approach is that we are leaning on the countries that have patients coming in. We've organized around those patients to ensure that they have access to the centers, access to local labs, access to home health care if needed and also ensure that as those sites that are COVID contingent, as they open up, we're one of the first groups in there. As an example, the U.K. should be opening up for both sickle cell and beta thalassemia in the coming month, and we have all of our (inaudible) in order from approvals to site contracts, and we're ready to go.

Your next question comes from the line of Yigal Nochomovitz from Citi.

This is Carly on for Yigal. In the data you presented from the OLE, are you able to comment on how many of the 12 patients were receiving background hydroxyurea? And understanding it's small numbers, but were there any trends you observed with respect to the increases in HbF and F-cells in patients on 687 alone versus on top of background HU?

Thank you for the question. So we have 24 patients enrolled, 22 ongoing. The breakdown between HU and non-HU is 17 and 7. 7 on HU. And we have not done the analysis to see if patients on the HU background are benefiting more, but we do plan to keep monitoring this part in our medical meeting in the future including covering some of the patient journey experiences from Phase IIa study into the OLE and specifically looking at that comparison, whether or not they're on HU, to your question, but also what dose of IMR-687 they were on.

Okay. Great. And assuming you get the green light to dose escalate up to 300 or 400 milligrams in the OLE, just wondering when we might expect to see updated data that would include those higher doses, specifically trying to figure out if that would be potentially before the interim data from the Phase IIb or would it likely be after that?

That's a good question. So if we get that approval, obviously, contingent on the DMC from the Phase IIb, we'll immediately amend the protocol. 80% of our patients are in the U.K. and if you just follow the timelines from protocol and then into implementation, you're probably starting to look at data at the end of this year around those OLE patients at a higher dose. So our planned interim analysis for the Ardent Phase IIb studies also in the second half of this year, and so we see data around the same time, both the OLE patients as well as the Ardent Phase II patients.

Okay. Perfect. And last question from us is, just in Phase IIa, I know you've faced some challenges due to COVID with missed visits specifically in the placebo arm. So wondering if you could talk a little bit about how you've accounted for potential COVID impact in your powering assumptions for the Phase IIbs or just anything you're seeing with respect to missed visits?

Yes. It's a great question. So we've taken a different approach for the Phase IIb that allows us to avoid those issues that we encountered in Phase IIa. And with all kind of -- all things being equal, the Phase IIa enrolled the A1 population between November of 2019 through August of 2020. So it was kind of an acute phase of COVID, where U.K. was locked down a number of times and certainly in the U.K., in that particularly IIa trial was really driving our patient enrollment in patient dataset.

As I said earlier, I think what we've done in the Phase IIb is accounted for some of that risk by having a number of sites across the world, up to 50, that will be activated sickle cell trial. And allowing the sites that are open and having patients come in, taking extra precautions with those patients by enabling home health visits, local lab analysis as well as tracking those patients very carefully. And so that just from an organizing principle is a completely different approach. And more importantly, is a distributed approach across the world versus necessarily relying just on the U.K., which in some ways has been hit the hardest with the COVID waves as well as the variants. And so in conclusion, we feel pretty confident that we won't have those missing visits in the same way we did in the IIa.

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

This is Kelly Girskis on for Joe. We were hoping you might be able to provide additional color on the 12 OLE patients reported today. How many of those were able to clear that 3% threshold on HbF?

So we are providing all the spaghetti plots in our corporate deck. There were a number of patients that cleared that bar and instead of kind of giving you color over the phone, happy -- corporate deck will provide the spaghetti plus of each individual patient, but there is certainly a few.

Great. We will definitely look at those slides. And maybe given the Phase IIa data and OLE data, they -- and what's known about red blood cell turnover, what gets you confidence that the 6-month interval you'll be looking at for Ardent will be enough time to see IMR-687's impact on HbF and F-cells?

Yes it's a good question. There's a number of things that give me confidence in that data readout. Number one, in the OLE patients at 200-milligram, we're already seeing at month 4, almost a 2% increase in the treatment-interrupted patients and over a 2% increase in the patients that are continuing on. And so for us, I think, fundamentally, as we think about both the PK/PD modeling, we're doing internally as well as where we think the exposure response data will ultimately lie, higher doses of IMR-687 are going to confer additional benefit. And remember, the Phase IIa was a titrated dose design where patients on background HU started at doses as low as 50 milligram. In our Phase IIb design, a patient on HU will start at as low as 200 milligram, so 4x higher than where the IIa started and potentially as high as 400 milligram, 8-fold higher than where they started in Phase IIa.

Similarly, for the monotherapy patients that started at 100-milligram in the Phase IIa, they'll be starting at doses of 200, 300 or potentially 400-milligram Phase IIb, 4-fold higher than the Phase IIa. So there is a multiple fold increase in dose. And that 6-month time point allows those patients to stay on the same dose for the full 6 months as opposed to be titrated into Phase IIA. And so our confidence level, when you just think about the dose paradigm is high. And if you think about the PK/PD modeling, as you get to those higher doses, you get trough concentration from IMR-687 that gives us confidence that we're inhibiting the PDE9 degradation mechanism for the full 24-hour period at the 400-milligram dose.

And so when we kind of juxtapose both the increased dose, certainly, the time over the IC90 or concentration trough levels as well as the fact that the study is of 1 year study in addition to that 6 different endpoints, confidence level across all of those changes in the Phase IIb makes us feel that that endpoint will be hit.

There are no more questions at this time. Presenters, please continue.

Great. Thank you so much for your time and attention this morning. We look forward to our additional data readouts in 2021. And have a very good day.

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