Enliven Therapeutics Inc (ELVN) 2020 Q3 法說會逐字稿

Good morning and welcome to the Imara Inc. Q3 earnings conference call and webcast. (Operator Instructions)

I would now like to turn the conference over to Mr. Mike Gray. Sir, you may begin.

Okay, thank you. Good morning, everyone and welcome to Imara's third-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 quarterly report on Form 10-Q 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 should change. Therefore, you should not rely on these forward-looking statements as representing our views as of any date subsequent to today.

Okay, 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 third-quarter financial results, and then we'll open the call for any questions. Rahul?

Thank you, Mike. Good morning, everyone and thanks for joining our third-quarter 2020 conference call. We have continued with what has been a productive year for Imara as we made progress across the business and accomplished several of the key objectives that we set in 2020. Importantly, in August we dosed our first patient in our Ardent Phase 2b clinical trial of IMR-687 in patients with sickle cell disease. We then followed that milestone with the first patient dosed in the Forte Phase 2b beta-thalassemia clinical trial of IMR-687 in October.

In addition to dosing patients in these Phase 2b trials, our team has made important progress in receiving regulatory approval in multiple countries to conduct these studies as well as activating multiple clinical centers to expand the global footprint of these trials. We anticipate all these efforts will further support our patient enrollment goals.

We have also continued to progress our ongoing clinical trials of IMR-687 including our Phase 2a trial of adult patients with sickle cell disease as well as our open label extension or OLE trial in adult patients with sickle cell disease.

Regarding the Phase 2a, we completed patient dosing in this study during the third quarter and are finalizing data review from this study. These steps help keep us on track to report topline data from this trial toward the end of fourth quarter of this year.

Our OLE trial is a four-year open label trial which allow [us to complete the Phase 2a] to enroll in a longer safety and tolerability study of IMR-687. During our second-quarter conference call, we reported on what we believe our two key aspects of the trial. First, we reported that we had seen increased enrollment and I'm pleased today to report that trend has continued.

We now have 23 patients enrolled up from 8 that we reported during our second-quarter conference call. All patients on the OLE are receiving 200 milligrams of IMR-687. We also noted that we plan to analyze data from OLE patients at approximately six-month intervals and presented what we believe to be important data on the first two patients that had crossed that mark. We plan to present additional data regarding these two patients at the upcoming ASH Annual Meeting in December.

We also anticipate that we will report data from 10 to 15 patients including the two previously reported patients in the first quarter 2021. (technical difficulty) the OLE patients progress beyond approximately six months of treatment.

We also made important progress on the regulatory front during the third quarter as the European Commission granted IMR-687 Orphan Disease designation for the treatment of sickle cell disease. IMR-687 had previously been granted Orphan Drug, Fast Track and Rare Pediatric disease designations from the FDA for the treatment of patients with sickle cell disease.

In addition, the FDA [granted status of] (technical difficulty) and Rare Pediatric designations for the treatment of patients with beta-thalassemia during the third quarter of 2020 having previously granted Orphan Disease designation in beta-thalassemia earlier in 2020. We believe that these are important designations as we continue the development of IMR-687 in these diseases.

In the third quarter, we also began looking at clinical outcomes beyond the facilities. It could help further differentiate IMR-687 from approved sickle cell disease therapies and therapies still in development. Specifically with the help of well-known cardiologists, we began exploring IMR-687 and its potential ability to reduce cardiovascular risk in patients with sickle cell disease.

As part of that effort, an exploratory clinical analysis was conducted by Vanderbilt University Medical Center on our Phase 2a interim data and the results were presented at the 15th Annual Sickle Cell and Thalassemia Conference or ASCAT held virtually on October 26 to October 31 of 2020.

Briefly, (technical difficulty) IMR-687 impact on NT-proBNP, a well-established marker of avascular risk. Patients treated with IMR-687 plus hydroxyurea saw a mean decrease of 27.3% in NT-proBNP level from baseline while patients on background HU alone saw a mean increase of 27% in NT-proBNP from baseline.

Furthermore, among patients with higher baseline NT-proBNP values of greater than 400 pg/ml, those who received IMR-687 plus hydroxyurea showed a mean reduction in NT-proBNP of 67.9% from baseline as compared to a mean increase of 28% from baseline in patients who received HU alone. As part of our Ardent and Forte Phase 2b studies, we have implemented NT-proBNP as a biomarker to help further explore changes in cardiac risk when patients are treated with IMR-687 on these studies.

The ASCAT presentation also contained preliminary preclinical data from studies we are conducting in models of heart failure, specifically (technical difficulty) literature suggests the inhibition of PDE9 and resulting increases in cyclic guanosine monophosphate or cyclic GMP through natriuretic peptide modulation can serve as an attractive target for the prevention and treatment of vascular disease, including HFpEF.

We are gaining confidence in this indication from our recent preclinical work. In a model that recapitulates the HFpEF phenotype, we showed that treatment of IMR-687 attenuates cardiac hypertrophy, reduces [cardiac fibrosis] and decreases cardiac inflammation in a dose dependent manner.

Lastly, we believe that there could be an improvement link between our sickle cell studies that examined cardiovascular biomarkers like NT-proBNP and future HFpEF efforts with IMR-687.

I would now like to spend a few minutes with further details on our core programs before turning the call back over to Mike to review financial results. Beginning with the Phase 2a clinical trial of IMR-687 sickle cell disease, we presented interim results in adult patients with sickle cell disease at the virtual EHA Congress in June. In the higher dose cohort, where patients started at 100 mg/day for three months and they were dose escalated to 200 mg/day for three months.

IMR-687 monotherapy showed a statistically significant increase in the cells which are red blood cells containing fetal hemoglobin as well as a dose-dependent increase in fetal hemoglobin levels. We believe that this data provides important proof of concepts for the potential of IMR-687 to be developed as an oral once-a-day disease modifying treatment for sickle cell disease.

As I mentioned earlier, we expect to report topline data (technical difficulty) from this trial late in the fourth quarter of 2020. Patients completing the Phase 2a study can enroll to (technical difficulty) open label extension trial and we are pleased to increase enrollment in this study over the last few months.

We currently have 23 enrolled patients, all of which are on the 200-milligram dose. If patients were on a stable dose of HU in the Phase 2a trial, they continue that same dose of HU for the open label extension trial.

We plan to analyze data from the OLE patient at approximately six-month intervals and presented data from two patients during our second quarter conference call. Patient 1 was originally randomized to the 100 milligram/200 milligram dose group of the monotherapy sub study of the Phase 2 clinical trial and completed one year of treatment on the OLE in June 2020. Data from this patient at the one-year mark indicated potential benefits of IMR-687 for this patient with respect to reported vaso-occlusive crises or VOCs trends and healthcare facility use and quality of life (technical difficulty).

Patient 2 (technical difficulty) entered the Phase 2a trials per the HU combination sub study and was randomized with the placebo dose group therefore never receiving IMR-687 during the Phase 2a clinical trial. Patients who had completed six months of treatment on the OLE as of August 2020, data from this patient at the six-month mark also indicated potential benefits of IMR-687 for this patient with respect to VOCs disease biomarkers.

We view data from both these patients as encouraging with regards to potential longer duration effects of IMR-687 administration in these patients. We look forward to updating data from these patients as well as several additional patients on this trial during the first quarter of 2021 and in future periods.

I would now like to turn to our Phase 2b studies of IMR-687 including our Ardent trials in patients with sickle cell disease and Forte trials in patients with beta-thalassemia. We expended substantial efforts this year in initiating these trials and are pleased to have begun dosing in patients in both these trials in recent months. In addition, we have continued to increase the number of active clinical sites and expand the global footprint in which these sites will operate.

Briefly, the Ardent Phase 2b trial, will enroll 99 patients with sickle cell disease and is a double-blind, randomized trial where patients will be stratified by use of HU as well as by region. We are utilizing weight-based dosing to maximize exposure across (technical difficulty) up to 300 milligram and 400 milligram. Recall that 200 milligram was the top dose in our Phase 2a trial and the Ardent Phase 2b test higher doses and (technical difficulty) with IMR-687.

The primary efficacy objective is to evaluate the proportion of patients with fetal hemoglobin response as there's an increase [of HbF of] 3% or greater from baseline to week-24 versus placebo. And the trial is powered for statistical significance for this endpoint.

Patients will continue on treatment through 52 weeks to provide data for planned secondary and additional endpoints, including the evaluation of IMR-687 versus placebo on VOCs HbF associate biomarkers, indices of red cell hemolysis, white blood cells adhesion, quality of life measures and NT-proBNP.

The Forte trial (technical difficulty) placebo-controlled (technical difficulty) adult patients with beta-thalassemia. The trial will evaluate the safety and tolerability of IMR-687 in approximately 60 transfusion dependent patients and approximately 60 non transfusion dependent patients. Additionally, for transfusion dependent patients, we plan to evaluate the effect of IMR-687 versus placebo or transfusion burden and the change in iron load as a result of transfusion during the trial and in comparison, to recorded rates 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 study, we plan to continue utilizing weight-based dosing with potential doses as high as 400 milligram. Safety and tolerability will be assessed after 24 weeks of dosing.

As a reminder, we plan to report formal interim analysis (technical difficulty) Forte Phase 2b trials with 33 and 30 patients respectively have completed 24 weeks of treatment. Due to COVID-19 enrollment delays we are adjusting our expected time to report interim data on these trials from our previously estimated timeline of the first half of 2021 to the second half of 2021.

I can assure you that our team is working diligently internally as well as with our CRO and clinical site to minimize delays as much as possible. For example, we continue to increase the global reach of the Ardent and Forte studies with 16 active clinical centers across multiple countries. For the Ardent sickle-cell disease study, we have seven active clinical centers in three countries and have received approval (technical difficulty)

In the Forte beta-thalassemia trial, we have nine active clinical centers in five countries with regulatory approval in 14 of 15 planned countries, with final approval expected later this month. We are continuing to activate multiple clinical centers for each of these studies across multiple countries despite COVID-19.

I will touch briefly on our pediatric development program in sickle-cell disease next. Most (technical difficulty) to accelerate our originally planned timeline to initiate this clinical program, primarily due to advancements in our oral solution formulation of IMR-687, which includes promising preclinical stability data and progress in scaling up third party manufacturing.

Oral solutions are generally preferred in younger patients and enable dosing to be more customized based on weight, age, and other parameters. We currently anticipate initiating the clinical program in the first half of 2021, approximately six months ahead of our previous expectations. We plan to conduct a single ascending dose trial and expand the program to a multiple dose extension study in adolescents and younger children.

In summary, we believe the third quarter marked another productive period for Imara, and we look forward (technical difficulty) progress.

Thank you. And I will now turn the call back to Mike to review our third-quarter financial results.

Okay, thanks Rahul. Our third-quarter results can be found in the press release we issued this morning which I'll summarize now. More details are also included within the 10-Q that we filed with the SEC earlier this morning.

R&D expenses were $9.5 million for the third quarter of 2020 as compared to $5.1 million for the third quarter of 2019. The increase of $4.4 million is primarily related to the conduct of our clinical trials and manufacturing of clinical materials related to the development of IMR-687 as well as increased personnel related and other R&D operating costs.

General and administrative expenses were $3 million for the third quarter of 2020 as compared to $1.7 million for the third quarter of 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 attributable to common stockholders was $12.4 million or $0.72 per share for the third quarter of 2020 as compared to a net loss of $6.6 million, or $9.43 per share for the third quarter of 2019. We ended the third quarter with cash, cash equivalents and investments of $96.1 million, and we expect that this will be sufficient to fund our planned operations into mid-2022.

That concludes our prepared remarks. Operator, if you could open the line for questions? Thank you.

(Operator Instructions) Matthew Harrison, Morgan Stanley

Hey good morning, everyone. This is Costa Sean for Matthew. I have a quick question on your Phase 2b study. I'm wondering in case you achieved a 3% or higher rise in fetal hemoglobin whether you have discussed with regulators, what are the next steps towards registration? For example, how much would you need to expand the study in the selected dose or may be additional studies that will be needed. Can you please provide some clarity on that? Thank you.

Sure, nice to hear from you Costa. Yes, we at our Type-B meeting in (technical difficulty) with the FDA on the interim data and they actually suggested that we should put in a formal interim analysis and we certainly believe depending on the data that we would go back to them with that interim analysis and have a discussion about a number of the different parameters you've talked about, both on the fetal hemoglobin, surrogate discussion which we had started that discussion in January. as well as some of those clinical outcome measures that we've discussed including VOCs, ACS, patient reported outcomes and others. And so, we certainly believe that (technical difficulty) a catalyst and certainly an important dataset for us to go back to the agency (technical difficulty) and have discussion with them on it.

Okay, thank you. And maybe one more quick question. Can you disclose how many patients you have dosed so far in the Phase 2b study in sickle cell or not at this point?

Yes. So, we're not guiding on that, closest to think, we've dosed several and I think it is important for us to kind of continue (technical difficulty) using the ability to increase the global footprint of the study so that in places where COVID-19 has caused shutdowns, we can leverage sites that are in other less intense COVID-19 areas to actually increase enrollment. And so, what we've really tried to convey on this call is our multiple clinical center approach to avoid slip outs.

Okay. Great. Thank you.

Joseph Schwartz, SVBLeerink

Great, thanks very much and congrats on all the progress. I was just wondering if you could talk a little bit about the data that will be seen at ASH on the first two patients to come through the open label extension? And will there be any data beyond what you've reported on your second quarter call? And what's in the abstract that's available now that we should be looking for?

Sure, Joe. Nice to hear from you. Number one, the ASH abstract has a little bit more color on opioid use and a little bit more color on how patients are feeling anecdotally. We were obviously very careful in some of our commentary on the second-quarter conference call. As stated already, (technical difficulty) data.

Number two, certainly our plan is to -- if we have incremental data on these patients when that abstract is actually presented to pull some of that data into those presentations well, and that incremental data is still on its way.

Okay, great, thanks. And then do you think that the current pandemic environment could select for any particular types of patient profiles that could results in Ardent enrollment based on criteria being meaningfully different than how you've already studied IMR-687 and monotherapy in combination with hydroxyurea, or you're not that sensitive to the types of patients coming in?

I'm just wondering because it seems like there is a baseline effect that you could get increasing efficacy with increasing baseline levels of HbF up until a point, and then may be diminishing returns after a certain point. I'm just wondering if you thought about this phenomenon whether or not the environment can select for any different types of patients and whether that matters at all?

It is actually a really good question. Thanks for asking it. And the short answer is, we sought a priority to COVID-19 about some of the selection bias. So pre-built into the protocol we have two important components. Number one, patients will be stratified by HU and stratified by region. So, no one arm will get patients with too many background HU. Patients or no one arm will get too many patients for sake of discussion from the US. And so, we think we've done a good (technical difficulty) [so we keep patients above the spectrum] of disease in sickle cell going into the different arms of the study. And so thus far I'd say there's still selection bias.

And the only other comment I'd make is that certainly we anticipate from the type of centers we pick, we will have enough patients on background HU to look at the combination effects of IMR-687 and HU and look at the monotherapy effects of IMR-687 which we've done mostly through the Phase 2 studies. So we feel pretty good about the design of the backend analytics to enable us to see (technical difficulty).

Thanks very much.

Thanks, Joe.

Yigal Nochomovitz, Citi

Great. Thanks very much and congrats on all the progress. I just had a question in terms of the interim analysis for Ardent and for Forte. Could you just talk in a little bit more detail as to what will be conveyed in that interim analysis?

Are we just going to get HbF or might we get some more additional details on secondary endpoints like vaso-occlusive crises or red cell hemolysis, white cell adhesion, quality of life, biomarkers and so forth? Could you just provide a little bit more perspective on how much we're going to learn at the interim analysis for both trials? Thanks.

(technical difficulty) Yes, the answer is, we plan because there are formal interim analyses. We'll be doing substantial database cleaning. So we'll be providing three buckets of information. The first one as you noted, HbF cells markers of hemolysis. The second one as you noted, already the selectins in related white cell adhesion markers (technical difficulty) [it would be important] in terms of my initial comments regarding going back to the FDA. It is the relevant clinical endpoints related to the first two buckets, specifically VOCs. We'll be looking at some of the PROs.

So we -- as you look at those three different buckets, we would say there would be a broad range of different markers and clinical outcome measures related to that interim analysis. And since it's formal and protocol driven, we will do the appropriate QCing and cleaning to make that a dataset that we could actually have a discussion hopefully with the FDA on it.

That will be the same case with the Forte trial just to extend your question. We'd be looking obviously carefully at transfusion burden, markers of hemolysis including hemoglobin in this case, as well as the white cell markers.

Okay thanks. I'm assuming I know the answer to this question, but just to confirm, the reason that the interim analysis is figured for 33 for the sickle-cell study, and 30 for the beta cell. Is that just based on the total enrollment being different or is there another reason?

Yes, I think it's based on enrollment. As you know, in the sickle cell study, it's approximately 99 patient study so we wanted to look at approximately a third of the patients which we thought would be patients both in the lower dose group as well as potentially in the higher dose group. The same goes for the thalassemia study.

That study is 120 patients. But remember, it's a study of two different groups: transfusion dependent patients numbering about 60, non-transfusion dependent patients numbering about 60. So that the 30 number would be to look at approximately half of each of those subgroups for the 120 total patients.

Okay, great. Thank you very much.

Thanks, Yigal.

And at this time, there are no questions.

Okay. Thank you.

Sorry, I was on mute. Okay, if there's no more questions, we can wrap up the call.

Thanks, everyone.

This concludes today's conference. You may now disconnect.