Q1 2021 Imara Inc Earnings Call

Ladies and gentlemen, thank you for standing by and welcome to the Emera Q1 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 keypad.

Operator: Ladies and gentlemen, thank you for standing by, and welcome to the Amara, Inc. Q1 Earnings conference call and webcast. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press Star 1 on your telephone keypad. If you require any further assistance, please press Star then 0. I would now like to hand the conference over to your speaker today, Mike Gray. Thank you, and please go ahead, sir.

If you require any further assistance. Please press star then zero.

I would now like to hand, the conference over to your Speaker today, Mike Great. Thank you and please go ahead Sir.

Okay. Thank you and good morning, everyone and welcome to <unk> first quarter 2021 conference call I'd.

Mike Gray: Okay, thank you, and good morning, everyone, and welcome to OMARA's first quarter 2021 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 that we filed with the SEC this morning, as well as any other filings that we make with the SEC.

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 that we filed with the FCC. 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 day well.

Mike Gray: 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.

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.

Mike Gray: With that, I'll now turn the call over to Amar's president and CEO, Rahul Balal. I'll return following his discussion to review our first quarter financial results, and we'll then open the call for questions.

With that I'll now turn the call over to <unk>, President and CEO Rahul ball I'll return following where holds discussion to review our first quarter financial results and we'll then open the call for questions Rahul Thanks, Mike.

Rahul Balal: Thanks, Mike. Good morning, everyone, and thank you for joining us on this morning's call. The start of 2021 has been a productive period for Mara and marks the beginning of a data-rich year for both our sickle cell and beta thalassemia clinical programs. We have made substantial enrollment progress in our Phase IIb clinical trials for patients with sickle cell disease and beta thalassemia, which are designed to test higher doses of IMR687. We are now conducting these studies at 75 clinical trial sites across 20 countries and have fully enrolled the transfusion-dependent beta thalassemia arm of the FORTE trial, closing new screening activities for that subgroup.

Good morning, everyone and thank you for joining this morning's call.

The start is 2021 has been a productive period for Mara and marks the beginning of a data rich year for both our sickle cell and betas house EMEA critical programs.

We have made substantial enrollment progress in our phase two b clinical trials for patients with sickle cell disease, and beta thalassemia, which are designed to test higher doses of INR 687.

We are now conducting these studies at 75 clinical trial sites across 20 countries and have fully enrolled the transfusion dependent beta thalassemia arm of the Forte trial closing new screening activities for that subgroup.

Rahul Balal: We remain on track to complete the protocol-driven interim analyses from the Arden and Forte trials and expect to report interim data in the second half of 2021 for both these programs. We also expect to report data from the primary analyses for both these studies in the first half of 2022 and data from the final analysis in the second half of 2022. This progress is a testament to the entire company across every function, and I'm appreciative and excited by this moment.

We remain on track to complete the protocol driven interim analyses from the <unk>.

And for T trials.

And expect to report interim data in the second half of 2021 for both these programs.

Also expect to report data from the primary analysis for both these studies in the first half of 2022 and data from the final analysis in the second half of 2022.

This progress is a testament to the entire company across every function and I'm appreciative and excited by this momentum.

Importantly, following the recommendation of independent data monitoring committees, we have opened the higher dose treatment arms in both phase two b clinical trials and are currently testing I am on succeed seven daily doses of up to 400 milligram.

Rahul Balal: Importantly, following the recommendation of independent data monitoring committees, we have opened the higher dose treatment arms in both phase 2b clinical trials and are currently testing IMR 687 at daily doses of up to 400 milligrams. With the high-dose open in both trials, three out of every four patients are being randomized to an active treatment arm, with the high-dose being enriched in a two-high-dose, one-low-dose, one- Both interim readouts in the second half of 2021 will involve patients from the high-dose arm.

With the high dose open in both trials three out of every four patients are being randomized to an active treatment arm with the high dose being enriched in a too high dose one low dose one placebo schema, which is a two to one to one randomization.

Both interim readout in the second half of 2021 we'll have patients from the high dose arm.

Rahul Balal: In addition to our progress in the Phase 2B clinical trials, we reported top-line data from our Phase 2A clinical trial of IMR687 in sickle cell disease, in which IMR687 was well-tolerated and in which we saw promising reductions in the rate of vaso-occlusive crises, or VOCs, with variable changes in HBF and F cells. We also reported preliminary data from our Phase IIa open-label extension trial, which showed that IMR687 at doses of 200 milligrams was well-tolerated and in which increases in fetal hemoglobin and F cells were observed.

In addition to our progress in the phase two B clinical trials, we reported top line data from our phase Iia clinical trial of INR 687 in sickle cell disease in which I'm, a 67 was well tolerated and in which we saw promising reductions in the rate of basal occlusive crises or B O S. He with variable changes.

H B S. N S cells. We also reported preliminary data from our Phase Iia open label extension trial, which showed that INR 687 at doses of 200 milligram was well tolerated and in which increases in fetal hemoglobin F cells were observed we plan to present comprehensive V O.

Rahul Balal: We plan to present comprehensive VOC data from the larger 93 patient Phase IIa parent study, as well as additional data from the ongoing open-label extension trial, at the European Hematology Association, or EHA, 2021 virtual Congress in June. We've also been working to explore the therapeutic potential of IMR687 in additional indications. We're pleased to have successfully completed preclinical studies of IMR687 in heart failure with preserved ejection fraction, or HEPF, and have submitted an abstract to an upcoming cardiovascular meeting later in 2021.

Data from the larger ninety-three patient phase Iia parents study as well as additional data from the ongoing open label extension trial at the European Hematology Association or <unk> 2021 virtual Congress in June.

We've also been working to explore the therapeutic potential of <unk> 67 in additional indications. We're pleased to have successfully completed preclinical studies of INR 607 in heart failure with preserved ejection fraction or have passed and have submitted an abstract to the upcoming cardiovascular meeting later in 2021.

Rahul Balal: We continue to formulate a protocol for a proof-of-concept study with our clinical advisory board, which is made up of leading cardiologists. Lastly, in March, we launched the second annual Real Impact Grants Program to support local community-based organizations serving patients and families affected by rare blood disorders. 2020 marked an incredibly difficult time for those living with sickle cell disease and beta thalassemia, and many of these challenges remain as we move through 2021

We continue to formulate a protocol for a proof of concept study with our clinical Advisory Board, which is made up of leading cardiologists.

Lastly in March we launched the second annual real impact grants program to support local community based organizations, serving patients and families affected by rare blood disorders.

'twenty 'twenty marked an incredibly difficult time for those living with sickle cell disease, and beta thalassemia and many of these challenges from me as you move through 2020 one.

Rahul Balal: We expect to increase grant funding under the Real Impact Program from $125,000 in 2020 to up to $150,000 in 2021 across three key areas, including Social Determinants of Health, including COVID-19 relief, virtual support program, and community-based organization or CBO capacity.

Back to increased grant funding under the real impact program from 125000, 2022 up to 150000 in 2020, one across three key areas, including social determinants of health, including COVID-19 relief virtual support program.

And community based organization or C. B O capacity we.

Rahul Balal: We continue to strive to put our patients first, and the Real Impact Grant Program is a key embodiment of our core mission. Awards will be made in June, and we look forward to supporting the 2021 recipients and their ongoing commitment to the patient community. I would now like to spend a few minutes providing further details on our core programs before turning the call back to Mike to review financial results.

We continue to strive to put our patients first and the real impact Grand program is a key embodiment of our core mission. We expect awards to me made in June and we look forward to supporting the 2021 recipient and their ongoing commitment.

To the patient community.

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 an overview of recent progress from our phase two b clinical trials of INR 687 <unk>.

Rahul Balal: I'll begin with an overview of recent progress from our Phase IIb clinical trials of IMR687, including the ARDENT trial in adult patients with sickle cell disease and the FORTE trial in adult patients with beta thalassemia. We continue to expand the global footprint for our Arden and Forte studies with 35 and 40 active clinical centers, respectively, and across 20 countries with additional near-term activation of centers. This clinical operations effort has resulted in accelerated enrollment in both the ARDAT and Forte trials, and we have now fully enrolled the transfusion-dependent beta thalassemia arm of the Forte trial, having randomized over 60 patients in this arm.

Including the art in trial in adult patients with sickle cell disease, and the four T trial in adult patients with beta thalassemia.

Continue to expand the global footprint for Arden and 40 studies with 35, and 40 active clinical centers, respectively and across 20 countries with additional near term activation of centers disc.

This clinical operations effort has resulted in accelerated enrollment in both the Rd and four T trials and we now have fully enrolled the transfusion dependent beta thalassemia arm on the four T trial, having randomized over 60 patients in this arm.

As mentioned earlier, we remain on track to complete the respective protocol driven interim analyses for the sales to be trials in the second half of 2021 and I'm pleased to reaffirm this guidance from earlier this year.

Rahul Balal: As mentioned earlier, we remain on track to complete the respective protocol-driven interim analyses for these Phase IIb trials in the second half of 2021, and I'm pleased to reaffirm this guidance from earlier this year. With increasing enrollment, we now expect data from the primary analysis from each of these trials in the first half of 2022, and data from the final analysis from each of these trials in the second half of 2022.

With increasing enrollment we now expect data from the primary analysis from each of these trials in the first half of 'twenty 'twenty, two and data from the final analysis from each of these trials in the second half of 'twenty 'twenty two.

This is a significant accomplishment and demonstrates our team's ability to effectively conduct these studies and the backdrop of our go global plant pandemic and I'd like to take this opportunity to thank them for their tireless commitment studies.

Rahul Balal: This is a significant accomplishment and demonstrates our team's ability to effectively conduct these studies in the backdrop of a global pandemic. And I'd like to take this opportunity to thank them for their tireless commitment to these studies.

During the first quarter separate independent data monitoring committees for the art. It in four T trials recommended opening of the higher dose INR 67 treatment arm in each of these studies following review of the available safety and Tolerability data. These additional arms were pre specified in the two protocols.

Rahul Balal: During the first quarter, separate, independent data monitoring committees for the ARDAN and FORTADE trials recommended opening of the higher dose IMR-687 treatment arm in each of these studies following review of available safety and tolerability data. These additional arms were pre-specified in the two protocols, and enrollment is proceeding in each study at the higher dose, which is one daily dosing of 300 milligram or 400 milligram based on patient weight. IMR 687's lower dose, which is a once daily dose, is 200 mg or 300 mg based on patient weight or placebo.

And enrollment is proceeding in each study at the INR 67, higher dose, which is once daily dosing of 300 milligram or 400 milligram based on patient way.

INR 687 overdose, which is once daily doses 200 milligram or 300 milligram based on patient weight or placebo.

As a reference point.

Our recently completed phase Iia clinical trial in sickle cell disease started as low as 50 milligram per day, an escalated sequentially 200 milligram or 200 milligram per day over 16 to 24 weeks dosing in the phase two b clinical trials is substantially higher both at the starting dose and.

Rahul Balal: As a reference point, our recently completed Phase IIa clinical trial in sickle cell disease started as low as 50 mg per day and escalated sequentially to 100 mg or 200 mg per day over 16 to 24 weeks.

Through the treatment period, starting as high as 400 milligram on day, one and without a dose titration.

Rahul Balal: Dosing in the Phase IIb clinical trials is substantially higher both at the starting dose and through the treatment period, starting as high as 400 mg on day one and without a dose titration. As a reminder, the ARDENT Phase IIb trial will enroll approximately 99 adult patients with sickle cell disease and is a double-blind, randomized trial where patients will be stratified by their use of hydroxyurea as well as by region. The planned primary efficacy objective is to evaluate the proportion of patients with fetal hemoglobin response, defined as an increase of HPF or 3% or greater from baseline to week 24 versus placebo, and the trial is powered for statistical significance for this endpoint.

As a reminder, the.

Art and phase <unk> trial will enroll approximately 99 adult patients with sickle cell disease and is a double blind randomized trial, where patients will be stratified by use of hydroxyurea as well as by region.

Planned primary efficacy objective is to evaluate the proportion of patients with fetal hemoglobin response defined as an increase of H P F for 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 key secondary endpoint evaluating INR 67 versus placebo on annualized the ocs.

Rahul Balal: Patients will continue on treatment through 52 weeks to provide data for planned secondary and additional endpoints, including the key secondary endpoint evaluating IMR-687 versus placebo on annualized VOCs. Other secondary endpoints include time-till-first VOC, HBF-associated biomarkers, indices of red cell hemolysis, white blood cell adhesion, and quality-of-life measures. The 4-day trial will evaluate safety and tolerability of IMR687 in approximately 60 transfusion-dependent patients and approximately 60 non-transfusion-dependent patients. For transfusion-dependent patients, we plan to evaluate the effects of IMR687 versus placebo on transfusion burden, pre-transfusion hemoglobin, and the change in iron load as a result of transfusions during the trial and in comparison to historical rates in the 12 weeks prior to study start The Forte trial will also examine additional exploratory endpoints, as well as safety and PK endpoints. Safety and tolerability of IMR-687 will be assessed after 24 weeks of dosing.

Other secondary endpoints include time till first POC.

H B S associated Biomarkers indices of Red cell hemolysis, white blood cell adhesion and quality of life measures.

For T trial will evaluate safety and Tolerability of INR 607, and approximately 60 transfusion dependent patients and approximately 60 non transfusion dependent patients.

For transfusion dependent patients we plan to evaluate the effects of INR 67 versus placebo on transfusion burden.

Pre transfusion hemoglobin and the change in Ireland iron load as a result of transfusion during the trial and in comparison to historical rate and the 12 weeks prior to study start.

The four T trial will also examine additional exploratory endpoint as well as safety and PK end points safety and Tolerability of IMI RCC Saturn It will be assessed after 24 weeks of dosing.

I'll next turn very briefly to our phase Iia clinical trial, we disclosed top line results in January and which I'm Ars 67 was well tolerated and in which promising reduction in the range of visa occlusive crises and variable changes in certain biomarkers, including H P. F F cells Burbs.

We look forward to presenting comprehensive V O see data from this completed ninety-three patient placebo controlled phase Iia clinical trial at <unk> next month as V. O sees remain an important clinical outcome for this program.

Rahul Balal: I'll next turn, very briefly, to our Phase IIa clinical trial. We disclosed top-line results in January in which IMR687 was well-tolerated and in which promising reductions in the rates of vaso-occlusive crises and variable changes in certain biomarkers, including HPF and F-cells, were observed. We look forward to presenting comprehensive VOC data from this completed 93-patient placebo-controlled Phase IIa clinical trial at EHA next month as VOCs remain an important clinical outcome for this program.

I'll now turn to our Phase Iia open label extension trial on OLED trial for which we reported new data in March we believe this new data help reestablish each P F and F saw activity from treatment with 200 milligram of INR 67, after seeing variables results from these biomarkers in the phase II.

A trial.

As a reminder, the four year OLED trial allows patients from the phase Iia program to enroll any long term safety and Tolerability study of INR 67, following completion of the phase Iia trial. The oily trial was initially designed for patients who were administered a daily dose of 100 milligram of Iris.

Rahul Balal: I'll now turn to our Phase 2a Open Label Extension Trial, or OLE trial, for which we reported new data in March. We believe this new data helped re-establish HBF and F-cell activity from treatment with 200 mg of IMR687 after seeing variable results from these biomarkers in the Phase 2a trial. As a reminder, the four-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 trial.

<unk> seven and in the second quarter of 2020, a protocol amendment increased the daily dose 200 milligram.

A preliminary review of 24 patients enrolled in the oily program as of December 31, 2020 demonstrate that I'm on 67 was well tolerated and had a safety profile similar to that observed in the phase Iia clinical trial approximately 12 of these patients had evaluable PD.

Our marker data for at least four months of treatment on the OLED trial.

Rahul Balal: The OLE trial was initially designed so patients were administered a daily dose of 100 mg of IMR 687, and in the second quarter of 2020, a protocol amendment increased the daily dose to 200 mg. A preliminary review of 24 patients enrolled in the OLE program as of December 31, 2020 demonstrated that IMR687 was well tolerated and had a safety profile similar to that observed in the Phase IIa clinical trial. Approximately 12 of these patients had evaluable PD biomarker data for at least four months of treatment on the OLE trial. Biomarker results demonstrated absolute increases in both HPF and F-cells after four months of treatment.

Biomarker results demonstrated absolute increases in both H P. F N F cells after four months of treatment.

In addition to this form on data in March we also provide an update on two case narratives that we most recently reported at the American Society Hematology annual meeting December 'twenty 'twenty.

Both patients continued to see increased H P F from baseline of greater or equal to 4.5% and increases from baseline in F sell measure.

Yeah.

Falling in line with our higher dose arm in the phase <unk> studies, a separate safety review Committee has approved dose escalation in the OLED trial to a minimum daily dose of 300 milligram with certain patients being eligible for a daily dose of 400 milligram based upon their weight. This.

Rahul Balal: In addition to this forum on data, in March, we also provided an update on two case narratives that we most recently reported at the American Society of Hematology Annual Meeting in December 2020. Both patients continued to see increased HPF from baseline of greater or equal to 4.5% and increases from baseline in F cell measures. Falling in line with our higher-dose arm in the Phase IIb studies, a separate Safety Review Committee has approved dose escalation in the OLE trial to a minimum daily dose of 300 mg, with certain patients being eligible for a daily dose of 400 mg based upon their weight. This same weight-gait-driven approach is employed in both of our Phase IIb programs and is an efficient way to maximize exposure and maintain safety.

Same weight gain driven approach is employed in both of our phase two b programs and is an efficient way to maximize exposure and maintain safety. We have submitted a revised protocol to the F. T E and M HRA and expect to start transitioning patients who higher doses of <unk> 67 in mid 2021 on the <unk>.

L. A study we also expect to present additional data from the oily, including eight month by a PD biomarker and V O see data at the upcoming <unk> Congress.

In conclusion.

We believe that the first quarter marked another productive period for Mara in both enrollment gains and the important transition to administering higher doses of INR 687, and we look forward to updating you on our further progress including multiple data Readouts planned in 2021 thank you and I will now.

Rahul Balal: We have submitted a revised protocol to the FDA and MHRA and expect to start transitioning patients to higher doses of IMR-687 in mid-2021 in the OLE study. We also expect to present additional data from the OLE study, including 8-month PD biomarker and VOC data, at the upcoming EHA Congress. In conclusion, we believe that the first quarter marked another productive period for AMARA in both enrollment gains and the important transition to administering higher doses of IMR-687.

I'll turn the call back to Mike to review our financial results bikes. Thank you roll our first quarter 'twenty 'twenty. One results can be found on the press release that we issued this morning, which I'll summarize now.

More details are also included in the 10-Q that we filed with the SEC also earlier this morning.

R&D expenses were $7 $1 million for the first quarter of 2021 as compared to $5 $8 million for the first quarter of 2020.

The increase of $1.3 million was primarily related to our development efforts of INR 687, as well as increased personnel related and other R&D operating costs.

General and administrative expenses were $3 $2 million for the first quarter 2021 as compared to $1.6 million for the first quarter of 2020, the increase of $1.6 million was primarily due to increased personnel related and other G&A operating costs as a result of operating as a public company.

Mike Gray: We look forward to updating you on our further progress, including multiple data readouts planned in 2021. Thank you, and I will now turn the call back to Mike to review our financial results. Mike?

Mike Gray: Thank you, Rahul. Our first 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 that we filed with the SEC also earlier this morning. R&D expenses were $7.1 million for the first quarter of 2021, as compared to $5.8 million for the first quarter of 2020. The increase of $1.3 million was primarily related to our development efforts for IMR-687, as well as increased personnel-related and other R&D operating costs.

Net loss attributable to common stockholders was $10 $3 million or 58 cents per share for the first quarter of 2021 as compared to $15 $1 million or $4 31 per share for the first quarter of 2020.

First quarter 2020, net loss attributable to common stockholders included a $7 $9 million charge associated with the accretion of series B convertible stock.

We ended the first quarter with cash cash equivalents and investments of $75 $6 million and we expect that this will be sufficient to fund our planned operations into mid 2022.

And that concludes our prepared remarks could you. Please open the line for questions.

Okay.

Brandy.

For questions. If you could open the line.

Mike Gray: General and administrative expenses were $3.2 million for the first quarter of 2021, as compared to $1.6 million for the first quarter of 2020. The increase of $1.6 million was primarily due to increased personnel-related and other G&A operating costs as a result of operating as a public company. The net loss attributable to common stockholders was $10.3 million, or $0.58 per share, for the first quarter of 2021 as compared to $15.1 million, or $4.31 per share, for the first quarter of 2020.

Certainly at this time, if you would like to ask a question. Please price.

And then the number one on your telephone keypad.

Your first question comes from the line of.

In Asia.

Citigroup.

IRA on my thanks, very much for taking the questions I had a few on the interim analysis for Ida.

Hey.

Oh I thought I heard you say that the interim analysis will include patients that are enrolled on the higher dose arm. So can you confirm that second what aspect of the protocol triggers the timing of the interim analysis for our Forte and finally what.

Your view on constitute a positive outcome for the interim analysis for both of these trials.

Mike Gray: The first quarter of 2020 net loss attributable to common stockholders included a $7.9 million charge associated with the appreciation of Series B convertible stock. We entered the first quarter with cash equivalents and investments of $75.6 million, and we expect that this will be sufficient to fund our planned operations into mid-2022. And that concludes our prepared remarks. Could you please open the line for questions?

Thanks, Yigal I appreciate the questions number one yes, I can confirm for both interim analyses for the artist and 44 T trial that they will include higher doses and the higher dose arm of INR 687.

And number two the pre specified protocol driven analysis for those trials to report are the following 33 patients randomized at 24 weeks for the sickle cell artisan trial.

In approximately 30 patients for the beta thal.

<unk> trial, the <unk> trial, and then finally I think your question was in reference to what do we see as positive outcomes.

They're slightly different for the beta thalassemia trial, we'll be looking at a combination. This is our first trial in patients who will be looking at a combination of safety and efficacy.

Operator: Please open the line for questions.

Operator: If you could open the line,

Operator: Certainly, at this time, if you would like to ask a question, please press star, then the number 1 on your telephone keypad. Your first question comes from the line of Yagel Nishimodes with Citigroup.

Specifically for the transfusion dependent subgroup will be looking for reduce transfusion burden as long as in addition to looking for pre transfusion hemoglobin.

Yagel Nishimodes: Hi Ravel and Mike. Thanks very much.

Rahul Balal: I had a few questions on the interim analysis for ARDENT. First, or what I thought I heard you say that the interim analysis will include patients that have enrolled on the higher dose arm. Second, what aspect of the protocol triggers the timing of the interim analysis for our study, And finally, what in your view would constitute a positive outcome for the interim analysis? Thanks, Seagal.

And safety for the non transfusion patients, we'll be looking at PD biomarker, specifically fetal hemoglobin in hemoglobin and what constitutes success for me is seeing that higher doses of INR 687 in that trial are well tolerated in a beta thalassemia patient population as well as star.

Going to see some of those improvements in transfusion burden in the transfusion dependent patients as well as some improvements in biomarkers in the non transfusion dependent patients. So that's the betas how seamless study.

Rahul Balal: Number one, yes, I can confirm for both interim analyses for the ARDIT and FORTE trials that they will include higher doses and the higher dose arm of IMR-687. Number two, the pre-specified protocol-driven analysis for those trials to report are the following: Thirty-three patients randomized at 24 weeks for the sickle cell ARDENT trial and approximately 30 patients for the beta-thal trial, the FORTE trial. And then finally, I think your question was in reference to what we see as positive outcomes. They're slightly different.

Sickle cell study is slightly different is our second trial in sickle cell and it is a powered study so for those interim analyses. The 33 patients at 24 weeks, we'll be looking specifically at the efficacy endpoint of fetal hemoglobin as well as ourselves and making sure that we understand.

And that the response rate in those 33 patients is trending positive vis a V placebo I can't give you a number in terms of what I would say as a successful outcome, but certainly we'd like to see improved response rate in those patients on active and hopefully we see some of the dose.

Rahul Balal: For the beta-thalassemia trial, we'll be looking at a combination. This is our first trial in patients, so we'll be looking at a combination of safety and efficacy. Specifically, for the transfusion-dependent subgroup, we'll be looking for reduced transfusion burden as long as in addition to looking for pre-transfusion hemoglobin and safety. For the non-transfusion patients, we'll be looking at PD biomarkers, specifically fetal hemoglobin and safety. And what constitutes success for me is seeing that higher doses of IMR687 in that trial were well tolerated in a beta-thalassemia patient population as well as starting to see some of those improvements in transfusion burden in the transfusion-dependent patients as well as some improvements in biomarkers in the non-transfusion-dependent patients.

Dependent improvements because there are two arms that are active in the sickle cell trial, a low dose on high dose versus placebo, so it'd be nice to see.

Most dependent improvement in response as well as fetal hemoglobin response.

In the active versus placebo arms.

Okay great.

Paul.

Just had a question on the additional indications for INR 687 could you just summarize quickly the conclusions from the preclinical heart failure studies and what.

About the mechanism for 687 suggests an opportunity in half half but.

Not in half rack or aircraft just a potential Avenue that you would consider down the road when you.

Rahul Balal: So that's the beta-thalassemia study. Sickle cell research is slightly different. It's our second trial in sickle cell, and it is a powered study. So for those interim analyses, the 33 patients at 24 weeks, we'll be looking specifically at the efficacy endpoint of fetal hemoglobin, as well as F cells, and making sure that we understand that the response rate in those 33 patients is trending positive vis-a-vis placebo. I can't give you a number in terms of what I would say is a successful outcome, but certainly we'd like to see an improved response rate in those patients on active treatment, and hopefully, we see some of the dose-dependent improvements because there are two arms that are active in the sickle cell trial, a low-dose and high-dose versus placebo.

More information.

Yeah sure. So we've run three preclinical studies in the heart failure with preserved E F phenotype.

Two of them are preventative Ah they require they have an insult of an agent that creates the <unk> phenotype.

Through an angiotensin two and aldosterone two treated mouse model those two a preventative models. So you treat the patient the mouse with a caustic agent and ultimately on top at INR 687, and INR 67 has been protective of those spin.

Typically in three areas. The first one in hypertrophy the second one in fibrosis and the third one in inflammation. So it works in a multi modal approach and a preventative model. Then we took it one step further into a therapeutic model we treated D V D b mice that had.

Rahul Balal: So it would be nice to see a dose-dependent improvement in response, as well as a fetal hemoglobin response in the active versus placebo arms. I actually had a question on the additional indications for IMR-687. Could you just summarize the conclusions from the preclinical heart failure study quickly and what's specifically about the mechanism? Yeah, sure.

Generated the phenotype after 20 weeks of eating and getting bigger and those mice have phenotype for pass.

Rahul Balal: So we've run three preclinical studies in heart failure with preserved EF phenotype, and two of them are preventative. They have an insult of an agent that creates the HF-PEF phenotype through an angiotensin II and aldosterone II treated mouse model. Those two are preventative models, so you treat the mouse with a caustic agent and, ultimately, on top add IMR-687, and IMR-687 has been protective of these, specifically in three areas, the first one in hypertrophy, the second one in So it works in a multimodal approach in a preventative model. Then we took it one step further into a therapeutic model.

Then you treat those mice, who have the phenotype in a treatment approach for eight weeks at the INR 67, and we saw the similar reductions in cardiac hypertrophy productions inflammation and reduction in fibrosis across all three models. The key takeaway finding as we see a reduction in NT.

Pro BNP as a biomarker of cardiac stress and as you asked a question about mechanistically why that could be relevant.

P D nine uniquely works in the Knepper license cyclic GMP pathway and so it is a uniquely configured for half half versus half breath.

And specifically, we found pre clinically that P. D. Nine is over expressed in a number of models and have tests and our three models showed an increase in P. D. Nine expression when that phenotype developed and we were able to reduce that PD nine expression with our PD.

Rahul Balal: We treated dbdb mice that had generated the phenotype after 20 weeks of eating and getting bigger, and those mice have the phenotype for HF-PEF. Then you treat those mice who have the phenotype in a treatment approach for eight weeks with IMR-687, and we saw similar reductions in cardiac hypertrophy, reductions in inflammation, and reductions in fibrosis. Across all three models, the key takeaway finding is that we see a reduction in NT-proBNP as a biomarker of cardiac stress, and as you asked a question about why that could be relevant, PD-9 uniquely works in the neprilysin cyclic GMP pathway, and so it is uniquely configured for HF-PEF versus HF-REF.

Inhibitor. So there's a mechanistic direct mechanistic relevance of P. D nine over expression in the half Perth model and so that's why we believe it's uniquely positioned for this indication versus half threat.

And we will be as I said as I said on the call will be presented is that whole package.

The fall of 2021 at a cardiovascular meeting.

Got it thank you Rahul.

Thanks, Hugo boss growth.

Yes.

Your next question comes from the line of Matthew Harrison.

With Morgan Stanley.

Okay.

Hi, Good morning, everybody on this has cost us on for Matthew.

Rahul Balal: Specifically, we found preclinically that PD-9 is overexpressed in a number of models in HF-PEF, and our three models showed an increase in PD-9 expression when that phenotype developed, and we were able to reduce that PD-9 expression with our PD-9 inhibitor. So there is a mechanistic, direct mechanistic relevance of PD-9 overexpression in the HF-PEF model, and that' And we will be, as I said in the call, presenting that whole package in the fall of 2021 at a cardiovascular meeting. Got it. Thank you, Rahul.

A question from us on sickle cell disease, you kept the common data that youre preclinical work suggested that the driver of the 687 efficacy ease the time debt. The PK remains have both IC 90, we are wondering whether you have validated these in the phase Iia data.

And how your expectations would change in case of the PK part on meet their success. They see marks on AUC turning out to be via free cash guidance. Thank you.

Operator: Thank you, guys.

Operator: Your next question comes from the line of Matthew Jarison with Morgan Stanley.

Thank you.

So couple of answers to that question and I. Appreciate you asking it we will be presenting some additional data at ehow that look at exposure response and help start determining that concept around time above the IC 90 or trough levels. In addition to looking at C. Max and AUC So that day.

Matthew Jarison: Hi, good morning everyone. This is Costas On for Matthew.

Rahul Balal: A question from us on sickle cell disease. You have commented that your preclinical work suggested that the driver of 687 efficacy is the time that the PK remains above IC90. We are wondering whether you have validated this in the phase 2a data and how your expectations would change in case other PK parameters suggest the C-max or AUC turn out to be the efficacy driver.

Ada is in front of us and certainly will be presenting part of that at <unk>.

Number two the advantage of going up on dose up to 400 milligram is you check the box across a number of these different PK parameters number one you increase AUC exposure by going up to 400 milligram, you certainly increased C. Max and your increased trough levels.

Rahul Balal: Thank you. So, a couple answers to that question. I appreciate you asking it.

Rahul Balal: We will be presenting some additional data at EHA that look at exposure response and help start determining that concept around time above the IC90 or trough levels, in addition to looking at CMAX and AUC. So, that data is in front of us, and certainly we'll be presenting part of that at EHA. Number two, the advantage of going up on dose up to 400 milligrams is that you check the box across a number of these different PK parameters.

Pass the debt the IC 90 for 24 hours and so part of the reason that we like going up on dose and this is not just for the phase two b program, but for the open label extension is we get to see the advantages of those PK parameters play out across the exposure response curve and so as you think about the phase <unk> data.

Coming in in the interim analyses will be doing additional work on the PK.

Rahul Balal: Number one, you increase AUC exposure by going up to 400 milligrams. You certainly increase CMAX, and you increase trough levels past the IC90 for 24 hours. And so, part of the reason that we like going up on dose—and this is not just for the Phase IIb program but for the open-label extension—is that we get to see the advantages of those PK parameters play out across the exposure response curve. And so, as you think about the Phase IIb data coming in the interim analyses, we'll be doing additional work on the PK side of things, specifically for beta thalassemia, to help us understand and continue to realize the potential of higher-dose treatment, including AUC, C24, as you noted, and CMAX.

Syed of things specifically for beta thalassemia.

To help us understand and continue to realize the potential of higher dose treatment, including AUC see 24, as you noted and C. Max.

Thank you Paddy good looking forward to the data.

Thank you.

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

Leerink.

Alright, thanks, very much I have a quick my first question is similar to your golf first question on when he asked about the interim analysis on what that entails I was I was hoping you could do the same and walk us through what the primary analysis will entail is that a new look I only recall interim.

Operator: And thank you, very useful; I'm looking forward to the data.

On all analyses before.

Operator: Your next question comes from the line of Joseph Schwartz with SVB Lirine.

But maybe I missed something.

Joseph Schwartz: Hi, thanks very much. My first question is similar to Yigal's first question when he asked about the interim analysis and what that entails. I was hoping you could do the same and walk us through what the primary analysis will entail. Is that a new thing... I only recall interim and final analyses before, but maybe I missed something. [inaudible] and Blinding, looks. Yeah, it's a good question.

Yeah.

In addition to what primary entails.

Will you be able to make any course corrections based on what you're seeing in each of these analysis analyses.

On a regulatory agencies, okay with you.

On block.

Ending.

<unk>.

And each of these looks on keeping that.

The trial.

<unk>.

Yeah. It's good question, let me, let me walk you through so we've always had a primary and interim a primary and a final Joe.

Rahul Balal: So we've always had an interim, a primary, and a final, Joe, and that's in part due to the fact that the studies are quite long, as you know. Let me walk you through both studies, both sickle and beta thalassemia, to give you at least a snapshot of what we expect to see and report. The interim analysis, as we've guided to in the second half of this year, will look at 33 patients at 24 weeks.

And that's in part two.

Two the fact that the.

The studies are quite long as you know, let me walk you through both studies, both sickle and beta thalassemia to give you at least a snapshot of what we expect to see and report out the interim analysis as we've guided to in the second half of this year. We will look at 33 patients at 24 weeks and I really look at that.

As a as a check the box on.

Rahul Balal: And I really look at that as checking the box on exposure, safety, tolerability, and initial. The primary analysis, which is the statistically powered time point, which is 99 patients at 24 weeks, will be a rigorous and statistically powered analysis of HBF in 99 patients and looking for that response of 3% or greater. It will also step down in a hierarchical fashion to look at annualized VOCs at that primary analysis, as well as look at time till first VOC and then a litany of other secondary and exploratory biomarkers that will be done in a hierarchical fashion to maintain power and preserve alpha.

Exposure safety Tolerability and initial understanding of PD biomarker.

The primary analysis, which is the statistically powered time point, which is 99 patients at 24 weeks will be a rigorous.

And statistically powered analysis of H B S.

At in 99 patients and looking for that response of 3% or greater it will.

We'll also step down in a hierarchical fashion to look at annualized V. O sees at that primary analysis.

As well as looking at on time till first POC and then a litany of other secondary and exploratory biomarkers that will be done in an hierarchical fashion to maintain power and preserve alpha and as you know the study is a 52 week treatment paradigm, so patients will be red.

Rahul Balal: And as you know, the study is a 52-week treatment paradigm. So patients will be read out at week 24, but those 99 patients, or the ones that continue, will go through a 52-week treatment length, and so that 52-week period will be part of the final analysis, and of course, we'll look at annualized VOC. The primary analysis, as we've guided, will be in the first half of 2022. That final analysis, which will look at the 52-week time point, specifically focused on VOCs, will be in the second half of 2022. The beta thalassemia program is slightly different; it's shorter in length. It's a nine-month treatment. Paradigm, and a six-month primary.

Out at week 24, but those 99 patients are the ones that continue will go through a 52 treatment.

Link and so that 52 week period will be part of the final analysis and of course, we will look at annualized V. O C. The primary analysis as we've guided will be in the first half of 'twenty 'twenty two that final analysis, which will look at the 52 week time point.

<unk> focused on V O six will be in the second half of 2022.

At the beta Thalassemia program is slightly different it's shorter in length.

It's a nine month treatment.

Paradigm and a six month primary and so for the interim analysis will be again looking at a subset of patients 30 patients at 24 weeks in the second half of this year.

Rahul Balal: And so for the interim analysis, we'll be, again, looking at a subset of patients, 30 patients at 24 weeks in the second half of this year. In the first half of 2022, we'll be looking at 60 patients in the TDT arm and a subset of those in the NTDT arm at 24 weeks. And in the second half of 2022, we'll be looking at that nine-month or 36-week time point for beta thalassemia.

In the first half of 'twenty 'twenty, two we'll be looking at 60 patients in the T. D T arm and a subset of those in the N T. D. T arm at 24 weeks and in the second half of 2022, we will be looking at that nine months or 36 week time point in beta thalassemia.

So just taking a step back that will be the full 120 patients in both the N T D and TD subgroup in those final analyses and so the difference overall between primary and final.

Rahul Balal: So just taking a step back, that will be the full 120 patients in both the NTD and TD subgroups in those final analyses. And so the difference overall between primary and final in beta thalassemia is 24 weeks versus 36 weeks. The difference in sickle between primary and final is 24 weeks versus 52 weeks, and I've already delineated the time frames for that. Thank you, it's helpful to have that laid out again.

In beta Thalassemia is 24 weeks versus 36 weeks.

The difference in sickle between primary and final is 24 weeks versus 52 weeks and I'm already delineated the time frame for that.

Uh-huh.

Does that help that makes a lot of times absolutely. Thank you that's helpful to have that laid out again.

Rahul Balal: And then, in your queue, it highlights that you're planning to perform a STATMAD study looking at what appears to be... that are being studied currently. Talk about that decision; is that based on anything that you've seen so far from a response exposure analysis? Yeah, sure.

And then.

In your Q it highlights that you're planning to.

Perform.

Net Mad study looking at.

What appears to be.

Up to twice the dose that are being studied currently.

Could you talk about that decision is that based on anything that you've seen so far from response exposure analyses.

Rahul Balal: So, you know, when we opened up the higher dose arms for the phase 2b studies for both beta thalassemia in January and sickle cell in March, we opened those dose arms and wanted to see how higher doses were doing and if they were well tolerated. Those doses are proceeding. We believe, obviously we're blinded, that the safety signal from those higher doses points to tolerability. And so part of the rationale to start a SAD-MD study is to continue to explore higher doses beyond 400 milligrams, as you noted.

Okay.

Yeah sure. So you know when we opened up the higher dose arms for the phase <unk> studies for both beta thalassemia in January.

And sickle cell in March.

We opened those dose arms and wanted to see how higher doses were doing and if they're well tolerated those doses are proceeding.

We believe obviously, we're blinded we believe that the safety signal from those higher doses.

Points to Tolerability and so part of the rationale to start a sad Mds study is continue to explore higher doses beyond 400 milligram as you noted and so certainly we believe that this sad and the study will allow us to potentially expand.

Rahul Balal: And so certainly, we believe that this SAD-MD study will allow us to potentially expand the dose range for IMR687. And we just wanted to have that optionality as we had and are going through the phase 2b programs. Will we implement higher doses of IMR687 potentially? That is data dependent on that SAD-MD study, but we wanted to make sure that we had an opportunity to do that, which is why we started the study now versus later; very helpful. Thanks again for taking my advice.

The dose range for INR 687.

And we just wanted to have that Optionality as we had in.

And are going through the phase two b programs.

Will we implement higher doses of imo's exceed seven potentially.

That is data dependent on that said M. D study, but we wanted to make sure that we had an opportunity to do that which is why we started this study now versus later.

Very helpful. Thanks, again for taking my question.

Thanks, Joe.

And there are no further questions at this time I would now like to turn the call back over to the speakers for any closing remarks.

Operator: And they're in there for the questions at this time. I would now like to turn the call back over to the speakers for any closing remarks.

Rahul Balal: Thank you, everyone. Well, I appreciate you joining us this morning. We look forward to future updates. It is a data-rich year, and we're excited to move forward in enrollment to have that data later this year. And see you at EHA. Thank you, conference call.

Thank you everyone. We appreciate you joining us. This morning, we look forward to future updates is a data rich year and we're excited to have you.

Forward and enrollment to have that data.

Later this year in CODI.

Q.

This concludes today's conference call you may now disconnect.

Okay.

[music] Atlanta.

Hum.

Operator: This concludes today's conference.

Yeah.

[music].

Operator: [inaudible]