Q4 2021 Imara Inc Earnings Call

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Ladies and gentlemen, thank you for standing by and welcome to the EMR, Inc. Q4, and 2021 earnings conference call and webcast. At this time all participants are in a listen only mode. After the speaker presentation. There will be a question and answer session to ask a question during the session you will.

Ladies and gentlemen, thank you for standing by, and welcome to the EMARA Inc. Q4 and 2021 Earnings Conference Call-In Webinar.

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 1 on your telephone. If you require any further assistance, please press star, then 0. I would now like to hand the conference over to your speaker, Mr. Mike Gray, Chief Financial and Chief Operating Officer for EMARA. Please go ahead, sir.

Need to press Star one on your telephone if you require any further assistance. Please press Star then zero.

I would now like to hand, the conference over to your Speaker, Mr. Mike Gray, Chief financial and Chief operating Officer for EMR. Please go ahead Sir.

Mike Gray: Okay, thank you, Shuri. Good morning, everyone, and welcome to Amara's fourth quarter 2021 conference call. I'm joined this morning by Amara's president and CEO , Rahul Balal, and our chief medical officer.

Okay. Thank you Sherry good morning, everyone and welcome to <unk> fourth quarter 2021 conference call.

I'm joined this morning by <unk>, President and CEO , Rahul ball and our Chief Medical Officer Kennedy.

Mike Gray: Before we begin, I'd like to remind everyone that various statements we make during this conference call about the company's future expectations, plans and prospects constitute forward looking statements for purposes of the safe harbor provisions under the private securities litigation reform act of 1995.

Before we begin I'd like to remind everyone that various statements. We make during this conference call about the company's future expectations plans and prospects constitute forward looking statements for purposes of the safe Harbor provisions.

Under the private Securities Litigation Reform Act of 995.

Mike Gray: Actual events or results could differ materially from those expressed or implied by these forward-looking statements as a result of various important factors, including those set forth in the risk factors section of our most recent annual report on Form 10-K that we filed with the SEC this morning, as well as other filings that we may

Actual events or results could differ materially from those expressed or implied by these forward looking statements as a result of various important factors, including those set forth in the risk factors section of our most recent annual report on Form 10-K that we filed with the SEC. This morning.

As well as other filings that we may make with the SEC.

Mike Gray: Any forward-looking statements may 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.

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.

Mike Gray: 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.

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.

Speaker Change: Okay, with that, I'll turn the call over to Amar's President and CEO , Wahood Bilal, who will provide an overview of our fourth quarter and key recent accomplishments.

Okay with that I'll turn the call over to <unk>, President and CEO who'll ball.

We'll provide an overview of our fourth quarter and key recent accomplishments as well as for our expectations around interim analyses from each of our Arden.

Wahood Bilal: as well as for our expectations around interim analyses from each of our Arden and Forte phase 2b clinical trials in sickle cell disease and beta thalassemia respectively.

<unk> phase II clinical trials in sickle cell disease, and beta thalassemia, respectively.

Speaker Change: I'll then return following Rahul's discussion to review our 2021 financial results, and we'll then open the call for any questions. Rahul.

I'll then return following rules discussion to review our 2021 financial results and we'll then open the call for any questions.

Thank you Mike Good morning, everyone and thank you for joining today's call.

Rahul Balal: Thank you, Mike. Good morning, everyone, and thank you for joining today's call.

Rahul Balal: The fourth quarter and the start of 2022 have enabled important pipeline expansion for AMARA, including the clearance by the FDA of our IND for tovinitrine and heart failure with preserved ejection fraction, or HEFTEF.

The fourth quarter and the start of 2022 have enabled important pipeline expansion from lora, including the clearance by the FDA of our A&D for Vinatieri and heart failure with preserved ejection fraction or half tests.

Rahul Balal: as well as introduction of IMR261, an oral, clinic-ready activator of Nrf2. I'll spend some time on each one of these exciting new programs. Would like to begin this morning's call with a review of our key phase 2b sickle cell disease and beta thalassemia programs.

As well as the introduction of INR 261, and oral clinic ready activator of nerve too I'll.

I'll spend some time on each one of these exciting new programs I would like to begin this mornings call with a review of our key phase two be sickle cell disease, and beta thalassemia programs, including a review of timing and descriptions of the important interim readouts or T N for ardent and <unk> clinical trials.

Rahul Balal: including a review of timing and descriptions of the important interim readouts in our ARTES and FORTE clinical trials, both of which are on track for expected release the first week of April .

Both of which are on track for expected release, the first week of April .

Rahul Balal: I'll begin with our sickle cell disease program for IMR-687, which is also known as to the...

I'll begin with our sickle cell disease program for INR 67, which is also known as to the industry in.

Rahul Balal: In 2021, we, number one, reported data from our completed phase 2A trials finitrin, demonstrating reductions in annualized rate of VOCs. Number two, successfully completed enrollment of the ARDENT phase 2B trial. And number three, had important regulatory interactions with the FDA, resulting in a change of the primary efficacy endpoint of the ARDENT trial to annualized rate of VOCs.

In 2021, we number one reported data from our completed phase Iia trials phenanthrene demonstrated reductions in annualized rate of D. O. Six number two successfully completed enrollment of the art in phase two B trial and number three had important regulatory interactions with the S. T. A.

A resulting in a change of the primary efficacy endpoint of the art and trial to annualized rate of V O sees.

Rahul Balal: All these advancements are an encouraging setup to what we believe will be an important 2022 for this development program.

All of these advancements are an encouraging set up to what we believe will be an important 2022 for this development program.

Rahul Balal: First, I will discuss the decision to change the primary efficacy endpoint in our sickle cell ARDANT Phase IIb clinical trial of Tavitri.

First I will discuss the decision to change the primary efficacy endpoint and our sickle cell phase <unk> clinical trial of <unk> to treat.

Rahul Balal: Following our presentation of positive phase 2a VOC data at the European Hematology Association meeting in June 2021.

Following our presentation of positive phase Iia V O see data at the European Hematology and Hematology Association meeting in June 2021.

Rahul Balal: We engaged the FDA on several topics, including getting feedback on a draft statistical analysis plan for the ARDENT trial.

We engage the FDA on several topics, including getting feedback on a draft statistical analysis plan for the art and trial.

Rahul Balal: In reviewing the draft plan, the FDA recommended in November that we change the primary endpoint of the trial to the annualized rate of VOCs, and we agreed with the FDA's written recommendation.

In reviewing the draft plan the FTA recommend recommended in November that we changed the primary endpoint of the trial to be annualized rate of the Ocs and we agreed with the Fda's written recommendation.

Rahul Balal: knowing we had a study already configured for VOC endpoints and seeing encouraging VOC benefits at low doses to Vinodre.

Knowing we had a study already configured for boc endpoints and seeing encouraging boc benefit at low doses to the industry.

Rahul Balal: The prior primary endpoint, HBF response, will continue to be evaluated as a key secondary endpoint, along with other key secondary endpoints, including time of

The prior primary endpoint H B S response will continue to be evaluated as a key secondary endpoint along with other key secondary endpoints, including time first POC.

Rahul Balal: The endpoint revisions did not affect the conduct of the trial or operational aspects of the study. As part of its recommendation,

The endpoint revisions did not affect the conduct of the trial or operational aspects of the study.

As part of this recommendation the F. D. A suggested further engagement on the potential of the current program for regulatory decision, making and we look forward to these future interactions following the phase II interim analysis.

Rahul Balal: further engagement on the potential of the current program for regulatory decision-making and we look forward to these future interactions following the Phase 2b interim analysis.

Rahul Balal: The basis for the Page 2b Interim Readout from the Ardent Trial is when all ongoing subjects have completed assessments through at least week 24 and will rely on an intent-to-treat analysis population.

The basis for the phase two be interim readout from the Arctic trial is when all ongoing subjects have completed assessments through at least week 24.

We will rely on an intent to treat analysis population.

Rahul Balal: Since this is a fixed-sequence approach, the interim efficacy readout will be for our primary endpoint.

Since this is a fixed sequence approach the interim efficacy readout will be for our primary endpoint.

Rahul Balal: which is a comparison of the annualized VOC rate between the high-dose treated group versus placebo.

Which is a comparison of the annualized V O E rate between the high dose treated group versus placebo the.

Rahul Balal: The high-dose group is once daily dose of 300 or 400 mg based on a weight gauge.

The high dose group is once daily dose of 300 or 400 milligram based on a weight gain.

Rahul Balal: We expect this efficacy readout to consist of approximately 80 patients in those two groups.

We expect this efficacy readout to consist of approximately 80 patients in those two groups. Additionally, because we are spending a small amount of alpha to review efficacy results, we will generate and report a P value for this V. O C analysis. We also plan to report safety data for all 115 patients enrolled.

Rahul Balal: Additionally, because we are spending a small amount of alpha to review efficacy results, we will generate and report a p-value for this VOC analysis.

Rahul Balal: We also plan to report safety data for all 115 patients enrolled in the ARDENT trial, which includes the high-dose, low-dose, and placebo arms.

In the art and trial, which includes the high dose low dose and placebo arms. We are limiting our data review in this interim analysis to the primary efficacy endpoint and safety data to minimize the alpha spend there.

Rahul Balal: We are limiting our data review in this interim analysis to the primary efficacy endpoint and safety data to minimize alpha spend, thereby preserving the vast majority of alpha for the final analysis.

Thereby preserving the vast majority of alpha for the final analysis, which is expected in the second half of 2022 in summary, this interim data will be a robust look at an approvable endpoint.

Rahul Balal: which is expected in the second half of 2022. In summary, this interim data will be a robust look at an approvable DOC endpoint.

Rahul Balal: statistical analysis plan has been reviewed by the FDA twice.

The statistical analysis plan has been reviewed by the FDA twice.

Rahul Balal: and the studies powered at 80% to 85% to show a 35% to 40% difference between the high dose and placebo arm.

And the study is powered at 80% to 85% to show a 35% to 40% difference between the high dose and placebo arms.

Rahul Balal: It is an important data set for the company and provides a launching pad for potential phase three planning as well as for regulatory interactions in the coming months.

It is an important data set for the company and provides a launching pad for potential phase III planning as well as for regulatory interactions in the coming months.

Rahul Balal: We expect the interim Phase 2b ARDIN data to build on existing VOC results we presented at medical meetings in 2021.

We expect the interim phase two be art and data to build on existing V. O C results, we presented at medical meetings in 2020 one.

Rahul Balal: Most recently, we reported 12-month data from the ongoing Phase IIa Open Label Extension, or OLE, clinical trial of subinutriene.

Most recently, where we reported 12 month data from the ongoing phase Iia open label extension or Oh early clinical trials in a tree, which was presented at the American Society of hematology or Ash annual meeting in December the OLED data showed patients who are onto the entry in the <unk>.

Rahul Balal: which was presented at the American Society of Hematology, or ASH, annual meeting in December .

Rahul Balal: The OLE data showed patients who were on Savinitrine in the completed Phase IIa trial maintained a reduced annualized rate of VOCs while on the OLE trial.

Pleaded phase Iia trial maintained a reduced annualized rate of Voc's file on the O N E trial.

Rahul Balal: In addition, a 38% reduction in median annualized VOC rate was observed in patients that received placebo in the Phase IIa trial and switched to tevinitrine as part of the OLE trial.

In addition, a 38% reduction in median annualized V. S. E rate was observed in patients that received placebo in the phase Iia trial and switch to <unk> as part of the OLED trials.

Rahul Balal: We are encouraged by the durable VOC benefit observed in the Phase 2a OLE trial through 12 months and the consistent VOC benefit across studies and time.

We are encouraged by the durable V O see benefit observed in the phase Iia OLED trial through 12 months and the consistent V O see benefit across studies in time points.

Rahul Balal: Recall that the VOC data that has been presented to date has been for subjects treated with daily doses of up to 200 milligram of tavinotriene.

Recall that the V O C data that has been presented to date has been for subjects treated with daily doses of up to 200 milligram.

Divinatory.

Rahul Balal: PK-PD modeling suggests that higher doses of tevinitrine, as administered in our current Phase IIb studies, may further reduce VOC reach, which is why we're optimistic about the upcoming Phase IIb high dose interim reading.

PK PD modeling suggests that higher doses of <unk> as administered in our current phase <unk> studies may further reduce boc rage, which is why we're optimistic about the upcoming phase two b high dose interim readout.

I'll turn now to our phase two B program in beta thalassemia.

Rahul Balal: I'll turn now to our Phase IIb program in beta thalassemia. We also expect to report interim data from our Forte Phase IIb clinical trial of davinotrene in beta thalassemia patients in the first week of April alongside our interim Phase IIb sickle cell.

We also expect to report interim data from our <unk> phase two b clinical trial of <unk> to the nutrient in beta thalassemia patients in the first week of April alongside our interim phase two b sickle cell data.

Rahul Balal: During the fourth quarter of 2021, we reported the first interim clinical data from the transfusion-dependent cohort of the Phase IIb clinical trial.

During the fourth quarter of 2021 we reported the first interim clinical data from the transfusion dependent cohort of the phase <unk> clinical trial. This marked an important milestone for lora and patients seeking oral therapies for this disease.

Rahul Balal: This marked an important milestone for Mara and patients seeking oral therapies for this disease.

Rahul Balal: We observed a positive trend for transfusion burden reduction at the higher dose of tovendatrine as compared to placebo, and we are hopeful that this signal will strengthen with more patient data at our upcoming TDT interim announce.

We observed a positive trend for transfusion burden reduction at the higher doses to the industry as compared to placebo and we are hopeful that this signal will strengthen with more patient data at our upcoming PDT interim analysis.

We're also pleased that the interim data demonstrated a favorable tolerability profile at once daily doses of today between up to 400 milligrams.

Rahul Balal: We're also pleased that the interim data demonstrated a favorable and tolerability profile at once daily doses of timonitrine up to 400 millisieverts.

Rahul Balal: In the first week of April , we expect to report additional data on transfusion burden from the transfusion-dependent cohort of the Phase IIb trial and the first clinical data from the non-transfusion-dependent cohort of this trial. The efficacy data set will consist of approximately 50 transfusion-dependent patients at 24 weeks and approximately 30 non-transfusion-dependent patients at 24 weeks for a total of approximately 80 patients.

In the first week of April we expect to report additional data on transfusion burden from the transfusion dependent cohort of the phase <unk> trial and the first clinical data from the non transfusion dependent cohort of this trial. The efficacy dataset will consist of approximately 50 transfusion dependent patients at <unk>.

24 weeks and approximately 30 non transfusion dependent patients at 24 weeks for a total of approximately 80 patients.

Rahul Balal: It will include safety and biomarker data, and we are looking forward to this near-term readout.

It will include safety and biomarker data and we are looking forward to this near term readout.

Turning to our heart failure program, we're very excited about <unk> potential in heart failure with preserved ejection fraction or have passed we have made significant progress in the last year and have transformed this program from a promising preclinical effort to a phase two proof of concept study with clearance from the F. T H.

Rahul Balal: Turning to our heart failure program, we're very excited about savinotriene's potential in heart failure with preserved ejection fraction, or FPEF. We have made significant progress in the last year and have transformed this program from a promising preclinical effort to a phase two proof of concept study with clearance from the FDA to proceed with the study.

<unk> to proceed with the study.

Rahul Balal: We have also built a leading internal development team and an external KOL team to support a development effort.

We have also built a leading internal development team and an external K O L team to support the development efforts.

Rahul Balal: including recently adding Peter Ponikowski from Wroclaw Medical University in Poland to the executive.

<unk> recently, adding Peter Pan of Koski from Broadsoft Medical University in Poland to the Executive Committee.

Rahul Balal: Our excitement for the HFPAF program comes from the results of in vivo studies of timiditrine in different models of HFPAF.

Our excitement for the half Pep program comes from the results of in vivo studies of <unk> in different models of half past, which were presented at the a H a scientific sessions in November 2021.

Rahul Balal: which were presented at the AHA Scientific Sessions in November 2021.

Rahul Balal: Furthermore, our clinical approach focuses on identifying HFPF patients with high PD9

Furthermore, our clinical approach focuses on identifying <unk> patients with high PD lone expression.

Rahul Balal: creating a targeted approach in this highly prevalent disease.

Creating a targeted approach in this highly prevalent disease. We also believe we have the best in class PD nine inhibitor for evaluation in this patient population with in vitro data demonstrating superior potency and selectivity when compared to other available PD Lone inhibitors.

Rahul Balal: We also believe we have the best-in-class PD9 inhibitor for evaluation in this patient population, with in vitro data demonstrating superior potency and selectivity when compared to other available PD9s.

Rahul Balal: To briefly cover the study design, the SPIN Phase II Clinical Trial will be a randomized, double-blind, placebo-controlled study in which we expect to enroll approximately 170 patients, randomized on a one-to-one basis, to receive either placebo or placebo-controlled

To briefly cover the study design the spin phase II clinical trial will be a randomized double blind placebo controlled study in which we expect to enroll approximately 170 patients randomized on a one to one basis to receive either placebo.

Rahul Balal: or a twice-daily dose of either 300mg or 400mg of tevinitrine, depending on a weight gain. Patients will be dosed

Or a twice daily dose of either 300, Meg or 400, Meg of divinatory, depending on a weight gain.

Patients will be dosed for 16 weeks and the primary study endpoint will be the change in plasma NT Pro BNP <unk>.

Rahul Balal: And the primary study endpoint will be the change in plasma in T-ProBNP, a clinically relevant biomarker of cardiac stress.

A clinically relevant biomarker of cardiac stress.

Rahul Balal: Secondary endpoints include safety and tolerability and quality of life measures, such as Kansas City cardiomyopathy questionnaire, KCCQ, and New York Heart Association, NYHA classification. We will also look at exploratory endpoints.

Secondary endpoints include safety, and Tolerability and quality of life quality of life measures, such as Kansas City Cardiomyopathy questionnaire, Casey CQ, and New York Heart Association N Y J classification.

We will also look at exploratory endpoints, such as clinical composite scores six minute walk test and evaluation of cardiac structure and function.

Rahul Balal: six minute walk test and evaluation of cardiac structure and function.

Rahul Balal: Additional details on the SPIN trial will be available on clinicaltrials.gov, and we look forward to dosing the first subject in our Phase II program, which is anticipated to occur in the second quarter of 2020.

Additional details on the spin trial will be available on clinical trials Gov, and we look forward to dosing the first subject in our phase II program, which is anticipated to occur in the second quarter 2022.

Rahul Balal: Finally, our head of the HFREF program is a seasoned cardiologist with deep connections among key opinion leaders.

Finally, our head of the half first program is a seasoned cardiologist with deep connections among key opinion leaders.

Rahul Balal: In Q4 of 2021, we appointed Tony Bransford, MD, as Vice President of Clinical Development to work with Ken Addy and lead clinical development of tevinitrine as a treatment for half-past.

In Q4 of 2021, we appointed Tony brands for M. D. As Vice President of clinical development to work with Ken Addy and lead clinical development of <unk> as a treatment for half path.

Rahul Balal: A cardiologist, Tony comes to Amara with 15 years of clinical development experience within global pharmaceuticals, biotech, and CROs.

A cardiologist Tony comes Tomorrow, with 15 years of clinical development experience within global Pharmaceuticals.

Kotek N Cro's Tony has accumulated extensive experience in the cardiovascular therapeutic area, including for example, as senior medical director within the global clinical development program and Novartis, where she was the clinical lead for the half tab program conducting that Paramount and Paragon trials.

Rahul Balal: Toni has accumulated extensive experience in the cardiovascular therapeutic area, including, for example, as Senior Medical Director within the Global Clinical Development Program at Novartis, where she was the clinical lead for the HFPEP program conducting the Paramount and Paragon trials. We're delighted to have Toni on board.

We're delighted to have Tony on board.

Rahul Balal: In addition, to our internal HFF team, we have also established a leading external executive committee to oversee the SPIN trial, which is chaired by Deepik Gupta of Vanderbilt University Medical Center, and includes Maggie Redfield of the Mayo Clinic, Sanjeev Shah of Northwestern, Thomas Wang of UT Southwestern, and now Peter Ponikowski from Watsuf University.

In addition, our internal have tours to our internal <unk> team. We have also established a leading external executive committee to oversee the spin trial, which is chaired by debate Cooper Gupta of Vanderbilt University Medical Center and includes Maggie Redfield of the Mayo Clinic Sanjiv shop.

Northwestern Thomas Wang of Ut southwestern and now Peter Punit Koski from Whatsapp University in Poland. We are very excited about the development of decision tree NFS and we look forward to updating you on our progress.

Rahul Balal: We are very excited about the development of daviditrine and HF-PF, and we look forward to updating you on our progress.

In addition to the progress we've made with <unk> in the fourth quarter of 2021, we announced the addition of INR 261, an activator of nuclear factor Erythroid, two related factors, two or N F bar too to our pipeline.

Rahul Balal: In addition to the progress we've made with Tevinitrine in the fourth quarter of 2021, we announced the addition of IMR261, an activator of nuclear factor erythroid-2-related factor 2, or NFR2, to our pipeline.

Rahul Balal: We recently showed preclinical data at an oral presentation on IMR261 at the ASH annual meeting in December 2021. In preclinical sickle cell models, IMR261 was observed to activate expression of HBF and reduce VOCs.

We recently showed preclinical data at an oral presentation at a INR 261 at the Ash annual meeting in December 2021, and preclinical sickle cell models. INR 261 was observed to activate expression of H B F and reduce voc's in a preclinical beta thal model.

Rahul Balal: In a preclinical beta cell model, IMR261 increased hemoglobin and enabled red blood cell maturation. We've initiated work on drug product manufacturing for IMR261, and we are exploring potential clinical development paths, which could include treating iron disorder.

261 increased hemoglobin and enabled red blood cell maturation, we've initiated work on drug product manufacturing for INR 261, and we are exploring potential clinical development path, which could include treating iron disorders.

Rahul Balal: We look forward to providing further updates on IMR 261 later this year.

We look forward to providing further updates on INR 261 later this year.

Rahul Balal: In conclusion, we believe the fourth quarter and beginning of 2022 have been productive periods for Mara.

In conclusion, we believe the fourth quarter and beginning of 'twenty two 2022 had been productive periods for Mara we.

Rahul Balal: We are fast approaching key interim analyses and readouts for our ARDENT and FORTE Phase IIb clinical trials. We have expanded the tovinitrine opportunity into HFPEP.

We are fast approaching key interim analyses and readouts for our Arden and <unk> phase <unk> clinical trials, we've expanded that to the nutrient opportunity into half path.

Rahul Balal: and are developing a clinic-ready pipeline with the addition of IMR-268.

And are developing a clinic ready pipeline with the addition of biomarker 261.

Rahul Balal: We look forward to updating on our further progress, beginning with expected data readouts from the ARDENT and FORTE trials in the first week of April .

We look forward to updating you on our further progress beginning with expected data readouts from the Arden and <unk> trials in the first week of April .

Rahul Balal: Thank you, and I will turn the call back to Mike to review our financial

Thank you and I will turn the call back to Mike to review our financial results.

Yeah.

Mike Gray: Okay, thanks Rahul. Our full 2021 financial results can be found in the press release that we issued this morning, which I'll summarize now. More details are also included in the 10K that we filed with the SEC earlier this morning.

Okay. Thanks Rahul.

Our full 2021 financial results can be found in the press release that we issued this morning.

Which I'll summarize now more details are also included in the 10-K that we filed with the SEC earlier this morning.

Mike Gray: R&D expenses were $38.4 million for the year ended December 31st, 2021, as compared to $32.2 million for the year ended December 31st, 2020.

R&D expenses were $38 $4 million for the year ended December 31, 2021, as compared to $32 $2 million for the year ended December 31 2020.

Mike Gray: The increase of $6.3 million was primarily related to the conduct of clinical trials and manufacturing of clinical materials related to our ongoing development of tibetan.

The increase of $6 $3 million was primarily related to the conduct of clinical trials and manufacturing of clinical materials related to our ongoing development and training as well as increased personnel related and other R&D operating costs.

Mike Gray: as well as increased personnel related and other R&D operating costs.

Mike Gray: G&A expenses were $13 million for 2021 as compared to $9.5 million for 2020. The increase of $3.5 million was primarily due to increased costs associated with certain insurance premiums, as well as increases in personnel related and other G&A operating costs as a result of operating as a public company.

G&A expenses were $13 million for 2021 as compared to $95 million for 2020.

The increase of $3 $5 million, which primarily due to increased costs associated with certain insurance premiums as.

As well as increases in personnel related and other G&A operating costs as a result of operating as a public company for the full year in 2021.

Mike Gray: Net loss attributable to common stockholders was $51.4 million or $2.37 per share for 2021 as compared to a net loss of $49.2 million or $3.53 per share for 2020.

Net loss attributable to common stockholders was $51 4 million or $2 37 per share for 2021 as compared to a net loss of $49 2 million or $3 53 per share for 2020.

Mike Gray: Cash, cash equivalents, and investments were $90.3 million as of December 31st, 2021, as compared to $88.2 million as of December 31st, 2020.

Cash cash equivalents and investments were $93 million as of December 31, 2021, as compared to $88 $2 million as of December 31, 2020.

Okay.

Mike Gray: We currently expect that full year 2020 R&D expenses will range between $60 and $65 million, and that our full year 2022 G&A expenses will range between $13 and $15 million.

We currently expect that full year 2020, R&D expenses will range between 60 and $65 million and that our full year 2022, G&A expenses will range between 13% and $15 million we.

Mike Gray: We expect that our cash, cash equivalents and investments as of December 31st, 2021 will be sufficient to fund our planned operations substantially through the first quarter of 2023 for approximately one year from our reporting of interim data from our art and forte phase to be clinical trials in the coming week.

We expect that our cash cash equivalents and investments as of December 31, 2021 will be sufficient to fund our planned operations substantially through the first quarter of 2023 for approximately one year from our reporting of interim data from our <unk> and <unk> phase <unk> clinical trials in the coming weeks.

Speaker Change: That concludes our prepared remarks. Sheree, if you wouldn't mind, could you please open the line for questions? Thank you. My pleasure. As a reminder, to ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster.

That concludes our prepared remarks sheree if you wouldn't mind could you. Please open the line for questions. Thank you my pleasure as a reminder to ask a question you will need to press star one on your telephone to withdraw your question press the pound please.

Please standby, while we compile the Q&A roster.

Speaker Change: Our first question will come from Idan Notomovich with Citigroup. Please go ahead. Thank you. Thank you. Thank you.

Our first question will come from Aegon.

<unk> with Citigroup. Please go ahead.

Alright, Thank you for taking the question.

Idan Notomovich: As you noted, Virhul, the FDA cited potential for regulatory decision-making following the interim look for...

As he noted her whole the FDA cited the potential for regulatory decision, making following the interim look for SPP. So I'm. Just wondering is there any potential that you could file for an accelerated approval. If the results of the SPD interim are sufficiently problems.

Speaker Change: So I'm just wondering, is there any potential that you could file for an accelerated approval if the results would be as.

Speaker Change: Thanks, Yigal. I appreciate the question. Nice to hear from you.

Thanks, Yigal I appreciate the question nice to hear from you. So.

Speaker Change: The FDA interaction around the VOC endpoint is slightly different than the accelerated approval pathway because the annualized rate of VOC is an approvable endpoint. So as opposed to taking the accelerated approval pathway with a post-marketing commitment.

The FDA interaction around the V O C endpoint.

Is slightly different than the accelerated approval pathway because the annualized rate of Yossi is an approvable endpoint, so as opposed to taking the accelerated approval pathway.

With a post marketing commitment.

Speaker Change: we could be in a position to talk to the FDA about an approvable endpoint and getting full approval on the drug. I would just cite the experience with chrysalizumab versus global blood therapeutics. With chrysalizumab, they got a full approval on their monoclonal antibody to P-selectin versus chrysalizumab.

We could be in a position to talk to the FDA about a provable endpoint and getting full approval on the drug I would just cite the experience with Chris Elysium App.

<unk> global blood therapeutics with Chrysalis Mab, they've got full approval.

On there.

Unequal antibody to P selectin versus.

Ox Friday, which got an accelerated approval pathway with hemoglobin. So we would be taking the approach that with a regulatory endpoint that is approvable.

Speaker Change: Oxprida, which got an accelerated approval pathway with hemoglobin. So, we would be taking the approach that with a regulatory endpoint that is approvable.

Speaker Change: we would not need to use the accelerated approval pathway.

Would not need to use the accelerated approval pathway now that being said because this is a phase two study and we are hoping that it's something more than a phase II study could always be post marketing commitments that the F. D. A.

Speaker Change: Now, that being said, because this is a Phase II study and we are hoping that it's something more than a Phase II study, there could always be postmarking commitments that the FDA may consider, but that would always be a discussion with them in the future.

May consider but that would always be a discussion with them in the future.

Got it okay. Thanks, and just operationally can you just clarify for the interim so everyone understands the P value threshold going to be the point.

Speaker Change: And just operationally, can you just clarify for the interim so everyone understands, is the P value threshold going to be the .05 or is it something more stringent?

Or is it something more stringent and begin to learn.

Yes, it's a great question.

Speaker Change: Yeah, it's a great question. I'll turn it over to our chief medical officer, Ken, to give a perspective on alpha spend and p-value.

I'll turn it over to our Chief Medical Officer tend to give a perspective on an alpha spend in N P values Ken.

Speaker Change: Ken? Yeah. Thanks, Raul, and thanks for the question.

Ken.

Yeah, Thanks, Rob and thanks for the question.

Ken Addy: Yeah, as is typically done, we.

As is typically done.

Raul: in order to perform the analysis at the interim, we have to spend some alpha. However,

In order to.

The form the analysis at the interim we have to spend some alpha. However, these data mature as the study reaches its completion at 52 weeks. So we would want to preserve as much alpha as possible for the final analysis when all patients have completed the study therefore as you guessed.

Ken Addy: These data mature as the study reaches its completion at 52 weeks, so we would want to preserve as much alpha as possible for the final analysis when all patients have completed the study.

Ken Addy: Therefore, as you guessed, at the interim analysis, there will be a very small alpha spend, and that means that we will provide a nominal p-value, which

At the interim analysis will be a very small alpha spend and that means that we will provide a nominal P value, which we hope will be.

Ken Addy: you know, below or around 0.05, but that would not be sufficient to

Below around 0.05, but that would not be sufficient to.

Ken Addy: declare victory for the study at the interim analysis, that would be a much smaller p-value, which is the amount of alpha-SMIT.

Declare victory for the study at the interim analysis that would be a much smaller P value.

As the amount of Alpha spent.

Okay.

Hi, guys.

Yes.

Ken Addy: And then for the beta cell arum, can you talk about what you're looking to see with respect to the creatine?

And then for our whole for credit for the beta cells.

Can you talk about what you are looking to see with respect to decrease in transfusion burden from baseline.

And is that something that youre going to be attaching a P value chain where is that can be.

Ken Addy: And is that something that you're going to be attaching key values to, or is that going to be...

More of a descriptive statement.

Speaker Change: Yeah, it's a good question. So the analysis for beta-thalassemias are per protocol analysis. That's our patient population. And we are signal finding, to your point.

Yes. Good question. So the analysis for beta thalassemia, So per protocol analysis patient population and we are signal finding to your point so in.

Speaker Change: In general, if you look across the beta thalassemia landscape, when you look at a reduction in transfusion burden, and remember, from a beta thalassemia perspective, unlike sickle, you're comparing to historical transfusion burden. So we're looking for a difference compared to a historical rate.

In general if you look across the beta thalassemia landscape. When you look at a reduction in transfusion burden and if you remember from our beta thalassemia perspective, unlike sickle youre comparing to historical transfusion burden. So we're looking for a difference.

Compared to a historical rate.

Speaker Change: both looking at the placebo arm on study versus 12 weeks prior to study, and the high-dose arm and low-dose arm 12 weeks on study and 12 weeks prior to study.

Looking at the placebo arm on study versus 12 weeks prior to study and the high dose arm and low dose arm 12 weeks on study at 12 weeks prior to study.

Speaker Change: In general, and looking at what's been approved in terms of Revazol, we'd like to see anywhere from a 20 to 30 percent reduction in transfusion burden in the transfusion-dependent

In general.

And looking at what's been approved in terms of rebels, all we'd like to see.

Anywhere from 20% to 30% reduction in transfusion burden in the transfusion dependent.

Speaker Change: thalassemia patients, and that is a difference between arms, between high dose, for example, and placebo. That would be for the transfusion-dependent analysis.

Thalassemia patients and that is a difference between arms between high dose for example, and placebo that would be for the transfusion dependent analysis.

Speaker Change: As you know, for the non-transfusion-dependent analysis, you're not really measuring transfusion burden in the same way. So we would certainly be looking for biomarker signals in the fetal hemoglobin and hemoglobin context. And those numbers, we haven't put a number on it. But generally speaking, you'd want to see something that looked greater than 30% in the high-dose versus placebo of patients above one gram per deciliter or above 3% for fetal hemoglobin.

As you know for the non transfusion dependent analysis youre, not really measuring transfusion burden at the same way. So we would certainly be looking for biomarker signals in the fetal hemoglobin and hemoglobin context, and those numbers, we haven't put a number on it but generally speaking you'd want to see something that looked greater than.

30% in the high dose versus placebo of patients above one gram per deciliter or above 3% for fetal hemoglobin.

Speaker Change: And again, it's signal finding, it's our first study in beta-thal, so those aren't hard numbers, but that's generally where we are in terms of evaluating this data set.

And again, it's a signal finding its our first study in beta thal. So those arent hard numbers, but that's generally where we are in terms of.

Evaluating this dataset.

Okay.

Speaker Change: Okay, thanks. And if I could just throw out one more on the hashtag.

If I could just one more on <unk>.

Speaker Change: uh... mentioned that you know i i i i i i i i i i i i i i i i i i i

You mentioned the PD.

Question what percent of population people need we're following that inspection.

Construction bucket.

Speaker Change: Yeah, it's a good question. So there has been quite a bit of triangulation at our executive committee on exactly what constitutes high PD9 expression. But roughly, roughly, we think it's about a third of HFPAF patients.

Yeah. It's a good question. So there has been quite a bit of triangulation at our executive Committee on exactly what constitutes high PD lone expression.

But roughly roughly we think it's about a third of half past patients.

Speaker Change: give or take, and so if HEF passes anywhere from 3 to 3.5 million, you're looking at patients that are enriched for PD9 in that.

Give or take and so it has passed us anywhere from three to three and a half million youre looking at patients that are enriched repeating in debt.

Speaker Change: million to sub million categories. So there are a lot of patients we think that are

Into sub million category. So there are a lot of patients we think that our.

Speaker Change: have increased PD9 expression, and of course, we're using an exclusion inclusion criteria to help target for those.

Have increased PD nine expression and of course, we're using it and exclusion inclusion criteria to help target for those.

Great. Thank you.

Yeah.

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

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

Joseph Schwartz: Hi. Thanks very much and congrats on all the progress. A couple of questions on the interim analysis for the ARDENT study. Did you discuss with the FDA how looking at annualized VOC rate instead of HVF at the interim analysis?

Hi, Thanks, very much and congrats on all the progress a.

Couple of questions on the interim analysis for the study.

Did you discuss with the FDA and how we're looking at.

Annualized GIC rates instead of hbf at the interim analysis.

Joseph Schwartz: can be done in a manner that won't risk blinding or biasing the final analysis. Did you discuss, you know, to the extent to which each of these endpoints is objective or subjective?

Can be done in a manner that.

Blinding revising the final analysis.

Uh huh.

Did you discuss.

<unk>.

That points us objective or subjective.

Those considerations and then I have a follow up.

Sure. That's a great question and I'll turn it to Ken add you to give some perspective on that.

Speaker Change: Sure, that's a great question. I'll turn it to Ken Addy to give some perspective on that first question. Ken?

First question Ken.

Ken Addy: Yeah, thanks. Yeah, it's a good question. I think the FDA was transparent in in those

Thanks.

Yeah. It's a good question I think the FDA was.

Transparent and and.

Those factors and our statistical analysis plan that were of interest and of concern to them. So they actually passed along first of all the recommendation to make annualized rate of the Ocs our primary endpoint.

Ken Addy: factors in our statistical analysis plan that were of interest and of concern to them. So they actually passed along, first of all, the recommendation to make annualized rate of VOCs our primary endpoint, and then suggestions on how to preserve alpha by, you know, what other data can be looked at. So, for example, even for our safety data, we're being very careful not to become unblinded to any individual patient's randomization assignment.

And then suggestions on how to preserve alpha by.

You know what other data can be looked at so for example, even for our safety data, we're being very careful not to become unblinded to any individual.

Patients Panelization assignment.

Ken Addy: And the same holds true for efficacy. Everything will be based on group changes, medians for the group. Even when we describe the medians, we don't look at all the descriptive stats in the epi to be sure not to be unblinded at any time.

And the same holds true for efficacy everything will be based on group changes medians for the group even when we described the mediums. We don't look at all the descriptive stats and the outcome to be sure not to be unblinded at any point, so I think.

Ken Addy: So I think we're in alignment with FDA on the approach to the interim analysis.

We are in alignment with FDA on the approach to the interim analysis.

Okay. That's helpful. Thank you and then.

Speaker Change: That's helpful. Thank you. And then just to confirm, will you not be looking at the lower doses in the trial? And what's the reasoning?

Just to confirm.

B looking at them at the.

A lower dose in the <unk>.

Trial.

What's the reasoning for that.

Speaker Change: I think that is correct. At this interim analysis, we won't report data for the low-dose except for safety data. And again, this is in the effort to preserve alpha. And so each analysis, if you will, requires an alpha spend. And we really are trying to preserve as much of the 0.05 alpha for the final analysis as possible.

I think that is correct.

This interim analysis, we won't report data for the low dose except for safety data and again. This is in the effort to preserve alpha and so each analysis. If you will requires an alpha spend and where we really are trying to preserve as much of the Plano five alpha for the final analysis.

Possible.

Okay, great and maybe one more.

Speaker Change: Give us an update on the proportion of patients in ARDENT that have been eligible to.

Could you give us an update on the proportion of patients in Arden.

Have been eligible to rollover into the extension trial phases, and how many have elected to do that.

Speaker Change: trial phases and how many have elected to do that.

So it's a good question we're in the process of getting our open label extension studies started for that program. So we don't have a number to date, but I will say that the interest level has been extremely high.

Speaker Change: So it's a good question. We're in the process of getting our open-label extension study started for that program. So we don't have a number to date. But I will say that the interest level has been extremely high across almost all of our sites to get their patients onto this open-label extension.

Across almost all of our sites to get their patients onto this open label extension and I think it's worth noting that that open label extension as of right now.

Speaker Change: And I think it's worth noting that that open label extension, as of right now, is designed for patients to roll over.

Is designed for patients to rollover to the high dose arm of the phase <unk> studies. So the 300 Slash 400 milligram arm is currently noted as the high dose arm in the phase two be artist study is a dose that patients would roll over to in other words a plus.

Speaker Change: to the high-dose arm of the Phase IIb studies, so the 300-slash-400-milligram arm as currently noted as the high-dose.

Speaker Change: in the Phase 2b ARDIN study is the dose that patients would roll over to. In other words, a placebo patient would go from...

<unk> patient would go from placebo to 300 or 400, a low dose patient would go from 200 to 300 to the high dose arm of 300 to 400, and obviously the high dose patients from the art in phase two b would rollover to that same dose in the open label extension so.

Speaker Change: placebo to 300 or 400. A low-dose patient would go from 200 to 300, to the high-dose arm of 300 to 400, and obviously the high-dose patients from the

Speaker Change: ARD and PHQ-B would roll over to that same dose in the open label extension. So I think the OLE will be really important for us to get long-term safety data and hopefully see continued VOC benefit. I also think it is indicative of our confidence level that the high dose 300 slash 400 is well tolerated and will be well tolerated.

The OLED it will be really important for us to get long term safety data and hopefully see continued VNC benefit I also think it is.

Indicative of our confidence level that the high dose 300, slash 400 is well tolerated.

And we will be well tolerated.

Great. Thanks for all the color.

Thanks, Joe.

Speaker Change: I'm showing no further questions in the queue at this time. I will now turn the call back over to management for any closing remarks.

I'm showing no further questions in the queue at this time I will now turn the call back over to management for any closing remarks.

Management: Thank you very much. I appreciate everyone's time this morning. We're excited by the momentum and start into 2022 and look forward to these upcoming data readouts for the ARDIN and Forte trials in the coming weeks. Everyone stay safe and healthy and look forward to talking again soon. Have a good morning.

Thank you very much.

I appreciate everyone's time. This morning, we're excited by the momentum and start into 2022 and look forward to these upcoming data readouts for the Arden and <unk> trials in the coming weeks, everyone stay safe and healthy and look forward to talking again soon have a good.

Morning.

Thank you.

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

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

Speaker Change: ?

[music].

Yeah.