Q3 2025 Fulcrum Therapeutics Inc Earnings Call
Speaker #2: recent
Speaker #2: presentation .
Call is being webcast live and can be accessed on the investors section of <unk> website at Www, <unk> Com, TX dot com and is being recorded.
Speaker #2: Earlier this
Speaker #2: month
Speaker #2: at the
Speaker #2: annual conference for the Academy for Sickle Cell and
Speaker #2: Thalassemia , or Ascat . for
Speaker #2: demonstrated a
Please be reminded that remarks during this call may contain forward looking statements within the meaning of the private Securities Litigation Reform Act of 1995.
Speaker #2: correlation between increased
Speaker #2: fetal hemoglobin
Speaker #2: levels
Speaker #2: and reduced
Speaker #2: vaso
Speaker #2: occlusive
Speaker #2: crises people
May include statements about the company's future expectations and plans clinical development timelines and financial projections.
Speaker #2: in sickle cell disease living
Speaker #2: . This
Speaker #2: together with
Speaker #2: the
Speaker #2: that we
Speaker #2: Good morning and welcome to the Fulcrum Therapeutics . Third quarter 2020 financial results and Business Update conference call . Currently , all participants are in a listen only mode .
Speaker #2: shared upcoming Ash in
Speaker #2: July .
While these forward looking statements represent four close views as of today, they should not be relied upon as representing the companys views in the future.
Speaker #2: Gives us confidence
Speaker #2: that we plan
Speaker #2: has the potential
Speaker #2: to for
Speaker #2: provide
Speaker #2: a one meeting
Speaker #2: differentiated
Our may update these statements in the future, but it's not taking on any obligation to do so.
Speaker #2: , therapeutic
Speaker #2: option for
Speaker #2: This call is being webcast live and can be accessed on the investor section of Fulcrum's website.
Speaker #2: people
Speaker #2: living with
Speaker #2: sickle cell stage of
Speaker #2: disease .
Speaker #2: We look forward to sharing additional results from the pioneer
Please refer to four comes to most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with the company's business.
Speaker #2: at the upcoming Ash conference in
Speaker #2: fulcrum
Speaker #2: Com and is being
Speaker #2: December, we plan to...
Speaker #2: recorded
Speaker #2: engage
Speaker #2: .
Speaker #2: with the of
Speaker #2: Please be
Speaker #2: FDA
Speaker #2: reminded that
Speaker #2: remarks
Speaker #2: during
Speaker #2: this call Business Update
Leading the call today will be Alex Sapir, CEO and president of Fulcrum, Tony Alexander call. Our Ele me, So chief Financial Officer, and Dr. Ian Frazier Senior Vice President clinical development.
Speaker #2: end of phase one
Speaker #2: contain forward looking statements within the meaning of the private Securities Litigation Reform Act of 1995 . May include statements about the company's future expectations and plans , clinical development timelines and financial
Speaker #2: meeting in Q1 Additionally ,
Speaker #2: of we 2026 to align on the
Speaker #2: next stage of our clinical development recently for posterior . Now , outside of
Speaker #2: Syria, presented. We continue to advance our program for the...
Speaker #2: projections . While these forward looking statements represent Fulcrum's views as of today , this should not be relied upon as representing the company's views in the future or may update these statements in the future , but is not taking on any obligation to do so .
They are providing updates on the Companys key programs there will be a brief Q&A in which the fulcrum management team will be available for questions.
Speaker #2: treatment
Speaker #2: of bone Esma this marrow failure syndromes such as diamond-blackfan anemia
Speaker #2: Five deletion syndrome, Shwachman-Diamond syndrome, month.
With that it's my pleasure to turn the call over to Alex.
That's great. Thanks, Shannon and good morning, everybody and thank you all for joining us today.
Speaker #2: anemia , and we plan for an to submit an
Speaker #2: Please refer to full most recent filings with the
Speaker #2: IND for resistant these benign hematological conditions in the fourth quarter of 2025 . Additionally , we recently presented preclinical data at Esma this month
The past several months has certainly been a busy but more importantly, a very exciting time for fulcrum marked by significant progress with our lead program <unk> for the treatment of sickle cell disease, which is an inherited blood disorder with a high unmet need.
Speaker #2: Exchange Commission for discussions of certain risks and uncertainties associated with the company's business. Private leading the.
Speaker #2: call today Securities
Speaker #2: fulcrum .
Speaker #2: Joining as
Speaker #2: Alan Musso chief
Speaker #2: financial officer and doctor Ian Frazier , senior vice president , clinical development . After providing in the
<unk> approximately 100000 people in the U S and approximately $7 7 million people worldwide.
There is an ever increasing need for better treatment options for sickle cell disease patients, who face not only and impaired quality of life due to chronic pain.
Speaker #3: Shannon , and good
Speaker #3: morning , everybody , and thank you all for joining very high us today
Speaker #3: have
Speaker #3: certainly been a busy , but more importantly , a very exciting time for fulcrum marked by a significant
Teig and acute complications like basal occlusive crises, but also very high rates of mortality patients.
Speaker #3: progress greater with our
Speaker #3: treatment of sickle cell disease , which is an inherited blood
Patients with sickle cell disease phase a greater than 20 year reduction in life expectancy with a mortality rate that is nine times higher than the general population.
Speaker #3: disorder with a
Speaker #3: high than the unmet need . Afflicting approximately 100,000 people in the US and
Speaker #3: approximately 7.7 million general people worldwide . There is an ever increasing need for better treatment options for sickle cell disease patients who face not
And so as we continue on our journey to find better treatment options for these patients. We were very encouraged with the data presented this past July from the 12 milligram dose cohort of the phase one b pioneer trial, which demonstrated a potential for <unk> to meaningfully.
Speaker #3: only population , an impaired quality of life due to chronic pain , fatigue , and acute complications
Speaker #3: like and vaso occlusive crises . But
Speaker #3: also so as we very high rates of mortality .
<unk> improved outcomes for people with sickle cell disease.
Speaker #3: Patients with continue sickle
Speaker #3: cell disease face a greater than 20 year reduction in life expectancy , with a mortality rate that
Now digging into that data a little bit more at a high level.
<unk> demonstrated a dose dependent and clinically meaningful increase in fetal hemoglobin.
Speaker #3: is nine times journey to higher than the general population
Speaker #3: . And so as we continue find on our journey to find
Near Pan cellular induction of that fetal hemoglobin or hbf it.
Speaker #3: better treatment options
Speaker #3: for these patients , we were very
Speaker #3: encouraged options with the data presented
Speaker #3: this for these past July from the 12mg dose cohort of the phase one B pioneer trial , which demonstrated a potential for posterior dear to meaningfully improve
Improvement in key Biomarkers of hemolysis, resulting in a subsequent increase in total hemoglobin.
And finally, encouraging reduction in basal occlusive crises or voc's.
Speaker #3: outcomes for patients , we
Speaker #3: people with sickle cell
Equally as important <unk> continued to be well tolerated with all treatment aes being grade one in severity and all resolving during the treatment period without any disruption in study drug.
Speaker #3: disease
Speaker #3: . Now
Speaker #3: , digging
Speaker #3: into July that data a
Speaker #3: little bit more at a
Speaker #3: high level
Speaker #3: , posterior
Speaker #3: demonstrated a
Speaker #3: dose
Speaker #3: dependent and clinically
Speaker #3: meaningful
Speaker #3: increase in
Speaker #3: fetal
Speaker #3: hemoglobin
Speaker #3: near
Speaker #3: pan
These encouraging results achieved our target product profile criteria and position <unk> as a potentially best in class once daily oral therapy for sickle cell disease.
Speaker #3: of that fetal hemoglobin or Hbf . Improvement in key biomarkers of hemolysis
Speaker #3: , resulting hemolysis , in a subsequent increase in total hemoglobin . And finally encouraging reduction in vaso
In August of this year, we submitted a protocol to the FDA to initiate an open label extension or <unk> trial, which will allow patients to continue receiving <unk>. After completing the pioneer trial trial, enabling thus longer term evaluation of safety.
Speaker #3: occlusive, resulting in a crisis or VOCs.
Speaker #3: Equally subsequent as important, posterior continued to be well tolerated, with all.
Speaker #3: treatment AES being
Speaker #3: grade one . in In severity
Speaker #3: and all
Speaker #3: resolving
Speaker #3: treatment
Speaker #3: period without
Speaker #3: any
Speaker #3: In study . Drug
Speaker #3: . These encouraging
And durability of response.
Speaker #3: results achieved our
Speaker #3: target product
We're also pleased to share today that we have completed enrollment in the 20 milligram dose cohort with a total of 12 evaluable patients and we will present data from this cohort at the American Society of Hematology or Ash conference in early December.
Speaker #3: profile
Speaker #3: criteria and
Speaker #3: position
Speaker #3: posterior as a
Speaker #3: best in
Speaker #3: class
Speaker #3: once daily
Speaker #3: oral
Speaker #3: therapy any for sickle cell
Speaker #3: disease disruption
Speaker #3: . In in August of
Speaker #3: this study . year , we submitted a
Speaker #3: protocol
Speaker #3: to the
Speaker #3: to
Speaker #3: an open
Speaker #3: label
Speaker #3: extension or
Speaker #3: only
Speaker #3: trial ,
The over enrollment seen in the 12 and 20 milligram cohorts is a testament to the enthusiasm from the physicians involved in the study.
Speaker #3: which will allow
Speaker #3: patients to
Speaker #3: receiving posterior .
Speaker #3: Dear after
Speaker #3: completing the pioneer
Speaker #3: , enabling
Speaker #3: thus longer term
Now with a number of these 12 patients starting drug in September we expect approximately half of the 12 patients will have completed their day 84 visits and all patients will have completed their day 42 visit at the time of our data cutoff for the Ash meeting.
Speaker #3: evaluation of safety
Speaker #3: durability of response . We're also pleased
Speaker #3: today
Speaker #3: that we have patients to completed enrollment in
Speaker #3: the
Speaker #3: cohort with a
Speaker #3: total
Speaker #3: of 12 evaluable
Speaker #3: patients and will
Speaker #3: present
Speaker #3: data
Speaker #3: from longer this
Speaker #3: at the American
Speaker #3: Society of
Approximately 60% of the patients enrolled in this 20 milligram cohort have come from the U S with the remainder coming primarily from sites in Nigeria, which are newer sites that were not yet activated at the top in time to participate in the 12 milligram cohort.
Speaker #3: , or Ash
Speaker #3: conference
Speaker #3: in
Speaker #3: . The over
Speaker #3: enrollment seen in the
Speaker #3: 20 milligram cohorts is
Speaker #3: a
Speaker #3: testament to the
Speaker #3: from the physicians
Speaker #3: involved in the study
Speaker #3: . Now , with
Speaker #3: a number
Speaker #3: of
Speaker #3: these 12 patients starting
Speaker #3: drug in
Speaker #3: September ,
I mean, and median hbf levels at the start of the study for this cohort were seven 1% and seven 3% respectively.
Speaker #3: expect approximately
Speaker #3: half of
Speaker #3: the
Speaker #3: 12 patients will
Speaker #3: have
Speaker #3: completed
Speaker #3: their day
Speaker #3: all
Speaker #3: patients will have testament to
Speaker #3: completed their the
Speaker #3: day
Speaker #3: day 42 physicians
Speaker #3: visit involved in
Speaker #3: At the time of the earnings call.
Speaker #3: our data
We're also pleased to see patients remaining in this study with a greater than 90% adherence to the once daily oral drug regimen.
Speaker #3: for the
Speaker #3: Ash number of meeting
Speaker #3: 60% of the patients
Speaker #3: enrolled in
Speaker #3: 20 milligram cohort have come
We continue to believe that inducing fetal hemoglobin is the optimal strategy for treating sickle cell disease.
Speaker #3: with the
Speaker #3: remainder coming
Speaker #3: from sites in
Speaker #3: Nigeria , which are
Speaker #3: sites that
Speaker #3: were
Speaker #3: not
Speaker #3: yet
Speaker #3: activated
Evidence for this approach continues to grow as highlighted in our recent presentation earlier. This month at the annual conference for the Academy for sickle cell and thalassemia or as cat for short, where we demonstrated a quantitative correlation between increased fetal hemoglobin levels.
Speaker #3: at the time . cutoff for In
Speaker #3: participate
Speaker #3: the
Speaker #3: 12 milligram cohort . The
Speaker #3: mean and median
Speaker #3: Hbf
Speaker #3: levels at the start of the study for this cohort were 7.1% and 7.3% , respectively . We're also pleased to see patients remaining in
And reduce vasal occlusive crises in sickle cell disease.
Speaker #3: the come
Speaker #3: study with a
Speaker #3: once
This data together with the 12 milligram cohort data that we shared in July gives us confidence that <unk> has the potential to provide a differentiated therapeutic option for people living with sickle cell disease, we look forward to sharing additional results from the pioneer trial.
Speaker #3: drug
Speaker #3: regimen
Speaker #3: We continue
Speaker #3: that
Speaker #3: fetal
Speaker #3: hemoglobin
Speaker #3: is
Speaker #3: the optimal
Speaker #3: strategy
Speaker #3: treating sickle cell
Speaker #3: disease
Speaker #3: .
Speaker #3: Evidence for pleased this
Speaker #3: approach
Speaker #3: continues to
Speaker #3: grow as
Speaker #3: highlighted in our
Speaker #3: recent greater
Speaker #3: Earlier
Speaker #3: this
Speaker #3: at the
Speaker #3: annual conference
Speaker #3: for the Academy for
Speaker #3: Sickle
Speaker #3: Cell and
At the upcoming Ash conference in December and we plan to engage with the FDA for an end of phase one meeting in Q1 of 2026 to align on the next stage of our clinical development for <unk>.
Speaker #3: Thalassemia ,
Speaker #3: Ascat for short ,
Speaker #3: quantitative
Speaker #3: correlation between
Speaker #3: increased fetal hemoglobin levels
Speaker #3: and
Speaker #3: reduced
Speaker #3: vaso
Speaker #3: occlusive
Speaker #3: crises in
Speaker #3: sickle cell
Speaker #3: disease
Speaker #3: This data
Now outside of <unk>, we continue to advance our program for the potential treatment of bone marrow failure syndromes, such as Diamond Black fanned anemia, <unk> deletion syndrome, Schwartzman Diamond syndrome, and fan Kony anemia, and we plan to submit an IND for <unk>.
Speaker #3: , short , together with
Speaker #3: the where we 12 milligram cohort data that we shared in July , gives us confidence
Speaker #3: that
Speaker #3: posterior has the quantitative potential
Speaker #3: to
Speaker #3: provide a
Speaker #3: differentiated
Speaker #3: therapeutic option
Speaker #3: for
Speaker #3: with sickle cell disease . We
Speaker #3: look forward to
Speaker #3: sharing data , additional
Speaker #3: results from the
Speaker #3: pioneer trial at the
These benign hematological conditions in the fourth quarter of 2025.
Speaker #3: conference in
Speaker #3: December , and
Speaker #3: to engage with
Speaker #3: To engage with the Pacira FDA.
Speaker #3: an end of phase
Additionally, we recently presented preclinical data at ESMO. This month for Fts 60 to 70 for an oral <unk> inhibitor, which demonstrated robust efficacy in castration resistant prostate cancer models. We are encouraged by these findings which highly.
Speaker #3: in
Speaker #3: Q1
Speaker #3: of
Speaker #3: 2026 to align on the
Speaker #3: next
Speaker #3: our clinical
Speaker #3: development
Speaker #3: for
Speaker #3: posterior . Dear . Now , outside of posterior Dear , we continue to advance our trial
Speaker #3: the potential treatment
Speaker #3: bone marrow
Speaker #3: failure syndromes such as Diamond-blackfan anemia , five q deletion syndrome , Schwachman-diamond syndrome , and Fanconi anemia , and we plan to submit an IND for these benign haematological conditions in the fourth quarter of 2025 .
The potential of <unk> inhibition beyond our current hematology programs.
And so with that overview, let me now turn it over to Alan Musso, Our Chief financial officer to run through the numbers for the quarter Alan over to you.
Speaker #3: preclinical
Thank you Alex.
Speaker #3: data at potential
Ill go over our results for the third quarter ended September 32025.
Speaker #3: for
Speaker #3: FT 6274, an oral inhibitor, which demonstrated robust efficacy in castration.
Our research and development expenses were $14 3 million for the third quarter of 2025 compared to $14 6 million for the third quarter of 2024.
Speaker #3: prostate cancer
Speaker #3: models . We are Ft encouraged by these findings , which highlight the potential of EED inhibition beyond our current
The decrease of <unk> 3 million was primarily due to decreased employee compensation costs. As a result of the workforce reduction we implemented in September of last year as well as a decrease in costs associated with our discontinued loss Mathematic program.
Partially offset by increased costs relating to advancing our <unk> program.
The general and administrative expenses were $7 6 million for the third quarter of 2025 compared to $8 4 million for the third quarter of 2024.
The decrease of <unk> 8 million was primarily associated with decreased professional service discussed.
The net loss was $19 6 million for third quarter of 2025 compared to a net loss of $21 7 million in the third quarter of 2024.
Now turning to the balance sheet. We ended the third quarter of 2025 with cash cash equivalents in marketable securities of $200 6 million compared.
Compared to $241 million as of December 31, 2024.
The decrease of $40 4 million is primarily due to cash to the cash used to fund our operating activities.
And finally, turning to cash guidance based on our current operating plans, we expect our existing cash cash equivalents in marketable securities will be sufficient to fund our current operating requirements into 2028, providing sufficient runway to substantially progress the clinical development of <unk>.
And with that Alex Let me turn the call back over to you great. Thanks, So much Alan so before opening it up to Q&A with all of you. Let me just conclude with just a couple of.
Final comments <unk> has achieved meaningful milestones in the first three quarters of this year with one of two planned data readouts for our lead program <unk> Dear yielding very encouraging results in sickle cell disease. We're excited about the upcoming data readout at ash and the opportunities ahead.
We are fortunate to have a committed and talented team coupled with a strong balance sheet, which positions us well to achieve our goal of delivering transformative therapies.
And with the opening remarks concluded Shannon, Let's go ahead and.
Operator: Please enter your dial-in PIN and press pound when finished.
Opening up the line for questions.
Thank you Alex to ask a question at this time. Please press star one on one on your telephone and wait for your name to be announced to withdraw your question. Please press star one again.
Alex C. Sapir: Yielding very encouraging results in sickle cell disease. We are excited about the upcoming data readout at ASH and the opportunities ahead. We are fortunate to have a committed and talented team, coupled with a strong balance sheet, which positions us well to achieve our goal of delivering transformative therapies. With the opening remarks concluded, Shannon, let's go ahead and open up the line for questions.
Our first question comes from the line of Kristen <unk> with Cantor Fitzgerald. Your line is now open.
Hi, good morning, everybody. Thanks for taking the questions and for the update today.
I appreciate you disclosing the baseline characteristics for this cohort and it looks pretty similar to what we saw for cohort three.
Operator: Thank you, Alex. To ask a question at this time, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Our first question comes from the line of Kristen Kluska with Cantor Fitzgerald. Your line is now open.
I'm wondering now that we know the baseline characteristics are relatively similar and now that we know.
The inclusion and exclusion criteria is more appropriate to compare apples to apples to these how are you internally thinking about what is a win here and whether ways to measure if there's a dose response.
[Analyst 1]: Hi, good morning, everybody. Thanks for taking the questions and for the updates today. I appreciate you disclosing the baseline characteristics for this cohort, and it looks pretty similar to what we saw for Cohort 3. I'm wondering, now that we know the baseline characteristics are relatively similar, now that we know the inclusion/exclusion criteria is more appropriate to compare apples to apples to these, how are you internally thinking about what is a win here and whether ways to measure if there's a dose response?
Yes, Chris it's a great question, we're going to handle that in two parts.
Start and then I'll turn it over to Ian because I do think there is a there was a nuance for the approximately 50% of the patients for which we have full day 84 data, but in terms of I guess your question about what does the win Yep I would argue.
That we've already won.
If you go back and you look at the 12 milligram cohort, we essentially achieved that target product profile that we felt like we needed to achieve we saw robust and rapid increases in fetal hemoglobin. We saw we were nearing levels of Pan cellular <unk>, we were seeing all of the markers of <unk>.
Alex C. Sapir: Yeah, Kristen, it's a great question. We're going to handle that in two parts. I'll start, and then I'll turn it over to Ian, because I do think there is a nuance for the approximately 50% of the patients for which we have full day 84 data. In terms of, I guess, your question about what is a win, I would argue that we've already won. If you go back and you look at the 12 milligram cohort, we essentially achieved that target product profile that we felt like we needed to achieve. We saw robust and rapid increases in fetal hemoglobin. We saw we were nearing levels of pan-cellularity. We were seeing all of the markers of hemolysis going down as we would have expected, and a subsequent increase in total hemoglobin nearing 1 gram per deciliter at the end of that 12 weeks.
<unk> going down as we would've expected and a subsequent increase and total hemoglobin nearing one gram per deciliter at the end of that 12 weeks, we saw a trend toward a reduction in <unk>, which obviously, we need to confirm and Reggie.
Registrational study and the drug was extremely well tolerated with all of the treatment emergent aes being grade one and severity. So so I would argue that I think.
We have one with the 12 milligram cohort now do we expect to see.
An increase in efficacy for.
For the 'twenty relative to the 12 I think to answer that question, we really have to look at the healthy volunteer data in which we did show a dose response again in healthy volunteers at day 14, when measuring the fold induction of not the protein not fetal hemoglobin, but the <unk>.
Alex C. Sapir: We saw a trend toward a reduction in VOCs, which obviously we need to confirm in a registrational study. The drug was extremely well tolerated with all of the treatment emergent AEs being grade 1 in severity. I would argue that I think we have won with the 12 milligram cohort. Now, do we expect to see an increase in efficacy for the 20 relative to the 12? I think to answer that question, we really have to look at the healthy volunteer data, in which we did show a dose response, again, in healthy volunteers at day 14 when measuring the fold induction of not the protein, not fetal hemoglobin, but the HPG mRNA.
Yeah, Christian, it's a great question. We're going to handle that in, in 2 parts. I'll I'll start. And then I'll turn it over to Ian because I do think there is a, there is a Nuance for the approximately 50% of the patients for which we have full day 84 data. But in terms of, uh, I guess your question about what, what is a win? Yeah, I would argue that, we've already won. Um, if you go back and you look at the 12 milligram cohort, uh, we essentially achieved that Target product profile, that we felt like we needed to achieve. We saw robust and Rapid increases in fetal hemoglobin. We saw, we were nearing levels of pan. Cellularity, we were seeing all of the markers of hemolysis going down, as we would have expected and a subsequent increase in total hemoglobin nearing 1 gram per deciliter, at the end of that 12 weeks, we saw a trend toward a reduction in BC's, which obviously we need to confirm in a in a registrational study and
So I think based on that healthy volunteer data alone. We would expect 20 to outperform the 12, but we will obviously know that.
In just a matter of weeks when we present this data at ash.
And I do think it is probably important to talk a little bit about what we've seen with the.
And the drug was extremely well, tolerated with all of the treatment emerging aees being grade 1 and severity. So, so I would argue that, I think, um, we have 1 with the 12 milligram cohort. Now, do we expect to see, um, an increase in efficacy?
Basically the first half of patients that started on the study and what we plan to present at ash coming up in December.
I'd be happy to address that question from Kristen So based on when the last patients enrolled in the study which was really towards the end of September we expect that about half of the cohort will have completed that.
Alex C. Sapir: I think based on that healthy volunteer data alone, we would expect 20 to outperform the 12, but we will obviously know that in just a matter of weeks when we present this data at ASH. Ian, I do think it is probably important to talk a little bit about what we've seen with basically the first half of patients that started on the study and what we plan to present at ASH coming up in December.
The 84 treatment visit at the time of the data cutoff that will serve.
The ash meeting data presentation, and we expect that we should have 42 day visit available for all the patients all 12 patients in that 20 milligram cohort.
For the 20th to the 12th. I think, to answer that question, we really have to look at the healthy volunteer data in which we did show a dose response again in healthy. Volunteers at day 14 when measuring the fold induction of not the protein, not feel hemoglobin but the hpg MRNA. So I think based on that healthy volunteer data alone, we would expect 20 to outperform the 12, but we will obviously know that in in in in just a matter of weeks when we present this data um at Ash, um, Ian, I do think it is probably, um, important to talk a little bit about what we've seen with the
Interestingly for those.
Ian: Yeah, absolutely, Alex. Happy to address that question from Kristen. Based on when the last patient was enrolled in the study, which was really towards the end of September, we expect that about half of the cohort will have completed the day 84 treatment visit at the time of the data cutoff that will serve the ASH meeting data presentation. We expect that we should have a 42-day visit available for all the patients, all 12 patients in that 20 milligram cohort. Interestingly, for those patients that have completed the full 84-day treatment period, and these were the earliest patients enrolled in the cohort, their baseline HbFs have tended to skew on the lower end of the range.
Patients that have completed the full 84 day treatment period.
And these were the earliest patients enrolled in the cohort their baseline hbf have tended to skew on the lower end of the range and so when we present that data once we have the exact number of patients for that cutoff I think it will be very important.
To accommodate the baseline for those 60% or so of the patients.
And then obviously when we released the full 84 data once everybody has completed the full treatment period.
Basically the first half of patients that that started on the study and what we plan to present at uh at Ash coming up in December. Yeah, absolutely Alex happy happy happy to address that question from Kristen. So based on when the last patients enrolled in the study which was really towards the end of September, we expect that about half of the cohort will have completed the the day 84 uh, treatment visit at the time of the day to cut off, that will serve um, the the ash meeting data presentation and we expect that we should have 42 day. Uh, visit available for all the patients, all 12 patients in that 20 Mig cohort
That will reflect the seven 1%. So it did just wanted to highlight that piece for the for the partial cohort data that we'll be sharing later this year.
Ian: When we present that data, once we have the exact number of patients for that cutoff, I think it'll be very important to accommodate the baseline for those 50% or so of the patients. Obviously, when we release the full day 84 data, once everybody's completed the full treatment period, that'll reflect the 7.1%. I did just want to highlight that piece for the partial cohort data that we'll be sharing later this year.
Okay. Thanks for that color and then the OLED study I know in the past you've noted it was something you are looking into but I think this is the first time, you've officially announced plans to.
Sorry.
I'm curious if there was interest from the patients that were in the trial of the physicians that have been investigators in the study and also how this study may also help with some of your future FDA discussions. Thanks again, yes, great.
Great Great question, Kristen and Youre, absolutely right I think that the timing of starting the <unk> study was quite frankly, it was really born out of discussions that I had with.
Interestingly for those uh patients that have completed the full 84 day, treatment period and and these were the earliest patients enrolled in the cohort their Baseline, HBS have tended to skew on the lower end of the range. And so, when we present that data, uh, once we have the exact number of patients, uh, for that cutoff, I think it'll be very important, um, to, uh, to accommodate the Baseline for those 50% or so of the patients. Um, and then, obviously, when we release the full day 84 data, once everybody's completed the full treatment period, um, that will reflect the 7.1%. So, I did just want to highlight that piece for the, for the partial cohort data, that we'll be sharing later this year.
[Analyst 1]: Okay, thanks for that color. The open-label extension (OLE) study, I know in the past you've noted it was something you're looking into, but I think this is the first time you've officially announced plans to start that. I'm curious if there was interest from the patients that were in the trial, the physicians that have been investigators in the study, and also how this study may also help with some of your future FDA discussions. Thanks again.
With several of the investigators in which they were expressing to me some of their patients anxiety as those patients were getting closer and closer to day 84, and that we really didn't have anything at the time to offer them. Once the 12 weeks of dosing was was up and so in light of that we really decided.
To kick off this OA study.
Alex C. Sapir: Yeah, great question, Kristen. You're absolutely right. I think that the timing of starting the open-label extension study was, quite frankly, really born out of discussions that I had had with several of the investigators, in which they were expressing to me some of their patients' anxiety as those patients were getting closer and closer to day 84, in that we really didn't have anything at the time to offer them once the 12 weeks of dosing was up. In light of that, we really decided to kick off this open-label extension study earlier than we had initially planned in order to allow some of those patients in the PIONEER trial to come off of, once they come off of drug, to be able to roll into an open-label extension.
Earlier than we had initially planned in order to allow some of those patients in the pioneer trial to come off of.
Once they come off the drug to be able to roll into an open label extension.
I will tell you that in the conversations that I've had with the investigators they were they were quite happy that.
Their voice is heard and as a result of their voice being heard we reacted.
Accordingly in terms of how this Ian maybe in terms of how this data may help inform future discussions with the agency do you want to comment a little bit on that yeah happy to do that Alex. So that study is now being operationalized at the moment and I think one of the key aspects of that.
Okay, thanks for that color and then the, um, Ole study, I know in the past you've noted it was something you're looking into, but I think this is the first time you've officially announced plans to start that. So, I'm curious if there was interest from the patients that were in the trial, the Physicians that have been uh, investigators in the study and also how this study may also help with some of your uh, future FDA discussions. Thanks again. Yeah, great, great question, Kristen and you're absolutely right. I I think that the timing of starting the Ole study was quite frankly. It was really born out of discussions that I had had, uh, with several of the investigators in which they were expressing, to me, some of their patients anxiety. As those patients were getting closer and closer to, to day 84 in that, we really didn't have anything at the time to offer them, once the 12 weeks of dosing was was up. And so, in light of that we really decided
Following us too to continue treatment in those patients who previously were restricted to three months contained within the pioneer study allows us to generate additional safety data in that patient population, which I think overall for the program is going to be an important piece.
Alex C. Sapir: I will tell you that in the conversations that I've had with the investigators, they were quite happy that their voice was heard, and as a result of their voice being heard, we reacted accordingly. In terms of how this, Ian, maybe in terms of how this data may help inform future discussions with the agency, do you want to comment a little bit on that?
Decided to kick off this Ole study, um, earlier than we had initially planned in order to allow some of those patients in the Pioneer trial to come off of, uh, when once they come off of drug to be able to roll into an open label extension. So I I, I will tell you that in the conversations that I've had with the investigators, they were, they were, they were quite happy that
Thanks, a lot.
Kristen next question Shannon.
Our next question comes from the line of Joseph P. Schwartz with Leerink partners. Your line is now open.
Ian: Happy to do that, Alex. That study is now being operationalized at the moment, and I think one of the key aspects of that, allowing us to continue treatment in those patients who previously were restricted to the three months contained within the PIONEER trial, allows us to generate additional safety data in that patient population, which I think overall for the program is going to be an important piece.
Great. Thanks, so much and congrats on the progress I was wondering if you can give us any insight into the baseline level of hbf.
For the patients in the first half of the 20 milligram cohort that will get data on first and how it compares to the second half of patients who were enrolled.
Yes, great Great question, Joe I think to answer that let me, let me turn that one over to Ian He's obviously been very very close to each of these patients and very close to the study as well yes.
[Analyst 1]: Thanks a lot.
You know, their their voice was heard and as a result of their voice being heard, we reacted um, accordingly in terms of how this Ian maybe in terms of how this data may help inform future discussions that the agency. Do you want to comment a little bit on that? Yeah, happy to do that. So that that study is now being operationalized at the moment. And I think 1 of the key aspects of that um, allowing us to to continue treatment in those patients who previously were restricted to the 3 months? Um, contained within the Pioneer study allows us to generate additional safety data in that patient population. Which I think overall, for the program is going to be an important piece.
Alex C. Sapir: Thanks, Kristen. Next question, Shannon.
Operator: Our next question comes from the line of Joseph P. Schwartz with Leerink Partners. Your line is now open.
As we said the <unk>.
Thanks a lot. Thanks Christian. Next question, Shannon.
Initial patients enrolled have tried.
Lower than that seven 1%, which reflects the entire 12 patients in the cohort.
Alan Musso: Great, thanks so much, and congrats on the progress. I was wondering if you can give us any insight into the baseline level of HbF for the patients in the first half of the 20 mg cohort that we'll get data on first and how it compares to the second half of patients who were enrolled?
Our next question comes from the line of Joseph P. Schwarz. With luring Partners your line is now open.
Because we don't know exactly where the cut is going to be with a 50% depending on which samples to the lab and plans of the data cutoff.
Haven't given the precise number there.
Alex C. Sapir: Yeah, great question, Joe. I think to answer that, let me turn that one over to Ian. He's obviously been very, very close to each of these patients and very close to the study as well.
We will obviously have that when we have those exact data and we will reveal that at the time of the data disclosure, but I think it is important just thinking ahead that that <unk>.
Great. Thanks so much. Um, and congrats on the progress. Um, I was wondering if you can give us any insight into the Baseline level of hbf. Uh, for the patients in the first half of the 20 milligram cohort that will get data on First and how it compares to the second half of patients, who are enrolled.
Ian: Yeah, as we said, Joe, the initial patients enrolled have trended lower than that 7.1% mean that reflects the entire 12 patients in the cohort. Because we don't know exactly where the cut is going to be with the 50%, depending on which samples get to the lab in time for the data cutoff, we haven't given the precise number there. We will obviously have that when we have those exact data, and we'll reveal that at the time of the data disclosure. I think it is important, just thinking ahead, that overall the trend there was, just by chance, the initial patients enrolled in the cohort were on average lower than the 7.1% mean.
<unk> the trend there was just by tons. The initial patients enrolled in cohort four on average lower than the seven one.
Yes.
Just to sort of add a little bit on what Christian said earlier now we can look at sort of apples to apples and the fact that we now have a lower baseline for the roughly 50% of patients will have completed data for by by the time of Ash.
We're looking really more like apples to orange is and the way to account for differences in baseline is to really look at that fold induction curve. So thats one of the slides that we included in our investor presentation, comparing the six milligram to the 12 milligram. So I encourage everybody to look at that because the fact that these patients.
Yeah, great. Great question Joe. I think to answer that, let me, let me turn that 1 over to uh, to Ian. He's obviously been very, very close to each of these patients and and and very close to the study as well. Yeah. And as we said, Joe the, the, the initial patients enrolled have tried to lower than that 7.1% mean that reflects the entire 12 patients in the cohort. Um, because we don't know exactly where the cut is going to be with the 50% depending on which samples, get to the lab in times of the data cut off. Um, we haven't given the precise number there. Uh, we, we will obviously have that when we, we have those exact data and, and we'll reveal that at the time.
Alex C. Sapir: Yeah, maybe just to sort of add a little bit on what Kristen said earlier, now we can look at sort of apples to apples, and the fact that we now have a lower baseline for the roughly 50% of patients that will have completed day 84 by the time of ASH, we're looking really more at like apples to oranges. The way to account for differences in baselines is to really look at that fold induction curve. That's one of the slides that we've included in our investor presentation, comparing the 6 milligram to the 12 milligram.
Of the data disclosure, but I think it is important. Just thinking ahead that that overall the trend there was just by chance, uh, the initial patients enrolled in the cohort who are, uh, on average lower than the 7.1 mean,
The first half of patients had tended to be on the lower end of that average we will certainly look at that sort of full deduction because that is one way to essentially sort of normalize for differences in.
The baseline, but I think suffice it to say Joe clearly the first half of the patients had a lower baseline and then obviously the second half of those patients tended to be a bit higher than the seven one to seven three that we mentioned in our in our opening remarks.
Alex C. Sapir: I encourage everybody to look at that, because the fact that these patients, the first half of patients, had tended to be on the lower end of that average, we'll certainly look at that sort of fold induction, because that is one way to essentially sort of normalize for differences in the baselines. I think suffice it to say, Joe, clearly the first half of the patients had a lower baseline, and then obviously the second half of those patients tended to be a bit higher than the 7.1 and the 7.3 that we mentioned in our opening remarks.
Okay, great. Thanks for the insight and then how are you currently thinking about the addressable market. Following our spreaders withdraw and can you give us some insight into your assumptions that go into your current estimate.
Yeah, and maybe just to sort of add a little bit on on, what Kristen said earlier. And, you know, now we can look at sort of Apples to Apples. A, and the fact that we now have a lower Baseline for the roughly 50% of patients that will have completed data. 84, by, by the time of Ash, um, we're looking really more at like apples to oranges. And the way to account for differences in baselines is to really look at that fold. Induction curve. So that's 1 of the slides that we've included in our um investor presentation comparing the 6 milligram to the 12 milligrams. So I I encourage everybody.
Yes.
It's a great question so.
We really have sort of evaluated the market based on.
The data that exist out there in terms of what percent of patients have what have what number of doses in the course of.
Given year and our belief is that.
Alan Musso: Okay, great, thanks for the insight. How are you currently thinking about the addressable market following Aspartase withdrawal? Can you give us some insight into your assumptions that go into your current estimate? Thanks.
To look at that because the fact that these patients the the the first half of patients had tended to be on the lower end of that average will certainly look at that sort of full deduction because that is 1 way to essentially sort of normalize for differences in um, in in the baselines. But I think suffice it to say, Joe clearly the first half of the patients had a lower Baseline. And then, obviously the second half of those patients tended, to be a bit higher than the, than the 7.1 and the 7.3 that we mentioned in our, in our opening remarks,
About 25%.
Patients have either four vlccs during a 12 month period of time or <unk>. During a six month period of time, but obviously because our drug at present cannot be concomitantly use with hydroxyurea. Some of those patients are currently on Hydroxyurea and.
Alex C. Sapir: Yeah, it's a great question. We really have sort of evaluated the market based on the data that exists out there in terms of what % of patients have what number of VOCs in the course of a given year. Our belief is that about 25% of patients have either four VOCs during a 12-month period of time or two VOCs during a six-month period of time. Obviously, because our drug at present cannot be concomitantly used with hydroxyurea, some of those patients are currently on hydroxyurea, and we've taken a bit of a haircut. What we estimate right now is that roughly about 20% of the 100,000 patients in the U.S. currently meet the inclusion/exclusion criteria as defined in the PIONEER trial.
Some insight into your assumptions, uh, that go into your current estimate. Um,
Thanks. Yeah, it's uh, it's it's it's a great question. So um
So we've taken a bit of a a bit of a haircut. So what we estimate right now is that roughly about 20% of the 100000 patients in the U S.
Currently meet.
The inclusion exclusion criteria as defined in the.
In the pioneer trial now obviously, when when we get to.
Those conversations with the agency certainly one of the questions that we will be asking them is the potential to expand to a broader set of patients, but I will say overarching Lee.
Sure.
Our our overarching goal with this program is to get this drug to the market as quickly as possible because as you mentioned.
Patients don't have the treatment options that they did several years ago with the withdrawal of ox brighter the cell and gene therapy is really not been too terribly successful commercially because of the costs and risks risks and the complexities of that of that therapy. So our overarching goal and something that I continue to stress to this team is.
Alex C. Sapir: Obviously, when we get to those conversations with the agency, certainly one of the questions that we will be asking them is the potential to expand to a broader set of patients. I will say, overarchingly, our overarching goal with this program is to get this drug to the market as quickly as possible, because, as you mentioned, patients don't have the treatment options that they did several years ago with the withdrawal of Aspartame. The cell and gene therapy is really not being too terribly successful commercially because of the cost and risks and the complexities of that therapy.
We we really have sort of evaluated the market based on, um, the data that exists out there in terms of what percent of patients have, what have have, what number of boc's in the course of a of a given year. And our belief is that um, about 20% of patients have either 4 VOC during a 12-month period of time or 2 vaccines period of time. But obviously, because our drug at present cannot be conveniently used with hydroxyurea, some of those patients are currently on hydroxy Rhea and so we've taken a bit of a, a bit of a haircut. So what we estimate right now is that roughly about 20% of the 100,000 patients in the US, um, currently meet, um, the inclusion exclusion criteria is defined in the uh, in in, in the Pioneer trial. Now, obviously, when when
<unk>.
We have to make sure that we get this drug to the market as quickly as possible to help as many patients as we possibly can not just in the U S. But globally for the $7 7 million patients who have sickle cell disease outside of the U S.
When we get to um those conversations with the agency, you know, certainly 1 of the questions that we will be asking them is the potential to expand to a broader um set of patients. But I will say, you know, overarching you know our our
Makes sense. Thank you, yes. Thanks, Joe Thanks for the question Shannon next question.
Our next question comes from the line of Karen Johnson with Goldman Sachs. Your line is now open.
Alex C. Sapir: Our overarching goal, and something that I continue to stress to this team, is we have to make sure that we get this drug to the market as quickly as possible to help as many patients as we possibly can, not just in the U.S., but globally, for the 7.7 million patients who have sickle cell disease outside of the U.S.
I think maybe.
Two from us.
Think about kind of the 20 million dose cohort, maybe think about the full data set that you would get later, what do you need to see from that for that to be they'll go for phase III considering your point earlier that you've kind of already won with 12 Meg.
And then what's included in the cash runway guidance with respect to the scope of the phase III program, maybe you could speak about duration and endpoints that would be.
Alan Musso: Makes sense, thank you.
Our our overarching goal with this, uh, program is to get this drug to the market as quickly as possible, because as you mentioned, you know, patients don't have the treatment options that they did several years ago with the withdrawal of ox braa the cell and gene therapy is really not being too terribly, successful commercially, because of the costs and Rick's risks and the complexities of that of that therapy. So our overarching goal and something that I continue to stress to this team is, you know, we, we have to make sure that we get this drug to the market as quickly as possible to help as many patients as we possibly can not just in the US. But but globally for the 7.7 million patients who have sickle cell disease outside of the US.
Alex C. Sapir: Yeah, thanks, Joe. Thanks for the question. Shannon, next question?
And that guidance. Thank you yeah, yeah, great two great questions, Great, maybe I'll turn it over to Ian for the first half of that question and then turn it over to Alan for your for your second question.
Operator: Our next question comes from the line of Corinne Johnson with Goldman Sachs. Your line is now open.
Makes sense. Thank you. Yeah, thanks, Joe. Thanks for the question, Shannon. Next question.
[Analyst 2]: Thanks. Maybe two from us. As you think about kind of the 20 mg dose cohort, and maybe think about the full data set that you get later, what do you need to see from that for that to be the go-forward Phase 3 dose, considering your point earlier that you've kind of already won with 12 mg? What's included in the cash runway guidance with respect to the scope of a Phase 3 program? Maybe you could speak about duration and endpoints that would be included in that guidance. Thank you.
Our next question comes from the line of Corin Johnson with Goldman Sachs your line is now open.
Thanks maybe. Um,
Yeah. Thanks, Karen.
Importantly, we'll be looking across the totality of the data and the 20 milligram cohort.
And we obviously would be delighted to see that the efficacy endpoints in the study are indicating improvements.
2 from us as you think about kind of the 20 mg dose cohort and maybe think about this the full data set that you get later. What do you mean to see from that for that to be the go forward phase 3 dose? Considering your point earlier that you've kind of already won with 12 meds.
With an ongoing favorable tolerability and safety profile and ongoing good adherence to the study drug.
Alex C. Sapir: Yeah, great, two great questions, Corinne. Maybe I'll turn it over to Ian for the first half of that question, and then turn it over to Alan for your second question.
We will obviously be paying close attention to the hbf levels with a particular emphasis as we've alluded to in some of the comments that we've made this morning on the dose response as measured by a fold induction of hbf.
Ian: Yeah, thanks, Corinne. I think importantly, we'll be looking across the totality of the data in the 20 milligram cohort, and we obviously would be delighted to see that the efficacy endpoints in the study are indicating improvement with an ongoing favorable tolerability and safety profile and ongoing good adherence to the study drug. We'll obviously be paying close attention to the HbF levels, with a particular emphasis, as we've alluded to in some of the comments that we've made this morning, on the dose response as measured by a fold induction of HbF. Based on the induction of HBG mRNA that we observed at 14 days in the prior healthy volunteer study, we do expect that the 20 milligram dose cohort could well outperform that which we observed at the 12 milligram cohort.
And then what's included in the cash Runway, guidance is respect to the scope of a phase 3 Program. Maybe you could speak about duration and inputs, that would be, um, included in that guidance. Thank you. Yeah, yeah, great to 2 2, great questions. Grim, maybe I'll I'll turn it over to Ian for the first half of that question. And then turn it over to Alan for your for your second question.
Based on the induction of HBV mrna that we observed at 14 days in the prior healthy Volunteer study, we do expect that the 20 milligram dose cohort could well outperform that which we observed at the 12 milligram cohort and I think one of the key learnings from the 12 milligram data.
Readout as we compare there the 12 milligram to the previous six milligram readout I think it really was very important to look at that.
Yeah, thanks, Karen. Um, so I think importantly, we'll be looking at the totality of the data in the 20 milligram cohort, um, and, and we obviously would be delighted to see that the efficacy endpoints in. The study are indicating improvements uh with an ongoing favorable, tolerability and safety profile and ongoing. Good adherence to the study drug.
As a fold induction because the baselines across those cohorts with different in that please plays a big role will also be looking to ensure that we are seeing a response in hbf across all patients were focused on the extent to which we achieve and.
So the authority, we're looking at improvements of markers of hemolysis.
Ian: I think one of the key learnings from the 12 milligram data readout, as we compare the 12 milligram to the previous 6 milligram readout, it really was very important to look at that as a fold induction, because the baselines across those cohorts were different, and that plays a big role. We'll also be looking to ensure that we are seeing a response in HbF across all patients. We're focused on the extent to which we achieve pan-cellularity. We're looking at improvements of markers of hemolysis, improvements in anemia, and trends of improvements in VOCs, while obviously the study isn't powered specifically around the VOCs. Overall, we expect and will be looking for continued safety and tolerability, as we've observed across both the healthy volunteers and the patients that we've treated to date.
Improvements in anemia and trends of improvements in POC as well obviously the study is powered specifically around the doses and then overall we expect.
And we'll be looking for continued safety and Tolerability as well as we have observed across both healthy volunteers and the patients that we've treated to date.
And Karen on the your question on cash runway and guidance.
That is a full success sort of forecast for the organic programs. So we basically.
You know, obviously be paying close attention um, to the hbf levels with a particular emphasis as we've alluded to in some of the the comments that we've made this morning on the dose response as measured by a fold, induction of hbf. Um, based on the induction of hbg mRNA that we observed at 14 days in the prior healthy, volunteer study, we do expect uh that the 20 milligram dose cohort could well outperformed that which we observed at the 12 milligram cohort. I think 1 of the key learnings from the 12 milligram data readout as we compare their the 12 milligram to the previous 6 milligram readout. I think it really was very important to look at that um as a fold induction because the baselines across those cohorts were different in that place plays a big role. They'll also be looking to ensure that we are seeing a response in hbf across all patients. We're Focus.
Anticipate moving forward with posterior to the next trial, we've talked to a number of Crows have mapped out what we think that could look like and feel very good that that is fully accounted for as we move forward with the cash guidance. We also anticipate moving forward with the program for DB.
And some of those other bone marrow failure syndromes as well as continued.
Alan Musso: Yeah, Corinne, on your question on cash runway and guidance, that is a full success sort of forecast for the organic program. We basically anticipate moving forward with pociredir to the next trial. We've talked to a number of CROs who have mapped out what we think that could look like, and I feel very good that that is fully accounted for as we move forward with the cash guidance. We also anticipate moving forward with the program for DBA and some of those other bone marrow failure syndromes, as well as continued progression of work that's in the preclinical phase. It's sort of an all-in, full success of what we have going on in the pipeline at this time.
Progression, but work in the preclinical phase so it's sort of all in.
And we'll be looking for continued safety and tolerability. As we as we have observed across, both the healthy volunteers and the patients that we've treated today.
<unk> success.
We have going on in the pipeline at this time.
That's great. Thanks. Thanks for the question Karen Shannon next question. Our next question comes from the line of Edward <unk> with Piper Sandler. Your line is now open.
Great. Thank you good morning, everybody. Thanks for all the.
The detail that you provided really excited to see the results down in Orlando and I'll, just a couple of weeks.
My first question relates to deal with what do you think is actually going to be published.
In the.
Abstract clearly.
And it probably won't be the full data.
Yeah, and Karen on your question on cash Runway and guidance, uh, that is a full success, sort of forecast uh, for the organic program. So we basically, uh, anticipate moving forward with posterior dear to the next trial, we've talked to a number of crows have mapped out what we think that could look like, and I feel very good that that uh, is fully, uh, accounted for as we move forward with the cash guidance. We also anticipate moving forward with the uh, program uh, for DBA and some of those other bone marrow, failure, syndromes as well as continued, uh, you know, progression of a work that's in the pre-clinical phase. So it's sort of an all-in, uh, full success of what we have going on and in the pipeline at this time.
Alex C. Sapir: That's great. Thanks for the question, Corinne. Shannon, next question?
But just wanted to get a sense for what you think might actually be.
Operator: Our next question comes from the line of Edward Tenthoff with Piper Sandler. Your line is now open.
In the abstract versus what you sort of laid out in terms of what you'll be presenting at ash.
That's great. Thanks for the question, Karen. Uh, Shannon, next question.
[Analyst 3]: Great, thank you. Good morning, everybody. Thanks for all the detail that you provided. Really excited to see the results down in New Orleans in just a couple of weeks. My first question really has to do with what do you think is actually going to be published in the ASH abstract release? It probably won't be the full data set, but I just want to get a sense for what you think might actually be in the abstract versus what you sort of laid out in terms of what you'll be presenting at ASH. Do you think that'll be a poster or an oral presentation? Thank you.
And do you think that will be a poster or an oral presentation. Thank you.
Our next question comes from the line of Edward Tentoff with Piper Sandler. Your line is now open.
Great two great questions Ted Yes.
So the abstract that will be made public.
By Ash next Monday November 3rd.
It does not include any of the data from the from the 12 milligram sorry from that from the 20 milligram cohort. It does include data from the 12 milligram cohort, but theres no.
Great, thank you. Good morning, everybody. Thanks for all the detail that you provided. I’m really excited to see the results down in Orlando in just a couple of weeks. My first question really has to do with what do you think is actually going to be published?
In the um, Ash abstract release.
and,
Full data set. But
Data in the 20 milligram cohort was really up.
Holder to ensure that we could get a spot at the at the Ash Conference and then in terms of in terms of whether its a poster or an oral that that will get released by by ash on Monday. So we think it's just to respect the.
Alex C. Sapir: Yeah, great, two great questions, Ted. The abstract that will be made public by ASH next Monday, November 3rd, does not include any of the data from the 20 milligram cohort. It does include data from the 12 milligram cohort, but there's no data in the 20 milligram cohort. It was really a placeholder to ensure that we could get a spot at the ASH conference. In terms of whether it's a poster or an oral, that will get released by ASH on Monday. We think it's just to respect the process that ASH has. We feel like it's probably most appropriate and prudent to really let ASH share all of the abstracts in sickle cell and hematology that have been accepted, and then which of those have been accepted for poster, and which of those have been accepted for an oral presentation. Stay tuned.
In the abstract versus what you sort of laid out in terms of what you'll be presenting to us. And do you think that'll be a poster or an oral presentation? Thank you. Yeah. Great, two great questions, Ted. Yeah. So the abstract that will be made public...
The process that <unk> has we feel like it's probably most appropriate imprudent to really let ash share all of the abstracts in sickle cell and hematology that had been accepted and then which of those have been accepted for poster and which of those have been accepted for an oral presentation. So stay.
Hey tune, we'll know more we'll know a lot more on out on Monday.
Great and then one quick follow up if I may and I appreciate it.
Sort of the extra color with respect to the.
Early paces, maybe being on the lower baseline side, we saw that the higher the baseline the more.
We have the more response when you look at sort of all of the factors what really is most important.
Both to Kols.
So in terms of really defining the activity of course here there is it.
Alex C. Sapir: We'll know a lot more on Monday.
By Ash next Monday, November 3rd, um, does not include any of the data uh, from the from the 12 mil. Sorry, from the, from the 20m in data from the 12 milligram cohort, but there's no um, data in the 20 milligram cover, it was really a, a, a placeholder to ensure that we could get a spot at the, uh, at the ash conference and then in terms of, um, in terms of whether it's a poster or an oral that that will get released by um, by Ash on Monday. So we we think it's just to respect the the process that Ash has we feel like it's probably most appropriate and prudent to really let, um, Ash share all of the abstracts in sickle cell and hematology that um, have been accepted and then which of those have been accepted for posture and which of those have been accepted for an oral presentation. So state,
[Analyst 3]: Great. One quick follow-up, if I may, and I appreciate sort of the extra color with respect to the early patients maybe being on the lower baseline side, and we saw that the higher the baseline, the more HbF, the more response. When you look at sort of all of these factors, what really is most important, both to KOLs, regulators, and yourself, in terms of really defining the activity of FTX-6058? Is it the % HbF? Is it the percentage of patients above 20%? Is it the total HbG? What is really the most important, or is it the totality of all of that data?
The percent Hbf.
Stay tuned. We'll know more, we'll know a lot more on uh on on Monday.
Percentage of patients above.
'twenty is at the total HPT what is really the most important or is it the totality of all of that data.
Yes, it's a great question and I'll start, but Ian will probably have better a better answer than I will in the Congress and I've had a lot of conversations with a lot of investigators not only in the U S, but outside of the U S.
Since the data.
We released in July around the 12 milligram and when I sort of pressure tested youre very your question with them which is.
If you look across these five parameters rate increasing levels of fetal hemoglobin the pan cellular <unk>. The decrease in markers of hemolysis subsequent increase number for the subsequent increase in total hemoglobin and then a trend towards a reduction in voc's and doing that all with a once daily oral that obviously.
Alex C. Sapir: Yeah, it's a great question, and I'll start, but Ian will probably have a better answer than I will. In the conversation, and I've had a lot of conversations with a lot of investigators, not only in the U.S., but outside of the U.S., since the data we released in July around the 12 milligram. When I sort of pressure-tested your question with them, which is, if you look across these five parameters, right, increasing levels of fetal hemoglobin, the pan-cellularity, the decrease in markers of hemolysis, number four, the subsequent increase in total hemoglobin, and then a trend toward a reduction in VOCs, and doing that all with a once-daily oral that obviously is shown to be very well tolerated, I've asked that question, which of those five criteria are most important to you? They essentially have all come back to me and said it's really the totality.
Great. And then 1 quick follow up if I met and I appreciate um sort of the extra color with respect to the um early patients maybe being on the lower Baseline side and we saw that the higher, the Baseline, the, the more um hvf, the more response. When you look at sort of all of these factors what really is most important, um, both to kl's regulators and yourself, in terms of really defining the activity of pachare, is it? You know, the percent hbf, is it the percentage of patients above, um, 20 is it the total hbt. What is really the most important or is it the totality of all of that data?
As shown to be very well tolerated I've asked that question, which of those sort of five criteria are most important to you and they essentially have all come back to me and said, it's really the totality you can't you can't really pinpoint one versus another we know fetal hemoglobin will reduce the ocs, we know that increasing total here.
Yeah, it's a it's a great question and and, and I'll start but Ian will probably have a better better answer than than I will, you know, in the conversation. And I've had a lot of conversations with a lot of investigators. Not only in the US but outside of the US, uh, since the data
Mclaughlin will reduce fatigue that patients feel which is very important for them and we know that the increase in fetal hemoglobin. It is.
Imperative that that happens at a pan cellular level right. That's one of the sort of knocks on hydroxyurea is that they're not able to get to sort of 70% of all the red blood cells, having the presence of that so I really think it's it's each one of those criteria that.
Alex C. Sapir: You can't really pinpoint one versus another. We know fetal hemoglobin will reduce VOCs. We know that increasing total hemoglobin will reduce fatigue that patients feel, which is very important for them. We know that the increase in fetal hemoglobin, it's imperative that that happens at a pan-cellular level, right? That's one of the knocks on hydroxyurea, is that they're not able to get to 70% of all the red blood cells having the presence of ASH. I really think it's each one of those criteria that we shared in July that they find impressed with the overall profile of the product. Ian, anything you'd like to add?
That we shared in July that there that.
What they find.
Impressed with the overall sort of profile.
The product in anything you learned last night.
Sorry go ahead Kevin.
The thing I would add is that getting patients into that 20% plus range is obviously associated with really very dramatic benefits in the outcomes of the disease and I think thats important and what we showed at the 12 milligram dose where about half of the patients were able to achieve that I think is particularly helping.
But I do want to also recognize and we've heard this as well is that there are some patients who really have very low baseline hbf.
Two three.
<unk>, 4% ranged often associated with very severe disease for those patients to get right up into the Twenty's is a much bigger claim but providing them with a three fold induction.
Ian: Oh, yeah, sorry, go ahead. Go ahead, please. No, the only thing I would add is that getting patients into that 20%+ range is obviously associated with really very dramatic benefits in the outcomes of the disease, and I think that's important. What we showed at the 12 milligram dose, where about half of the patients were able to achieve that, I think is particularly encouraging. I do want to also recognize, and we've heard this as well, that there are some patients who really have very low baseline HbFs in the 2%, 3%, 4% range, often associated with very severe disease. For those patients to get right up into the 20s is a much bigger climb. Providing them with a threefold induction, an increase over their baseline, really is considered to be associated with significant benefit for those patients.
An increase over their baseline really is.
Is considered to be associated with significant benefit for those patients. So I think they are they are both aspects of our operational here that we will be able to get some of the patients into that really transformative range and for those starting out really low you can make a dramatic impact.
Doc's. We know that increasing total hemoglobin will reduce fatigue. That patients feel, which is very important for them. And we know that the increase in fetal hemoglobin, it's imperative, that that happens at a, at a pan cellular level, right? That's 1 of the sort of knots on hydroxyurea is that they're not able to get to sort of 70 cells having the presence of half. So I really think it's, it's each 1 of those criteria, um, that we shared in July that they're, you know, that they find, um, impressed with the overall sort of profile of the um, of of the product in anything you. Oh yeah, sorry, go ahead. Go ahead. Please know that. The only thing I I would add is that you know getting patients into that. 20% plus range is obviously associated with really, very dramatic benefits in the outcomes of the disease and I think that's important and uh what we showed at the 12 milligram dose were about half of the patients were able to achieve
Their disease, even though you may not quite get them up to that.
Fully transparent range.
And then lastly, when would we get the final pursuit pioneer.
Pioneer dataset, we think that would be the other way.
Next year, yes.
Yes.
It's a great question Ted.
That I think is particularly important, but I do want to also recognize and we've heard this as well, is that there are some patients who really have very low Baseline. HBS in the, you know, 2 3, uh, 4% range often associated with very severe disease and for those patients, to get right up into the 20s is is a much bigger climb. But providing them with, you know, A 3-fold induction, um, an increase over their Baseline.
Based on from what I can remember most patients should be wrapped up with their dosing sometime by the.
Ian: I think both aspects are operational here, that we will be able to get some of the patients into that really transformative range. For those starting out really low, you can make a dramatic impact on their disease, even though you may not quite get them up to that fully transformative range.
Very much to the very end of this year and so we would expect to have the full data set to share with everybody sometime in the first quarter of next year.
Great. Thanks, guys really a credit for all the upcoming Dana yes. Thanks, Ted So we I appreciate I appreciate the questions.
[Analyst 3]: Lastly, when would we get the final PIONEER data set? Do you think that would be all the way at EHA next year?
Really is is is considered to be associated with significant benefit for those patients. So I think they're they're both aspects are operational here that we will be able to get some of the patients into that early transformative range. And for those starting out really low, you can make a dramatic impact on their disease, even though you may not quite get them up to that, that that fully transforms range.
Shannon next question.
Our next question comes from the line of Matthew Biegler with Opco. Your line is now open.
Alex C. Sapir: Yeah, it's a great question, Ted. Based on, from what I can remember, most patients should be wrapped up with their dosing sometime very much to the very end of this year. We would expect to have the full data set to share with everybody sometime in the first quarter of next year.
Hey, guys. Thanks for the update.
To follow up on the demographics I know, we've talked about it a bit but it sounds like if I'm reading between the lines from <unk> comments earlier that the Nigerian patient patients might be a bit thicker.
And then lastly what would we get the final percent um, Pioneer data set? Do you think that would be all the way at eha next year? Yeah, it's a it's a, it's it's a great question. Ted, um, based on from what I can remember, most patients should be wrapped up with their dosing sometime by the uh,
Or would you say overall the two cohorts are largely similar in terms of baseline severity and like maybe the heterogeneity in baseline hemoglobin is just random variation.
[Analyst 3]: Great, thanks, guys. Really excited for all the upcoming data.
Very much to the very end of this year and so we would expect to have the full data set to share with everybody sometime in the first quarter of next year.
Alex C. Sapir: Thank you, Ted. We appreciate the questions. Shannon, next question?
Yes, it's a great question, Matt Thanks, Yes, I wouldn't take.
Great. Thanks guys. And really excited for all the upcoming data. Yeah, thanks Ted. So, so are we? I appreciate appreciate the questions.
Operator: Our next question comes from the line of Matthew Biegler with Oppenheimer. Your line is now open.
Shannon. Next question.
Take away from this the assumption that it's the Nigerian patient specifically that are more severe.
[Analyst 2]: Hey, guys, thanks for the update. I had a follow-up on the demographics. I know we've talked about it a bit, but it sounds like if I'm reading between the lines from Ian's comments earlier, that the Nigerian patients might be a bit sicker, or would you say overall the two cohorts are largely similar in terms of baseline severity, and like maybe the heterogeneity in baseline hemoglobin is just random variation?
Our next question comes from the line of Matthew biegler with opco to your line is now open.
It's really just the way in which patients came into this cohort I think it's it's by chance.
That that's the case.
Some patients enrolling earlier just happened to have close low baselines I don't think its a geographic.
Aspects related to that.
<unk>.
Okay.
Gotcha, maybe a bigger picture question for me is on assuming 20, Meg looks good or maybe marginally better than 12 do you keep dose escalating or do you think that 20 is your recommended phase II dose.
Alex C. Sapir: Yeah, it's a great question.
Hey guys, thanks for the update. Um, I had a follow-up on the demographics. I know we've we've talked about it a bit, but it sounds like if I'm reading between the lines from Ians comments earlier that the Nigerian patient patients might be a bit sicker. Um, or would you say overall the 2 cohorts are largely similar in terms of Baseline severity and like, maybe the heterogeneity and Baseline hemoglobin is just uh, random variation.
Alan Musso: Yeah, Matt, thanks. I wouldn't take away from this the assumption that it's the Nigerian patients specifically that are more severe. It's really just the way in which patients came into this cohort. I think it's by chance that that's the case, you know, that some of the patients enrolling earlier just happened to have those lower baselines. I don't think it's a geographic aspect related to that.
And you want to take that and I think what we've indicated previously is that the current version of the protocol does allow us to dose escalate up to 30 milligram.
But based on what we saw at the healthy volunteer level looking at the HBV mrna, we didn't see much of an increment at the 14 day Mark when we escalated there from 20 milligram 30 milligram. So based on that along with the promising data that we've already seen the 12 milligram cohort.
Yeah, it's a great question. Yeah, yeah, yeah, Matt Matt, thanks. Yeah, I I wouldn't take, um, take away from this, the assumption that it's the Nigerian patients specifically that are more severe. Um, you know, the it's really just the way in which patients came into this cohort. I think it's, it's by chance, um, that, that, that that's the case. You know, that, um, some, the patients enrolling earlier just happened to have
[Analyst 2]: Okay. Gotcha. Maybe a bigger picture question for me is, assuming 20 mg looks good or maybe marginally better than 12, do you keep dose escalating, or do you think that 20 is your recommended Phase 2 dose?
Those lower baselines. It's I I don't think it's a geographic uh aspect related to that. You may want to mention
Okay.
And our expectations around the 20 milligram cohort.
Alex C. Sapir: Yeah, Ian, you want to take that?
We're not planning to proceed with that 30 milligram dose.
Ian: Yeah, I think what we've indicated previously is that the current version of the protocol does allow us to dose escalate up to 30 milligram. Based on what we saw at the healthy volunteer level, looking at the HBG mRNA, we didn't see much of an increment at the 14-day mark when we escalated there from 20 milligram to 30 milligram. Based on that, along with the promising data that we've already seen at the 12 milligram cohort and our expectations around the 20 milligram cohort, we're not planning to proceed with that 30 milligram dose.
Gotcha, like maybe a bigger picture question for me, is an, assuming 20 meg looks good or maybe marginally better than 12. Do you do, you keep dose escalating or do you think that 20 is your recommended Phase 2 dose?
Got it makes sense I appreciate it.
No.
Thanks, Matt.
Okay.
Great.
Our next question comes from the line of Andre smell Donato with H C. Wainwright. Your line is now open.
Hey, guys. Thanks for taking my question and congrats on the progress one quick one for me. So I guess when you have the 20 milligram data in hand. The question becomes how do you feel how generalizable, Chris surgeries efficacy will be in the less severe patients and can you maybe walk us through.
The mechanistic argument for why that will be thank you very much yeah. It's a great question Andreas.
[Analyst 2]: Got it. Makes sense. Appreciate it.
Yeah. And you want to take that? Yeah. And and I think what we've indicated previously is that the, the current version of the protocol does allow us to dose escalate up to 30 milligram. Uh, but based on what we saw at the healthy volunteer level, looking at the hpg MRNA we didn't see much of an increment, um, at the 14-day Mark when we, uh, escalated their from 20 milligram to 30 milligram. So, based on that, along with the promising data that we've already seen at the 12, milligram cohort in our expectations around the 20 milligram cohort. We're not planning to proceed with with that 30 milligram dose.
Alex C. Sapir: Yeah, thanks, Matt.
Got it makes sense. Appreciate it.
Thanks Matt.
Want to take that.
Operator: Our next question comes from the line of Andres Maldonado with HC Wainwright. Your line is now open.
Thanks, Thanks, Andreas I think we do have some data from the early part of the study.
[Analyst 4]: Hi, guys, thanks for taking my question, and congrats on the progress. One quick one for me. I guess when you have the 20 milligram data in hand, the question becomes, you know, how do you feel how generalizable FTX-6058's efficacy will be in the less severe patients? Can you maybe walk us through the mechanistic argument for why that will be? Thank you very much.
In the less severe patient population or at least in a patient population that didn't have the same severity criteria.
Our next question comes from the line of Andre smaldon with HC Wayne Wright. Your line is now open,
The 12, and the 20 milligram cohorts have had that early part of this study was in all comers sickle cell disease patient population, including some patients who were on concomitant <unk> at the time and we observed, albeit at the lower end of the dosing scales of six milligrams and two milligrams and a few it at.
Alex C. Sapir: Yeah, it's a great question, Andres. Ian, you want to take that?
Quick 1 uh for me. So I guess when you have the 20 milligram data in hand, the the question becomes, you know, how do you feel how generalizable periods efficacy will be and the less severe patients and can you maybe walk us through the mechanistic argument for why that will be? Thank you very much.
Ian: Yeah, and I think, thanks, Andres. I think we do have some data from the early part of the study in the less severe patient population, or at least in the patient population that didn't have the same severity criteria that the 12 and the 20 milligram cohorts have had. That early part of the study was an all-comers, sickle cell disease patient population, including some patients who were on concomitant hydroxyurea at the time. We observed, albeit at the lower end of the dosing scale, so 6 milligrams and 2 milligrams and a few at 12 in that cohort, that we saw very robust effects on HbF induction. We don't expect that there would be a difference in the ability of FTX-6058 to induce HbF based on the patient disease severity.
12 in that cohort that we saw a very robust effects on hbf induction.
We don't expect that there would be a difference in the ability of posts to induce hbf based on the patient's disease severity.
And we have that and then in addition, we have.
Preclinical data CD 34 cells differentiate it in vitro and so on are showing.
Robust induction of hbf across a range of.
Different donors, we also see induction, obviously and in healthy volunteers, who don't have sickle cell disease, and we see induction.
Individuals with sickle trait.
The heterozygous.
For the sickle mutation and seeing robust induction there. So we're not expecting that the disease severity per se.
It's going to impact the ability of <unk> to induce hbf.
Ian: We have that, and then in addition, we have preclinical data, CD34 cells differentiated in vitro and so on, showing robust induction of HbF across a range of different donors. We also see induction, obviously, in healthy volunteers who don't have sickle cell disease, and we see induction in individuals with sickle trait, so they're heterozygous for the sickle mutation, and seeing robust induction there. We're not expecting that the disease severity per se is going to impact the ability of FTX-6058 to induce HbF.
Alright, Thank you very much. Thanks Andreas Thanks for the question Shannon next question.
Yeah, it's a great question Andreas. Um, and you want to take that? Yeah. And and I I think thanks, thanks Andrea. I think, you know, we do have some data from the early part of the study in in a less VR patient population or at least in a patient population, that didn't have the same severity criteria that that, that the 12 and the 20g cohorts have had. So that, that early part of the study was an all Commerce single cell disease, patient population, including some patients, who were on combined hu at the time. And we we observed um albeit at at the lower end of the dosing scale. So 6 milligrams and 2 milligrams in a few at at 12 in that cohort that that we saw very robust effects on hbf induction. So so we don't expect that. There would be a difference in the ability of posterior to induce hbf based on the on the patient's disease severity. Um and we have that and then in addition we have
Thank you as a reminder to ask a question at this time. Please press star. One one are you touched on telephone. Our next question comes from the line of Luca <unk> with RBC. Your line is now open.
Oh, great. Thanks, so much for taking my question Congrats on all the progress.
Maybe a quick one actually on safety.
Obviously, we appreciate that it is really really hard to call.
A negative here, but what is the FDA, telling you about how many patients and maybe how long of a follow up are they hoping to see in order to feel comfortable about safety here and any conflicts there much appreciated and then maybe just a quick one on the plan going forward here.
[Analyst 4]: Great, thank you very much.
Preclinical data, cd34 cells differentiated in vitro. And so on showing, um, robust induction of hbf across a range of of of different donors. We also see induction obviously in in healthy volunteers who don't have sickle cell disease and we see induction in in uh individuals with sickle trait. So they they heterozygous um for for the sickle mutation and seeing robust induction there. So we're not expecting that. The disease severity per se, uh, is going to impact the ability of posteriority to induce hbf
Alex C. Sapir: Yeah, thanks, Andres. Thanks for the question. Shannon, next question?
Operator: Thank you. As a reminder, to ask a question at this time, please press star 11 on your touch-tone telephone. Our next question comes from the line of Luca Issi with RBC. Your line is now open.
Right. Thank you very much. Yeah, thanks Andreas. Thanks for the question. Um, Shannon next question.
Can you just talk about the clinical plan beyond this phase.
[Analyst 5]: Oh, great. Thanks so much for taking my question. Congrats on all the progress. Maybe, Ian, a quick one actually on safety. Obviously, we appreciate that it is really, really hard to prove a negative here, but what is the FDA telling you about how many patients and maybe how long of a follow-up are they hoping to see in order to feel comfortable about safety here? Any context there much appreciated. Maybe just a quick one on the plan going forward here. Can you just talk about the clinical plan beyond this Phase 1b? Should we assume that you start directly a registrational trial after this, or is it still possible that you will need to run intermediate Phase 2 before you go into a registrational trial? Any color there much appreciated. Thanks so much.
<unk> like should we assume that can start directly registrational trial. After this or is it still possible that you will need to run the intermediate phase II before you go into a Registrational trial, you got any color there much appreciate it. Thanks. So much that's great Yeah, Luca two great questions great to have you on the call as well.
Thank you as a reminder to ask a question at this time. Please press star 1, 1, 1 on your touchtone, telephone telephone. Our next question comes from the line of Luca isy with RBC your line is now open.
I'll turn that turn that one over to you yeah. Thanks Luca.
As we've indicated previously in our discussions with the agency.
There is obviously a context of risk and benefit.
<unk>.
In our discussions with them. The plan was to complete the pioneer study is we're coming towards the end of that and to bring those data as well as all the data from our phase one program back to the agency to.
Oh, great. Thanks so much for, uh, taking my question from. Congrats on all the progress. Uh, maybe just a quick one actually on safety. Uh, obviously we appreciate it. It's really, really hard to, uh, you know, prove a negative here. But what is the FDA telling you about how many patients and maybe how long of a follow-up they are hoping to see in order to feel comfortable about safety here? Again, any context would be much appreciated. And then maybe just take a quick one on the plan going forward here, um, to just talk about the clinical plan beyond this Phase 1b.
To discuss next steps with them.
Alex C. Sapir: That's great. Yeah, Luca, two great questions. Great to have you on the call as well. Ian, maybe I'll turn that one over to you.
There was no specific numerical criteria provided.
Around that obviously, we expect that the ongoing fee.
Ian: Yeah, thanks, Luca. As we've indicated previously in our discussions with the agency, there's obviously a context of risk and benefit. In our discussions with them, the plan was to complete the PIONEER trial, as we're coming towards the end of that now, and to bring those data, as well as all the data from our Phase 1 program, back to the agency to discuss next steps with them. There was no specific numerical criteria provided around that. Obviously, we expect that the ongoing favorable safety and tolerability profile is going to be important, but that also needs to be contextualized with the potential benefit that the therapy is bringing. No specific criteria outlined there, but certainly the plan to bring that back to the agency for that discussion.
Favorable safety and Tolerability profile is going to be important, but that's also needs to be contextualized with the potential benefits.
<unk> is bringing so no specific criteria outlined there, but certainly the plan to bring that back.
To the agency for that discussion.
The design of the next study is obviously going to be based on our discussions with the regulators and will be influenced very much by the data emerging from the pioneer study along with our other.
Phase one studies, we do believe that there is the potential for.
For the next study to be.
Registrational study.
In the context of what's previously been used in the setting of an agent that induces hbf.
Should we assume that it will start directly registration or trial after this? Or or is it still possible that you will need to run an intermediate Phase 2 before you go into registrational trial again any color? They are much appreciated, thanks so much, that's great. Yeah, Luka 2, great questions. Great to have you on the call as well. Um, Ian, maybe, I'll turn that turn that 1 over to you. Yeah, thanks Luca. And, and as we've indicated previously, in our discussions, with the agency, um, there's obviously a context of risk and benefit, um, and, and um, in our discussions with them, the plan was to complete the Pioneer study, as we're coming towards the end of that now and to bring those data as well as all the data from our Phase, 1 program back to the agency. Um to discuss next steps with them. Uh there was no specific numerical criteria provided uh around that. Obviously we expect that the ongoing uh favorable safety and tolerability profile is going to be important.
We would expect that a clinical endpoints such as boc reduction would likely be the primary primary clinical endpoint in that study.
Ian: The design of the next study is obviously going to be based on our discussions with the regulators and will be influenced very much by the data emerging from the PIONEER trial, along with our other Phase 1 studies. We do believe that there is the potential for the next study to be a registrational trial in the context of what's previously being used in the setting of an agent that induces HbF. We would expect that a clinical endpoint, such as VOC reduction, would likely be the primary clinical endpoint in that study. There's also the potential, as we've discussed previously, about the association between increasing HbF levels and the association between that and beneficial clinical outcomes. A potential there for an earlier look at the study, an interim look potentially, where HbF could be evaluated as a surrogate endpoint for a potential accelerated approval in sickle cell disease.
But theres also the potential as we have discussed previously about the association between increasing hbf levels and the association between that and beneficial clinical outcomes. So a potential there for an early look at the study an interim look potentially where hbf could be.
Important. But that's also needs to be contextualized with the potential benefit, uh, that the therapy is, is bringing so, so no specific criteria outlined there. But certainly the plan to bring that back, um, to the agency for that discussion. Um, the design of the next study is obviously going to be based on our discussions with the regulators and we'll be influenced very much by the data emerging from the Pioneer study along with our other, um, Phase 1 studies. We do believe,
<unk> as a surrogate endpoint.
For a potential accelerated approval in sickle cell disease, but of course all of this is is something that we will be discussing with the regulators with the context of the full pioneer dataset.
And prior to initiating the next study.
Got it thanks, so much.
Yeah. Thanks Luca.
Our next question comes from the line of Divina Mod with Bank of America. Your line is now open.
Hi, guys. Good morning, Thanks for taking my questions I have a couple.
Just in terms of the rules regarding embargo for us when the abstracts do got released on Monday.
Ian: Of course, all of this is something that we'll be discussing with the regulators with the context of the full PIONEER data set and prior to initiating the next study.
Is there a requirement that you would not be.
Allowed to talk about the additional data that would be shown at the meeting itself or would you be in a position to potentially release.
[Analyst 5]: Got it. Thanks so much.
The new data before the actual presentation.
And beneficial clinical outcomes. So, a potential there for an earlier, look at the study and interim, look, potentially where hpf could be evaluated as a surrogate endpoint, uh, for a potential accelerated approval, uh, in single cell disease. But of course, um, all of this is, is something that we'll be discussing with The Regulators, with the context of the full Pioneer data set, um, and prior to initiating the next study.
Ian: Yeah, thanks, Luca.
I did. Thanks so much.
Presentation slot, whether it be a poster or an oral <unk> and then just to clarify a couple of points from earlier.
Operator: Our next question comes from the line of Tazeen Ahmad with Bank of America. Your line is now open.
Yeah, thanks Luca.
[Analyst 2]: Hi, guys. Good morning. Thanks for taking my questions. I have a couple. In terms of the rules regarding embargo for ASH, when the abstracts do get released on Monday, is there a requirement that you would not be allowed to talk about the additional data that would be shown at the meeting itself? Would you be in a position to potentially release the new data before the actual presentation slot, whether it be a poster or an oral at the meeting? To clarify a couple of points from earlier, what additional data from prior cohorts are you expecting to show, if any, at your presentation at ASH? I just want to get a sense of what metrics to expect beyond what we saw for cohort three. Thanks.
Our next question comes from the line of Tazeen Ahmad with Bank of America. Your line is now open.
What is this data from prior cohorts are you expecting to show if any.
At your presentation at Ash basically just wanted to get a sense of what metrics to expect beyond what we saw for cohort three.
Yes, two great questions to Zane I'll start and then I'll turn it over to Ian for maybe additional color, yes. So so.
As I mentioned in the question that that Ted asked.
The abstracts, when they get released by Ash on or specifically the pioneer with CRD or abstract that gets released on Monday will not have any of the 20 milligram data and we will not be sharing any of that data until such time as that data gets obviously either presented in the poster session or in the oral <unk>.
Hi guys. Good morning. Um, thanks for taking my questions. Uh, I have a couple, um, just in terms of the rules uh, regarding embargo for ash, when the abstracts do get released on Monday. Um, is there a requirement that you would not, um, be allowed to talk about the additional data? That would be shown at the meeting itself? Would you be in a position to potentially release? Um, the new data before the actual, um, presentation slot, whether it be a poster or an oral at the meeting and then, um, just to clarify a couple of points from earlier. Um,
Session that you mentioned in and we'll find out on.
Alex C. Sapir: Yeah, two great questions, Tazeen. I'll start, and then I'll turn it over to Ian for maybe additional color. As I mentioned in the question that Ted asked, the abstracts, when they get released by ASH, or specifically the PIONEER pociredir abstract that gets released on Monday, will not have any of the 20 milligram data. We will not be sharing any of that data until such time as that data gets obviously either presented in the poster session or in the oral session that you mentioned. We'll find out on Monday whether that data has been accepted for an oral presentation or a poster. There won't be any data that we'll share until such time.
On Monday, whether that.
Whether that data has been accepted for a price for oral presentation or a poster. So there won't be any data that we'll share until such time. However, there may be an opportunity for us to do.
Call, maybe after that data gets presented.
Either over the weekend or at some point in the not too in the not too distant future. So we can provide a little bit more sort of color on that information so stay tuned for that.
In terms of additional data hub, Ian answer that question, but I do just want to say that the data that we would plan to share.
Either in that or poster followed by what may be a more sort of.
Type of.
What additional data from prior cohorts? Are you expecting to show? If any um, at your presentation at Ash basically just want to get a sense of what metrics to expect beyond what we saw for cohort 3, thanks. Yeah, 2. Great questions to Zen. I, I'll start and then I'll, I'll turn it over to Ian for maybe additional caller. Yeah, so so, um, as I mentioned in the question that that Ted asked, um, the abstracts, when they get released by Ash on or specifically, the Pioneer poster, dear abstract that gets released on Monday will not have any of the 20 milligram data and we will not be sharing any of that data until such time, as that data, gets obviously either presented in the poster session or in the oral session that you mentioned. And, and we'll find out on, uh, uh, on Monday whether that, uh, whether that data has been accepted for, for a oral presentation, or, or
Mike.
Alex C. Sapir: However, there may be an opportunity for us to do a call maybe after that data gets presented, either over the weekend or at some point in the not-too-distant future, so we can provide a little bit more sort of color on that information. Stay tuned for that. I think in terms of additional data, I'll have Ian answer that question, but I do just want to say that the data that we would plan to share, either in that oral or poster, followed by what may be a more sort of type of like a video call or a conference call, we would try to be as forthcoming and transparent with the 20 milligram data as we were with the 12 milligram. We'll share with you all the data that we have up until that ASH cut point. If it's only approximately half of the patients, we'll share that.
A video call or conference call.
We would try to be as <unk>.
Forthcoming and transparent with the 20 milligram data as we were with the 12 milligram. So we'll share with you all the data that we have up until that ash cut point, if it is only approximately.
Approximately half of the patients will share that if it's all of the patients will share that so it will be very very specific in terms of.
What what data we have at the different time points for the 20 milligram in terms of additional data that we'll share on the 12 milligram. Ian do you want to take that one yes sure happy to do that thanks disease. So as you as you will recall for the 16 patients in the 12 milligram cohort. We previously presented in the end of at the end of July.
A poster. So there won't be any data that we'll share until such time. However, there may be an opportunity for us to do, uh, you know, a call maybe after that day to gets presented, um, either over the weekend or at some point in the in in the not too, in the not too distant future so we can provide a little bit more sort of color on that information. So so stay tuned for that. Um, I think in terms of additional data, I'll have Ian answer that question, but I do just want to say that, um, the data that we would plan to share
The data for.
For the full day 84 treatment period, we did not have the follow up data. So there is a four week safety follow up with those patients are no longer on drug.
Alex C. Sapir: If it's all the patients, we'll share that. We'll be very, very specific in terms of what data we have at the different time points for the 20 milligram. In terms of additional data that we'll share on the 12 milligram, Ian, do you want to take that one?
Those data were not all available at that time.
Um either in that oral or poster followed by what may be a more sort of um type of um um like a a a video call or or or a conference call. Um we would try to be as uh forthcoming and transparent with the 20g data as we were with the 12 milligrams. So we'll share with you all the data that we have up until that Ash cut Point. Um if it's only, you know, approximately half of the patients will share that if it's all the patients will share that. Um so we'll be very, very specific in terms of um,
That will be presented.
At the time of the of the Ash presentation and in addition.
Ian: Yeah, sure, happy to do that. Thanks, Tazeen. As you will recall, for the 16 patients in the 12 milligram cohort we previously presented at the end of July, the data for the full day 84 treatment period, we did not have the follow-up data. There is a four-week safety follow-up where those patients are no longer on drug, and those data were not all available at that time. That will be presented at the time of the ASH presentation. In addition, we will provide the full safety data set. We did provide all of the safety data that was available at the time of our previous data release, including some AEs that occurred during that safety follow-up period. We'll round that out to make that a more complete data set around the 12 milligram cohort.
We will provide the food safety dataset, we did provide all of the safety data that was available at the time of our previous data release, including some.
Some ease that occurred during that safety follow up period, but we will round that out to make that a more a more complete dataset around the 12 milligram cohort.
Great. Thanks for the question <unk>.
Shannon there are there any more questions in the queue.
I'm currently showing no further questions at this time.
This does conclude today's conference call. Thank you all for your participation you may now disconnect.
What, what data we have at at at at the different time points for the 20 milligram in terms of additional data that we'll share in the 12 milligram? And you want to take that 1? Yeah, sure. Happy to do that. Thanks to Z. So as you as you will recall for the 68 patients in the 12 milligram cohort, we previously presented in the end of at the end of July. Um, the the data for the full day, 84 treatment period, we did not have the follow-up data. So there's a 4 week safety follow-up where where those patients are no longer on drug. Um and and that those data were not all available at that time. Uh, so that will be presented um at at the time of the of the ash presentation. And um in addition, we will provide the full safety data set. We did provide all of the safety data that was available at the time of our previous uh data release including some
Um, some aees that occurred during that safety follow-up, period, but we're around that out to make that a more a more complete data set around the 12g cohort.
Alex C. Sapir: Great, thanks for the question, Tazeen. Shannon, are there any more questions in the queue?
Great. Thanks for the question to Zen.
Operator: Currently, Sean, no further questions at this time. This does conclude today's conference call. Thank you all for your participation. You may now disconnect.
Uh, Shannon, are there any more questions in the queue?
Um, currently showing no further questions at this time. This does conclude today's conference call. Thank you all for your participation. You may now disconnect