Fulcrum Therapeutics, Inc. Q4 FY2025 earnings call

• Alex Sapir introduced the call, mentioned excitement about 12-week data from 20-milligram cohort of PIONEER trial. • Iain Fraser provided overview of sickle cell disease, clinical relevance of HbF, and detailed clinical data from 20-milligram cohort including HbF induction, F cells, markers of hemolysis, erythropoiesis, total hemoglobin, VOCs, and safety. • Dr. Martin Steinberg gave expert perspective on clinical data, comparing to hydroxyurea, discussing haplotypes, and importance of pociridir as a potential first-line therapy. • Alexander Sapir discussed 2026 plans including update on next trial design, engagement with EMA, and activating sites for open-label extension study

For the 20-milligram cohort of the Phase 1b PIONEER trial of pociridir in sickle cell disease: Mean absolute increase in HbF from baseline 7.1% to 19.3% at week 12, a delta of 12.2%; more than half (7 of 12) achieved HbF ≥20%; F cells doubled from ~31% baseline to 63% at 12 weeks; LDH reduced by 34% and indirect bilirubin by 40% at week 12; reticulocytes dropped 42%; total hemoglobin increased by 1.1 gram per deciliter at 20-milligram cohort; 7 of 12 patients had no VOCs during treatment; pociridir well tolerated at 20-milligram dose with no treatment-related serious adverse events

• Plan to provide update on next trial design in Q2 2026 following FDA meeting minutes. • Pending FDA feedback, plan to initiate registration-enabling trial in second half of 2026. • Plan to engage with EMA in mid-2026 for protocol assistance and feedback. • Activating sites for open-label extension study for PIONEER patients to evaluate longer-term safety and durability of response

• Actual results may differ materially from forward-looking statements due to risks and uncertainties. • Logistics issues with sample shipping causing missing data at certain time points which could impact biomarker analysis. • Variability in assay results for certain biomarkers which could affect interpretation of data. • Uncertainty around regulatory approval and the appropriate path forward for the registrational trial. • Competition from other HbF inducer developments which could impact market position

Q: Congrats on the excellent update today. The VOC data is pretty encouraging. I was wondering if you can give us any additional insight into when -- into which patients had VOCs and when during the study they occurred?

A: The VOCs were spread throughout the treatment period. This 12-week treatment period is relatively short and patients had not reached their steady state. There were more VOCs in patients with lower increases in HbF but no further details of individual patients revealed Q: Given the response to pociridir seems to depend somewhat on the underlying sample type, I was wondering if you have a sense of how well the 20-milligram cohort represents the population of sickle cell patients who might enroll in a Phase III as well as how well it represents the population of sickle cell patients who are living with the disease in the U.S. and other major markets?

A: The 20-milligram cohort likely represents a middle slice. It had one patient from South Africa and more from Nigeria, more heterogeneous than 12-milligram cohort which had patients from South Africa with CAR haplotype. Represents more global population with no ArabIain IndIain haplotype patients enrolled Q: When you look at the totality of the biomarker updates, which ones would you highlight that would take a little bit more time, let's say, beyond 12 weeks to kind of show a clear dose response and then sort of an increased depth of effect?

A: HbF induction is primary mechanism. Markers of hemolysis (LDH, bilirubin) are downstream but affected by other factors. RDW normalizing, reticulocytes coming down but not to baseline, total hemoglobin needing to reach new steady state. These are lagging indicators behind HbF Q: Now that the Fulcrum team has seen the full data set here, I'm curious how you're going to approach your meeting with the agency in terms of what you're going to ask for on your wish list? And then for a registrational trial, how do you think about wanting to expand the TAM as much as possible, but also keeping a good balance of the patients that you do enroll to ensure that the trial is successful, just given some of the recent unfortunate failures we've seen in the space?

A: Based on data strength, appropriate to advance to registration-enabling study. Discuss PIONEER data with FDA. Studying more severe patient population helps with power and success. Label may specify recurrent vaso-occlusive events or severe disease. Around 20% of patients currently meet inclusion/exclusion criteria, which would increase if label is specific Q: I wanted to ask a follow-up on the pancellularity data and the remark by Dr. Steinberg. -- that on hydroxyurea, F cells tend to increase over time as the non-F cells die out. I think I understand that. But just to confirm, does that mean we should expect pancellularity to increase as patients stay on pociredir for longer than 12 weeks? And I just had a quick follow-up on those 2 patients that didn't have the 12-week assessment. Are we going to get those? Or because that does seem like it kind of swayed the average downward?

A: Expect pancellularity to increase over time as seen in MSH trial. Missing data due to logistics issues with sample shipping. 2 patients missing at week 12 had high F cell percent at week 10. Numerical value at individual time points sensitive to missing data but overall response in F cells across board Q: Now that you've seen the 20 mg data and the 12 mg, et cetera, do you feel confident that you've fully explored the dose range to move forward into registrational study here, both with respect to what the FDA might require and for purposes of just realizing the full value or benefit of this agent. And this is a bit nitpicky, but on the patient level, it looks like patient 10 kind of achieved a higher percent HbF earlier on at day 56 and then came back, obviously still having a good response. But could you provide any color on what happened with that individual?

A: Based on data, comfortable with dose range. PIONEER protocol allowed up to 30 mg but no further induction of HBG mRNA. Anomaly in patient 10's HbF levels due to small numbers and assay variability, not clinically meaningful Q: I just had one on sort of safety. I know that the cutoff here is late December. So presumably, there's some additional kind of safety follow-up. And -- just curious if there's any color you can provide kind of beyond sort of what we've seen in this deck. And then more broadly, this drug has been studied in a lot of people now and just curious sort of your comfort that this is enough of a data set you think to get the FDA comfortable with kind of expanding the study population here kind of over time?

A: No untoward safety events post data cutoff. Comfortable with safety profile. Unmet need in sickle cell disease is huge, so important to move forward with registrational study considering disease severity and unmet need Q: Great. Thanks Alex [indiscernible] congratulations on the updates as well, and I appreciate you are taking my question. Alex, as you're looking towards a potential registrational trial and certainly international implications when it comes to trialing and exploring next steps. Just curious if you can comment perhaps on how you're thinking about just optimizing the strategic value of pociredir globally, this may be the time to think about the best way to perhaps penetrate commercially to do that work internationally. I'm just curious how you're thinking about going global, especially with markets of high unmet need ex U.S.

A: Plan to have global study including sites in U.S., Europe, and Sub-Sahara Africa. Want to ensure all patients worldwide have access to pociredir. Market opportunity exists in developed and developing worlds. Strategically thinking about maximizing uptake and revenue while ensuring access for all patients Q: Okay, team, this is Shelby on for Luca, and congrats on all the progress. It looks like the total number of VOCs when we look at the treatment period plus the safety follow-up went from 6 at ASH to 9 today. Appreciate that it's a very sick population, as you've highlighted in the baseline characteristics. So how should we think about that increase in such a short period of time? And does that modestly decrease your confidence that this drug can lower VOCs in a pivotal trial? Any color to it much appreciated.

A: VOCs observed in PD analysis set: 6 in 5 patients during treatment, 3 during safety follow-up. Observation of increase from ASH to now due to short study period, patients not at steady state, severe patient population. Not dissuaded or discouraged, remain encouraged by trends