Fulcrum Therapeutics Announces Positive 12-Week Results from the 20 mg Dose Cohort of the Phase 1b PIONEER Trial of Pociredir in Sickle Cell Disease

Rhea-AI Summary

Fulcrum Therapeutics (Nasdaq: FULC) reported positive 12-week results from the 20 mg cohort of the Phase 1b PIONEER trial of pociredir in sickle cell disease. Mean absolute fetal hemoglobin (HbF) rose by 12.2% to 19.3%, F-cells increased from 31% to 63%, mean hemoglobin rose by 1.1 g/dL, and markers of hemolysis improved. Seven of 12 patients achieved HbF ≥20% and seven reported zero VOCs during treatment. Pociredir was generally well-tolerated with no treatment-related SAEs. Fulcrum plans a potential registration-enabling trial in H2 2026 and will discuss next-step design with regulators.

Positive

• HbF +12.2% absolute increase to 19.3% at Week 12
• F-cells +32 percentage points (31% to 63%), suggesting pan-cellular progression
• Hemoglobin +1.1 g/dL mean increase at Week 12
• 58% of patients (7 of 12) achieved HbF ≥20%; 58% reported zero VOCs
• No treatment-related serious adverse events reported in 20 mg cohort

Negative

• Small evaluable cohort (n=12) limits statistical confidence and generalizability
• Results reported at 12 weeks; longer-term durability and safety data pending

Key Figures

HbF increase: 12.2% (7.1% to 19.3%) Patients HbF ≥20%: 7 of 12 patients (58%) F-cells increase: 31% to 63% +5 more

8 metrics

HbF increase 12.2% (7.1% to 19.3%) Mean absolute HbF change at Week 12, 20 mg cohort (n=12)

Patients HbF ≥20% 7 of 12 patients (58%) Achieved absolute HbF ≥20% at Week 12, 20 mg cohort

F-cells increase 31% to 63% Mean F-cell proportion from baseline to Week 12 (n=10)

Hemoglobin change +1.1 g/dL (7.3 to 8.4 g/dL) Mean total hemoglobin change at Week 12, 20 mg cohort

Indirect bilirubin 40% decrease Marker of hemolysis over 12 weeks, 20 mg cohort

Reticulocyte counts 42% decrease Marker of erythropoiesis over 12 weeks, 20 mg cohort

VOCs expected vs observed 16 expected vs 6 observed Vaso-occlusive crises during 12-week treatment period

Patients with zero VOCs 7 of 12 patients (58%) Reported no VOCs during 12-week treatment period

Market Reality Check

Price: $10.89 Vol: Volume 1,121,077 is 1.88x...

high vol

$10.89 Last Close

Volume Volume 1,121,077 is 1.88x the 20-day average, indicating elevated pre-news activity. high

Technical Price at 10.89 sits 30.81% below the 52-week high and 370.41% above the 52-week low, trading above the 200-day MA of 8.64.

Peers on Argus

FULC was down 1% pre-news with mixed peer moves: LXRX (-0.66%), LRMR (-5.07%), A...

FULC was down 1% pre-news with mixed peer moves: LXRX (-0.66%), LRMR (-5.07%), AUTL (+2.37%), PRTC (+0.63%), SLDB (+3.53%). This pattern points to stock-specific factors rather than a uniform biotech move.

Common Catalyst Select peers had unrelated catalysts (FDA designation for LRMR, conference participation for AUTL), suggesting today’s Fulcrum news is idiosyncratic to its sickle cell program.

Historical Context

5 past events · Latest: Feb 17 (Positive)

Pattern 5 events

Date	Event	Sentiment	Move	Catalyst
Feb 17	Data presentation notice	Positive	+0.3%	Announced timing of 20 mg PIONEER data webcast and discussion.
Feb 06	Inducement option grant	Neutral	+5.0%	Granted 70,000 stock options to a new employee under inducement plan.
Jan 09	Inducement option grants	Neutral	-3.5%	Granted 30,400 options to three new employees under inducement plan.
Jan 07	Conference participation	Neutral	-0.1%	Planned presentation at 44th Annual J.P. Morgan Healthcare Conference.
Dec 10	Equity offering	Negative	-5.5%	Priced upsized $175M stock and pre-funded warrant offering under an effective shelf.

Pattern Detected

Recent news flow was largely corporate/housekeeping, with limited price impact except for the December 2025 financing, which coincided with a sharper decline.

Recent Company History

Over the past few months, Fulcrum has mixed routine corporate updates with one major financing. An announcement of upcoming PIONEER 20 mg data on Feb 17, 2026 had a modest +0.28% reaction. Multiple inducement option grants in early 2026 produced small, mixed moves. The upsized $175.0M equity and pre-funded warrant offering on Dec 10, 2025 coincided with a -5.48% move, highlighting sensitivity to dilution. Today’s detailed positive SCD data adds substantive clinical content on top of this largely capital-markets-driven backdrop.

Market Pulse Summary

This announcement highlights clinically meaningful 12-week PIONEER results at the 20 mg dose, includ...

Analysis

This announcement highlights clinically meaningful 12-week PIONEER results at the 20 mg dose, including a 12.2% absolute HbF increase, a 1.1 g/dL hemoglobin gain, and fewer VOCs than expected. The company reported no treatment-related SAEs and plans a potential registration-enabling trial in the second half of 2026. Against recent financing and insider activity, investors may focus on durability data, regulatory feedback, and future trial design as key next milestones.

Key Terms

fetal hemoglobin (hbf), hemolysis, erythropoiesis, serious adverse events (saes), +3 more

7 terms

fetal hemoglobin (hbf) medical

"Mean absolute fetal hemoglobin (HbF) increased by 12.2% (from 7.1% to 19.3%)"

Fetal hemoglobin (HbF) is a form of hemoglobin normally found in unborn babies that carries oxygen in the blood; in adults it is usually low but can be increased by certain drugs or gene therapies. Investors care because higher HbF levels can reduce symptoms of blood disorders like sickle cell disease and beta-thalassemia, so treatments that raise HbF can change patient outcomes and affect the commercial value of related therapies—think of HbF as a safety buffer that eases a faulty system.

hemolysis medical

"reductions in markers of hemolysis and associated improvements in anemia"

Hemolysis is the breaking apart of red blood cells so that their contents leak into the bloodstream, like a burst water balloon spilling its load. It matters to investors because hemolysis can harm patients, skew lab test results, complicate clinical trial data and safety reviews, and trigger additional testing, regulatory scrutiny, product changes or recalls—outcomes that can affect a healthcare or diagnostics company's revenue and stock value.

erythropoiesis medical

"Improvements in markers of hemolysis, improved erythropoiesis, and a >1 g/dL increase"

The body's process for making red blood cells in the bone marrow, driven by signals such as a hormone that tells immature cells to mature and enter the bloodstream. Think of it as a factory assembly line that builds the blood’s oxygen delivery trucks; when the line speeds up or breaks down it changes demand for drugs, diagnostics and treatments. Investors watch it because therapies that boost or regulate this process can reshuffle market value in hematology, transfusion services and related drugs.

serious adverse events (saes) medical

"Pociredir was generally well-tolerated, with no treatment-related serious adverse events (SAEs)"

Serious adverse events (SAEs) are significant negative outcomes, such as severe health issues, hospitalizations, or death, that occur during a medical study or treatment. For investors, SAEs matter because they can signal potential risks associated with a product or company, potentially affecting its reputation, regulatory approval, or financial performance. Recognizing SAEs helps gauge the safety and reliability of medical-related investments.

phase 1b medical

"Phase 1b PIONEER trial of pociredir in sickle cell disease (SCD)"

"Phase 1b" is an early stage in testing a new medical treatment or vaccine, where it is given to a small group of people to evaluate its safety and determine the right dose. For investors, this phase signals progress in development, indicating the treatment is advancing through initial safety checks, which can influence expectations for future success and potential market impact.

open-label medical

"PIONEER is a Phase 1b open-label dose-escalation clinical trial evaluating the safety"

Open-label describes a situation where everyone involved in a study or process knows the full details, such as who is receiving a treatment or intervention. For investors, understanding whether a project or product is open-label helps gauge the level of transparency and potential biases, influencing trust and decision-making. It’s like knowing whether a test or experiment is conducted openly or behind closed doors.

dose-escalation medical

"Phase 1b open-label dose-escalation clinical trial evaluating the safety and efficacy"

Dose-escalation is the part of an early-stage clinical trial where researchers gradually increase a drug’s dose in small groups of participants to find the safest and most effective amount. Think of it like turning up the volume slowly to find the sweet spot: investors watch these results closely because they reveal safety risks, potential effectiveness, and how quickly a drug can move to later trials or approval, all of which affect the development timeline and commercial prospects.

AI-generated analysis. Not financial advice.

― Mean absolute fetal hemoglobin (HbF) increased by 12.2% (from 7.1% to 19.3%) at Week 12 (n=12), representing a rapid, robust, and clinically relevant response, with progression toward pan-cellular HbF induction as F-cells increased from 31% to 63% ―

― 7 of 12 patients (58%) achieved absolute HbF levels ≥20%; all patients achieved at least a 6.5% absolute increase in HbF ―

― Improvements in markers of hemolysis, improved erythropoiesis, and a >1 g/dL increase in total hemoglobin ―

― 7 of 12 patients (58%) reported zero VOCs during the treatment period ―

― Pociredir was generally well-tolerated, with no treatment-related serious adverse events (SAEs) ―

― Fulcrum plans to initiate a potential registration-enabling trial in the second half of 2026 ―

― Conference call and webcast scheduled for 8:00 a.m. ET today ―

CAMBRIDGE, Mass., Feb. 24, 2026 (GLOBE NEWSWIRE) -- Fulcrum Therapeutics, Inc.^® (Fulcrum) (Nasdaq: FULC), a clinical-stage biopharmaceutical company focused on developing small molecules to improve the lives of patients with genetically defined rare diseases, today reported positive 12-week results from the 20 mg dose cohort of the Phase 1b PIONEER trial of pociredir in sickle cell disease (SCD).

“The 12-week data from the complete 20 mg cohort demonstrated robust and rapid HbF induction and progression toward pan-cellular distribution, accompanied by reductions in markers of hemolysis and associated improvements in anemia,” said Alex C. Sapir, Fulcrum’s President and Chief Executive Officer. “Importantly, the HbF levels achieved are consistent with levels historically associated with reductions in sickling and hemolysis in sickle cell disease. These encouraging results in a severe patient population strengthen our conviction as we prepare for discussions with regulators regarding the design of the next study.”

“The magnitude of HbF induction observed at 20 mg, together with the concomitant increase in F-cells and associated reductions in markers of hemolysis and improvements in anemia, is consistent with what we would expect from a therapy that may be capable of altering the underlying pathophysiology of sickle cell disease,” said Dr. Martin Steinberg, Professor of Medicine, Pediatrics, Pathology and Laboratory Medicine at Boston University Chobanian & Avedisian School of Medicine. “Achieving HbF levels in this range represents an important step toward understanding the potential of pociredir to improve clinical outcomes for patients living with sickle cell disease.”

Trial Design and Data Cut Overview

PIONEER is a Phase 1b open-label dose-escalation clinical trial evaluating the safety and efficacy of pociredir, an oral once-daily HbF inducer, in adult patients with severe SCD. The 20 mg cohort of the clinical trial enrolled adults with severe SCD. As of the December 23, 2025 data cutoff, all 12 evaluable patients in the 20 mg cohort completed the 12-week treatment period and are included in the pharmacodynamic (PD) analysis set. One patient discontinued on Day 1 due to an unrelated Grade 5 serious adverse event and is excluded from the PD analysis set but is included in the safety analysis set. Five patients remained in the 4-week follow-up period as of the data cutoff. Fulcrum plans to report additional data from the 20 mg cohort, including through the 4-week follow-up period, at a future medical conference.

PIONEER Study 20 mg Dose Cohort Data

Results from the 12 week treatment period of the 20 mg dose cohort of the Phase 1b PIONEER trial (n=12) are as follows:

• Mean absolute HbF increased by 12.2% at 12 weeks of treatment with pociredir (vs. 8.6% at Week 12 in the 12 mg cohort), increasing from a baseline of 7.1% to 19.3%. Seven of 12 patients (58%) achieved absolute HbF levels ≥20% at Week 12, and all patients demonstrated a clinically relevant HbF increase. HbF levels of 20% are associated with ~90% of patients experiencing zero VOCs per year, based on real-world data that Fulcrum presented at the 20th Annual Sickle Cell & Thalassemia Conference in October 2025. 
• The proportion of HbF-containing red blood cells (F-cells) increased from a mean of 31% at baseline to 63% at Week 12 (n=10), indicating progression toward pan-cellular HbF induction (HbF distributed across a substantial proportion of red blood cells (RBCs)). F-cells are more resistant to sickling and hemolysis because of HbF-mediated inhibition of sickle hemoglobin (HbS) polymerization. Higher proportions of F-cells are associated with improved RBC health.
• Mean changes in markers of hemolysis and erythropoiesis improved during the 12-week treatment period:
  • Indirect bilirubin decreased by 40% (vs. 37% at Week 12 in the 12 mg cohort)
  • Lactate dehydrogenase decreased by 34% (vs. 28% at Week 12 in the 12 mg cohort)
  • RBC distribution width decreased by 26% (vs. 27% at Week 12 in the 12 mg cohort)
  • Reticulocyte counts decreased by 42% (vs. 31% at Week 12 in the 12 mg cohort)
• Mean hemoglobin increased by 1.1 g/dL at Week 12 (vs. 0.9 g/dL at Week 12 in the 12 mg cohort), increasing from a baseline of 7.3 g/dL to 8.4 g/dL.
• Based on treating physician-documented medical records from the 6-12 months prior to enrollment, approximately 16 VOCs would have been expected during the 12-week treatment period. During the 12-week treatment period, six VOCs were reported. Seven of 12 patients (58%) reported no VOCs during the treatment period.
  
  

Pociredir Safety Update

• As of the December 23, 2025 data cutoff, pociredir has been dosed in 148 adults, including 89 subjects in multiple dose cohorts up to 12 weeks.
  • 103 healthy subjects, including 44 who received pociredir for 10 to 14 days treatment duration
  • 45 SCD patients who received pociredir for up to 12 weeks treatment duration
• The safety profile observed in the 20 mg dose cohort as of the December 23, 2025 data cutoff remained generally consistent with previously reported safety data. Pociredir was generally well-tolerated, with no treatment-related SAEs and no discontinuations due to treatment-related AEs as of the December 23, 2025, data cutoff.

Next Steps
Fulcrum plans to provide additional details regarding the design of its next trial in the second quarter of 2026 following receipt of meeting minutes from its End-of-Phase meeting with the FDA. Pending feedback from the FDA, Fulcrum plans to initiate a potential registration-enabling trial in the second half of 2026. Fulcrum also plans to engage with the European Medicines Agency (EMA) in mid-2026 to obtain protocol assistance and feedback on the design of the next trial. In addition, Fulcrum is activating sites for an open-label extension trial for participants in the PIONEER trial to evaluate the safety and durability of response with pociredir.

Conference Call and Webcast
Fulcrum Therapeutics, Inc. will host a conference call and webcast featuring company leadership and a medical expert today at 8:00 a.m. ET to discuss the results to date from the PIONEER Phase 1b trial. Individuals may register for the conference call by clicking the link here. To register to participate in the conference call, individuals can use the conference call link here. Once registered, participants will receive dial-in details and unique PIN, which will allow them to access the call. The event can be accessed under “Events and Presentations” in the Investor Relations section of Fulcrum’s website (www.fulcrumtx.com), with a recording available following the event.

About Fulcrum Therapeutics
Fulcrum Therapeutics is a clinical-stage biopharmaceutical company focused on developing small molecules to improve the lives of patients with genetically defined rare diseases in areas of high unmet medical need. Fulcrum’s lead clinical program is pociredir, a small molecule designed to increase expression of HbF for the treatment of SCD. Fulcrum uses proprietary technology to identify drug targets that can modulate gene expression to treat the known root cause of gene mis-expression. For more information, visit www.fulcrumtx.com and follow us on X (@FulcrumTx) and LinkedIn.

About Pociredir
Pociredir is an investigational oral small-molecule inhibitor of Embryonic Ectoderm Development (EED) that was discovered using Fulcrum’s proprietary discovery technology. Inhibition of EED leads to potent downregulation of key fetal globin repressors, including BCL11A, thereby causing an increase in HbF. Pociredir is being developed for the treatment of SCD. In the PIONEER Phase 1b clinical trial in people with SCD, pociredir has demonstrated dose-dependent increases in HbF, pan-cellular HbF induction, and improvements in markers of hemolysis and anemia. Across the 12 mg and 20 mg dose cohorts, pociredir has been generally well-tolerated with up to three months of exposure, with no treatment-related serious adverse events reported. Pociredir has been granted Fast Track and Orphan Drug Designation from the FDA for the treatment of SCD. To learn more about clinical trials of pociredir please visit ClinicalTrials.gov.

About Sickle Cell Disease
SCD is a genetic disorder of the red blood cells caused by a mutation in the HBB gene. This gene encodes a protein that is a key component of hemoglobin, a protein complex whose function is to transport oxygen in the body. The result of the mutation is less efficient oxygen transport and the formation of red blood cells that have a sickle shape. These sickle shaped cells are much less flexible than healthy cells and can block blood vessels or rupture cells. People with SCD typically suffer from serious clinical consequences, which may include anemia, pain, infections, stroke, heart disease, pulmonary hypertension, kidney failure, liver disease, and reduced life expectancy.

About PIONEER
PIONEER (NCT05169580) is a Phase 1b open-label dose-escalation clinical trial evaluating the safety and efficacy of pociredir, an oral once-daily HbF inducer, in adult patients with severe SCD. Secondary endpoints include HbF induction, hemolysis, and anemia. Exploratory endpoints include globin gene expression, % F-cells and incidence of VOCs. Fulcrum has previously completed cohort 1 (6 mg, n=10), cohort 2 (2 mg, n=2), cohort 3a (12 mg, n=4), and cohort 3b (12 mg, n=16). Updated results of cohort 4 (20 mg, n=12) are reported today. A total of 13 patients enrolled, but there was one discontinuation due to death, which was determined by the investigator to be unrelated to treatment following complications from VOC reported on Day 1 of the study. The pharmacodynamic (PD) analysis data for cohort 4 includes 12 patients. The safety analysis set for 20mg includes all 13 patients who enrolled.

Forward-Looking Statements
This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties, including express or implied statements regarding the significance of results from the 20 mg cohort; Fulcrum’s goals for pociredir; pociredir’s best-in-class potential for the treatment of SCD; pociredir’s ability to induce HbF; the durability or clinical relevance of HbF, hemolysis improvements, and VOCs during the 12-week treatment period; plans to engage with FDA and EMA and receipt of feedback on trial design; initiation of a registration-enabling trial; and conducting an open-label extension trial of pociredir; among others. All statements, other than statements of historical facts, contained in this press release are forward-looking statements, including express or implied statements regarding Fulcrum’s strategy, future operations, future financial position, prospects, plans and objectives of management, are forward-looking statements. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in, or implied by, such forward-looking statements. These risks and uncertainties include, but are not limited to, risks associated with Fulcrum’s ability to continue to advance pociredir and its other product candidates in clinical trials, including feedback on trial design with regulators, as well as enrollment and completion; estimating the potential patient population and/or market for Fulcrum's product candidates; interpreting initial clinical data, including the risk that 12-week data may not be predictive of longer-term outcomes, later timepoints, or future studies; replicating in clinical trials positive results found in preclinical studies and/or earlier-stage clinical trials of pociredir and any other product candidates; obtaining, maintaining or protecting intellectual property rights related to its product candidates; managing expenses; and managing risks associated therewith; and raising the substantial additional capital needed to achieve its business objectives; among others. For a discussion of other risks and uncertainties, and other important factors, any of which could cause Fulcrum’s actual results to differ from those contained in the forward-looking statements, see the “Risk Factors” section, as well as discussions of potential risks, uncertainties, and other important factors, in Fulcrum’s most recent filings with the Securities and Exchange Commission. In addition, the forward-looking statements included in this press release represent Fulcrum’s views as of the date hereof and should not be relied upon as representing Fulcrum’s views as of any date subsequent to the date hereof. Fulcrum anticipates that subsequent events and developments will cause Fulcrum’s views to change. However, while Fulcrum may elect to update these forward-looking statements at some point in the future, Fulcrum specifically disclaims any obligation to do so.

Contact:

Kevin Gardner
LifeSci Advisors, LLC
kgardner@lifesciadvisors.com
617-283-2856

FAQ

What were the Week 12 HbF results for Fulcrum (FULC) pociredir 20 mg in PIONEER on Feb 24, 2026?

Mean absolute HbF increased by 12.2% to 19.3% at Week 12. According to the company, seven of 12 patients (58%) achieved HbF ≥20% and all patients had at least a 6.5% absolute HbF increase, indicating robust induction.

How did pociredir 20 mg affect hemoglobin and hemolysis markers in the PIONEER Phase 1b results?

Mean hemoglobin rose by 1.1 g/dL at Week 12 and markers of hemolysis improved. According to the company, indirect bilirubin decreased 40% and lactate dehydrogenase decreased 34% versus baseline, reflecting improved RBC health.

What safety profile did Fulcrum (FULC) report for pociredir 20 mg in the Feb 24, 2026 update?

Pociredir was generally well-tolerated with no treatment-related serious adverse events in the 20 mg cohort. According to the company, there were no discontinuations due to treatment-related adverse events as of the data cutoff.

Did pociredir reduce vaso-occlusive crises (VOCs) in the PIONEER 20 mg cohort reported Feb 24, 2026?

Seven of 12 patients (58%) reported zero VOCs during the 12-week treatment period. According to the company, six VOCs occurred versus an expected ~16 based on prior 6–12 month records, indicating fewer than expected events during treatment.

What are Fulcrum's next steps and timeline for pociredir after the Feb 24, 2026 results?

Fulcrum plans to seek FDA feedback and aims to initiate a potential registration-enabling trial in H2 2026. According to the company, additional design details will be provided after End-of-Phase meeting minutes and EMA engagement is planned in mid-2026.