Executive Summary / Key Takeaways

• Fulcrum Therapeutics is strategically repositioning as a focused rare disease innovator, prioritizing pociredir for sickle cell disease (SCD) and advancing a promising preclinical pipeline in inherited aplastic anemias, following the discontinuation of its losmapimod program.
• Pociredir, an oral fetal hemoglobin (HbF) inducer, has demonstrated encouraging Phase 1b results in SCD, including a mean absolute HbF increase of 8.6% and a trend towards reduced vaso-occlusive crises (VOCs), positioning it as a potential best-in-class oral therapy.
• The company maintains a robust liquidity position with $200.6 million in cash, cash equivalents, and marketable securities as of September 30, 2025, providing a projected cash runway into 2028 to fund its core development programs.
• Key upcoming milestones include clinical data from the 20 mg dose cohort of the PIONEER trial by year-end 2025 and an end-of-Phase 1 FDA meeting in Q1 2026 to align on registrational study plans.
• Despite a highly competitive landscape with gene therapies, Fulcrum's small molecule approach offers potential advantages in accessibility and administration, aiming to address significant unmet needs in SCD and other rare hematological conditions.

A Focused Future: Redefining Value in Rare Disease Therapeutics

Fulcrum Therapeutics, Inc. (NASDAQ:FULC), established in 2015, is a clinical-stage biopharmaceutical company dedicated to developing small molecules for genetically defined rare diseases with high unmet medical needs. The company's journey has been marked by both strategic pivots and promising advancements, most notably its sharpened focus on pociredir for sickle cell disease (SCD) after a significant realignment. This strategic clarity, coupled with a differentiated technological approach, underpins Fulcrum's investment thesis in a competitive and evolving rare disease landscape.

The biopharmaceutical industry, particularly in rare diseases, is characterized by intense competition from major pharmaceutical companies, specialty biotechs, and academic institutions. Competitors like Sarepta Therapeutics (SRPT), Vertex Pharmaceuticals (VRTX), BioMarin Pharmaceutical (BMRN), and CRISPR Therapeutics (CRSP) are formidable, often leveraging gene therapies or enzyme replacement strategies. Fulcrum differentiates itself through its proprietary small-molecule technology designed to modulate gene expression, offering a potentially simpler and less invasive treatment modality compared to complex gene-editing or cell-based therapies. This approach aims to provide targeted efficacy for specific genetic pathways, potentially leading to more accessible and affordable treatments.

Technological Edge: Small Molecules with Big Impact

Fulcrum's core technological differentiation lies in its ability to discover and develop small molecules that can precisely modulate gene expression. This platform led to the identification of pociredir, an oral fetal hemoglobin (HbF) inducer. HbF induction is a well-validated mechanism for treating SCD, as increased HbF levels are known to reduce the sickling of red blood cells, thereby mitigating disease severity.

The tangible benefits of pociredir's technology were highlighted in the 12 mg dose cohort of the Phase 1b PIONEER trial. Results announced in July 2025 demonstrated a robust and clinically meaningful absolute mean HbF induction of 8.6% from a baseline of 7.6% to 16.2% at 12 weeks of treatment. Crucially, seven of 16 patients (44%) achieved absolute HbF levels greater than 20%, a threshold associated with a near abolition of vaso-occlusive crises (VOCs) and dramatically improved patient outcomes. The therapy also showed near pancellular HbF induction, with F-cells (HbF-containing red blood cells) increasing from a mean of 34% at baseline to 67% at 12 weeks. This pancellular distribution is vital for widespread protection against sickling.

Beyond HbF induction, pociredir demonstrated improvements in key biomarkers of hemolysis, including a mean decrease of 37% in indirect bilirubin, a 28% decrease in lactate dehydrogenase, and a 27% decrease in red cell distribution width, indicating a healthier, more uniform red blood cell population. Mean hemoglobin concentration also increased by 0.9 g/dL, from 7.8 g/dL to 8.7 g/dL, suggesting reduced red blood cell destruction and improvements in anemia. A trend of reduced VOC rates was observed, with 50% of patients reporting no VOCs during the 12-week treatment period. The drug was generally well-tolerated, with all treatment-related adverse events being Grade 1 in severity and no drug-related serious adverse events or discontinuations.

For investors, these quantifiable benefits underscore pociredir's potential to offer a highly effective and well-tolerated oral treatment option for SCD. This positions Fulcrum to capture a significant market share, particularly given the recent global withdrawal of Oxbryta and the commercial complexities of gene therapies. The company's focus on an oral small molecule could provide a competitive advantage in terms of patient accessibility and ease of administration, potentially leading to strong customer loyalty and improved margins from a more efficient development and delivery pathway.

Strategic Evolution and Operational Focus

Fulcrum's history includes a significant strategic shift. In September 2024, the company discontinued the development of losmapimod for facioscapulohumeral muscular dystrophy (FSHD) after its Phase 3 REACH trial did not meet primary or key secondary endpoints. This decision, despite an $80 million upfront payment from Sanofi in May 2024 for ex-U.S. rights, led to a 40% workforce reduction to refocus resources. The Sanofi agreement was subsequently terminated in April 2025. This pivot highlights management's commitment to judicious capital allocation and a disciplined focus on programs with the highest probability of success and market impact.

The company's current operational focus is squarely on advancing pociredir. Enrollment in the 20 mg dose cohort of the PIONEER trial is complete with 12 evaluable patients, and data is anticipated by year-end 2025. An open-label extension (OLE) trial has been initiated, driven by investigator and patient interest, to gather longer-term safety and durability data, which will be crucial for future regulatory discussions. Management plans an end-of-Phase 1 meeting with the FDA in Q1 2026 to align on the next stage of clinical development, with the potential for a registrational study. Discussions are also ongoing with the FDA regarding the potential use of HbF as a surrogate endpoint for accelerated approval, leveraging the strong correlation between HbF levels and reduced VOCs.

Beyond SCD, Fulcrum is advancing its preclinical pipeline, particularly in inherited aplastic anemias such as Diamond-Blackfan anemia (DBA), 5q deletion syndrome, Shwachman-Diamond syndrome, and Fanconi anemia. The company plans to submit an IND for these conditions in Q4 2025, building on a $0.60 million preclinical milestone achieved in April 2025 under its license agreement with CAMP4 Therapeutics Corp. Additionally, preclinical data for FTX-6274, an oral EED inhibitor, demonstrated robust efficacy in castration-resistant prostate cancer models at ESMO 2025, hinting at broader potential for EED inhibition beyond hematology.

Financial Performance and Liquidity

Fulcrum's financial performance reflects its clinical-stage nature and strategic shifts. The company reported a net loss of $54.50 million for the nine months ended September 30, 2025, compared to a net income of $6.80 million for the same period in 2024. The 2024 net income was primarily due to the $80 million collaboration revenue from the Sanofi agreement.

Research and development (R&D) expenses decreased by $11 million for the nine months ended September 30, 2025, to $40.687 million, largely due to the discontinuation of losmapimod and a $1 million reimbursement from the former Sanofi (SNY) collaboration, partially offset by increased investment in the pociredir program. General and administrative (G&A) expenses also saw a decrease of $7.3 million to $21.389 million for the same period, attributed to lower professional services, legal costs, and reduced employee compensation from the workforce reduction.

As of September 30, 2025, Fulcrum held a strong cash position with $200.6 million in cash, cash equivalents, and marketable securities. This liquidity is projected to fund operating expenses and capital expenditure requirements into 2028, providing a substantial runway for the continued development of pociredir and the advancement of its preclinical programs.

The anticipated cash burn for 2025 is expected to be between $55 million and $65 million. While the company has an at-the-market (ATM) offering program for up to $100 million, no shares have been issued under it as of September 30, 2025.

Competitive Dynamics and Market Opportunity

The market for SCD treatments is undergoing significant changes. While gene therapies like CASGEVY and LYFGENIA were approved in December 2023, their commercial success has been limited due to high costs, risks, and complexities. The withdrawal of Oxbryta has also created a greater unmet need for effective oral therapies. Fulcrum estimates that approximately 20% of the 100,000 SCD patients in the U.S. currently meet the inclusion/exclusion criteria for the PIONEER trial, representing a significant addressable market.

Fulcrum's small molecule approach for pociredir positions it uniquely against gene therapies, potentially offering a more accessible and less invasive treatment option. The company's ability to induce HbF pancellularly and demonstrate improvements in key hematological markers, along with a favorable safety profile, could make pociredir a compelling alternative. While current trials exclude concomitant use with hydroxyurea, management intends to discuss relaxing this criterion with the FDA for future pivotal studies, which would significantly expand the commercial opportunity.

Risks and Challenges

Despite the promising outlook, Fulcrum faces inherent risks common to clinical-stage biopharmaceutical companies. These include the lengthy, expensive, and uncertain nature of clinical drug development, where early-stage results may not predict future success. The prior clinical hold on pociredir due to hematological malignancies in nonclinical studies, though lifted, underscores the ongoing safety monitoring required, particularly given that EED inhibitors are in a class of drugs with outlined safety risks. Patient enrollment challenges, even with expanded sites, could delay development timelines.

Financially, Fulcrum's reliance on additional funding through equity offerings or collaborations remains a risk, especially in volatile capital markets. The company has a history of significant operating losses and an accumulated deficit of $573.90 million as of September 30, 2025, highlighting the need for successful commercialization to achieve profitability.

Furthermore, changes in tax laws, such as the Section 382 ownership change in September 2024, have limited the utilization of prior net operating loss carryforwards. Broader macroeconomic factors, geopolitical events, and evolving healthcare regulations, including drug pricing initiatives like the Inflation Reduction Act, could also impact future revenues and profitability.

Conclusion

Fulcrum Therapeutics is at a pivotal juncture, having strategically refocused its efforts on pociredir for sickle cell disease, a program demonstrating compelling clinical data and significant market potential. The company's small molecule technology, which enables robust and pancellular HbF induction, offers a differentiated approach in a landscape increasingly dominated by complex gene therapies. With a strong cash runway extending into 2028, Fulcrum is well-positioned to advance pociredir through its next clinical stages and progress its promising preclinical pipeline in inherited aplastic anemias. The successful execution of its clinical development plan, particularly the upcoming 20 mg cohort data and FDA alignment on registrational pathways, will be critical in realizing the full potential of its technological leadership and addressing the profound unmet needs of patients with genetically defined rare diseases.