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iStock/ YuLi4ka In the wake of Pfizer’s voluntary market withdrawal of the popular sickle cell disease therapy, BioSpace looks at five investigational drugs currently making their way through the pipeline. A recent fumble has left the sickle cell disease community reeling . Last month, Pfizer abruptly pulled Oxbryta from all global markets after new data showed a higher risk of deaths and complications in treated patients. “[Oxbryta] was one of four medications which we would describe as disease-modifying,” Clifford Takemoto, director of clinical hematology at St. Jude Children’s Research Hospital, told BioSpace . Since the approval of Bristol Myers Squibb’s hydroxyurea for sickle cell disease (SCD) in 1998, only three disease-modifying medications have entered the market, he said. Oxbryta, which won FDA accelerated approval in November 2019, was one of these. Another, Novartis’ Adakveo, has also been called into question after failing to reduce vaso-occlusive crises (VOC) in people with SCD in a Phase III trial last year. EU regulators formally revoked Adakveo’s approval in August 2023, but it remains available in the U.S. “We were optimistic that things were changing,” Takemoto said. “People had hoped that these medications would make a difference.” SCD affects more than 100,000 people in the U.S. and 8 million worldwide. With so few treatment options, it remains a seriously underserved population . Takemoto said the Oxbryta withdrawal has left some patients a “bit angry” and distrustful of new medications, and the question for the community remains: “What’s next?” For Takemoto, the ultimate hope for SCD treatment lies in next-gen transplantation and gene therapy. With the approval of bluebird bio’s Lyfgenia and Vertex and CRISPR Therapeutics’ Casgevy, the potential for gene therapies in SCD is there, even if the rollout is slow and for most, not very accessible, he said. St. Jude is developing its own gene therapy, which the research hospital hopes to move into clinical trials sometime next year. Takemoto also pointed to work being done in bone marrow transplantation intended to reduce toxicity and improve success rates. St. Jude is working on a process that will utilize a “half match,” where a parent’s bone marrow can be used instead of a sibling. These treatments could be transformative, Takemoto said. Here, BioSpace looks at five investigational therapies making their way through the SCD pipeline. Pfizer’s Inclacumab and Osivelotor Oxbryta is not the only SCD asset Pfizer brought onboard with its 2022 acquisition of Global Blood Therapeutics . Two other investigational therapies, inclacumab and osivelotor, were also part of the deal. Inclacumab, a P-selectin inhibitor, is currently being assessed in a Phase III trial to determine its safety and efficacy in reducing VOC. The drug works by binding to P-selectin, a cell adhesion molecule found on platelets. According to Pfizer, this prevents platelets from aggregating, which in turn, is expected to help maintain normal blood flow. Like Oxbryta, osivelotor is a sickle hemoglobin polymerization inhibitor, but with a next-generation design. The asset is currently being studied in a Phase II/III study slated for completion in 2028. While Pfizer has not stated whether the recent findings related to Oxbryta will impact the development of osivelotor, Leerink Partners noted that a Phase II study raised safety concerns, with treatment-emergent adverse events seen in 8 out of 35 patients. Agios Pharmaceuticals’ Mitapivat Agios Pharmaceuticals is developing mitapivat, a pyruvate kinase (PK) activator that is already approved for the treatment of hemolytic anemia in adults with PK deficiency, for SCD. Red blood cells require the PK enzyme for energy, Takemoto explained. In December 2023, the company presented positive data from the Phase II portion of its pivotal RISE UP study. The annualized rate of sickle cell pain crises for patients in the higher dose treatment arm was 0.51 compared to 1.71 for participants in the placebo arm. Takemoto said the oral medication seems to benefit red blood cell health in general and noted that the data look favorable for patients with SCD and other hemolytic anemias. But not everyone is as convinced. Leerink Partners analysts wrote last month of concerns that similar physiological effects could be seen with both Oxbryta and mitapivat. A Phase III readout is expected next year, and the company is targeting a label expansion in 2026. Novo Nordisk’s Etavopivat In 2022, Novo Nordisk paid $1.1 billion to acquire Forma Therapeutics, gaining a lead SCD asset, etavopivat, in the deal. Like mitapivat, etavopivat is also a PK activator, but Novo’s candidate comes with a potential advantage —once daily dosing, versus mitapivat’s twice daily regimen. Etavopivat is currently being studied in a Phase III trial slated for completion in 2026. Phase I data presented by Forma at the American Society of Hematology’s annual meeting in 2021 showed a “sustained increase in hemoglobin and improvement in biomarkers of hemolysis and red blood cell health.” The results, from 15 patients dosed for up to 12 weeks, also showed a trend toward decreasing VOC compared to the 12 months prior to their entering the trial. Takemoto said the candidate “looks very promising” so far but acknowledged that “there are things we don’t know about it. We may learn new side effects as it’s used.” St. Jude will serve as a site for the Phase III trial. Fulcrum Therapeutics’ Pociredir Fulcrum Therapeutics ’ pociredir, a polycomb repressive complex 2 (PRC2) inhibitor, is designed to induce expression of fetal hemoglobin to compensate for the mutated hemoglobin that occurs in SCD. The development path for pociredir has not been without bumps. In February 2023, the FDA slapped Fulcrum with a clinical hold based on previously submitted preclinical data and non-clinical and clinical evidence of hematological malignancies observed with other PRC2 inhibitors. The hold was released six months later. The small molecule, which is currently being studied in a Phase Ib trial, has been well-tolerated in people with SCD with no treatment-related adverse events reported after up to three months exposure, according to a press release announcing the lifted clinical hold.

Pfizer confirmed Wednesday that the termination of a Phase III study in the THRIVE programme for inclacumab will not affect its filing plans for the anti-P-selectin inhibitor in sickle cell disease. A spokesperson told FirstWord that a marketing submission to the FDA remains on track for 2026.A recent update on ClinicalTrials.gov indicated that Pfizer had ended the trial “due to poor accrual and associated recruitment challenges.” The entry noted that 72 patients with sickle cell disease and recurrent vaso-occlusive crises had been enrolled into the study, out of a target of approximately 280. The spokesperson said the trial was halted “due to slow recruitment,” although it has no read across to another late-stage study in the THRIVE programme. That trial is scheduled to read-out in August. Pfizer gained inclacumab through its purchase of Global Blood Therapeutics in 2022. The acquisition also included the HbS polymerisation inhibitor GBT601, now known as PF-07940367. That drug is being investigated in a Phase II/III study for sickle cell disease, with the spokesperson noting that termination of the inclacumab trial does not impact the former programme.

Pictured: Exterior view of Pfizer's office in Belgium/iStock, Alexandros Michailidis Pfizer has discontinued one of its two Phase III studies evaluating the anti-P-selecting antibody inclacumab in sickle cell disease, according to an update on the ClinicalTrials.gov webpage. According to the online database, Pfizer terminated the late-stage study “due to poor accrual and associated recruitment challenges.” The trial was launched in December 2021. However, at the time of Monday’s update, the study had only enrolled 78 patients out of its target size of 280 participants. A Pfizer spokesperson confirmed to Fierce Biotech that the company ended the study “due to slow recruitment,” while adding that the pharma is still eyeing an approval for inclacumab in sickle cell disease by 2026. Originally developed by Global Blood Therapeutics (GBT), Inclacumab is a fully human monoclonal antibody that works by selectively blocking the P-selectin protein, which is known to play a role in cell adhesion and is a clinically validated target for reducing pain associated with vaso-occlusive crises (VOC) in patients with sickle cell disease (SCD). Inclacumab in June 2022 secured the FDA’s Orphan Drug and Rare Pediatric Disease designations for SCD treatment due to its best-in-class potential as well as its quarterly dosing regimen instead of monthly infusions. In August 2022, Pfizer moved to acquire GBT in a $5.4 billion deal for the biotech’s portfolio of SCD therapies, including the FDA-approved Oxbryta (voxelotor), an oral hemoglobin S polymerization inhibitor indicated for patients four years of age and older. Inclacumab was also part of the acquisition. Following the buyout, Pfizer took over the Phase III THRIVE program, which comprised two studies—including the subsequently terminated trial—designed to evaluate the efficacy and safety of inclacumab at reducing VOCs in SCD patients. The other trial remains active and has completed recruitment at 240 patients. According to its ClinicalTrials.gov page, a readout is expected later this year. The termination of Pfizer’s late-stage study follows back-to-back landmark approvals in the SCD space. In December 2023, the FDA on the same day gave its nod to CRISPR Therapeutics and Vertex Pharmaceuticals’ CRISPR-based Casgevy (exagamglogene autotemcel) and bluebird bio’s lentiviral delivery-based Lyfgenia (lovotibeglogene autotemcel). Casgevy and Lyfgenia are cell-based gene therapies. Both products are made from the patients’ own blood stem cells, which are modified, and are given back as a one-time, single-dose infusion. Casgevy has a U.S. list price of $2.2 million per patient, while bluebird set the wholesale acquisition cost of Lyfgenia in the U.S. at $3.1 million. In January 2024, the Centers for Medicare and Medicaid Services announced that it would seek outcomes-based agreements with the developers of these SCD gene therapies to help curb healthcare costs. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.