Pociredir

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.

Fulcrum Therapeutics said it would use its $273.8 million in cash and equivalents to swiftly pivot to its remaining pipeline. Just four months after Sanofi bet $80 million in upfront cash on Fulcrum Therapeutics’ losmapimod, the program has ended in a phase 3 failure.The licensing deal with the Big Pharma was agreed upon while counting down to the release of late-stage data in the progressive muscle wasting disorder facioscapulohumeral muscular dystrophy (FSHD) which, if successful, could have opened the door to the p38 inhibitor becoming the first approved therapy for the disease.But the results are just in, and it looks like a wipeout. Not only did the 260-patient study miss its primary endpoint of showing an improvement in an individual’s arm reach when taking a 15-mg losmapimod tablet twice a day compared to placebo, but the study’s secondary endpoints like muscle fat infiltration and patient-reported improvements “did not achieve nominal statistical significance,” Fulcrum explained in a Sept. 12 premarket release.Specifically, the primary endpoint of reachable workspace (RWS)—an analysis of how far an individual can reach—saw a 0.013 improvement among patients receiving losmapimod at Week 48 compared to a 0.010 improvement among those who received placebo. Fulcrum’s chief medical officer Pat Horn, M.D., Ph.D., blamed the results on the lack of deterioration among the placebo cohort.“These results in patients receiving losmapimod when compared to baseline were similar to those observed in our phase 2 study,” Horn said. “However, in contrast to what was seen in the ReDUX4 study as well as what has been reported in other FSHD studies, the patients receiving placebo in REACH did not show a decline in functional status as measured by RWS and shoulder dynamometry over the 48 weeks of the study.”The safety and tolerability of losmapimod was consistent with previously reported studies, according to Fulcrum, which said it will fully evaluate the data before sharing the results at an upcoming medical meeting.“We are deeply disappointed that the REACH trial did not replicate the clinical results observed in the phase 2 ReDUX4 trial,” Fulcrum’s CEO Alex Sapir said in the release. “In light of these results, we plan to suspend the losmapimod program in FSHD.”The biotech’s stock plummeted 70% in premarket trading Thursday morning to $2.60 from a Wednesday closing price of $8.85.Massachusetts-based Fulcrum said it would use its $273.8 million in cash and equivalents to swiftly pivot to its remaining pipeline. This is headed up by pociredir, a phase 1-stage small molecule designed to treat sickle cell disease by increasing expression of fetal hemoglobin. Today’s results mark a fork in the road for Fulcrum, which could have been on track to get the first-ever FSHD drug to market if the phase 3 data had shown promise. Losmapimod had a two- to three-year head start on Roche’s myostatin inhibitor that is being targeted at FSHD, while Avidity Biosciences and Arrowhead Pharmaceuticals both have antibody-oligonucleotide complexes in clinical development for the condition.It also means Fulcrum can wave goodbye to potentially $975 million in milestone payments that were tied to the Sanofi licensing deal. When the French Pharma secured the ex-U.S. rights to losmapimod in May, the drugmaker’s global head of rare disease Burcu Eryilmaz pointed to “meaningful clinical benefits” shown in phase 2 studies that “underscore the disease-modifying potential and opportunity to address the high unmet need for a safe and effective drug that slows disease progression.”But losmapimod already had a number of clinical misses on its scorecard. Fulcrum rescued the molecule in 2019 from the vault of GSK, where losmapimod had failed a phase 3 trial in patients with acute coronary syndrome and a midstage study in chronic obstructive pulmonary disease. Under its new owner, it had also failed a phase 2 trial in FSHD in 2021, although Fulcrum was heartened by phase 2b data showing losmapimod could still slow disease progression and improve function in FSHD patients.