Fulcrum Therapeutics, Inc.

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.

Boston-area biotechs Upstream Bio and CAMP4 Therapeutics are headed to the Nasdaq on Friday, the latest companies to IPO in what appears to be a recovery for startups trying to raise capital on the public market. Upstream Bio priced at $17 per share, the high end of the $15 to $17 range it set earlier this week . By selling 15 million shares — 2.5 million more than originally planned — it will raise $255 million in new cash. CAMP4, meanwhile, priced its shares $CAMP at $11 apiece, $3 below the low end of the $14 to $16 range it marketed to investors. It sold 6.82 million shares versus an initial plan to offer 5 million and will raise $75 million . The IPO window is “showing signs of recovery,” Oppenheimer bankers wrote in a quarterly analysis this week. GPCR biotech Septerna is also in the IPO queue, and Bain-backed obesity startup Rivus Pharmaceuticals is also considering a listing this fall, Bloomberg reported this week. For Upstream $UPB the offering will add to its coffers as it runs Phase 2 and later-stage trials of its TSLP receptor antagonist verekitug. The experimental treatment, licensed from Astellas, is being studied for severe asthma and chronic rhinosinusitis with nasal polyps . Upstream hopes to enter a similar market as Amgen and AstraZeneca’s Tezspire, as well as Blackstone-backed Uniquity Bio’s solrikitug . CAMP4 is working on regulatory RNA and has a Phase 1 trial of its lead drug, a CPS1-targeting medicine for urea cycle disorders. The IPO comes a few weeks after CAMP4 added BioMarin to its partnership lineup, which already includes Fulcrum Therapeutics and Eli Lilly. Earlier in its startup days, CAMP4 had pacts with Biogen and Alnylam.

Regulatory RNA startup CAMP4 Therapeutics has inked another collaboration deal as it prepares for an initial public offering. The Cambridge, MA-based startup has lined up a pact with BioMarin to create RNA-targeting antisense oligonucleotides, or ASOs, the companies said Tuesday morning. The deal comes with just $1 million upfront, but as much as $370 million in potential future payments if BioMarin goes all the way through commercialization with two programs, according to an earlier SEC filing . For BioMarin, it lets the company put a small bet on new technology after recently trimming its pipeline , cutting workers and changing leadership . CAMP4 unveiled its IPO ambitions on Sept. 20, and it could price and start trading within the next few weeks. The startup, which emerged in 2018, had tie-ups with Alnylam and Biogen in its early days, but those agreements were scrapped as CAMP4 shifted from a focus on bioinformatics to restoring gene expression through regulatory RNAs. It has since forged a license and discovery agreement with Fulcrum Therapeutics and an R&D pact for up to three ASOs with Eli Lilly. The company is currently in Phase 1 with a CPS1-targeting experimental drug for urea cycle disorders. It expects initial data in the first quarter of next year. The experimental medicine, dubbed CMP-CPS-001, has orphan drug and rare pediatric disease tags from the FDA. The 64-employee biotech is in the IPO queue alongside respiratory biotech Upstream Bio . If they follow through with their Nasdaq listings, they’d tack onto a relatively busy fall of debuts from Bicara, Zenas, MBX and BioAge .