Osivelotor

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.

2024年9月25日，辉瑞宣布自愿从目前所有获批的市场中撤回所有批次的镰状细胞病（SCD）治疗药物Oxbryta（voxelotor）。 同时，辉瑞还将停止所有正在进行的voxelotor的临床试验和全球扩展访问计划。 存在安全问题 Oxbryta是一种每日1次口服的SCD药物，于2019年11月获得美国首次批准，目前已经在全球超过35个国家/地区获批上市。Oxbryta由辉瑞于2022年以54亿美元收购Global Blood Therapeutics获得。 根据报道，辉瑞对于Oxbryta的决定是基于现有的全部临床数据，数据表明Oxbryta在SCD患者中的总体益处不再高于风险，患者的血管闭塞危象和致命事件已失衡，需要进一步评估。 辉瑞已将这些发现告知监管机构，并决定自愿将Oxbryta从市场上撤出并停止分销和临床研究，同时进一步审查现有数据并分析结果。 目前，辉瑞正在和临床医生讨论替代疗法。辉瑞表示，将继续分析和审该药物的安全性结果。 值得注意的是，该决定是在欧洲监管机构开会审查Oxbryta安全性的前一天做出的。EMA于周四建议暂停对Oxbryta的许可，EMA审查Oxbryta的原因是在两项研究中，一项试验死亡人数高于预期，另一项研究服用Oxbryta的患者比服用安慰剂的患者死亡人数更多。 辉瑞的SCD布局 辉瑞在镰状细胞病上曾寄予厚望，在2022年收购Global Blood Therapeutics时，预测Oxbryta和另外两款在研镰状细胞病药物未来的销售额可能超过30亿美元。 据辉瑞财报，2023年Oxbryta的全球销售额为3.28亿美元。Oxbryta在2024年第二季度的销售额为9200万美元。 Oxbryta的失败，将会导致辉瑞失去一大部分收入，也使得辉瑞在镰状细胞病上暂时失利。 但是辉瑞子公司Global Blood的两款SCD在研药物inclacumab和osivelotor已经推进到3期临床，尤其是osivelotor（GBT-601）被认为是Oxbryta的接任者，去年年底发布的数据显示出积极的前景。 来自osivelotor的2/3期研究A队列中35例SCD患者，其中17人接受了100mg剂量的osivelotor，18人接受150mg剂量。经过12周的治疗后，两个剂量组的患者的血红蛋白水平平均提高了3g/dL。 SCD药物市场 SCD是一种遗传性血液病，其中血红蛋白S（HbS）聚合导致红细胞镰状化，从而导致血管炎症和溶血性贫血。血管炎症与红细胞镰状化的出现可导致急性疼痛危象或血管闭塞危象，以及进行性终末器官损伤，包括中风。 根据报道，SCD是全球重大公共卫生难题，每年有大约500万人死于SCD。 相较于SCD的患病人群，SCD治疗药物选择不多： Hydroxyurea是最早获得批准的SCD药物，但是其具有严重的毒副作用，因此使用受到限制； Emmaus Medical的Endari，于2017年获得FDA批准，是20年来首个获得批准的SCD新药； 诺华的Adakveo，于2019年获得FDA批准，是首个SCD治疗的靶向药物； Global Blood的Oxbryta，于2019年获得FDA批准，后来Global Blood被辉瑞收购； bluebird bio（蓝鸟生物）的Lyfgenia，于2023年12月获得FDA批准，是一款细胞基因治疗产品，旨在通过一次性给药实现长期乃至终身有效，售价高达310万美元； Vertex和CRISPR Therapeutics的Casgevy，于2023年12月获得FDA批准，是一款CRISPR基因编辑疗法，售价为220万美元。 Oxbryta的失败，使得SCD患者的可选择药物少了一个。同时，两款基因治疗的获批虽然给患者提供了更好的治疗前景，但是治疗费用的门槛使得真正使用这两款药物的患者不多。 参考资料： 1.https://www.biopharmadive.com/news/pfizer-oxbryta-withdraw-pull-market-sickle-cell/728155/ 2.https://www.pfizer.com/news/press-release/press-release-detail/pfizer-voluntarily-withdraws-all-lots-sickle-cell-disease 本周好文推荐 如需转载请联系佰傲谷并在醒目位置注明出处 · · · · · · · ·