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Doppler ultrasound measurement has a significant impact in medical research. The study focused on clinical data from 236 patients in Egypt, Ghana, Kenya, Nigeria, Oman, Saudi Arabia, the United States and the United Kingdom. Specifically, in the Phase III GBT440-032 trial, patients treated with Oxbryta experienced more frequent vascular occlusion crises (VOCs) than those treated without Oxbryta, and unfortunately eight deaths were recorded. As one of the most common acute complications in patients with SCD (sickle cell disease), the severity of VOC cannot be ignored. SCD, as a hereditary blood disorder, has a core pathology in which glutamate, the sixth amino acid in the β-peptide chain, is replaced by valine, which leads to the production of abnormal hemoglobin, sickle hemoglobin (HbS). The presence of HbS causes red blood cells to deform (sickle) and even destroy, and this abnormal form of red blood cells not only has a short life span, but also is easy to block small blood vessels, resulting in pain, breathing difficulties, hemolysis and a series of complex symptoms and complications. Oxbryta, as the first drug approved by the FDA to directly inhibit HbS polymerization, its mechanism is to effectively inhibit the polymerization process of HbS by improving the affinity of hemoglobin to oxygen, thus reducing the degree of deformation and destruction of red blood cells. In addition, a second trial, GBT440-042 (also known as RESOLVE/NCT05561140), which investigated Oxbryta for leg ulcers in 88 12-year-old patients enrolled in Brazil, Kenya, and Nigeria, reported eight deaths in its open-label phase. Of note, the Phase III GBT440-038 trial (NCT04188509), which was scheduled to evaluate the long-term safety of Oxbryta and its efficacy in improving SCD-related complications in participants who completed treatment in earlier clinical studies, has been suspended. In response to the deaths in the trial, the European Medicines Agency (EMA) stated that there is no conclusive evidence that Oxbryta directly caused the deaths of patients. Given that most of the patients involved are from Africa, it cannot be ruled out that some of the cases are related to infectious diseases such as malaria. In light of the above, the U.S. Food and Drug Administration (FDA) has issued an official bulletin urgently urging patients and healthcare providers not to discontinue treatment and advising providers to suspend prescribing Oxbryta. At the same time, patients who have taken the drug should immediately contact their health care provider to discuss and adjust treatment options. As a rare disease with autosomal dominant inheritance, SCD has been included in the first Rare Disease Catalogue in China. Its medical history dates back to the first reported case in 1910 by American physician James B. Herrick, which detailed a 20-year-old patient from Jamaica with a distinctive "sickle" or "crescent" shape of red blood cells. In 1949, a landmark study by E. Anthony Beutler and James V. Neel revealed the genetic nature of SCD and its pathological mechanism driven by mutations in a single gene. Subsequent studies further elucidated the genetic pattern of SCD and its potential protective effect against malaria infection. SCD usually develops in early childhood, and the severity of the condition varies from person to person. At present, treatment strategies mainly include blood transfusion and drug therapy. Among them, hydroxyurea as the first drug approved by the FDA for the treatment of SCD, its development history and efficacy have been widely recognized. In addition, with the advancement of medical technology, a variety of new drugs, including Oxbryta, as well as gene therapies such as Casgevy and Lyfgenia, are gradually being applied to the clinic, providing patients with more treatment options. However, considering the limited scope and high cost of gene therapy, its application in the field of SCD therapy still needs to be further evaluated and explored.

Pfizer’s signage outside its office in Canada iStock, JHVEPhoto Based on new safety signals, Pfizer on Wednesday announced that Oxbryta’s overall benefit “no longer outweighs the risk” in patients with sickle cell disease. Guggenheim Securities analysts said the setback increases investor frustrations with the company’s business development track record. Pfizer on Wednesday announced that it will withdraw its sickle cell disease therapy Oxbryta (voxelotor) from worldwide markets after new data showed a higher risk of deaths and complications in treated patients. According to the company, new safety data for Oxbryta point to an “imbalance” of vaso-occlusive crises and mortality events in patients “which require further assessment.” Because of these findings, “the totality of the clinical data … now indicates the overall benefit of Oxbryta no longer outweighs the risk in the approved sickle cell patient population,” Pfizer said in its announcement. Wednesday’s withdrawal will also affect all active clinical trials and expanded access programs of Oxbryta. The company has informed global health authorities about the new safety signals and the drug withdrawal, and it will continue to evaluate these new findings. Pfizer CMO Aida Habtezion in a statement said that the decision to pull Oxbryta “is in the best interest of patients,” whose safety and well-being “is of the utmost importance” to the company. Patients on Oxbryta should discuss alternative treatment options with their physicians, Habtezion said. Oxbryta’s withdrawal is unlikely to affect Pfizer’s 2024 guidance, according to the announcement. Guggenheim Securities analysts wrote in an investor note that the financial impacts are likely to be “somewhat modest.” Still, another setback for the company’s business will “increase investor frustrations with Pfizer’s business development track record,” according to the analysts. “The news will likely also raise additional questions on Pfizer’s ability to grow through the 2025-2030 time period when it is facing a number of patent expirations and other challenges to their current growth drivers,” the analysts noted. Oxbryta is an orally available hemoglobin S polymerization inhibitor that works by suppressing the sickling of red blood cells. It was approved for the treatment of sickle cell disease (SCD) in November 2019, when it was still owned by Global Blood Therapeutics. Pfizer acquired the biotech in 2022 for $5.4 billion . The withdrawal of Oxbryta will be a “significant blow” to patients with SCD ”who have been historically underserved,” BMO Capital Markets analyst Evan Seigerman wrote in an investor note. There are new treatment options available, including two gene therapies—bluebird bio’s Lyfgenia (lovotibeglogene autotemcel) and Vertex Pharmaceuticals and CRISPR Therapeutics’ Casgevy (exagamglogene autotemcel)—that the FDA approved in December 2023 . Oxbryta’s new safety signals could also bring more scrutiny to these newer therapies, Seigerman wrote. “A similar lens is likely to be applied to gene therapies treating sickle cell disorder; although, these patients are generally sicker, which changes the conversation around risk/cost trade-off.”