FDA Action Alert: Blueprint, Opiant and Lexicon

2023-05-22

临床3期申请上市上市批准临床结果优先审批

FDA Action Alert logo/© Nicole Bean for BioSpace The FDA is set to decide on three drug applications this week, including ones for opioid overdose, heart failure and systemic mastocytosis. Read below for more. Blueprint Seeks Approval in Indolent Systemic Mastocytosis On May 22, the FDA is expected to reach a regulatory decision on Blueprint Medicines’ Ayvakit (avapritinib), an investigational kinase inhibitor being proposed for the treatment of indolent systemic mastocytosis (SM). SM is a rare, genetic condition characterized by the frenzied and uncontrollable activation and proliferation of mast cells, a type of white blood cell. Most SM patients have non-advanced—or indolent—disease, which is associated with a broad range of severe, chronic and often unpredictable symptoms such as anaphylaxis, pruritus, diarrhea, fatigue and bone pain. Patients with SM often suffer from poor quality of life due to the fear of developing unexpected symptoms. There are currently no approved treatments for indolent SM. In approximately 95% of cases, SM is caused by the D816V mutation in the KIT gene. Ayvakit works by targeting and binding to the mutant protein, thereby disrupting its downstream signaling cascade. In this way, Ayvakit suppresses the proliferation of mast cells bearing the D816V mutation. Blueprint backed Ayvakit’s supplemental NDA with data from the PIONEER trial, which found that the drug significantly and rapidly reduced all main measures of pathological mast cell compared to placebo. These effects were durable throughout 24 weeks of follow-up. Moreover, Ayvakit treatment led to significant and clinically meaningful improvements in quality of life, Blueprint reported. PIONEER is the largest randomized and placebo-controlled study in indolent SM. Ayvakit is already approved for advanced SM, SM with associated hematological neoplasms, aggressive SM, mast cell leukemia and unresectable or metastatic gastrointestinal stromal tumor. Opiant’s Overdose Spray Awaits Verdict Also on May 22, the FDA is expected to make a decision on Opiant Pharmaceuticals’ nasal spray candidate for opioid overdose, OPNT003. OPNT003 is Opiant Opiant’s nasal spray formulation for nalmefene, an opioid antagonist that blocks opioid receptors to achieve partial or complete reversal of overdose effects, such as hypotension and respiratory depression. Data from three clinical studies were used to support Opiant Opiant’s NDA. The first study compared OPNT003’s pharmacokinetic pro an intramuscular nalmefene injection and found that the nasal route of administration leads to faster absorption and higher plasma concentrations of the drug. Opiant ran another pharmacokinetic study looking at the different effects of administering OPNT003 in one or both nostrils, showing that even when administered as multiple doses, the candidate is safe and well-tolerated. The company also submitted data from a head-to-head pharmacodynamic study comparing OPNT003 against Emergent BioSolutions’ Narcan (naloxone HCl) nasal spray. This study found that Opiant Opiant’s nasal spray was not only non-inferior to Narcan but also induced nearly twice the reversal in opioid-induced respiratory depression. The California-based biotech completed its rolling submission for the NDA in November 2022, which the FDA accepted in January 2023, granting it Priority Review designation. Lexicon Proposes Sotagliflozin for Heart Failure Treatment The FDA’s final decision of the week, which it is scheduled to release by May 27, pertains to Lexicon Pharmaceuticals’ sotagliflozin for the treatment of heart failure. Sotagliflozin is an orally available drug that works by inhibiting both the SGLT1 and SGLT2 proteins, which play a role in glucose absorption in the gastrointestinal tract and kidneys, respectively. In its NDA, accepted by the FDA in July 2022, Lexicon is seeking approval of sotagliflozin to reduce the risk of cardiovascular death, hospitalization for heart failure and urgent heart failure visits in adult patients. The company is also proposing to use sotagliflozin to decrease the risk of these outcomes, along with nonfatal myocardial infarction and stroke, in adults with chronic kidney disease, type 2 diabetes and other cardiovascular risk factors. Lexicon supported its NDA with data from the randomized, double-blinded and placebo-controlled Phase III SOLOIST-WHF and SCORED studies. SOLOIST-WHF looked at the efficacy and safety of sotagliflozin in more than 1,200 type 2 diabetes patients who had recently been hospitalized for worsening heart failure. The study found that the drug significantly reduced heart failure events and readmissions. Meanwhile, SCORED enrolled more than 10,000 patients with type 2 diabetes, chronic kidney disease and risk factors for cardiovascular disease. Its results showed the drug significantly lowered rates of heart failure hospitalizations, cardiovascular deaths and urgent visits. Aside from heart failure, sotagliflozin is being assessed for chronic kidney disease and type 1 and type 2 diabetes. The drug is approved in the European Union for type 1 diabetes under the brand name Zynquista. Tristan Manalac is an independent science writer based in metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com