NEWS & ANALYSIS

News in BRief Industry’s interest in RNA-targeted​ FDA approves first BCMA-​targeted therapeutic small-molecule​ drugs is growing. In April, The FDA has approved GlaxoSmithKline on the drug’s label notes the associated risk Roche partnered with Arrakis Therapeutics (GSK)’s belantamab mafodotin for of severe vision loss. on RNA-targeted​ small-molecule drug relapsed or refractory multiple myeloma. GSK is still developing the ADC for earlier discovery. Other biotechs that are working The antibody–drug conjugate (ADC) is lines of therapy, and in combination with preclinically on RNA-targeted​ small molecules the first therapeutic from the crowded other agents. A benefit of the ADC approach include Expansion Therapeutics, Skyhawk BCMA-​targeted pipeline to secure approval. is that it provides an off-the-​ shelf​ product. Therapeutics and Ribometrix. BCMA, a member of the TNF-receptor​ BCMA-targeted​ CAR-T​ therapies that Asher Mullard superfamily, is expressed on normal B are made to order for each patient are also lymphocytes as well as on multiple myeloma approaching the market, setting the stage FDA approves first GPCR cells. Despite early efforts to target BCMA for a modality showdown. Bristol Myers with canonical monoclonal antibodies, early Squibb and Bluebird Bio resubmitted their biased agonist candidates did not have sufficient efficacy idecabtagene vicleucel for FDA approval The FDA has approved Trevena’s μ-​opioid to move forward. In recent years, however, in July, following an earlier submission agonist oliceridine for moderate to severe drug developers have had more success with and refuse-​to-​file letter. Johnson & Johnson acute pain in adults. Oliceridine was once ADCs, bispecific antibodies and CAR-T​ cell and partner Legend Biotech are expected heralded as an exemplar of the possibilities therapies. to file their CAR-T​ therapy JNJ-4528 for of biased GPCR agonists, drugs that can The FDA’s accelerated approval of approval by the end of the year. preferentially activate only a subset of a belantamab mafodotin, for patients with BCMA is the second most popular defined receptor’s signalling pathways. Even with multiple myeloma who have had at least cancer target in the global cell therapy the approval, however, the purported four prior therapies, was based on an pipeline, trailing only behind CD19. clinical benefits of these agents remain open-label​ trial in 97 heavily pre-treated​ Amgen’s BCMAxCD3-​targeted bispecific to be demonstrated. patients. The overall response rate in this T cell engager AMG 420, another off-the-shelf​ “I don’t think this is going to move the field trial was 31%, and 73% of responders had product, is in phase II trials. [of biased agonism] in one direction or another,” a response duration of at least 6 months. Belantamab mafodotin is the tenth ADC says Bryan Roth, a pharmacologist at the Common adverse reactions included corneal to secure FDA approval. University of North Carolina who discovered epithelium change, and a black box warning Asher Mullard another biased opioid agonist called PZM21. “It is a big win for Trevena,” he adds. FDA approves RNA-​targeting small molecule Traditional opioid agonists are associated with adverse events including respiratory The FDA has approved Roche and PTC of a full-length​ SMN protein, compensating depression and gastrointestinal complications. Therapeutics’ risdiplam, an RNA splice- for loss-​of-function​ mutations in SMN1 that Some evidence suggests, however, that the ​modifying small-​molecule drug, for spinal otherwise cause the muscle wasting disease. analgesic effects of these GPCR agonists may muscular atrophy (SMA). The FDA approved risdiplam on the basis be a result of associated G-protein​ signalling Drugs that can force the alternative of two studies. In an open-label​ study in whereas the adverse events are a result splicing of mRNA templates, shifting protein 21 patients with infantile-onset​ SMA, 41% of associated β-​arrestin 2 signalling. With production profiles, have long been on of patients were able to sit independently oliceridine, Trevena sought to preferentially industry’s watch list. Pioneering approvals for more than 5 seconds after 12 months of stimulate the G-protein​ signalling, in the hope in this space include Sarepta’s eteplirsen, treatment. Also, 90% of infants were alive of developing a next-generation​ opioid with a for Duchenne muscular dystrophy, and without permanent ventilation at 12 months cleaner safety profile. Biogen and Ionis Pharmaceuticals’ nusinersen, of treatment and reached 15 months of age The company first submitted the drug for for SMA. But whereas both these agents are or older. Natural history studies of untreated approval in 2017. An FDA advisory committee oligonucleotide therapeutics, risdiplam is infantile-​onset SMA suggest that infants voted against approving the drug in 2018, a small-​molecule drug. would otherwise not be able to sit indepen­ after the agency noted concerns with the Like nusinersen, risdiplam modulates dently, and only 25% would survive without drug’s safety and benefit–risk profile. Months the splicing of the SMN2 gene to promote permanent ventilation beyond 14 months later, the FDA rejected the drug. Now, even exon 7 inclusion. This results in the production of age. In a placebo-controlled​ trial in as the agency approved the drug, it noted 180 patients with later-onset​ SMA, treated that the safety profile of the drug “is similar patients experienced an increase in motor to other opioids”. function, as assessed by the MFM32 test, Earlier this year, three laboratories of 1.36 on treatment, compared with a reported on their efforts to collaboratively 0.19 decrease on placebo. evaluate whether the side effects of opioids Whereas nusinersen is dosed intrathecally are due to β-​arrestin 2 signalling. Writing in the clinic, risdiplam is orally available and in the British Journal of Pharmacology, they can be administered at home. concluded that their results “call into question In addition to competition from nusinersen, the concept of developing G protein-biased​ risdiplam will also face off against Novartis’s μ-​opioid receptor agonists as a strategy for the gene therapy onasemnogene abeparvovec, development of safer opioid analgesic drugs”.

Credit: S.Harris/Springer Nature Limited S.Harris/Springer Nature Credit: which delivers a functional SMN transgene. Asher Mullard

Nature Reviews | Drug Discovery volume 19 | OCTOBER 2020 | 659