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Upcoming market catalysts in Q4 2021

Upcoming catalysts for the fourth quarter of 2021 include approval decisions by the US Food and Drug Administration (FDA) on efgartigimod for the treatment of myasthenia gravis, pacritinib for the treatment of myelofibrosis and ciltacabtagene autoleucel for the treatment of multiple myeloma.

Efgartigimod is being developed by argenx for several autoimmune diseases that involve pathogenic immunoglobulin G (IgG) autoantibodies, including myasthenia gravis. Efgartigimod is a human antibody Fc fragment that is designed to bind to the neonatal Fc receptor (FcRn) and thereby reduce the recycling of IgG antibodies.

Intravenously administered efgartigimod was evaluated in a randomized placebo-controlled phase III trial known as ADAPT, involving 167 patients with generalized myasthenia gravis (gMG). The primary endpoint was the percentage of responders on the Myasthenia Gravis Activities of Daily Living (MG-ADL) score among patients who were acetylcholine receptor-a ntibody positive (AChR-Ab+). Responders were defined by having at least a two-p oint change on the MG-A DL for at least four consecutive weeks. The trial met its primary endpoint, showing 68% of efgartigimod-treated AChR-Ab+ patients were responders on the MG-A DL score compared to 30% of patients receiving a placebo. Efgartigimod was well tolerated, with a safety profile that was comparable to the placebo.

Credit: ADragan/iStock/Getty Images Plus

Based on these data, argenx submitted a Biologics License Application (BLA) to the FDA for efgartigimod for the treatment of gMG. The Prescription Drug User Fee Act (PDUFA) action date for efgartigimod (intravenously administered) is 17 December 2021. If it were to be approved, it would be the first product to be approved for argenx, and also only the second medication to be approved by the FDA for the treatment of myasthenia gravis.

Pacritinib is an orally administered JAK2/FLT3 inhibitor with negligible activity against JAK1 that also inhibits the interleukin-1-d irected inflammatory pathway via suppression of interleukin 1 receptor-associated kinase 1. Pacritinib is being developed by CTI BioPharma for the treatment of several diseases, including myelofibrosis, an indication with a history of clinical failures and only two approved drug therapies, the JAK inhibitors ruxolitinib and fedratinib.

Pacritinib was previously submitted for FDA approval, but withdrawn in 2016 amidst concerns about excess mortality and adverse events, including intracranial haemorrhage and cardiac failure/arrest in the PERSIST-1 trial, and a clinical hold was implemented. The company's complete response submission to the FDA was composed of final clinical study reports for the PERSIST-1 and 2 trials and the dose-e xploration PAC203 trial, requested by the FDA.

In the PERSIST-2 study, which involved 311 patients with myelofibrosis, 29% of patients had a reduction in spleen volume of at least 35%, compared to 3% of patients receiving the best available therapy, including ruxolitinib. It was also found that 23% of patients had a reduction in total symptom scores of at least 50%, compared to 13% of patients receiving the best available therapy. Platelet counts and haemoglobin levels were also stabilized. Adverse events were generally low-grade.

CTI BioPharma commenced a rolling New Drug Application (NDA) submission

for pacritinib for the treatment of patients with myelofibrosis and severe thrombocytopenia (platelet counts less than 50 ? 109 per litre) in October 2020 and completed this application by March 2021. The NDA was granted a priority review and the PDUFA date is 30 November 2021. Despite its safety-troubled history, pacritinib has shown clinical benefit in patient populations not addressed by ruxolitinib and has the potential to be one of the few approved therapies for myelofibrosis.

Johnson & Johnson and Legend Biotech are developing ciltacabtagene autoleucel, a B-c ell maturation antigen (BCMA)-directed chimeric antigen receptor T cell (CAR-T ) therapy, for the treatment of patients with relapsed and/or refractory multiple myeloma. It is built using a lentiviral vector, with a 4-1BB co-s timulatory domain.

Initial results from the phase Ib/II CARTITUDE-1 trial, a single-a rm study involving 113 patients with multiple myeloma, suggested that ciltacabtagene autoleucel is highly effective in heavily pre-treated multiple myeloma. Data showed early and deep responses among patients who had received a median of five prior multiple myeloma treatment regimens. In later analysis, ciltacabtagene autoleucel showed an overall response rate of 97%, with 67% of patients achieving a stringent complete response at 18 months follow-up, as well as a progression-free survival rate of 77%. Such unprecedented results established ciltacabtagene autoleucel as a potential best-in-class BCMA-targeted agent.

Based on these data, Johnson & Johnson completed its rolling BLA to the FDA for ciltacabtagene autoleucel for the treatment of adults with relapsed and/or refractory multiple myeloma in December 2020. The PDUFA date for ciltacabtagene autoleucel is 29 November 2021. If it were to be approved, this would be the second CAR-T product to be approved for the treatment of multiple myeloma, shortly following Bristol Myers Squibb's idecabtagene vicleucel, which was approved by the FDA in March 2021.

Kaniaw Dilzer and Zhyar Said

Sagient Research Systems, London, UK. e-mail: Kaniaw.Dilzer@;

Zhyar.Said@



Competing interests The authors declare no competing interests.

Nature Reviews | Drug Discovery

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volume 20 | October 2021 | 729

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