This move, prompted by EMA requests for more up-to-date clinical data, could delay the regulatory approval of the drug and has caused Pharming’s stock price to drop by 10%.
Leniolisib is a small molecule compound touted by Pharming Group to be the first potential drug treatment for activated phosphoinositide 3-kinase delta syndrome (APDS), a rare genetic immunodeficiency that impairs the ability of the patient’s immune cells to develop properly.
Pharming first moved leniolisib to the EMA’s accelerated approval track in August 2022, shortening the timeframe of the EMA regulatory process from 210 days to 150 days. The Marketing Authorization Application (MAA) for leniolisib hinges on results from a phase 2/3 trial of the drug in APDS patients released last year. According to the data, leniolisib met the trial’s co-primary endpoints of reducing lymph node size and increasing the percentage of naïve B cells in patients with APDS. The MAA was also supported by interim data from an ongoing open-label extension clinical trial of leniolisib in APDS.
However, Pharming recently revealed that the EMA sent back a list of questions about the MAA, including a request for updated data from the extension study. As a result, the company dropped leniolisib to a longer standard review process and expects a regulatory decision from the EMA in the second half of 2023.
"We are continuing to work with EMA through the MAA review process and remain dedicated to seeking regulatory approval of leniolisib within the European Economic Area,” stated Sijmen de Vries, CEO of Pharming. “In the U.S., the Food and Drug Administration (FDA)'s priority review of the leniolisib NDA remains on track, with a PDUFA goal date of March 29, 2023. We remain focused on achieving regulatory approvals and bringing leniolisib to patients living with APDS worldwide."
Leniolisib is designed to treat APDS by blocking an isoform of the enzyme phosphoinositide 3-kinase delta (PI3K) called PI3Kδ. The enzyme is linked to immune system functions, including in cell proliferation, cell survival and the production of cytokines. The mutations causing APDS hyperactivate the PI3Kδ pathway, so blocking this isoform could treat the disease with fewer side effects than current approaches to manage the symptoms, including antimicrobial prophylaxis and the drug sirolimus.
There are already PI3K blockers approved to treat solid tumors and blood cancers, including Gilead’s PI3Kδ-specific idelasib (Zydelig). However, idelasib also comes with side effects including pneumonitis, transaminitis, and colitis. A mixture of issues with safety and clinical efficacy in the PI3K blocker class has caused headaches for developers including Incyte, Gilead and Secura Bio. GSK was also developing a PI3Kδ-focused blocker called nemiralisib for the treatment of APDS in phase 2, but dropped the development in 2020 in a strategic review of its pipeline.
Pharming believes that leniolisib, licensed from Novartis in 2019, has the potential to tackle APDS. This is because leniolisib is considered to be a second-generation PI3K blocker that is specific to PI3Kδ and doesn’t bind so much to other isoforms of PI3K. Additionally, APDS is caused by a small number of mutations, whereas cancer typically involves a complex mix of molecular mechanisms.