This week, the U.S. Food and Drug Administration (FDA) granted Priority Review to a treatment for lung and thyroid cancers with a RET fusion or mutation; gave Breakthrough Therapy designation to a doublet therapy for TP53-mutated myelodysplastic syndromes; and issued an update to their prioritization policy for abbreviated new drug applications, amendments, and supplements.
Priority Review for Selpercatinib in Lung and Thyroid Cancers
The FDA granted Priority Review for the new drug application for selpercatinib, also known as LOXO-292, for the treatment of patients with advanced RET fusion–positive non–small cell lung cancer (NSCLC), RET-mutant medullary thyroid cancer, and RET fusion–positive thyroid cancer. The new drug application is based on data from the LIBRETTO-001 phase I/II trial in RET-altered lung and thyroid cancers. The FDA has set a Prescription Drug User Fee Act date for the third quarter of 2020.
Selpercatinib is a highly selective and potent oral investigational new medicine in clinical development for the treatment of patients with cancers that harbor abnormalities in the rearranged during transfection (RET) kinase. RET fusions and mutations occur across multiple tumor types with varying frequency. Selpercatinib was designed to inhibit native RET signaling as well as anticipated acquired resistance mechanisms.
RET fusions have been identified in approximately 2% of NSCLC, 10% to 20% of papillary and other thyroid cancers, and a subset of other cancers. Activating RET point mutations account for approximately 60% of medullary thyroid cancer.
In previous regulatory actions, based on early data from LIBRETTO-001, the FDA granted selpercatinib Breakthrough Therapy designation for treatment in people with:
- Metastatic RET fusion–positive NSCLC who require systemic therapy and have had disease progression following platinum-based chemotherapy and an anti–programmed cell death protein 1 or anti–programmed cell death ligand 1 therapy
- RET-mutant medullary thyroid cancer who require systemic therapy, have had disease progression following prior treatment, and have no acceptable alternative treatment option
- Advanced RET fusion–positive thyroid cancer who require systemic therapy, have had disease progression following prior treatment, and have no acceptable alternative treatment options.
In 2019, selpercatinib received Orphan Drug designation for the treatment of RET fusion–positive NSCLC and for the treatment of RET fusion–positive and RET-mutant thyroid cancers including poorly differentiated thyroid cancer, undifferentiated or anaplastic thyroid cancer, medullary thyroid cancer, and locally advanced or metastatic follicular or papillary thyroid cancer.
In December 2019, Lilly opened two phase III trials further investigating selpercatinib: LIBRETTO-431 for patients with treatment-naive RET fusion–positive NSCLC, and LIBRETTO-531 for patients with treatment-naive RET-mutant medullary thyroid cancer. Each trial will enroll 400 patients.
The LIBRETTO-001 phase I/II trial was the largest clinical trial of patients with RET-driven cancers treated with a RET inhibitor. The trial included a dose-escalation phase (phase I) and a dose-expansion phase (phase II). The phase II portion of the trial had a primary endpoint of objective response rate and secondary endpoints of duration of response, progression-free survival, and safety. Results from the NSCLC population were presented at the 2019 International Association for the Study of Lung Cancer World Congress on Lung Cancer, while results from the thyroid populations were presented at the European Society for Medical Oncology Congress 2019.
Breakthrough Therapy Designation for APR-246 in Combination With Azacitidine for TP53-Mutated Myelodysplastic Syndromes
The FDA granted Breakthrough Therapy designation for APR-246 in combination with azacitidine for the treatment of myelodysplastic syndromes (MDS) with a susceptible TP53 mutation.
APR-246 is a small molecule that has demonstrated reactivation of mutant and inactivated p53 protein by restoring wild-type p53 conformation and function, thereby inducing programmed cell death in human cancer cells. Preclinical antitumor activity has been observed with APR-246 in a wide variety of solid and hematologic cancers, including MDS, acute myeloid leukemia, and ovarian cancer, among others. Additionally, strong synergy has been seen with both traditional anticancer agents, such as chemotherapy, and newer mechanism-based anticancer drugs and immuno-oncology checkpoint inhibitors. In addition to preclinical testing, a phase I/II clinical program with APR-246 has been completed, demonstrating a favorable safety profile and both biologic and confirmed clinical responses in hematologic malignancies and solid tumors with mutations in the TP53 gene.
The p53 tumor-suppressor gene is the most frequently mutated gene in human cancer, occurring in approximately 50% of all human tumors. These mutations are often associated with resistance to anticancer drugs and poor overall survival, representing a major unmet medical need in the treatment of cancer.
A pivotal phase III clinical trial of APR-246 and azacitidine for front-line treatment of TP53-mutant MDS is ongoing. APR-246 has received Orphan Drug and Fast Track designations from the FDA for MDS, and Orphan Drug designation from the European Medicines Agency for MDS, acute myeloid leukemia, and ovarian cancer.
FDA Updates Prioritization Policy for ANDAs, Amendments, and Supplements
Sally Choe, PhD, Director of the Office of Generic Drugs in the FDA’s Center for Drug Evaluation and Research, issued the following statement this week:
“…The FDA is making critical updates to our policy for prioritizing the review of abbreviated new drug applications (ANDAs) to advance the public health, efficiently allocate limited agency resources, and ensure fairness to applicants, which reflects the FDA’s long-standing practice to prioritize the review of ANDAs that would have the greatest potential impact on public health, if approved.
“Under the previous prioritization policy, roughly half of all ANDA submissions were designated as priority submissions, including many products that could not be marketed for several years as a result of blocking patents or exclusivities. This practice strained the agency’s limited resources and did not support the agency’s goal of ensuring that ANDAs for those drugs with the greatest potential impact on public health are prioritized.
“The changes being announced … will allow the FDA to focus its priority review resources on those submissions that are most likely to have a meaningful impact on generic drug access, potentially lowering costs by expediting the availability of safe, high-quality, effective generic medicines in areas of the market with limited competition.”
The Manual of Policies and Procedures (MAPP) 5240.3, Prioritization of the Review of Original ANDAs, Amendments, and Supplements ('Prioritization MAPP') describes how the FDA prioritizes the review of ANDAs, amendments, and supplements. The FDA may grant an ANDA submission a shorter goal date or an expedited review, as defined in the Prioritization MAPP, if the ANDA meets a public health priority identified in the MAPP, known as a prioritization factor.
The new revision also updates the MAPP’s prioritization factors and procedures, including changes to how the agency will prioritize submissions in the absence of an explicit request for priority review, modifications to the prioritization factors under which the agency will prioritize supplements, and clarifications and modifications to factors under which the agency will prioritize original ANDAs, including changes to the factors regarding submissions from “first filers” and other applications with a paragraph IV patent certification, which is a generic applicant’s assertion that the brand-name product’s patents listed in the Orange Book are invalid, unenforceable, or will not be infringed by the proposed generic product.
Under the previous version of the MAPP, the FDA prioritized submissions from first filers and from applicants with paragraph IV certifications, even though the applicants’ drugs would not be able to come to market for years due to a patent, 30-month stay, or exclusivity blocking final approval. This practice strained the agency’s limited resources and did not have a meaningful impact on generic drug access. This MAPP revision will allow the FDA to focus its limited priority review resources on submissions that are more likely to lead to approval of a product that will be marketed and made available to consumers, meaningfully impacting generic drug access.
This MAPP only applies to ANDAs and is separate from the FDA’s Priority Review program for new drug applications.
