5 Key FDA Decisions to Keep an Eye on in the Latter Half of 2024

5 Key FDA Decisions :This year has been notable for numerous significant FDA approvals. These include the first tumor-infiltrating lymphocytes (TIL) therapy, the first gene therapy for a rare pediatric condition, and the initial targeted treatment for MASH, marking 2024 as a pivotal year.

Amtagvi stands out not only as the inaugural TIL therapy but also as the first single-dose cell therapy for a solid tumor. Additionally, Orchard’s Lenmeldy brings hope to children suffering from metachromatic leukodystrophy, a deadly genetic metabolic disorder, while Madrigal’s Rezdiffra marks their first approved product.

While the first half of 2024 highlighted advancements in cell and gene therapy, the latter half is set to focus on FDA decisions regarding other treatment modalities for cancer and brain diseases. Here are five important action dates to look out for in the second half of the year:

Eli Lilly’s Donanemab Indication: Alzheimer’s disease PDUFA: Unknown 5 Key FDA Decisions

Eli Lilly has moved closer to a significant decision regarding its Alzheimer’s therapy, donanemab, following a unanimous vote in favor by an advisory committee. In June, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee concluded that donanemab is an effective treatment for Alzheimer’s patients with mild cognitive impairment and mild dementia, determining that its benefits outweigh its risks.

The regulatory journey for donanemab has been challenging. In January 2023, the FDA denied accelerated approval for the therapy, citing concerns with a Phase II trial design that allowed patients to discontinue treatment once amyloid plaques were reduced beyond a certain threshold. Consequently, fewer than 100 patients received donanemab for a full 12 months, a requirement highlighted by the FDA in its Complete Response Letter.

Lilly applied for traditional approval of donanemab in the second quarter of 2023. In the Phase III TRAILBLAZER-ALZ 2 study, participants with low to medium levels of tau experienced about a 35% reduction in cognitive decline on two clinical rating scales compared to a placebo. For all amyloid-positive early symptomatic participants, the reductions were 22% and 29%, respectively.

If donanemab is approved, it will directly compete with Biogen and Eisai’s Leqembi, which received full FDA approval in July 2023.

Adaptimmune’s Afami-cel:5 Key FDA Decisions

Indication: Advanced Synovial Sarcoma

PDUFA Date: August 4

Adaptimmune is set to capitalize on advancements in cell and gene therapy with its T cell therapy, afami-cel, expected to receive approval by August 4. If approved, afami-cel will be the pioneering engineered T cell therapy for solid tumors and the first viable treatment for synovial sarcoma in over ten years, according to the company.

Synovial sarcoma accounts for 5% to 10% of soft tissue sarcomas, typically affecting individuals under 30 years old. The five-year survival rate for metastatic cases is around 20%.

In the SPEARHEAD-1 trial, about 40% of patients showed clinical responses, with the median response lasting roughly 12 months. Median overall survival was about 17 months, compared to historical data showing less than 12 months for patients who had undergone two or more prior therapies. Notably, 70% of those who responded to afami-cel were still alive two years post-treatment.

If afami-cel is approved, it will be the first product in Adaptimmune’s sarcoma portfolio.

Lykos Therapeutics’ MDMA therapy,5 Key FDA Decisions

Lykos Therapeutics’ MDMA therapy is seeking approval for treating post-traumatic stress disorder (PTSD), with the FDA decision scheduled for August 11. This decision is highly anticipated and could potentially redefine PTSD treatment options. However, a significant setback occurred on June 4 when an FDA advisory committee, in the first such meeting for a new PTSD treatment in this century, voted decisively against recommending approval.

The committee’s vote was 10-1 against approval, citing concerns that the benefits of the therapy do not outweigh its risks, despite proposed strict risk management measures. Most external advisors (7 out of 9) expressed doubts about the evidence presented by Lykos regarding MDMA’s effectiveness in treating PTSD. A major issue highlighted in FDA documents was “functional unblinding,” where a majority of trial participants correctly guessed their treatment assignments.

Lykos has based its New Drug Application on two pivotal Phase III studies, MAPP1 and MAPP2, which reportedly showed significant clinical improvements in PTSD symptoms with the MDMA-assisted therapy, according to the company’s briefing documents.

If granted approval, Lykos’s therapy would mark a groundbreaking achievement as the first psychedelic drug approved in the U.S. for a neuropsychiatric disorder.

Bristol Myers Squibb’s KarXT

Bristol Myers Squibb’s KarXT, under review for the treatment of schizophrenia with a decision expected by September 26, represents a significant advancement in neuropsychiatric therapy. Acquired from Karuna Therapeutics in December 2023, KarXT is an investigational muscarinic antipsychotic that could introduce the first new drug class for schizophrenia in decades, according to a Karuna press release. Unlike current treatments that block dopamine receptors, KarXT operates by activating both the M1 and M4 muscarinic acetylcholine receptors in the central nervous system. This dual mechanism is believed to enhance positive, negative, and cognitive symptoms associated with schizophrenia.

Karuna’s announcement highlighted combined data from three pivotal trials demonstrating “statistically significant and clinically meaningful improvements” compared to placebo. Additionally, interim results from a fourth study presented by BMS in April indicated sustained and significant symptom relief, with over 75% of patients treated with KarXT experiencing at least a 30% improvement in symptoms after 52 weeks. These findings were shared at the 2024 Annual Congress of the Schizophrenia International Research Society.

Daiichi Sankyo and AstraZeneca

Daiichi Sankyo and AstraZeneca are seeking FDA approval for Dato-DXd (datopotamab deruxtecan) as a treatment option for adults with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) who have previously undergone systemic therapy. The companies are supporting their Biologics License Application with data from the Phase III Tropion-Lung01 study. This study showed that Dato-DXd reduced the risk of disease progression or death by 25% compared to chemotherapy, with a median progression-free survival of 4.4 months and an overall response rate of 26.4% in patients.

Although overall survival results were numerically favorable for Dato-DXd in the overall trial population, they did not reach statistical significance. However, clinically meaningful improvements were observed in a specified subgroup of patients. Mark Rutstein, SVP and head of global oncology clinical development at Daiichi Sankyo, expressed optimism about Dato-DXd potentially becoming a significant treatment option for non-squamous NSCLC patients. If approved, Dato-DXd would mark the first TROP2-directed ADC available for lung cancer treatment.