5 FDA Decisions to Watch in the Second Half of 2024

The next six months for the FDA are primed to be as groundbreaking as the first six, with Eli Lilly’s donanemab and Lykos Therapeutics’ MDMA-assisted PTSD therapy on the docket, among others.

Pictured: FDA headquarters with money and pill bottles/Taylor Tieden for BioSpace

There has been no shortage of landmark approvals from the FDA this year. From the first tumor-infiltrating lymphocytes therapy to the first gene therapy for a rare pediatric disease to the first targeted therapy for MASH, 2024 has already seen its fair share.

Along with being the first TIL therapy, Amtagvi is also the first one-time cell therapy for a solid tumor. Meanwhile, Orchard’s Lenmeldy offers a glimmer of hope to children with metachromatic leukodystrophy, a fatal genetic metabolic disease, and Rezdiffra is Madrigal’s first approved product.

While the first half of the year belonged to cell and gene therapy, the second half is dominated by FDA decisions for other modalities in cancer and diseases of the brain. Here are five target action dates to watch for in the second half of 2024:

Eli Lilly’s Donanemab

Indication: Alzheimer’s disease
PDUFA: Unknown

Eli Lilly is one step closer to the long-anticipated decision on its Alzheimer’s therapy, donanemab, after an advisory committee voted unanimously in favor of the anti-amyloid antibody. In June, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee deemed donanemab to be an effective treatment for Alzheimer’s patients with mild cognitive impairment and mild dementia and said the benefits outweighed the risks.

Donanemab has not had the smoothest regulatory path. The FDA refused accelerated approval for the candidate in January 2023, taking issue with a Phase II trial design that allowed patients to end treatment when amyloid plaques had been cleared past a certain pre-defined level. This meant that fewer than 100 patients were on donanemab for 12 continuous months, something the regulator requested in its Complete Response Letter.

Lilly submitted for traditional approval of donanemab in the second quarter of 2023. In the Phase III TRAILBLAZER-ALZ 2 study, study participants with low-medium levels of tau saw their cognitive decline decrease by around 35% on two different clinical rating scales compared to placebo. Across all amyloid-positive early symptomatic participants, these numbers were 22% and 29%, respectively.

If approved, donanemab will be a direct competitor of Biogen and Eisai’s Leqembi, which received the FDA’s full nod in July 2023.

Adaptimmune’s afami-cel

Indication: Advanced synovial sarcoma
PDUFA: Aug. 4

Riding the momentum in the cell and gene therapy space, Adaptimmune is anticipating approval of its T cell therapy afami-cel on or before August 4. If approved, afami-cel would be the first engineered T cell therapy for solid tumors and “the first effective treatment option for synovial sarcoma in more than a decade,” according to Adaptimmune.

Synovial sarcoma, which makes up 5% to 10% of soft tissue sarcomas, typically affects individuals under 30, with a five-year survival rate of 20% for metastatic cases.

In the SPEARHEAD-1 trial, nearly 40% of patients experienced clinical responses, with a median response duration of around 12 months. Median overall survival was approximately 17 months, contrasting with historical data of less than 12 months for those who received two or more prior lines of therapy; 70% of responders to afami-cel were alive two years after treatment.

If successful, afami-cel would be the first product in Adaptimmune’s sarcoma franchise.

Lykos Therapeutics’ MDMA

Indication: Post-traumatic stress disorder
PDUFA: Aug. 11

One of the most-watched FDA decisions this summer, an approval for Lykos Therapeutics’ MDMA-assisted post-traumatic stress disorder (PTSD) therapy would be paradigm-changing. However, on June 4, an FDA advisory committee—the first held for a potential new PTSD treatment this century—voted overwhelmingly against such an approval.

In a 10-1 tally, the FDA’s Psychopharmacologic Drugs Advisory Committee said the candidate’s potential benefits do not outweigh its risk, even with a strict risk evaluation and mitigation strategy. Seven out of nine external advisors voted that Lykos had not provided sufficient proof of MDMA’s efficacy in PTSD. A key issue highlighted in FDA briefing documents was that of “functional unblinding,” where “the vast majority” of trial participants were able to accurately guess their treatment assignment.

Lykos is backing its New Drug Application with two pivotal Phase III studies, MAPP1 and MAPP2, in which the MDMA-assisted regimen “demonstrated clinically meaningful improvements in PTSD symptoms,” according to the company’s briefing documents.

If ultimately approved, Lykos’s therapy would be the first psychedelic drug for a neuropsychiatric disease in the U.S.

Bristol Myers Squibb’s KarXT

Indication: Schizophrenia
PDUFA: Sept. 26

By September 26, the FDA will render a decision on another highly anticipated neuropsychiatric treatment: Bristol Myers Squibb’s KarXT (xanomeline-trospium). BMS came into possession of KarXT following its December 2023 acquisition of Karuna Therapeutics.

If approved, KarXT, an investigational muscarinic antipsychotic treatment, would represent the first new drug class for schizophrenia in “several decades,” according to a Karuna press release announcing acceptance of the NDA. Unlike existing schizophrenia treatments, KarXT does not directly block dopamine receptors. Instead, it works through the dual activation of the M1 and M4 muscarinic acetylcholine receptors in the central nervous system, a mechanism believed to improve positive, negative and cognitive symptoms in patients with schizophrenia.

Combined data from three completed registrational and placebo-controlled trials show “statistically significant and clinically meaningful improvements,” Karuna reported in November. In April, BMS revealed interim data from a fourth study showing the drug can elicit significant and sustained symptom improvement in patients with schizophrenia. More than 75% of KarXT-treated patients saw at least a 30% improvement in symptoms at 52 weeks of follow-up, according to data presented at the Annual Congress of the Schizophrenia International Research Society 2024 conference.

Daiichi Sankyo and AstraZeneca’s Dato-DXd

Indication: Non-small cell lung cancer
PDUFA: Dec. 20

Daiichi Sankyo and AstraZeneca are looking to add Dato-DXd (datopotamab deruxtecan) to a limited club—antibody drug conjugates (ADCs) approved to treat non-small cell lung cancer (NSCLC). The partners are specifically seeking approval for Dato-DXd to treat adults with locally advanced or metastatic nonsquamous NSCLC who have previously received systemic therapy.

AstraZeneca and Daiichi Sankyo are backing the Biologics License Application with data from the Phase III Tropion-Lung01 study, in which Dato-DXd reduced the risk of disease progression or death by 25% compared to chemotherapy. Median progression-free survival was 4.4 months, and the overall response rate was confirmed in 26.4% of patients. In terms of overall survival, high-level results “numerically favored” DatoDXd in the overall trial population, but were not statistically significant, the companies reported in May. Clinically significant improvement was demonstrated in a prespecified subgroup of patients.

“We’re very optimistic about this, and we think that [Dato-DXd] can be an important drug for non-squamous non-small cell lung cancer patients,” Mark Rutstein, SVP and head of global oncology clinical development at Daiichi Sankyo, told BioSpace in May.

If approved, Dato-DXd could be the first TROP2-directed ADC for lung cancer.

Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.