5 FDA Decisions to Watch in Q1

 

Among the FDA’s pending decisions for this quarter are Vertex’s non-opioid pain drug and Sanofi’s RNA interference therapy for hemophilia A and B.

The FDA ended 2024 with a flurry of year-end decisions, capping off a productive year that saw 55 novel approvals. This list includes several potentially practice-changing drugs, including Bristol Myers Squibb’s Cobenfy, the first new mechanism of action for schizophrenia in over three decades, and Sanofi and Regeneron’s blockbuster therapy Dupixent, which in September 2024 became the first biologic approved for chronic obstructive pulmonary disease.

Last year, the FDA also greenlit the industry’s first-ever treatment for metabolic dysfunction-associated steatohepatitis in Madrigal Pharmaceuticals’ Rezdiffra, and introduced a much-needed alternative anti-amyloid treatment option for Alzheimer’s disease in Eli Lilly’s Kisunla.

The gene therapy space also saw several key approvals in 2024, including Pfizer’s Beqvez, indicated for hemophilia B, and PTC Therapeutics’ Kebilidi, which is used for the treatment of L-amino acid decarboxylase deficiencyand is the first direct-to-brain gene therapy cleared by the FDA.

Looking ahead, the FDA is expected to deliver several key verdicts that could shape the industry—and clinical practice—in profound ways. Here are BioSpace’s five most anticipated regulatory decisions in the first quarter of 2025.

Biogen and Eisai’s Leqembi

Indication: Intravenous maintenance for early Alzheimer’s disease

PDUFA: January 25

Amid a disappointing launch—and equally underwhelming sales—Biogen and Eisai are awaiting an FDA approval for the monthly intravenous maintenance regimen of their Alzheimer’s disease therapy Leqembi (lecanemab). The regulator’s final word is due on January 25.

Leqembi, the first anti-amyloid antibody Alzheimer’s drug to win the FDA’s traditional approval, is currently indicated as an intravenous medication administered once every two weeks in approximately hour-long infusion sessions. Under the proposed monthly regimen, the interval between Leqembi doses can be stretched to one month in patients who complete an initial bi-weekly initiation phase—though the exact duration of Leqembi initiation has yet to be determined, according to Biogen and Eisai.

As per the partners, monthly maintenance is designed to help maintain therapeutic levels of Leqembi in the body in order to suppress toxic protofibrils, which otherwise could result in nerve damage and brain injury even after the clearance of amyloid-beta clumps.

The companies are backing their application with modeling results using data from the Phase IIb Study 201 and its related open-label extension study. The models also include data from the Phase III Clarity AD and its open-label extension phase.

Biogen and Eisai are also advancing a subcutaneous injection formulation of Leqembi. In August 2024, Eisai noted that the partners had initiated a rolling Biologics License Application for injectable Leqembi and expect approval by March 2026.

In its most recent quarterly report in November 2024, Eisai lowered its full fiscal year sales forecast for Leqembi to $280 million from its previous guidance of approximately $370 million. Analysts from various firms said at the time that Leqembi’s U.S. launch so far has been disappointing and fraught with various infrastructure challenges.

Still, demand for Leqembi appears to be strong and growing, with Biogen and Eisai touting around 6,000 patients waiting to be initiated on the anti-amyloid therapy, which could translate to future growth once the companies address infrastructure and administrative challenges.

AstraZeneca and Daiichi Sankyo’s Dato-DXd

Indication: Metastatic, HR-positive, HER2-negative breast cancer

PDUFA: January 29

By January 29, the FDA is expected to have released its decision regarding AstraZeneca and Daiichi Sankyo’s Biologics License Application (BLA) for their antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd), which the partners are proposing for the treatment of a type of breast cancer.

Results are mixed for Dato-DXd. In the Phase III TROPION-Breast01 study—which the companies are using to back the BLA—the investigational ADC lowered the risk of death or disease progression by 37% versus the investigator’s choice of chemotherapy, according to an October 2023 readout. At the time, AstraZeneca and Daiichi Sankyo called this effect “statistically significant and clinically meaningful.”

However, a follow-up data drop in September 2024 showed Dato-DXd was unable to significantly boost overall survival in the study. TROPION-Breast01 enrolled patients with inoperable or metastatic breast cancer whose tumors were HR-positive and either HER2-negative or HER2-low.

As for safety, TROPION-Breast01 found Dato-DXd to be well-tolerated overall, with a better adverse event profile than chemotherapy. The most common grade 3 or higher side effects included neutropenia, fatigue and anemia.

Dato-DXd is an ADC designed to target the TROP2 protein, which is highly expressed in several cancers. This binding affinity allows Dato-DXd to deliver its exatecan derivative payload directly to the target cells, triggering their death.

Aside from breast cancer, AstraZeneca and Daiichi Sankyo are also testing Dato-DXd in non-small cell lung cancer, for which the ADC likewise failed to yield significant overall survival improvements in September 2024.

Vertex’s Suzetrigine

Indication: Moderate-to-severe acute pain

PDUFA: January 30

Vertex Pharmaceuticals is advancing a non-opioid analgesic, dubbed suzetrigine, for the treatment of moderate-to-severe acute pain. The FDA’s verdict is due on January 30.

Suzetrigine is an orally available pain signal inhibitor that selectively targets the NaV1.8 voltage-gated sodium channel, a genetically validated pain target that is typically found on peripheral neurons. NaV1.8 is believed to play a role in sensing pain and transmitting signals back to the central nervous system.

Vertex is backing suzetrigine with two Phase II and three Phase III studies, including the NAVIGATE 1 and NAVIGATE 2 trials, which looked at the analgesic efficacy of the drug candidate in patients who had undergone bunionectomy and abdominoplasty, respectively.

Full data from these two late-stage studies, presented in October 2024 at the annual meeting of the American Society of Anesthesiologists, showed that suzetrigine monotherapy improved pain scores by 48.4 points after a tummy tuck. In patients undergoing the toe procedure, suzetrigine lowered pain scores by 29.3 points. Both treatment effects were statistically significant versus placebo.

At the time of the readout, analysts appeared to be torn over suzetrigine. BMO Capital Markets said that the presentation “reaffirms our confidence in the strength of suzetrigine’s profile in acute pain,” while William Blair noted that while suzetrigine “has a strong argument for inclusion in the market,” its “pricing remains a point of investor contention.”

If approved, suzetrigine will represent the first new drug class for acute pain in more than two decades, according to Vertex.

Alnylam’s Amvuttra

Indication: Transthyretin amyloid cardiomyopathy

PDUFA: March 23

On the heels of BridgeBio’s recently approved Attruby is Alnylam’s Amvuttra, which the Massachusetts-basedbiotech is hoping to expand into transthyretin amyloid cardiomyopathy (ATTR-CM).

Amvuttra, which is currently indicated for polyneuropathy of hereditary transthyretin amyloidosis, is an RNA interference treatment that works by knocking down mutant and wildtype TTR mRNA, leading to an overall decrease in protein levels in the serum. Through this mechanism, Amvuttra also lowers TTR deposits in various organs, including the heart, that would otherwise give rise to the various symptoms of cardiomyopathy, including the stiffening of cardiac walls.

To support its ATTR-CM bid, Alnylam is using data from the Phase III HELIOS-B study, which found that Amvuttra had “favorable effects” on survival, cardiovascular events, functional capacity and quality of life in ATTR-CM patients, according to the biotech’s press announcement of the FDA’s acceptance of its supplemental New Drug Application. A presentation at the 2024 American Heart Association’s Scientific Sessions showed that Amvuttra treatment led to a 28% drop in the composite outcome of all-cause mortality and recurrent cardiovascular events.

The FDA is expected to release its verdict on March 23.

If approved, Amvuttra will be the first RNA interference therapeutic for ATTR-CM, in contrast to BridgeBio’s Attruby and Pfizer’s Vyndaqel and Vyndamax, which are TTR stabilizers.

Sanofi’s Fitusiran

Indication: Hemophilia A or B

PDUFA: March 28

To challenge the increasingly popular gene therapy approach to hemophilia, Sanofi is advancing fitusiran, an investigational small interference RNA therapy. The pharma is seeking approval for fitusiran for the treatment of hemophilia A and B patients, regardless of their inhibitor status. The FDA’s decision is due on March 28.

In support of fitusiran’s FDA bid are data from the ATLAS clinical development program. In April 2023, Sanofi announced publications in The Lancet and The Lancet Hematology touting encouraging late-stage results for the siRNA candidate.

One of these studies, dubbed ATLAS-INH, focused on patients with inhibitors and found that 66% of fitusiran-treated participants hit zero monthly bleeding episodes, as compared with 5% of control counterparts who were given an on-demand bypassing agent. The other trial, named ATLAS A/B, enrolled patients without inhibitors, of whom 51% had zero monthly bleeds after fitusiran treatment, versus 5% of comparators treated with on-demand clotting factors.

Taken together, both studies showed that prophylactic fitusiran could reduce the annualized bleeding rate by 90% versus their respective control arms, according to Sanofi.

If approved, fitusiran will introduce a new modality of treatment to a therapeutic space that is increasingly being addressed with gene therapies. Leading the charge is BioMarin’s Roctavian, which became the first FDA-approved gene therapy for hemophilia A in June 2023. It works by restoring the body’s ability to produce the blood-clotting protein factor VIII.

Pfizer is taking a similar approach to hemophilia A with its investigational gene therapy giroctocogene fitelparvovec. In July, the candidate aced its Phase III trial, maintaining over 5% factor VIII activity in 84% of treated patients at 15 months. In February, the pharma won the FDA’s approval for its hemophilia B gene therapy Beqvez.

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