FDA Updates for Week of May 31

The FDA has withdrawn the approval of Ukoniq, which is used to treat two specific types of lymphoma. In approvals, the regulatory agency has approved a new indication for Kymriah, two addition Opdivo regimens, and extended the use of Evrysdi in newborns with SMA. The agency also accepted for review Dupixent to treat skin lesions but extended the review of a new ALS therapy, refused to file an application for a rare metabolic disorder, and put a hold on the trial for Cialis OTC.

FDA withdraws approval of Ukoniq.

The FDA has withdrawn its approval for the cancer medicine Ukoniq (umbralisib). Ukoniq was approved to treat two specific types of lymphoma: marginal zone lymphoma and follicular lymphoma. The agency is advising healthcare professionals to stop prescribing Ukoniq and switch patients to alternative treatments.

This is happening in the wake of the increased scrutiny over accelerated approvals. Last year, FDA’s re-evaluation of previous accelerated approvals saw nine indications either withdrawn or revoked.

Updated findings from TG Therapeutics’ UNITY-CLL clinical trial continued to show a possible increased risk of death in patients receiving Ukoniq for the treatment of patients with chronic lymphocytic leukemia. As a result, regulators determined the risks of treatment with Ukoniq outweigh its benefits.

In January 2022, the company announced a partial clinical hold on Ukoniq for chronic lymphocytic leukemia and non-Hodgkin lymphoma. Although the trial met its endpoint progression-free survival, a first analysis of overall survival showed a hazard ration of 1.23. An overall survival hazard ratio above 1.00 implies potential risk that the investigational therapy is causing harm. But based on the ad hoc nature of the analysis, about 15% of patients had missing or outdated survival data. And when excluding deaths related to COVID-19, the hazard ration was 1.04.

FDA approves Kymriah for adults with follicular lymphoma.

The FDA has granted accelerated approval for Novartis’ Kymriah (tisagenlecleucel) for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. Kymriah is now FDA approved in three indications and is the only chimeric antigen receptor (CAR)-T cell therapy approved in both adult and pediatric indications.

Follicular lymphoma is the second most common form of non-Hodgkin lymphoma, representing about 22% of non-Hodgkin lymphoma cases. It is often an unrelenting malignancy with a relapsing and remitting pattern, and patients may be exposed to a median of five lines of prior treatment. The efficacy of these regimens drops off rapidly in later lines of treatment.

Kymriah is also approved to treat children and young adults with B-cell acute lymphocytic leukemia and adults with relapsed or refractory large B-cell lymphoma.

FDA approves two Opdivo regimens for metastatic esophageal cancer.

The FDA has approved both Opdivo (nivolumab) in combination with chemotherapy and in combination with Yervoy (ipilimumab) as a first-line treatment for adult patients with advanced or metastatic esophageal squamous cell carcinoma.

Both Opdivo and Yervoy were developed by Bristol Myers Squibb. The new combinations, including Opdivo with fluoropyrimidine- and platinum-containing chemotherapy, are approved for patients regardless of PD-L1 status.

The approvals are based on the phase 3 CheckMate-648 trial, which evaluated Opdivo in combination with chemotherapy and Opdivo plus Yervoy each compared with chemotherapy alone.

Opdivo is approved both as a monotherapy and in combination with chemotherapy and Yervoy for five indications in upper gastroesophageal cancers.

FDA approves Evrysdi in pre-symptomatic newborns with SMA.

The FDA has approved a label extension for Evrysdi (risdiplam) to include babies under two months old with spinal muscular atrophy (SMA). The approval is based on interim efficacy and safety data from the RAINBOWFISH study in newborns, which showed that the majority of pre-symptomatic babies treated with Evrysdi achieved key milestones such as sitting and standing with half walking after 12 months of treatment.

Evrysdi is now approved to treat SMA in children and adults of all ages. Genentech leads the clinical development of Evrysdi as part of a collaboration with the SMA Foundation and PTC Therapeutics.

FDA extends review of ALS therapy.

The FDA has extended the review timeline of the new drug application for Amylyx Pharmaceuticals’ AMX0035 (sodium phenylbutyrate/taurursodiol) for the treatment of patients with amyotrophic lateral sclerosis (ALS). The updated Prescription Drug User Fee Act (PDUFA) goal date is Sept. 29, 2022 (formerly June 29, 2022).

ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord.

The FDA has extended review time to allow for review of additional analyses of data from the company’s clinical studies. This move follows an advisory committee meeting in March 2022 in which six of the 10 members voted no on the question of whether the open-label extension of the phase 2 CENTAUR trial established a conclusion that AMX0035 is effective in the treatment of patients with ALS.

FDA issues refusal to file letter for pegzilarginase.

The FDA has issued a Refusal to File (RTF) letter for Aeglea BioTherapeutics’ biologics license application (BLA) for pegzilarginase for the treatment of arginase 1 deficiency (ARG1-D).

The FDA has requested additional data to support effectiveness, such as evidence showing that plasma arginine and metabolite reduction predicts clinical benefit in patients with ARG1-D or clinical data demonstrating a treatment effect on clinically meaningful outcomes. The FDA also requested additional information relating to chemistry manufacturing and controls.

The BLA was submitted in April 2022 and was based on positive results from Aeglea’s double-blind, placebo-controlled PEACE phase 3 study and its ongoing long-term extension study, as well as a phase 1/2 clinical trial and its open-label extension study.

FDA puts hold on trial for Cialis OTC.

The FDA has put a clinical hold on a trial to support the Rx-to-OTC switch for Cialis (tadalafil) because of an issue related to the protocol design. Sanofi’s Actual Use Trial (AUT) has not yet recruited any patients.

The Actual Use Trial design uses a real-world setting to assess the ability of consumers to use a product in an over-the-counter setting according to the proposed product labeling. This is key in applications for switching medications to nonprescription use.

Sanofi said in a statement that it continues to work with the FDA to move the Cialis program forward. Lilly, which developed Cialis, signed an agreement with Sanofi in 2014 for the nonprescription development of Cialis.

FDA accepts Dupixent application for treating skin lesions.

The FDA has accepted for priority review the supplemental biologics license application (sBLA) for Dupixent (dupilumab) to treat adults with prurigo nodularis, a chronic inflammatory skin disease that causes extreme itch and skin lesions. The target action date for the FDA decision is September 30, 2022.

Dupixent is a human monoclonal antibody that inhibits the signaling of the interleukin-4 (IL-4) and interleukin-13 (IL-13) pathways and is not an immunosuppressant. It is being developed jointly by Sanofi and Regeneron.

The sBLA is supported by data from two pivotal phase 3 trials evaluating the efficacy and safety of Dupixent in patients 18 years and older with uncontrolled prurigo nodularis. Both trials met the primary and key secondary endpoints, showing Dupixent significantly improved disease signs and symptoms compared with placebo, including reduction in itch and skin lesions.

Dupixent is approved for use in certain patients with atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis and eosinophilic esophagitis in different age populations. Its most recent approval in May 2022 was to treat patients with eosinophilic esophagitis, an inflammatory condition that causes the esophagus to narrow and makes it difficult to eat.