The FDA’s busy week ahead involves three decision dates for potential industry firsts and a highly anticipated advisory committee meeting for two CAR-T therapies.
Pictured: A scientist with pill bottles in front of FDA headquarters/Taylor Tieden for BioSpace
The FDA has four big target action dates this week, including one for a much-anticipated non-alcoholic steatohepatitis drug. CAR T cell therapies will also see a lot of action in the coming week, with one upcoming decision and one advisory committee meeting.
Read below for more.
Mirum Eyes Expansion of Livmarli into Familial Intrahepatic Cholestasis
By March 13, the FDA is expected to release its verdict on Mirum Pharmaceuticals’ supplemental New Drug Application (sNDA) to expand Livmarli’s label to include cholestatic pruritus in patients with progressive familial intrahepatic cholestasis (PFIC).
Livmarli is an orally available selective inhibitor of the ileal bile acid transporter that works by decreasing the reabsorption of bile acids from the terminal ileum. Its mechanism of action is not yet completely elucidated, according to its label. Livmarli first won the FDA’s approval in September 2021 for the treatment of cholestatic pruritus in patients with Alagille syndrome.
Mirum is backing Livmarli’s sNDA, which it submitted to the regulator in February 2023, with data from the Phase III MARCH PFIC trial, which enrolled 93 pediatric patients across various genetic PFIC subtypes. The study showed that Livmarli treatment significantly improved pruritus and serum bile acid levels, as well as bilirubin concentrations and patient growth.
The application also includes data from the Phase II INDIGO study, which focused on the PFIC2 genetic subtype, demonstrating better transplant-free survival in responders.
In October 2023, the regulator extended the review period for Mirum’s sNDA “to allow time for a full review of a submission provided in response to an FDA information request,” which was considered a major amendment.
BMS Targets First CAR-T Approval in CLL, SLL
Bristol Myers Squibb is seeking to expand the label of its CAR-T therapy Breyanzi (lisocabtagene maraleucel) to include chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL). The FDA’s decision is due by March 14.
BMS’s supplemental Biologics License Application (sBLA), which the FDA had granted Priority Review, positions Breyanzi as a treatment option for relapsed or refractory CLL and SLL patients with prior exposure to a Bruton tyrosine kinase inhibitor and a B-cell lymphoma 2 inhibitor.
The application is backed by data from the pivotal Phase I/II TRANSCENT CLL 004 trial, an open-label, single-arm study that, in May 2023, met its primary endpoint of complete response, according to a preliminary analysis. After a median follow-up of 21.1 months, 18.4% of patients achieved this endpoint, of whom none died or saw disease progression.
Breyanzi is an autologous CAR-T therapy that works by targeting and binding to the CD19 transmembrane protein, which in turn triggers the activation and proliferation of CAR T cells, promoting their anti-cancer activity and inducing the release of pro-inflammatory cytokines.
Currently, the cell therapy is indicated for large B-cell lymphoma (LBCL), including diffuse LBCL not otherwise specified, high-grade B-cell lymphoma, primary mediastinal LBCL and grade 3B follicular lymphoma refractory to first-line chemoimmunotherapy.
If approved, Breyanzi would be the first CAR-T therapy authorized to treat patients with CLL and SLL.
Madrigal Eyes First NASH/MASH Approval
Similarly gunning for an industry first is Madrigal Pharmaceuticals, which is proposing resmetirom for the treatment of non-alcoholic steatohepatitis (NASH)—recently renamed metabolic dysfunction-associated steatohepatitis (MASH). The FDA is set to release its verdict by March 14.
Designed to be orally available, resmetirom is a selective agonist of the thyroid hormone receptor (THR)-β, the signaling of which is crucial to maintaining liver health. According to Madrigal’s website, THR-β activity is impaired in MASH, which leads to worse mitochondrial dysfunction, lipotoxicity and fibrosis, thereby driving disease progression.
Resmetirom is backed by a comprehensive clinical development program comprising 18 clinical studies, four of which are Phase III trials. Madrigal is seeking the FDA’s accelerated approval for resmetirom, and the regulator has granted the application Priority Review.
The centerpiece of the application is the MAESTRO-NASH study, which in December 2022 met both of its primary endpoints. Resmetirom’s 80-mg and 100-mg doses led to significantly higher rates of MASH resolution and improvement in liver fibrosis versus placebo.
Last month, Madrigal published more detailed findings from MAESTRO-NASH in The New England Journal of Medicine, demonstrating that the 80-mg dose induced disease resolution without worsening fibrosis in 25.9% of patients, while the 100-mg dose elicited such a response in 29.9%.
If approved, resmetirom would be the first MASH therapy to make it through the regulatory gauntlet for the indication, besting at least 20 other programs that have been dropped, paused or otherwise experienced some sort of clinical roadblock.
Optinose Eyes First Chronic Rhinosinusitis Treatment
Optinose is likewise looking to make history by winning the FDA’s first approval in chronic rhinosinusitis for its nasal spray XHANCE (fluticasone propionate). The regulator’s decision is due on March 16.
XHANCE is a drug-device combination product that uses Optinose’s proprietary Exhalation Delivery System to deliver fluticasone propionate, an anti-inflammatory agent, into the high and deep regions of the nasal cavity. XHANCE was first approved in September 2017 for the treatment of nasal polyps.
Optinose is backing its sNDA, which the FDA accepted in May 2023, with data from the phase III ReOpen clinical trial program, which was comprised of two randomized, double-blinded and placebo-controlled trials. The first study enrolled patients with and without nasal polyps, while the second focused only on those without polyps. Both studies evaluated symptomatic improvement and change in sinus inflammation.
The FDA’s original target action date was December 16, 2023. A month earlier, however, the regulator asked Optinose to provide additional efficacy analyses in a subset of patients without nasal polyps plus those with nasal polyps of grade one or lower at entry. The FDA deemed this submission a major amendment and extended its review period by three months.
J&J/Legend’s Carvykti and BMS/2seventy’s Abecma Face ODAC Adcomm
On March 15, the FDA’s Oncologic Drugs Advisory Committee will meet to discuss regulatory applications from Bristol Myers Squibb and 2seventy bio, and Johnson & Johnson and Legend Biotech, which are seeking to move Abecma and Carvykti, respectively, into earlier lines of treatment for multiple myeloma.
Currently, both drugs are approved for the treatment of adults with relapsed and refractory multiple myeloma (RRMM) after four or more prior lines of therapy.
For Carvykti, the panel of external experts will review data from the Phase III CARTITUDE-4 trial, a randomized trial assessing the efficacy and safety of the therapy in patients with lenalidomide-refractory multiple myeloma who had been exposed to at least one previous line of systemic therapy.
Early data from CARTITUDE-4, which leaked in April 2023, demonstrated that the therapy cut the risk of disease progression by 74% versus standard treatment. Carvykti also showed an overall survival benefit of 22%, though this finding was not statistically significant.
For Abecma, the panel will look at data from the KarMMa-3 study in patients with RRMM. Abecma met its primary endpoint, with a statistically significant improvement in progression-free survival (PFS) compared to standard treatment, impacting both disease progression and death.
The advisory committee meeting comes after the European Medicines Agency last week backed J&J and Legend. The Committee for Medicinal Products for Human Use (CHMP) recommended the approval of Carvykti as a second-line treatment option in relapsed and refractory multiple myeloma. In January, the CHMP recommended greenlighting Abecma for RRMM after at least two prior therapies.
Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.
