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FDA Updates for the Week of Nov. 28, 2022


This week, the FDA made two approvals, the first-ever microbiota product and a second indication for Brexafemme, and issued a CRL for a therapy for brain metastasis from neuroblastoma. The regulatory agency also granted priority review for a Duchenne gene therapy, and accepted three applications: for a cutaneous T-cell lymphoma therapy, for an antibiotic for drug-resistant infections and Evkeeza for children with rare high cholesterol. Additionally, Genentech has withdrawn Tecentriq’s indication for bladder cancer and Aldeyra has submitted an NDA for the novel dry eye therapy reproxalap.

Genentech withdraws Tecentriq indication for bladder cancer.

Genentech is voluntarily withdrawing the U.S. accelerated approval of Tecentriq (atezolizumab) for the treatment of adults with locally advanced or metastatic urothelial carcinoma (bladder cancer). The FDA had granted accelerated approval for Tecentriq in 2018 for patients who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 or are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.

Genentech made this decision to withdraw this indication following consultation with the FDA after the phase 3 IMvigor130 trial did not meet the co-primary endpoint of overall survival for Tecentriq plus chemotherapy compared with chemotherapy alone.

Last year, Genentech withdrew the accelerated approval for Tecentriq in combination with chemotherapy (Celgene’s Abraxane, albumin-bound paclitaxel) for the treatment of adults with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1.

FDA approves Rebyota, the first-ever microbiota product.

The FDA has approved Rebyota, the first fecal microbiota product for the prevention of recurrence of Clostridioides difficile (C. diff) infection in people 18 years of age and older. C. diff is a serious disease that causes severe diarrhea, fever, stomach tenderness or pain, loss of appetite, nausea, and colitis. It has been estimated that up to 35% of cases recur after initial diagnosis.

Rebyota (formerly RBX2660) is a fecal microbiota transplantation therapy that was developed by Rebiotix, a Ferring Pharmaceuticals company. It is administered rectally as a single dose, and is prepared from stool donated by qualified individuals. The approval is based on the results from the clinical program including the phase 3 PUNCH CD3 trial in which a single dose of Rebyota demonstrated superiority to placebo as a treatment to reduce recurrence of C. diff infection after standard-of-care antibiotic treatment. The success rate at eight weeks for Rebyota was 70.6% versus 57.5% for placebo. More than 90% of study participants who achieved treatment success remained free of C. diff infection recurrence through six months.

FDA approves second indication for Brexafemme.

The FDA has approved a second indication Brexafemme (ibrexafungerp) to reduce the incidence of recurrent vulvovaginal candidiasis (VVC). Developed by Scynexis, Brexafemme is an oral triterpenoid antifungal that FDA approved to treat vulvovaginal candidiasis in June 2021. The therapy represents a new antifungal class in more 20 years and is the only treatment for vaginal yeast infections that is both oral and non-azole. It has broad activity on a range of Candida species, including azole-resistant strains.

The approval is based on positive results from the pivotal phase 3 CANDLE study that evaluated the safety and efficacy of monthly dosing of Brexafemme to reduce the incidence of recurrent vulvovaginal candidiasis. Results showed that 65.4% of patients receiving the treatment achieved clinical success by having no recurrence at all through week 24 compared with 53.1% of placebo-treated patient

FDA issues CRL for therapy for brain metastasis from neuroblastoma.

The FDA has issued a complete response letter (CRL) for the Y-mAbs Therapeutics’ biologics license application (BLA) for the investigational medicine omburtamab to treat patients with CNS/leptomeningeal metastasis from neuroblastoma. This follows the outcome of October 2022 advisory committee voted against omburtamab. The FDA’s Oncologic Drug Advisory Committee (ODAC) voted 16 to 0 that the company had not provided sufficient evidence to conclude that omburtamab improves overall survival.

Neuroblastoma is the most common solid tumor in childhood with about 650 cases diagnosed in the United States per year. Central nervous system/leptomeningeal metastases are a rare and difficult-to-treat late-stage complication in which cancer cells spread to the meninges in the brain.

Omburtamab is a monoclonal antibody radiolabeled with Iodine-131 that targets B7-H3, an immune checkpoint molecule that is widely expressed in tumor cells of several cancer types. The omburtamab BLA is for the treatment of pediatric patients with CNS/leptomeningeal metastasis from neuroblastoma.

Regulators’ concern centered around whether the studies demonstrated a treatment effect. Specifically, they said, the Study 03-133 was a single-arm trial. The FDA performed additional analyses to examine bias and these results indicated that differences in survival cannot be reliably attributed to omburtamab. Regulators indicated that the application did not include reliable response rate data to provide supportive evidence of the treatment effect of omburtamab.

FDA grants priority review for Duchenne gene therapy.

The FDA has accepted Sarepta Therapeutics’ biologics license application (BLA) for accelerated approval of SRP-9001 (delandistrogene moxeparvovec) to treat ambulatory patients with Duchenne muscular dystrophy. SRP-9001 has been granted priority review by the FDA, with a regulatory action date of May 29, 2023.

Duchenne is a rare genetic disease that is characterized by a mutation in the dystrophin gene. This results in the lack of dystrophin, which acts as a shock absorber for muscle at the membrane. Duchenne causes the muscles in the body to become weak and damaged over time and is eventually fatal.

SRP-9001, a gene therapy being developed in partnership with Roche, delivers to muscle a gene that codes for a shortened, functional form of dystrophin. It uses an adeno-associated virus (AAV) vector and a promoter that helps to drive gene expression. Sarepta submitted the BLA in September 2022. The submission is based on efficacy and safety data from Study SRP-9001-103 (ENDEAVOR), Studies SRP-9001-101 and SRP-9001-102, and an integrated analysis across these three clinical studies. In clinical results from more than 80 treated patients, SRP-9001 has demonstrated positive results at multiple time points, including one-, two- and up to four-years after treatment, in addition to demonstrating a consistent safety profile.

FDA accepts BLA for cutaneous T-Cell lymphoma therapy.

The FDA has accepted Citius Pharmaceuticals’ biologics license application (BLA) for I/Ontak (denileukin diftitox) to treat patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL). The Prescription Drug User Fee Act (PDUFA) target action date is Sept. 28, 2023. Cutaneous T-cell lymphoma is a type of cutaneous non-Hodgkin lymphoma (NHL) that comes in a variety of forms and is the most common type of cutaneous lymphoma. In CTCL, T-cells, a type of lymphocyte that plays a role in the immune system, become cancerous and develop into skin lesions.

I/Ontak is an engineered IL-2-diphtheria toxin fusion protein. I/Ontak specifically binds to IL-2 receptors on the cell surface, causing diphtheria toxin fragments that have entered cells to inhibit protein synthesis. It is a purified and more bioactive formulation than the previously FDA-approved Ontak. Ontak was marketed in the United States from 1999 to 2014, when it was voluntarily withdrawn from the market because of production issues related to the E. coli expression system and purification challenges. Company officials said manufacturing improvements resulted in a new formulation that maintains the same amino acid sequence but features improved purity and bioactivity.

The BLA is supported by a pivotal phase 3 study. Topline results released in April 2022 showed that I/Ontak demonstrated anti-tumor activity in the treatment of persistent or recurrent CTCL. I/Ontak provided disease control without cumulative toxicity and has an average time to response within one to two cycles of treatment in patients that have failed multiple prior therapies.

FDA accepts sBLA for Evkeeza for children with rare high cholesterol.

The FDA has accepted for priority review Regeneron Pharmaceuticals’ supplemental biologics license application (sBLA) for Evkeeza (evinacumab-dgnb) to treat children aged 5 to 11 years with homozygous familial hypercholesterolemia (HoFH). The FDA target action date is March 30, 2023.

Homozygous familial hypercholesterolemia is an ultra-rare inherited condition that affects about 1,300 patients in the United States and is the most severe form of familial hypercholesterolemia. People with this condition are at risk for premature atherosclerotic disease and cardiac events even in their teenage years.

Evkeeza is a fully human monoclonal antibody that binds to and blocks the function of ANGPTL3, a protein that inhibits lipoprotein lipase and endothelial lipase and regulates circulating lipids, including LDL-C. It was first approved by the FDA in February 2021 for patients 12 years of age and older.

The application is supported by data from a three-part trial evaluating Evkeeza in children aged 5 to 11 years with homozygous familial hypercholesterolemia. Data from the Part B portion of the trial were released in May 2022. The trial met its primary endpoint, showing children who added Evkeeza to other lipid-lowering therapies reduced their LDL-C by 48% at week 24 on average. Additionally, 79% saw their LDL-C reduced by at least half at 24 weeks following Evkeeza treatment.

FDA accepts application for antibiotic for drug-resistant infections.

The FDA has accepted for priority review Innoviva’s new drug application (NDA) for SUL-DUR to treat patients with infections caused by Acinetobacter baumannii-calcoaceticus complex (ABC). The agency is planning to hold an advisory committee meeting to discuss this application. The target PDUFA date is May 29, 2023.

Acinetobacter baumannii-calcoaceticus complex results in severe pneumonia and bloodstream infections, as well as infections of the urinary tract and the skin. Carbapenem-resistant Acinetobacter infections are among the top antibiotic-resistant threats, according to the Centers for Disease Control and Prevention. Those at risk include hospital-based patients who are on ventilators, have devices such as catheters, have open wounds and are in intensive care units. An estimated 8,500 infections in hospitalized patients and 700 estimated deaths in the United States are caused by carbapenem-resistant Acinetobacter, according to the CDC.

Sulbactam-durlobactam (SUL-DUR) is an intravenous drug that is a combination of sulbactam, an IV β-lactam antibiotic, and durlobactam, a broad-spectrum IV β-lactamase inhibitor, being developed to treat infections caused by ABC, including multi-drug and carbapenem-resistant strains.

Aldeyra submits NDA for the novel dry eye therapy reproxalap.

Aldeyra Therapeutics has submitted a new drug application (NDA) to the FDA for topical ocular reproxalap to treat patients with the signs and symptoms of dry eye disease. Dry eye disease is a common inflammatory disease estimated to affect 39 million or more adults in the United States.

Reproxalap is a first-in-class small-molecule modulator of RASP (reactive aldehyde species), which are elevated in ocular and systemic inflammatory disease. In patients with dry eye disease, RASP may contribute to ocular inflammation and changes in tear lipid composition.

The submission is supported by safety and efficacy data from five clinical trials encompassing data for ocular dryness symptom score, ocular redness, Schirmer test, and Schirmer test ≥10 mm responder analysis. Results of the phase 3 TRANQUILITY-2 trial, which were released in June 2022, showed that reproxalap was statistically superior to vehicle for each of the two prespecified primary endpoints, Schirmer test and ≥10 mm Schirmer test responder proportions after a single day of dosing. The Schirmer test, a measure of ocular tear production, is the dry eye disease objective sign most commonly used for drug approval.

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