MELANOMA
New combination therapy approved by FDA
Fixed-dose combination therapy nivolumab and relatlimab-rmbw (Opdualag, Bristol-Myers Squibb Company) is approved for adults and pediatric patients 12 years of age or older who have unresectable or metastatic melanoma.
Opdualag is a fixed-dose combination of the lymphocyte activation gene-3 (LAG-3) blocking antibody, relatlimab, and the programmed death receptor-1 (PD-1) blocking antibody, nivolumab.
Approval was based on the results of RELATIVITY-047 (NCT03470922). The trial was randomized (1:1), double-blinded, and included 714 patients with previously untreated metastatic or unresectable Stage III or IV melanoma. Excluded from the trial were those with active autoimmune diseases, medical conditions requiring systemic treatment with moderate- to high-dose corticosteroids or immunosuppressive medications, uveal melanoma, or untreated brain or leptomeningeal metastases.
Participants were randomized to receive either an I.V. infusion of Opdualag (nivolumab 480 mg and relatlimab 160 mg) every 4 weeks or nivolumab (480 mg) every 4 weeks. Treatments continued until disease progression or unacceptable toxicity.
Those receiving the Opdualag treatment compared with nivolumab showed a statistically significant improvement in progression-free survival (PFS). The median PFS in the Opdualag arm was 10.1 months, compared with 4.6 months in the nivolumab arm.
Adverse events to Opdualag reported throughout the trial included musculoskeletal pain, fatigue, rash, pruritus, and diarrhea. Lab abnormalities included decreased hemoglobin, decreased lymphocytes, increased alanine aminotransferase, increased aspartate aminotransferase, and decreased sodium.
Reference: U.S. Food and Drug Administration. FDA approves Opdualag for unresectable or metastatic melanoma. 2022. http://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-opdua.
PEDIATRICS
New seizure drug approved
The FDA has approved fenfluramine (Fintepla, Euronext) oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older.
It is available in the US via the Risk Evaluation and Mitigation Strategy, a restricted distribution program.
Approval was based upon results from safety and efficacy data collected in a global, randomized, placebo-controlled Phase 3 clinical trial that included 263 patients between 2 and 35 years old.
Fenfluramine at 0.7 mg/kg/day significantly reduced the frequency of drop seizures compared with placebo. Measured over 28 days, about 25% of participants experienced a greater than 50% reduction in drop seizures, 18% experienced between a 50% and 75% reduction, and 6% experienced a greater than 75% reduction.
Adverse reactions included diarrhea, decreased appetite, fatigue, somnolence, and vomiting.
Fenfluramine is contraindicated in those with hypersensitivity to the drug or any of the product's excipients. It is also contraindicated in those who have received a monoamine oxidase inhibitor within the past 14 days since fenfluramine can cause an increased risk of serotonin syndrome.
Reference: U.S. FDA approves FINTEPLA(R) [black down pointing small triangle](Fenfluramine) oral solution for treatment of seizures associated with Lennox-Gastaut syndrome (LGS). http://www.ucb.com/stories-media/Press-Releases/article/US-FDA-Approves-FINTEPLA.
REPRODUCTIVE HEALTH
Metformin linked to boys' genital birth defects
A father's use of metformin may contribute to major birth defects, particularly genital birth defects in boys, according to a paper published in the Annals of Internal Medicine.
Researchers examined health-registry data from Denmark in a nationwide prospective registry-based cohort study. Nearly 1.12 million offspring were included, all liveborn singletons from mothers without histories of diabetes or essential hypertension.
Offspring were considered exposed if their father had filled one or more prescriptions for a diabetes drug during the development of fertilizing sperm. Sex and frequencies of major birth defects were compared across drugs, times of exposure, and siblings.
About 3.3% of offspring examined had one or more major birth defects (reference). Insulin-exposed offspring (5,298) had the reference birth defect frequency, metformin-exposed offspring (1,451) had an elevated birth defect frequency, and sulfonylurea-exposed offspring (647) had an adjusted odds ratio of 1.34.
Offspring whose fathers filled metformin prescription in the year before or after sperm development (1,751 and 2,484, respectively), and unexposed siblings of exposed offspring, had reference birth defect frequencies.
Genital defects were more common among metformin-exposed offspring and were all found in boys.
The authors say further research is needed to replicate these findings and clarify causation.
Reference: Wensink MJ, Lu Y, Tian L, et al. Preconception antidiabetic drugs in men and birth defects in offspring: a nationwide cohort study. Ann Intern Med. 2022;175(5):665-673. doi:10.7326/M21-4389.
PEDIATRIC HEALTH
Effects of fetal cannabis exposure
Babies' metabolic health may be adversely affected when exposed to cannabis in the womb, according to a paper published in The Journal of Clinical Endocrinology & Metabolism.
Researchers found an association between fetal exposure to cannabis and increased adiposity and fasting glucose in childhood.
A subsample of 103 mother-child pairs from Healthy Start, an ethnically diverse Colorado-based cohort, were included in the study. At about 27 weeks gestation, the researchers measured maternal urine for 12 cannabinoids and metabolites of cannabis.
Fetal exposure was analyzed as a dichotomy. If any cannabinoid or metabolite was measured greater than the limit of detection (LOD) set by the researchers, the fetus was considered exposed. If any cannabinoid or metabolite was measured less than the LOD, the fetus was considered not exposed.
Fat and fat-free mass was measured via air displacement plethysmography at an average follow-up age of 4.7 years.
Glucose and insulin were obtained after an overnight fast.
The researchers used a generalized linear model to estimate the association between fetal exposure to cannabis and adiposity measures.
About 15% of the women in the study returned detectable levels of any cannabinoid, indicating fetal exposure to cannabis. The exposed offspring tended to have higher fat mass, fat-free mass, adiposity, and fasting glucose compared with nonexposed offspring. No association was found with fasting insulin, homeostatic model assessment of insulin resistance, BMI, or BMI z-scores.
The researchers say these results need to be validated in other cohorts.
Reference: Moore BF, Sauder KA, Shapiro AL, Crume T, Kinney GL, Dabelea D. Fetal exposure to cannabis and childhood metabolic outcomes: The Healthy Start Study. J Clin Endocrinol Metab. [e-pub March 31, 2022]
CROHN DISEASE
Potential new treatment
Guselkumab is a new treatment for Crohn Disease (CD) that has shown promising results according to a paper published in Gastroenterology.
The drug is a selective p19 interleukin-23 antagonist, approved for the treatment of plaque psoriasis and psoriatic arthritis.
Results published in Gastroenterology are from a phase 2, double-blind, placebo-controlled study, in which patients were randomized 1:1:1:1:1 to receive I.V. guselkumab 200 mg, 600 mg, or 1,200 mg at weeks 0, 4, and 8; I.V. ustekinumab, a human interleukin-12 and -23 antagonist, approximately 6 mg/kg at week 0 and 90 mg subcutaneously at week 8; or placebo.
A total of 309 patients were evaluated. Primary endpoints included the change from baseline in CD Activity Index Score, clinical remission, and clinical response. Major secondary endpoints concerned outcomes-2 remission, clinical-biomarker response, and endoscopic response.
At week 12, researchers noted significantly greater reductions in the CD Activity Index from baseline and significantly greater proportions of patients achieving clinical remission in each of the guseklumab groups compared with placebo. Furthermore, greater proportions of patients in the guselkumab groups achieved clinical response, patient-reported outcomes-2 remission, clinical biomarker response, and endoscopic response compared with the placebo group.
Safety events were reportedly similar across all treatment groups.
Reference: Sandborn WJ, D'Haens GR, Reinisch W, et al. Guselkumab for the treatment of Crohn's disease: induction results from the phase 2 GALAXI-1 study. Gastroenterology. 2022;162(6):1650-1664. doi:10.1053/j.gastro.2022.01.047.