An Endocrine News roundup of the week’s pharmaceutical news, breakthroughs, and general information. *

Topline Results Announced for CAH Studies

On March 13, Spruce Biosciences announced topline results from its CAHmelia-203 study of tildacerfont in adult classic congenital adrenal hyperplasia (CAH) and its CAHptain-205 study of tildacerfont in pediatric classic CAH.

Spruce is investigating tildacerfont, a second generation, once-daily oral antagonist of the CRF1 receptor, for the treatment of classic CAH. The global CAHmelia program in adult classic CAH is comprised of two Phase 2b studies designed to address the unmet medical needs of two distinct populations of adult CAH patients. CAHmelia-203 assesses androstenedione (A4) reduction in adult CAH patients with severe hyperandrogenemia, while CAHmelia-204 assesses glucocorticoid (GC) reduction, a potentially registrational endpoint, in adult CAH patients on supraphysiologic GC doses with normal or near normal levels of A4.

The Phase 2 CAHptain-205 study is focused on addressing the unmet medical need in pediatric CAH patients, which represents approximately 25% of the total patient population. The CAHmelia and CAHptain programs seek to address the unmet medical need across the entire spectrum of the CAH patient community, which has not seen a new standard of care since GCs were introduced in the 1950s.

CAHmelia-203 Study of Tildacerfont in Adult Classic CAH

CAHmelia-203 enrolled 96 subjects with a mean baseline A4 level of 1,151 ng/dL, which is more than five times above the upper limit of normal (ULN).

Data Highlights

• The clinical trial did not achieve the primary efficacy endpoint of the assessment of dose response for the change in A4 from baseline to week 12.
• 200mg QD of tildacerfont demonstrated a placebo-adjusted reduction from baseline in A4 of -2.6% at week 12 with a non-significant p-value.
• Compliance with study medication and GC was low with approximately 50% of patients reporting 80% or greater compliance, resulting in lower-than-expected tildacerfont exposure.
• Tildacerfont was generally safe and well tolerated at all doses with no treatment-related serious adverse events (SAEs). Most adverse events were reported as mild to moderate.

“We are grateful to all the patients, families, study team and investigators who supported the CAHmelia-203 clinical trial,” said Endocrine Society member Javier Szwarcberg, MD, MPH, chief executive officer, Spruce Biosciences. “CAHmelia-203 is the first study of its kind to address a difficult-to-treat CAH patient population with severe and more refractory hyperandrogenemia, which is often attributed to challenging real-life compliance with daily GCs. We garnered important data from this study which will inform ongoing development of tildacerfont in adult classic CAH.”

Szwarcberg added, “Looking ahead to the third quarter of 2024, we are eager to report topline results from CAHmelia-204, which is focused on assessing GC reduction, a potentially registrational endpoint, in a different population of adult CAH patients with relatively controlled A4 levels and historically better adherence to GC therapy. Assuming positive results from CAHmelia-204 and CAHptain-205, we plan to meet with the U.S. Food and Drug Administration (FDA) and comparable foreign regulatory authorities to outline the design of a registrational clinical program in adult and pediatric classic CAH.”

CAHmelia-203 and 204 Baseline Characteristics Highlight Two Distinct Patient Populations in Adult CAH with Differing Disease Status and Treatment Goals

Patients in CAHmelia-203 enrolled with severe hyperandrogenemia, as indicated with mean baseline A4 levels more than five times above the ULN. By contrast, patients in CAHmelia-204 enrolled with a mean baseline A4 value of 224 ng/dL, which is approximately the ULN, with 66% of patients enrolled with androgenic control, which is defined as having A4 values below the ULN at baseline.

FDA Approves First Drug for MASH

On March 14, it was announced that the U.S. Food and Drug Administration (FDA) granted an accelerated approval for resmetirom, a thyroid hormone receptor (THR)-β for the treatment of patients with metabolic dysfunction-associated steatohepatitis (MASH), also known as nonalcoholic steatohepatitis (NASH), with moderated to advanced liver fibrosis.

Conshohocken, Pa.-based biopharmaceutical company Madrigal Pharmaceuticals is marketing the drug under the name Resdiffra.

“NASH with moderate to advanced liver fibrosis is a serious and progressive liver disease that, until now, has not had an FDA-approved therapy,” said Madrigal CEO Bill Sibold. “The accelerated approval of Rezdiffra is a culmination of more than 15 years of research from our founder Becky Taub and a small R&D team that took on one of the biggest challenges in drug development. This is a historic moment for the NASH field and represents the best of what our industry is capable of. We’re excited to deliver Rezdiffra to patients in need.”

“Madrigal would like to thank the many patients who made the accelerated approval of Rezdiffra possible by participating in our clinical studies,” said Becky Taub, MD, the founder, chief medical officer and president of research & development of Madrigal. “We believe Rezdiffra will change the treatment paradigm for NASH with moderate to advanced liver fibrosis, giving physicians a liver-directed therapy to help improve fibrosis and resolve NASH before their patients progress to cirrhosis.”

Wayne Eskridge, co-founder and chief executive officer of the Fatty Liver Foundation, stated, “This is a day of celebration for patients with NASH who have been waiting many years for the first approved therapy. I believe this approval milestone will bring new energy and momentum to the NASH community, accelerating our efforts to improve disease education, build care pathways, and expand investment in NASH research.”

Rezdiffra is a once-daily, oral THR-β agonist designed to target key underlying causes of NASH. The accelerated approval of Rezdiffra was based on results from the Phase 3 MAESTRO-NASH trial, which was recently published in the New England Journal of Medicine. MAESTRO-NASH is an ongoing pivotal, multicenter, randomized, double-blind, placebo-controlled trial that enrolled 1,759 patients with biopsy-confirmed NASH. Following 52 weeks of treatment, both 100 mg and 80 mg doses of Rezdiffra demonstrated statistically significant improvement compared to placebo on two primary endpoints: NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points) with no worsening of fibrosis, and an improvement in fibrosis by at least one stage with no worsening of the NAFLD activity score. Fibrosis improvement and NASH resolution were consistent regardless of age, gender, type 2 diabetes status, or fibrosis stage.

Rezdiffra is expected to be available to patients in the U.S. in April and will be distributed through a limited specialty pharmacy network. Madrigal is committed to helping appropriate patients who may benefit from Rezdiffra access the medication through the Madrigal Patient Support program. This program is designed to help patients navigate insurance and affordability challenges and provide co-pay support for eligible patients. Madrigal has also established a patient assistance program (PAP) to help patients with no insurance access Rezdiffra.

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