RARE Daily

FDA Approves X4 Pharma’s Xolremdi for WHIM Syndrome

April 29, 2024

Rare Daily Staff

The U.S. Food and Drug Administration has approved X4 Pharmaceuticals’ Xolremdi capsules for use in patients 12 years of age and older with WHIM syndrome to increase the number of circulating mature neutrophils and lymphocytes.

WHIM syndrome is a rare, combined primary immunodeficiency and chronic neutropenic disorder caused by CXCR4 receptor dysfunction that results in impaired mobilization of white blood cells from the bone marrow into peripheral circulation. WHIM syndrome is named for its four classic manifestations: warts, hypogammaglobulinemia, infections, and myelokathexis, although only a minority of patients experience all four manifestations in the acronym. People with WHIM syndrome characteristically have low blood levels of neutrophils and lymphocytes, and as a result, experience serious and/or frequent infections.

Xolremdi, a selective CXC chemokine receptor 4 (CXCR4) antagonist, is the first therapy specifically indicated in patients with WHIM syndrome. The FDA granted Breakthrough Therapy designation to Xolremdi in WHIM syndrome and evaluated the New Drug Application under Priority Review, a designation for therapies that have the potential to provide significant improvement in the treatment, diagnosis, or prevention of serious conditions.

With the FDA approval of Xolremdi, X4 has received a Rare Pediatric Disease Priority Review Voucher that can be used to obtain priority review for a subsequent application or sold to another drug sponsor.

“The approval of Xolremdi is a transformational milestone both for X4 and, more importantly, for the WHIM syndrome community,” said Paula Ragan, president and CEO of X4 Pharmaceuticals.

The FDA approval of Xolremdi was based on results of the pivotal, 4WHIM phase 3 clinical trial, a global, randomized, double-blind, placebo-controlled, 52-week multicenter study that evaluated the efficacy and safety of Xolremdi in 31 people aged 12 years and older diagnosed with WHIM syndrome. The efficacy of Xolremdi was determined by improvement in absolute neutrophil counts, improvement in absolute lymphocyte counts, and a reduction in infections.

In the 4WHIM trial, Xolremdi treatment demonstrated increased time above threshold (≥500 cells/microliter) for absolute neutrophil count verse placebo and increased time above threshold (≥1000 cells/microliter) for absolute lymphocyte count verse placebo. The efficacy of Xolremdi was further assessed in a composite endpoint consisting of total infection score and total wart change score using a Win-Ratio method. Analyses of the individual components of this composite endpoint showed an approximate 40 percent reduction in total infection score, weighted by infection severity, in Xolremdi-treated patients compared with placebo-treated patients.

There was no difference in total wart change scores between the Xolremdi and placebo treatment arms over the 52-week period. Treatment with Xolremdi also resulted in a 60 percent reduction in the annualized infection rate compared with placebo-treated patients. The most common adverse reactions reported in the 4WHIM trial (≥10 percent and more frequently reported than placebo) were thrombocytopenia, pityriasis, rash, rhinitis, epistaxis, vomiting, and dizziness.

Photo: Paula Ragan, president and CEO of X4 Pharmaceuticals

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