FDA approval of Xolremdi (mavorixafor) capsules, first drug indicated in patients with WHIM syndrome

Xolremdi, a selective CXC chemokine receptor 4 (CXCR4) antagonist, is the first therapy specifically indicated in patients with WHIM syndrome, a rare, combined primary immunodeficiency and chronic neutropenic disorder caused by CXCR4 pathway dysfunction. People with WHIM syndrome characteristically have low blood levels of neutrophils (neutropenia) and lymphocytes (lymphopenia) and experience serious and/or frequent infections. The FDA granted Breakthrough Therapy Designation to mavorixafor in WHIM syndrome and evaluated the New Drug Application (NDA) under Priority Review, a designation for therapies that have the potential to provide significant improvement in the treatment, diagnosis, or prevention of serious conditions.

“Effective and innovative treatments are critical for those diagnosed with a primary immunodeficiency. The approval of Xolremdi marks an important advancement for people living with WHIM syndrome, who are susceptible to serious and frequent infections,” said Jorey Berry, President and Chief Executive Officer of the Immune Deficiency Foundation (IDF). “We are very pleased to have been a partner to X4 in their journey to bring this much-needed treatment to this underserved rare disease community.”

Teresa K. Tarrant, M.D., Associate Professor of Medicine, Rheumatology, and Immunology at Duke University School of Medicine and a principal investigator in the 4WHIM trial, commented on the news: “Until now, supportive care for people with WHIM syndrome has focused on symptom management and not the underlying cause of disease — the dysfunction of the CXCR4 pathway. I am thrilled that with the approval of Xolremdi, a therapy designed to address dysregulated CXCR4 pathway signaling, we now have a targeted treatment that has demonstrated the ability to elevate absolute neutrophil and lymphocyte counts, increasing WHIM patients’ ability to fight infections.”

The FDA approval of Xolremdi was based on results of the pivotal, 4WHIM Phase III clinical trial, a global, randomized, double-blind, placebo-controlled, 52-week multicenter study that evaluated the efficacy and safety of Xolemdi in 31 people aged 12 years and older diagnosed with WHIM syndrome.

The efficacy of Xolremdi was determined by improvement in absolute neutrophil counts (ANC), improvement in absolute lymphocyte counts (ALC), and a reduction in infections. In the 4WHIM trial, Xolremdi treatment demonstrated increased time above threshold ( greater than 500 cells/microliter) for absolute neutrophil count (TAT-ANC) vs. placebo (p<0.0001) and increased time above threshold (greater than 1000 cells microliter) for absolute lymphocyte count (tat-alc) v. placebo (p><0.0001). 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% 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% reduction in the annualized infection rate compared with placebo-treated patients. the most common adverse reactions reported in the 4whim trial ( greater than 10% and more frequently reported than placebo) were: thrombocytopenia, pityriasis, rash, rhinitis, epistaxis, vomiting, and dizziness.