The FDA has approved emapalumab-lzsg (Gamifant), marking the first treatment specifically indicated for primary hemophagocytic lymphohistiocytosis (HLH), an ultra-rare and life-threatening immune disorder that predominantly affects children. The approval represents the first significant improvement in primary HLH induction therapy in 24 years.
Primary HLH is a rapidly-progressive syndrome of hyper-inflammation in which the body produces too many activated immune cells. The condition typically manifests within the first year of life and can rapidly become lethal if left untreated, with a median survival of less than two months. Symptoms include fever, enlarged liver or spleen, decreased blood cell counts, and neurological abnormalities. Fewer than 100 cases of primary HLH are diagnosed annually in the United States.
Pivotal Trial Results Demonstrate Efficacy
The FDA approval was based on results from a global, multicenter, open-label, single-arm phase 2/3 clinical study that enrolled 34 primary HLH patients. The efficacy analysis focused on 27 patients with refractory, recurrent, or progressive disease during conventional HLH therapy or who were intolerant to conventional treatment.
In this cohort, 63% of patients demonstrated an overall response at the end of treatment (p=0.013), defined as achievement of either a complete or partial response, or HLH improvement. Critically, 70% of patients were able to proceed to hematopoietic stem cell transplant, which represents the only cure for the condition. Of the 27 refractory patients treated in the study, 82% had a genetically confirmed primary HLH diagnosis.
Novel Mechanism Targets Key Inflammatory Pathway
Emapalumab-lzsg is a monoclonal antibody that binds to and neutralizes interferon gamma (IFNγ), which nonclinical data suggest plays a pivotal role in HLH pathogenesis. The drug is administered concomitantly with dexamethasone through intravenous infusion over one hour twice per week until hematopoietic stem cell transplant.
"HLH is a disorder of immune regulation in which many cytokines are deranged, but interferon gamma appears to play a critical role," said Michael Jordan, MD, a physician-scientist in the division of Bone Marrow Transplantation and Immune Deficiency at Cincinnati Children's Hospital Medical Center HLH Center of Excellence and primary study investigator. "While we have long understood the pivotal role of this cytokine in HLH, until emapalumab's approval we did not have a medicine that could specifically hit this target."
Safety Profile and Regulatory Pathway
The most common adverse reactions reported during the study were infections (56%), hypertension (41%), infusion-related reactions (27%), and fever (24%). Patients receiving emapalumab should not be given live vaccines and should be tested for latent tuberculosis prior to treatment initiation.
The FDA granted this application Priority Review, Breakthrough Therapy designation, and Orphan Drug designation, reflecting the significant unmet medical need in this patient population.
"Primary HLH is a rare and life-threatening condition typically affecting children and this approval fills an unmet medical need for these patients," said Richard Pazdur, MD, director of the FDA's Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research.
Commercial Availability and Development Partnership
Gamifant is expected to be available for administration in treatment centers across the United States in the first quarter of 2019. The treatment was developed and submitted for FDA approval by Novimmune SA, with Sobi acquiring global rights through an exclusive licensing agreement announced in July 2018.
The approval addresses a critical gap in treatment options for primary HLH, where previous conventional induction therapies included steroids and chemotherapy that were not specifically approved to treat the condition. The targeted approach of emapalumab represents an entirely new therapeutic strategy for helping patients reach the curative hematopoietic stem cell transplant procedure.
