Primary hemophagocytic lymphohistiocytosis (HLH) is an inherited condition in which the body's immune system attacks its own organs, including the liver, brain, and bone marrow. Untreated, the majority of children will die of the disease. Even with currently recommended therapy, HLH is a frequently fatal condition. The early institution of therapy is critical to control the hypercytokinemia that otherwise will lead to end-organ failure and death.
The disease is classified into six different types based on genetic linkage analysis and chromosomal localization; five specific genetic defects have been identified, which account for approximately 90% of all patients. Type 1 is due to an as yet unidentified gene mutation located on chromosome nine; Type 2 is caused by mutations in the perforin (PRF1) gene; Type 3 by mutations in the Munc-13–4 (UNC13D) gene; Type 4 by mutations in the syntaxin 11 (STX11) gene; and Type 5 due to mutations in the gene encoding syntaxin binding protein 2 (STXBP-2).
Absent or decreased lymphocyte cytotoxicity is the cellular hallmark of FHL. Biochemical features such as hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia are usually present, along with high levels of soluble interleukin 2 receptor in the blood and cerebrospinal fluid. The disease is fatal unless a hematopoietic stem cell transplant (HSCT) is performed. Emapalumab-lzsg is the first and only treatment for primary hemophagocytic lymphohistiocytosis (HLH) and was FDA approved based on data from the pivotal phase 2/3 study in patients with primary HLH. The study's primary endpoint in patients with refractory, recurrent, or progressive disease during conventional HLH therapy or who were intolerant of conventional HLH therapy was achieved, with a clinically meaningful and statistically significant proportion of patients demonstrating an overall response at the end of treatment. In addition, 70 per cent of patients proceeded to hematopoietic stem-cell transplantation (HSCT).
Emapalumab-lzsg is an interferon gamma (IFNã) blocking antibody. Emapalumab-lzsg is produced in Chinese Hamster Ovary cells by recombinant DNA technology. Emapalumab-lzsg (Gamifant®) is indicated for the treatment of adult and pediatric (newborn and older) individuals with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent, or progressive disease or intolerance with conventional HLH therapy.
The efficacy of emapalumab-lzsg (Gamifant®) was evaluated in a multicenter, open-label, single-arm trial NI0501-04 (NCT01818492) in 27 pediatric individuals with suspected or confirmed primary HLH with refractory, recurrent, or progressive disease during conventional HLH therapy or who were intolerant of conventional HLH therapy.
Twenty-seven individuals enrolled and received treatment in the study, and 20 individuals (74%) completed the study. Seven individuals (26%) were prematurely withdrawn. Twenty-two individuals (81%) enrolled in the open-label extension study, which monitored individuals for up to one year after HSCT or after the last GAMIFANT infusion (NI-0501-05; NCT02069899).
The study treatment duration was up to eight weeks, after which individuals could continue treatment on the extension study. All individuals received an initial starting dose of emapalumab-lzsg (Gamifant®) of 1 mg/kg every three days. Subsequent doses could be increased to a maximum of 10 mg/kg based on clinical and laboratory parameters interpreted as unsatisfactory response.
The efficacy of GAMIFANT was based upon overall response rate (ORR) at the end of treatment, defined as achievement of either a complete or partial response or HLH improvement. HLH improvement was defined as ≥ 3 HLH abnormalities improved by at least 50 percent from baseline. ORR was evaluated using an algorithm that included the following objective clinical and laboratory parameters: fever, splenomegaly, central nervous system symptoms, complete blood count, fibrinogen and/or D-dimer, ferritin, and soluble CD25 (also referred to as soluble interleukin-2 receptor) levels. Complete response was defined as normalization of all HLH abnormalities (i.e., no fever, no splenomegaly, neutrophils > 1x109/L, platelets > 100x109/L, ferritin < 2,000 g/L, fibrinogen > 1.50 g/L, D-dimer < 500 ug/L, normal CNS symptoms, no worsening of sCD25 > 2-fold baseline). Partial response was defined as normalization of ≥ 3 HLH abnormalities. HLH improvement was defined as ≥ 3 HLH abnormalities improved by at least 50% from baseline. CR was achieved by 26 percent, PR by 30 percent, and HLH improvement by 7.4 percent.
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.