ORLANDO, Fla. — NI-0501 demonstrated safety and efficacy for the treatment of pediatric patients with hemophagocytic lymphohistiocytosis who did not respond to or who were intolerant of conventional therapy, according to study results presented during the late-breaking abstract session of the ASH Annual Meeting and Exposition.
Primary hemophagocytic lymphohistiocytosis (HLH) — a rare immune regulatory disorder driven by pathologic immune activation — often occurs due to underlying mutations affecting cytotoxic function. Immune-chemotherapy is currently the only treatment to control HLH, and mortality and morbidity remain high partly due to therapy-related toxicity.
Michael B. Jordan
“Treatment of HLH remains very challenging,” Michael B. Jordan, MD, a faculty member of the divisions of Immunobiology and Bone Marrow Transplantation and Immune Deficiency at Cincinnati Children’s Hospital Medical Center, said during his presentation. “Initial therapy is directed at trying to suppress the out-of-control immune response. Children at risk for recurrent episodes of HLH proceed to hematopoietic stem cell transplantation [HSCT], and hopefully this allows for long-term survival.”
First-line therapy includes an etoposide- and dexamethasone-based regimen.
“This regimen, as you might imagine in children who present already with cytopenias, is myelosuppressive and broadly immune suppressive,” Jordan said. “Although this does allow for long-term survival in these children, there is plenty of room for improvement in results.”
Further, there is no standard second-line therapy for children who do not respond well to first-line therapy, and survival in this cohort is poor, Jordan said.
When evaluating preclinical models to determine what drives HLH, Jordan and colleagues identified interferon gamma as a key target. Blockade of interferon gamma prolonged survival in preclinical models, and subsequent clinical data indicated interferon gamma appeared elevated in patients with HLH.
These data led to the development of NI-0501 (Novimmune), a fully human anti-interferon gamma monoclonal antibody that neutralizes human interferon gamma. Jordan and colleagues sought to evaluate the safety and efficacy of NI-0501 among pediatric patients with primary HLH.
The ongoing study, open to first and second line HLH patients, has enrolled 16 patients (median age, 1.2 years; range, 0.2-13 years).
Researchers noted that most patients were in a compromised condition and had significant toxicities from previous therapies. Twelve patients had elevated ferritin at baseline, seven had liver involvement and four had central nervous system involvement.
Patients received an initial 1-mg/kg dose of NI-0501 every 3 days, although the dose and interval were adjusted based on real-time pharmacokinetic monitoring and clinical assessment. Patients also received a dexamethasone dose of 5 mg/m2 to 10 mg/m2, which could be tapered throughout treatment depending on the patient’s status.
Fourteen of the patients received NI-0501 as second-line therapy after reactivating, obtaining unsatisfactory response with or being intolerant of conventional therapy. Most of these patients previously received etoposide. To date, two patients received NI-0501 as first line HLH treatment.
One of the 16 enrolled patients was subsequently excluded from the analysis due to the presence of a lymphoma. Two patients were receiving therapy at the time of data reporting, and 13 had completed therapy.
Four of the 13 patients had an insufficient response, two of whom subsequently died and two of whom proceeded to HSCT after receiving additional HLH-controlling therapy.
The other nine patients achieved a favorable response. Seven of these patients have undergone HSCT and the other two have well-controlled disease and are awaiting HSCT.
“So, of the 13 patients completing therapy, 11 have either proceeded to transplant with good control of HLH or have proceed with additional agents,” Jordan said.
One patient who underwent HSCT died from graft-versus-host disease at 45 days post HSCT.
The majority of patients had neutropenia at baseline, but most patients (n = 10) achieved a significant improvement in neutrophil and platelet counts by the end of therapy. Patients also experienced decreases in ferritin, improvement of splenomegaly and reduction in CNS involvement.
Most patients reduced their dexamethasone dose by more than 50% within the first 4 weeks of treatment.
Further, treatment response occurred regardless of the underlying causative mutation or presence of an infectious trigger, Jordan added.
Researchers assessed CXCL9 levels, a chemokine induced by interferon gamma. Overall, they found CXCL9 levels sharply decreased in patients and also appeared correlated with interferon gamma production, suggesting CXCL9 may be a new biomarker for HLH.
After over 160 infusions administered, there have not been any major safety concerns, no off-target effects identified and no patients have been withdrawn from the study due to toxicity, Jordan said.
Of the three deaths that occurred on the study, none were deemed related to the study drug.
“NI-0501 has shown the potential to improve or resolve clinical and laboratory abnormalities of HLH, including CNS signs and symptoms,” Jordan said. “The neutralization of interferon gamma in HLH by NI-0501 appears to be an innovative and targeted approach for the management of these patients.” – by Alexandra Todak
Reference: Jordan M, et al. Abstract LBA-3. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Disclosure: Jordan reports a consultant role with Novimmune. Other researchers report consultant roles and employment with and research funding from Novimmune and Roche.