Community Research and Development Information Service - CORDIS

FP7

FIGHT-HLH Report Summary

Project ID: 306124
Funded under: FP7-HEALTH
Country: Switzerland

Periodic Report Summary 3 - FIGHT-HLH (First Targeted Therapy to FIGHT Hemophagocytic Lymphohistiocytosis (HLH): A novel approach to HLH)

Project Context and Objectives:
FIGHT HLH is a research program which has the objective to develop of an anti-IFNγ monoclonal antibody as the first targeted therapy for Hemophagocytic lymphohistiocytosis (HLH) and to create awareness about this disease, its diagnosis and treatment.

The disease

HLH is a rare syndrome, potentially life-threatening, characterized by immune dysregulation, overwhelming immune activation, and inflammation. The impaired cytotoxic function present in HLH leads to hypercytokinemia and hemophagocytosis with deleterious consequences on various tissues and organs.

Hypercytokinemia and hemophagocytosis are responsible for all typical symptoms of HLH:
- persistent fever
- splenomegaly
- cytopenia, particularly thrombocytopenia with bone marrow hypoplasia
- hyperferritinemia
- hypertriglyceridemia
- hypofibrinogenemia.

The disease comprises primary forms (with documented genetic defect and/or familial recurrence) and secondary forms, consequent to infections, rheumatic diseases or malignancies.
Primary HLH (pHLH) is a heterogeneous autosomal recessive disorder which is invariably fatal if untreated. The onset is most often observed in infancy and early childhood with an estimated prevalence in Europe of 1/50,000 live birth.

There is no drug approved for the treatment of HLH and no drug in clinical development. However, because of the severity of the disease, and the extremely high mortality, Experts have established recommendations for the management of pHLH, which foresee off-label use of drugs approved for other indications and for which only very limited, if any, safety and efficacy data are available for pediatric use.

The treatment strategy for pHLH consists of 2 steps that are essential for survival and cure:
- Induction therapy: a combination of high dose corticosteroids, chemo-therapy (etoposide), and possibly immuno-therapy (e.g. antithymocyte globulin). This intervention, generally of the duration of 8 weeks, is aimed at suppressing the life-threatening tissue damage that characterizes HLH;
- Hematopoietic Stem Cell Transplantation (HSCT): the only curative treatment for pHLH.

The drugs currently used for the treatment of HLH, none of which has been formally developed for the treatment of this disease, carry significant short and long-term toxicities exposing the already fragile patients to a high risk of treatment-related morbidity, and, eventually mortality. Generalized immunosuppression, leading to an increased risk of severe bacterial, viral and fungal infections, hypertension, liver injury, renal impairment, encephalopathy, pulmonary or cardiac complications, delayed occurrence of acute leukemia, growth retardation and bone damage are among the safety concerns related to the use of immuno-chemotherapy.

Despite the introduction of the above recommendations, the overall mortality rate for pHLH remains around 40 to 50%, as reported for the HLH-94 study.
The need to use drugs characterized by severe short and long-term toxicities, further aggravates the already high mortality.
The lack of a significant improvement in survival over the last decades supports the effort of developing a novel therapeutic approach for the induction treatment of HLH and emphasizes the potential advantages of a targeted treatment, ensuring efficacy with less toxicity.

Rationale for targeting IFNγ for the treatment of HLH

IFNγ is one of the most potent and pleiotropic cytokines of the immune system and is associated with the pathogenesis and the maintenance of inflammatory diseases. During the last years, growing evidence of the pivotal role of IFNγ in the development of HLH has been accumulated.

Perforin knocked-out (KO) mice are considered a relevant model for the human disease. In fact, these mice, once infected with lymphocytic choriomeningitis virus (LCMV), develop the clinical and laboratory characteristic features of the human disease, and they die if untreated. For these reasons, perforin KO mice have been used to study the pathophysiology of HLH. The HLH-like pathology they develop is dependent on CD8+ T cells and IFNγ produced in response to antigen stimulation. It was demonstrated that when the high circulating levels of IFNγ are neutralized in these animals, not only the clinical and laboratory abnormalities are reverted, but also survival is dramatically improved. On the contrary, the ablation of the other cytokines has no impact on survival. Further strengthening the importance of IFNγ in HLH are the high concentrations of circulating IFNγ levels in pHLH patients.

The FIGHT project allowed to generate new data confirming the pivotal role of IFNγ also in the pathogenesis of secondary HLH (sHLH).
In a murine model of HLH secondary to infection (TLR9-mediated sHLH) we found, for the first time, that total IFNγ levels originating within tissues (mainly liver and spleen) upon TLR9 stimulation are 500- to 2,000-fold higher than those measured in serum. The hyper-production of IFNγ in tissues was intimately associated to disease progression and, as it is the case in models of primary HLH, ablation of IFNγ activity ameliorated HLH clinical and laboratory parameters. These findings demonstrate in this model of sHLH that IFNγ and signature gene products, CXCL9 and CXCL10, strictly correlate with disease manifestations and severity. We could also demonstrated in the context of an observational study in sHLH patients that, IFNγ, CXCL9 and CXCL10 levels sampled during active disease were markedly higher compared to patients in remission.
Very similar results have been obtained in a mouse model of HLH secondary to a rheumatic disease (MAS): transgenic mice for human interleukin-6 (IL-6TG), in which lipopolysaccharide (LPS) is administered to trigger the disease.

Taken together, these results provide insights into the pathophysiology of secondary forms of HLH, in particular the ones driven by infections or by a rheumatic disease, further supporting the hypothesis that IFNγ is the common mediator of all HLH forms, providing the rational for the therapeutic use of a monoclonal anti-IFNγ antibody in these diseases.

Objectives of the FIGHT HLH project

The objectives of the FIGHT HLH program are:
1. To develop NI-0501, an anti-IFNγ monoclonal antibody, as a targeted therapy for the induction treatment of HLH through the performance of a pilot and pivotal clinical trial
2. To investigate whether primary, but also secondary forms of HLH should be treated with an anti-IFNγ therapy through the performance of experiments in a murine model of secondary HLH and of an observational trial in Rheuma HLH patients in which circulating IFNγ levels are measured and the presence of mutations known to be HLH causative is investigated
3. To better profile HLH with the search for specific disease markers and disease genotypes through the performance of gene profiling in all patients
4. To disseminate the knowledge acquired.

Project Results:
Progress so far

The NI-0501-04 study in pHLH is currently on-going in 13 sites distributed in 6 European countries, and in 8 sites in the US and it is expected to complete enrolment in the first half of 2017 (https://clinicaltrials.gov/ct2/show/NCT01818492?term=NI-0501&rank=3). This study allows the administration of NI-0501 both in 1st and in 2nd line patients.

A long-term follow-up study which intends to monitor all patients who receive at least one dose of NI-0501 (NI-0501-05) is also ongoing (https://clinicaltrials.gov/ct2/show/NCT02069899?term=NI-0501&rank=1).

Orphan Drug Designation was granted and maintained for NI-0501 for the treatment of HLH in 2010 both in Europe and in the US.

NI-0501 has received Breakthrough Drug Designation from the FDA for the treatment of patients with primary HLH in March 2016. The Breakthrough Therapy Designation is intended to accelerate the development and review process of new therapies for serious or life threatening conditions, which have shown encouraging early clinical results demonstrating substantial improvement on a clinically significant endpoint over available therapies.

In May 2016 NI-0501 has also received PRIME (PRIority Medicines) designation from the European Medicinal Agency (EMA), which can be considered the equivalent of Breakthrough Designation for Europe.

Potential Impact:
The expected outcome of the FIGHT HLH project is to create a new and targeted therapeutic approach to treat HLH, formally approved by Regulatory Authorities.
This treatment is expected to deliver efficacy with less toxicity as compared to the treatment currently in use, although used off-label.

The characteristics of this new potential treatment will impact both on the well-being of patients (fast onset of action, limited or no short and long term toxicity), as well as on health management costs.

The objectives of the FIGHT HLH program are:
1. To develop NI-0501, an anti-IFNγ monoclonal antibody, as a targeted therapy for the induction treatment of HLH through the performance of a pilot and pivotal clinical trial
2. To investigate whether primary, but also secondary forms of HLH should be treated with an anti-IFNγ therapy through the performance of experiments in a murine model of secondary HLH and of an observational trial in Rheuma HLH patients in which circulating IFNγ levels are measured and the presence of mutations known to be HLH causative is investigated
3. To better profile HLH with the search for specific disease markers and disease genotypes through the performance of gene profiling in all patients referred to the Meyer’s Children’s Hospital for these assessments
4. To disseminate the knowledge acquired.

List of Websites:
not applicable

Reported by

NOVIMMUNE SA
Switzerland
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