Final Report Summary - FIGHT-HLH (First Targeted Therapy to FIGHT Hemophagocytic Lymphohistiocytosis (HLH): A novel approach to HLH)
Executive Summary:
FIGHT HLH is a research program which has the objective to develop 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. The need to use drugs characterized by severe short and long-term toxicities further aggravates the already high mortality.
The overall mortality rate for pHLH remains around 40 to 50%, as reported in details for the HLH-94 study. No survival improvement was shown either with the addition of cyclosporine A (Bergsten et al, Blood 2017) or with ATG (Jordan et al, Histiocyte Society Meeting October 17-19, 2016, Dublin) to the HLH-94 treatment protocol (etoposide and dexamethasone)
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.
Project Context and Objectives:
Objectives of the FIGHT HLH project
The objectives of the FIGHT HLH program are:
1. To develop NI-0501 (INN emapalumab), 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:
Confidential - Data may not be exchanged with the public before the clinical trial results are published in scientific journals.
Potential Impact:
There is currently no authorised treatment for HLH. Patients diagnosed with HLH are currently treated with immunosuppressant medicines and chemotherapy to improve their chance of survival and control the symptoms of the disease. However, these and other non-specific off-label drugs have adverse long term effects including an increased incidence of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) following the use of epipodophylotoxin derivates (etoposide). Additionally, as for most chemotherapy agents, etoposide induces cytopenia and in particular neutropenia which may enhance the risk of patients with HLH to develop fatal infectious complications. Despite these adverse effects the Histiocyte Society considers the use of these drugs acceptable as the disease is fatal in the absence of therapy. At the same time, the Society advises that prolonged administration of etoposide should be avoided where possible and also states that a targeted therapy which might control the pathophysiology of the disease and enable the avoidance of etoposide treatment would be a highly desirable improvement on current therapy. NI-0501 exactly offers this alternative.
After stabilisation of the disease, Hematopoietic Stem Cell Transplantation (HSCT) has been shown to be curative. However, many patients die after having undergone HSCT, both from recurrence of acute HLH and also from complications of transplantation including graft failure. IFNɣ interferes with hematopoiesis and high levels of it may contribute to graft failure among patients undergoing HSCT. In this project, it will also be investigated whether aAnti-IFNɣ mAb therapy (NI-0501) may improve the successfulness of HSCT. NI-0501 is not a substitute for HSCT, when required, but if found to be as effective as it is in the animal models of primary HLH is expected to:
• Decrease the mortality rate prior to HSCT, or in any case during the first weeks form diagnosis;
• Decrease the duration of treatment or possibly eliminating the use, or at least reducing the doses, of the cytoxic drugs currently used to induce clinical response prior to HSCT, therefore minimazing the safety risks;
• Increase the success rate of HSCT.
If successful, the anti-IFNɣ monoclonal antibody NI-0501 will be registered specifically for treatment of HLH providing a targeted, selective, safer and more effective alternative to current treatments. The lives of about 5000 children in the EU could be secured with this therapy.
Most importantly, the results of the FIGHT-HLH project are positive and once MAA granted then NI-0501 will be implemented as a new therapy for the rare disease HLH in line with achieving the main IRDiRC 2020 objective. In addition, the successful market launch of NI-0501 for HLH will financially enable development of the technology for other rare diseases, in particular sarcoidosis (Besnier-Boeck-Schauman disease). This will increase the chance of addressing more of the target 200 new interventions set by the IRCiRC by 2020.
Members of the consortium have experience in the development and commercialisation of orphan drugs and this project will add to that. Members of the consortium are willing to share their experiences with IRDiRC in order to help them bring additional products to the market. In particular, it is the intention that the coordinator NovImmune will join relevant working groups from the IRDiRC should the opportunity arise to promote the technology and uptake of the drug product as well as sharing experiences in drug development for mutual benefit with other members of the group.
The project will also contribute to IRCiRC goals through the generation of knowledge on the mechanism of HLH and the genetic role in secondary HLH. In addition to assisting the identification of sub-sets of HLH patients that are most likely to respond to NI-0501 treatment, the publication of this information will facilitate further research in this area by other workers in the field. Findings from this genetic characterisation could also assist in the development of diagnostics which are outside of the scope of the FIGHT-HLH project. The dissemination of information demonstrating anti-IFNɣ mAb as an effective technology will open up opportunities for applications in other rare diseases including systemic granulomatous diseases and tissue-specific granulomatous diseases (skin, liver, oro-facial and other tissular granulomas).
HLH market: Current figures indicate incidence of around 0.2 per 10,000 of live births for primary HLH with ten times this number for secondary HLH. Initial application across the US, Canada, Australia, Japan and the larger European countries (total population over 800 million and 13 births per 1,000) would mean around 2,300 cases per year. Th
The successful development of NI-0501 into a drug product will enable commercialisation by a European SME partner in the consortium, NovImmune, together with key members of the consortium. This will boost the revenue of these consortium members significantly which will lead to the creation of financial resources for the application of NI-0501 in other indications, to develop other mAbs to treat diseases and for HLH diagnostics. This will result in strengthening the SME basis in Europe and significant job creation in a knowledge based sector of the European economy.
Multiple press releases, scientific presentations and publications were the basis of the dissemination activities.
List of Websites:
https://www.novimmune.com/en/pipeline/emapalumab-ni-0501.html
FIGHT HLH is a research program which has the objective to develop 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. The need to use drugs characterized by severe short and long-term toxicities further aggravates the already high mortality.
The overall mortality rate for pHLH remains around 40 to 50%, as reported in details for the HLH-94 study. No survival improvement was shown either with the addition of cyclosporine A (Bergsten et al, Blood 2017) or with ATG (Jordan et al, Histiocyte Society Meeting October 17-19, 2016, Dublin) to the HLH-94 treatment protocol (etoposide and dexamethasone)
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.
Project Context and Objectives:
Objectives of the FIGHT HLH project
The objectives of the FIGHT HLH program are:
1. To develop NI-0501 (INN emapalumab), 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:
Confidential - Data may not be exchanged with the public before the clinical trial results are published in scientific journals.
Potential Impact:
There is currently no authorised treatment for HLH. Patients diagnosed with HLH are currently treated with immunosuppressant medicines and chemotherapy to improve their chance of survival and control the symptoms of the disease. However, these and other non-specific off-label drugs have adverse long term effects including an increased incidence of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) following the use of epipodophylotoxin derivates (etoposide). Additionally, as for most chemotherapy agents, etoposide induces cytopenia and in particular neutropenia which may enhance the risk of patients with HLH to develop fatal infectious complications. Despite these adverse effects the Histiocyte Society considers the use of these drugs acceptable as the disease is fatal in the absence of therapy. At the same time, the Society advises that prolonged administration of etoposide should be avoided where possible and also states that a targeted therapy which might control the pathophysiology of the disease and enable the avoidance of etoposide treatment would be a highly desirable improvement on current therapy. NI-0501 exactly offers this alternative.
After stabilisation of the disease, Hematopoietic Stem Cell Transplantation (HSCT) has been shown to be curative. However, many patients die after having undergone HSCT, both from recurrence of acute HLH and also from complications of transplantation including graft failure. IFNɣ interferes with hematopoiesis and high levels of it may contribute to graft failure among patients undergoing HSCT. In this project, it will also be investigated whether aAnti-IFNɣ mAb therapy (NI-0501) may improve the successfulness of HSCT. NI-0501 is not a substitute for HSCT, when required, but if found to be as effective as it is in the animal models of primary HLH is expected to:
• Decrease the mortality rate prior to HSCT, or in any case during the first weeks form diagnosis;
• Decrease the duration of treatment or possibly eliminating the use, or at least reducing the doses, of the cytoxic drugs currently used to induce clinical response prior to HSCT, therefore minimazing the safety risks;
• Increase the success rate of HSCT.
If successful, the anti-IFNɣ monoclonal antibody NI-0501 will be registered specifically for treatment of HLH providing a targeted, selective, safer and more effective alternative to current treatments. The lives of about 5000 children in the EU could be secured with this therapy.
Most importantly, the results of the FIGHT-HLH project are positive and once MAA granted then NI-0501 will be implemented as a new therapy for the rare disease HLH in line with achieving the main IRDiRC 2020 objective. In addition, the successful market launch of NI-0501 for HLH will financially enable development of the technology for other rare diseases, in particular sarcoidosis (Besnier-Boeck-Schauman disease). This will increase the chance of addressing more of the target 200 new interventions set by the IRCiRC by 2020.
Members of the consortium have experience in the development and commercialisation of orphan drugs and this project will add to that. Members of the consortium are willing to share their experiences with IRDiRC in order to help them bring additional products to the market. In particular, it is the intention that the coordinator NovImmune will join relevant working groups from the IRDiRC should the opportunity arise to promote the technology and uptake of the drug product as well as sharing experiences in drug development for mutual benefit with other members of the group.
The project will also contribute to IRCiRC goals through the generation of knowledge on the mechanism of HLH and the genetic role in secondary HLH. In addition to assisting the identification of sub-sets of HLH patients that are most likely to respond to NI-0501 treatment, the publication of this information will facilitate further research in this area by other workers in the field. Findings from this genetic characterisation could also assist in the development of diagnostics which are outside of the scope of the FIGHT-HLH project. The dissemination of information demonstrating anti-IFNɣ mAb as an effective technology will open up opportunities for applications in other rare diseases including systemic granulomatous diseases and tissue-specific granulomatous diseases (skin, liver, oro-facial and other tissular granulomas).
HLH market: Current figures indicate incidence of around 0.2 per 10,000 of live births for primary HLH with ten times this number for secondary HLH. Initial application across the US, Canada, Australia, Japan and the larger European countries (total population over 800 million and 13 births per 1,000) would mean around 2,300 cases per year. Th
The successful development of NI-0501 into a drug product will enable commercialisation by a European SME partner in the consortium, NovImmune, together with key members of the consortium. This will boost the revenue of these consortium members significantly which will lead to the creation of financial resources for the application of NI-0501 in other indications, to develop other mAbs to treat diseases and for HLH diagnostics. This will result in strengthening the SME basis in Europe and significant job creation in a knowledge based sector of the European economy.
Multiple press releases, scientific presentations and publications were the basis of the dissemination activities.
List of Websites:
https://www.novimmune.com/en/pipeline/emapalumab-ni-0501.html