NasVax announces the positive results of a Phase 2a clinical trial of a new oral immunotherapy for non-alcoholic steatohepatitis (NASH), an inflammatory disease associated with fatty liver disease and the metabolic syndrome. This trial was initiated in August 2010, and follows a successful Phase 1 clinical study in healthy subjects. This immunotherapy originated as a joint project between Brigham and Women’s Hospital-Harvard University in Boston and Hadassah-Hebrew University Medical Center in Jerusalem.
This Phase 2a trial investigated each of three dosage levels (0.2, 1.0, 5.0 mg) of anti-CD3 monoclonal antibody (MAb) given orally once daily for 30 days, with a final follow-up 30 days later (60 days after the first dose). Evaluations were for safety as primary endpoint, for immunological effects as co-primary endpoint, and for clinical biomarker effects as secondary endpoint. The trial was a single-blind randomized placebo-controlled study that enrolled 36 subjects aged 18-75 with NASH and altered glucose metabolism and included subjects with type-2 diabetes, and was conducted at the Liver Unit of the Hadassah-Hebrew University Medical Center in Jerusalem Israel, headed by Dr. Gadi Lalazar.
The clinical trial successfully met all three endpoints.
The immunotherapy resulted in positive trends in clinical biomarkers in groups receiving MAb but not in the placebo group – some of these trends were statistically significant in spite of the very small group sizes. These positive effects were reduced blood levels of two liver enzymes as markers for reduced liver inflammation, reduced blood levels of glucose and improved performance in glucose tolerance testing, which are favorable outcomes for subjects with NASH or metabolic syndrome and for subjects with type-2 diabetes or altered glucose metabolism. Several of the positive efficacy trends generally persisted to Day 60 following cessation of immunotherapy at Day 30. These clinical efficacy data show that oral anti-CD3 MAb immunotherapy may have benefit for subjects with NASH or type-2 diabetes.
The immunotherapy was found to be very safe and well tolerated, with no drug-related adverse effects or systemic complaints in any of the three dosage groups, as measured by blood hematology, chemistry, immunological safety markers and general physical signs. During the course of immunotherapy and compared to placebo, there were no changes in blood levels of CD3-positive cells or of CD4- or CD8-positive cells. Some subjects had increased levels of serum antibodies directed against the MAb, which did not affect the positive results observed. These results indicate that there were no adverse systemic or local effects of the MAb, consistent with its mechanism of action in animal model studies. The safety data are consistent with the Phase 1 safety data for oral anti-CD3 immunotherapy in healthy subjects.
The immunotherapy induced regulatory T cells in some of the patients, which generally persisted to Day 60. Subjects in groups receiving MAb showed increases in such markers, while those receiving placebo did not show such increases. Other immunomodulatory effects included trends in the induction of cytokines, which are natural molecules that influence the immune system. These immunological changes during the course of therapy are generally consistent with those observed during the Phase 1 clinical study as well as in multiple studies in animal model systems that demonstrated the relationship between induced regulatory T cells and selective suppression of certain inflammatory and autoimmune diseases with a good safety and immunological profile.
Fatty liver disease affects up to a third of the Western world, and NASH, the severe form of it, affects above 6% of the population, and can lead to cirrhosis of the liver or cancer.
Dr. Rom Eliaz, CEO of NasVax, said “This initial demonstration of positive proof of clinical benefit in an inflammatory disease is very encouraging as NasVax continues to develop this novel immunotherapy, which may be beneficial for a range of inflammatory and autoimmune indications having very large market potential and in need of improved therapies.”