Immunology and Biotherapies

CAMBRIDGE, Mass., Jun 12, 2015 (BUSINESS WIRE) -- Alnylam Pharmaceuticals, Inc.ALNY, -1.85% a leading RNAi therapeutics company, today announced initial positive results from its ongoing Phase 1/2 clinical trial with ALN-CC5, an investigational RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases. These new clinical data are being presented at the 20th Congress of the European Hematology Association (EHA) held June 11 – 14 in Vienna, Austria. Initial study results from 12 healthy volunteer subjects showed that single subcutaneous dose administration of ALN-CC5 resulted in potent, dose-dependent, durable, and statistically significant knockdown of serum C5 of up to 96%. In addition, single dose administration of ALN-CC5 achieved inhibition of serum complement activity of up to 92%, including an up to 61% inhibition of serum hemolytic activity. Further, ALN-CC5 has been found to be generally well tolerated to date. The company is continuing to dose healthy volunteer subjects in both the single ascending dose (SAD) and multiple ascending dose (MAD) stages of the study, and expects to present additional data from the trial in late 2015. Consistent with previous guidance, the company also plans to begin enrolling patients with paroxysmal nocturnal hemoglobinuria (PNH) into the trial by the end of 2015.

Abstract

Age-related macular degeneration (AMD) is the leading cause of vision loss in the western world. This multifactorial disease results from the combined contributions of age, environment and genetic predisposition. Antibody-based treatment of late-stage neovascular AMD with inhibitors of vascular endothelial growth factor has had great success, which is now the goal for currently untreatable AMD manifestations. The existence of an immune-privileged environment in the eye supports the feasibility of localized antibody therapy. Many different antibodies against various targets are being developed for the treatment of AMD, which reflects the etiological complexity of the disease. This review provides an overview of 19 potential therapeutic antibodies targeting angiogenesis, the complement system, inflammation or amyloid beta deposition in the eye. It summarizes the immunoglobulin structure, the specific target and study outcomes for each approach. The latter include beneficial results or adverse effects in AMD models and patients. Finally, this article discusses the challenges in the development of antibody-based drugs to treat degenerative processes in the posterior eye. In spite of these difficulties, to date, the following four antibodies have overcome the technical and preclinical hurdles and are being tested in active clinical studies: Lampalizumab, Sonepcizumab, GSK933776 and LFG316. We conclude that, while there are some antibody-based drugs that have made it into clinical practice, a successful transfer from bench to beside is still pending for many promising approaches.

 

The first indication is paroxysmal nocturnal hemoglobinuria (PNH), a rare disease of the bone marrow. Apellis' drug candidate APL-2, an inhibitor of complement component C3, is designed to provide PNH patients with an alternative to the current standard-of-care. In its second program, Apellis is testing whether APL-1, another inhibitor of complement component C3, can affect the underlying disease mechanism in COPD and slow down disease progression. Finally, Apellis' third program aims to reduce the growth of retinal lesions through the intravitreal injection of APL-2 in patients suffering from geographic atrophy, the advanced form of dry age-related macular degeneration (AMD), for which no treatments exist. All three complement immunotherapy programs focus on the potential of complement inhibition to correct pathogenic Th17 immune responses.

True North is developing novel humanized antibodies that inhibit pathogenic activity of the Complement pathway of the immune system. In contrast to conventional drug development approaches that focus primarily on inhibiting downstream components of the Complement cascade, True North’s therapeutics are designed to selectively target and block upstream processes in pathways of the Complement system.

True North’s deepest drug discovery expertise involves the Classical Complement pathway, which is a pathway that has not previously been successfully pursued for drug development. True North’s lead drug candidate, TNT009, selectively targets the Classical Complement pathway to address fundamental disease mechanisms.

Based on deep insights in Complement system biology, True North’s R&D engine is creating a pipeline of monoclonal antibodies focused on the treatment of Complement-mediated rare diseases in the hematologic, kidney transplant, and skin therapeutic areas.

Highlights

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The complement cascade: a fine molecular interplay regulates functional outcome.

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An imbalance by overactive or attenuated complement activation has severe pathological implications.

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Enhancement or inhibition of complement creates a powerful strategy for therapeutic intervention.

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Synergy between complement and cell-mediated effector functions impacts therapeutic efficacy.

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Antibody combination therapies, engineering approaches and optimized treatment designs provide exciting opportunities for new and improved therapies.