Alnylam Pharmaceuticals, Inc., a leading RNAi therapeutics company, announced that it has selected its fourth programme in its 'Alnylam 5x15' initiative: ALN-APC, an RNAi therapeutic targeting protein C for the treatment of haemophilia. By reducing levels of protein C, a natural anticoagulant pathway, ALN-APC is intended to act by increasing thrombin generation and reducing the frequency of bleeding in haemophilia patients, including those more severe patients with inhibitors against their replacement factors.

“Our 'Alnylam 5x15' product development strategy is the foundation of our transition from a platform company to a product company as we advance novel RNAi therapeutics to address genetically defined diseases with high unmet medical need. ALN-APC is the fourth programme to be designated as part of this strategic initiative. We are very encouraged by the pre-clinical data we have seen to date which includes robust and durable silencing of protein C, a key regulator of blood coagulation,” said Akshay Vaishnaw, Ph.D., MD, senior vice president, chief medical officer of Alnylam. “As with our other 'Alnylam 5x15' programmes, the ALN-APC programme is focused on a genetically defined target and will utilize Alnylam's existing delivery platform. In addition, with the opportunity to measure clinically meaningful biomarkers in a phase I trial, we expect to achieve early human data followed by execution on what we believe are clear and rapid development and commercialization paths. We anticipate advancing this programme into clinical development in 2013.”

Haemophilia is a hereditary disorder caused by deficiencies of various blood clotting factors, resulting in recurrent bleeds into joints, muscles, and other major internal organs. Haemophilia A is defined by loss-of-function mutations in factor VIII and Haemophilia B is defined by loss-of-function mutations in factor IX. The reduced levels of clotting factors result in attenuated thrombin generation, which is required for the formation of blood clots for normal haemostasis. Some haemophilia patients have been described who have inherited a prothrombotic mutation in factor V, known as factor VLeiden, which results in resistance to protein C, a key regulator of blood coagulation (Nichols et al., Blood, 1996, Vol 88, No 4: pp 1183-1187 and Kurnik et al., Haematologica, 2007; 92(07), pp 982-985). In addition, a small number of haemophilia patients have also been described as having co-inherited genetic deficiencies in protein C itself. The co-inheritance of prothrombotic factors in haemophilia patients is associated with a later onset of disease, lower frequency of bleeding, and reduced requirements for factor VIII or factor IX treatment as part of their disease management.

ALN-APC is a systemically delivered RNAi therapeutic targeting protein C, a genetically defined target. Protein C is expressed exclusively in the liver, circulates in plasma, and defines a key natural anticoagulant pathway. Activated protein C (APC) inactivates factors Va and VIIIa, both proteins in the blood coagulation pathway, resulting in reduced thrombin generation. ALN-APC provides a pharmacologic strategy to reproduce the human genetics observed with co-inheritance of prothrombotic factors in haemophilia. RNAi silencing of protein C is expected to increase thrombin generation in haemophilia patients thereby reducing the frequency of bleeding.

At the 7th Annual Meeting of the Oligonucleotides Therapeutics Society being held in Copenhagen, Denmark between September 8-10, 2011, Alnylam presented pre-clinical data from its new ALN-APC program. Specifically, ALN-APC showed dose-dependent silencing of the protein C mRNA with an ED50 of 0.02 mg/kg. When administered as a single intravenous dose of 0.3 mg/kg, the LNP-formulated siRNA achieved 90 percent silencing of protein C mRNA within 24 hours with effects lasting for over two weeks. Further, administration of the siRNA resulted in marked reductions in protein C plasma levels. Alnylam anticipates advancing this new 'Alnylam 5x15' program into clinical development in 2013.

“Effective therapies for haemophilia A and B (factor VIII and factor IX deficiency) have been developed using natural and recombinant proteins. However there is a need for new methods to improve therapy to treat the pathology associated with these congenital diseases. Approximately 20-25% of patients treated with current therapeutic products develop inhibitory antibodies to the therapeutic proteins which defeat the standard therapy; under ordinary circumstances the replacement therapy itself is expensive and requires frequent intravenous injections of the therapeutic proteins. New therapies which will improve the management of haemophilia so as to provide less frequent injections of these costly products requires new pharmaceuticals to improve the management for patients. The development of antibody inhibitors is an area of great need for significant improvement in therapy,” said Kenneth Mann, Ph.D., Professor of Biochemistry at The University of Vermont. “The procoagulant system is countered by anticoagulants which prevent blood from clotting inappropriately leading to the pathologies of thrombosis. The attenuation of these anticoagulant systems provides a window of opportunity to improve management of haemophilia. Clinical and basic studies suggest that decreasing the regulatory anticoagulant systems on a systemic basis may improve haemophilia management. In this regard, the systemic reduction of the functions of the protein C pathway is an attractive approach to target. Systemic reduction in protein C synthesis in the liver has the potential of providing a reduced need for the therapeutic proteins used in haemophilia therapy and providing a novel therapy for the treatment of individuals with inhibitory antibodies.”

Haemophilias are hereditary disorders caused by genetic deficiencies of various blood clotting factors, resulting in recurrent bleeds into joints, muscles, and other major internal organs. Haemophilia A is defined by loss-of-function mutations in factor VIII, and there are greater than 40,000 registered patients in the US and EU. Haemophilia B, defined by loss-of-function mutations in factor IX, affects greater than 9,500 registered patients in the US and EU. Standard treatment for haemophilia patients involves replacement of the missing clotting factor either as prophylaxis or on-demand therapy.

However, as many as one third of haemophilia A patients will develop an antibody to their replacement factor - a very serious complication; these 'inhibitor' patients become refractory to standard replacement therapy. There exists a small subset of haemophilia patients who have inherited a prothrombotic mutation in factor V (known as factor VLeiden) which results in resistance to protein C, a natural anticoagulant protein. Other haemophilia patients have been described that have co-inherited deficiencies in protein C itself. Haemophilia patients that have co-inherited these prothrombotic mutations are characterized as having a later onset of disease, lower risk of bleeding, and reduced requirements for factor VIII or factor IX treatment as part of their disease management. There exists a significant need for novel therapeutics to treat haemophilia patients.

Protein C is a serine protease blood coagulation factor that circulates as an inactive zymogen and is activated by thrombin during blood coagulation to form activated protein C (APC). APC is an endogenous anticoagulant that acts to reduce thrombin generation by inactivating factors Va and VIIIa. Protein C is expressed exclusively in the liver and circulates in blood. Protein C is a genetically defined target. Heterozygous protein C deficiency in humans is associated with an increased incidence of thrombosis, while complete deficiency is generally fatal at birth or shortly thereafter. Further, a common polymorphism in factor V, called factor VLeiden occurs in about five percent of the Caucasian population and results in a functional resistance to APC; factor VLeiden is associated with a hypercoagulable state and an increased risk of thrombosis in the general population. In contrast, haemophilia patients that have co-inherited protein C deficiency or factor VLeiden have been described as having a reduced frequency of bleeding with no known increased risk of thrombosis.

The "Alnylam 5x15" strategy, launched in January 2011, establishes a path for development and commercialization of novel RNAi therapeutics to address genetically defined diseases with high unmet medical need. Products arising from this initiative share several key characteristics including: a genetically defined target and disease; the potential to have a major impact in a high unmet need population; the ability to leverage the existing Alnylam RNAi delivery platform; the opportunity to monitor an early biomarker in phase I clinical trials for human proof of concept; and the existence of clinically relevant endpoints for the filing of a new drug application (NDA) with a focused patient database and possible accelerated paths for commercialization. This strategy leverages Alnylam's clinical progress on siRNA delivery, including definitive human proof-of-concept data for systemic delivery.

By the end of 2015, the company expects to have five such RNAi therapeutic programmes in advanced clinical development. These include ALN-TTR for the treatment of transthyretin-mediated amyloidosis (ATTR), ALN-PCS for the treatment of severe hypercholesterolemia, ALN-HPN for the treatment of refractory anaemia, ALN-APC for the treatment of haemophilia, and one additional program from the company's ongoing discovery efforts that will be designated and advanced into development later in 2011. Alnylam intends to commercialize the products arising under the "Alnylam 5x15" strategy itself in the United States and potentially certain other countries; the company will seek development and commercial partners in other global territories.

RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine.

It is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNAs (siRNAs), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.