Recently, Alnylam (NASDAQ:ALNY) received a $7 million milestone payment from Genzyme over the Phase II success of Patisiran, a RNAi therapy for the treatment of TTR-mediated amyloidosis. This follows the announcement that Patisiran received fast track designation by the FDA, following positive Phase II data released earlier in November.
Patisiran's Phase II outcome is consistent with Alnylam's track record in their pipeline development, demonstrating that the company's RNAi technology is capable of effectively silencing genetic translation of a designated target. For diseases caused by the expression of a mutant gene and accumulation of abnormal proteins, the potential for RNAi-based medicine to block the production of target proteins at the transcriptional level may provide a capability beyond the reach of conventional treatments.
Alnylam will begin enrollment for a Phase III trial for Patisiran, which will vet the RNAi therapy's ability to inhibit disease progression through genetic silencing. Additionally, Alnylam's application of a newly developed delivery system into their therapeutic candidates, and aggressive pipeline expansion through their 5x15 program, create a compelling story for those that have been following the Cambridge, Mass., biopharmaceutical company.
From Genetic Silencing to Clinical Outcome
Alnylam's Patisiran (ALN-TTR02) is a RNAi therapeutic for the treatment of TTR-mediated amyloidosis, a disease caused by the mutation of the TTR gene. Expression of the mutated TTR gene in the liver leads to the accumulation of abnormal amyloid proteins around the organ, causing tissue damage to the liver and leading to a degenerative condition with grim patient outcomes. For the 10,000 people worldwide with Familial Amyloidotic Polyneuropathy (FAP), patients face a life expectancy of five to 15 years, and treatment options are limited to a liver transplant.
The clinical relevance of knocking down the mutant TTR gene is found in patients that had a liver transplant, where the absence of abnormal TTR expression is attributed to an improvement in disease condition. Phase II data for Patisiran demonstrated strong knockout of the mutant TTR gene, with a mean 86% reduction in the serum concentration of the abnormal protein. The company announced the enrollment for the APOLLO Phase III trial, a randomized, double-blind, placebo-controlled, global study to valuate the safety and efficacy of Patisiran for treating patients with FAP. Primary endpoints of the APOLLO trial will be a change in modified Neuropathy Index Score (mNIS+7) -- a composite score index that quantifies sensation and muscle power impairment -- between Patisiran and placebo at 18 months.
New Delivery System
Additionally, Alnylam has been incorporating a newly developed delivery system into their pipeline, which creates the template for a robust RNAi therapeutic platform. Until now, previous approaches in the RNAi field encapsulated the nucleic acid medicine in a lipid shell -- the same structural material of the cell membrane -- as the vehicle to deliver the nucleic acid payload.
Rather than encapsulating the therapeutic payload in a lipid shell, Alnylam's GalNAc-siRNA Conjugate Platform attaches the nucleic acid strand to a sugar-based delivery system. The advantage of a sugar-based delivery system is that it can be easily recycled by the cell after the therapeutic payload is delivered. This allows for wider saturation of RNAi therapy, added flexibility in the range of therapeutic targets for pipeline development, and facilitates subcutaneous (SC) administration of the treatment.
Alnylam is field testing their new GalNAc-siRNA platform with their ALN-TTRsc therapy, which is targeting mutations in the TTR gene for patients with familial amyloidotic cardiomyopathy (FAC). FAC affects at least 40,000 people world-wide, with an average life expectancy of 2.5 years, and no approved therapies. Phase I data demonstrated strong genetic knockout of the target, with a 94% reduction of serum TTR proteins. Results from a Phase II trial are expected by the end of the year.
In addition to targeting mutations of the TTR gene with ALN-TTR02 and ALN-TTRsc, Alnylam is growing a pipeline that leverages their GalNAc-siRNA platform into subcutaneous RNAi therapies against a broad range of difficult-to-treat diseases.
Alnylam's ALN-PSC program is under development for treating hypercholesterolemia by targeting the PCSK9 gene, which is involved in the metabolism of LDL Cholesterol. Phase 1 and Preclinical studies for ALN-PSC demonstrated the RNAi therapy was effective at silencing PSCK9 translation, causing a declined presence of circulating PSCK9 and LDL-C proteins. Alnylam is leveraging their GalNAc-siRNA delivery system in their lead candidate, ALN-PCSsc, which showed positive preclinical results in October 2013, and is being developed in a partnership with the Medicines Company.
Additionally, Alnylam is developing a hemophilia treatment by silencing the antithrombin gene with ALN-AT3. The RNAi therapy is being pursued as a subcutaneous drug to restore hemostatis by returning patients to a healthy phenotype. ALN-AT3 is undergoing Phase 1 trials, where safety and tolerability for dose-escalation of the RNAi therapy will be studied, and data is expected by the end of 2014. The "Alnylam 5x15" program has also introduced ALN-AS1, a lead candidate for treating Hepatic Porphyrias, which will be pursued in further clinical trials by the beginning of 2014. Recent additions to Alnylam's pipeline includes candidates for treating Complement-Mediated Diseases (ALN-CCS), iron-overload disorders (ALN-TMP), and Alpha-1-Antitrypsin deficiency (ALN-AAT); all of which are at various stages of preclinical development.
Drug discovery is an unpredictable business. Nothing is certain on whether this venture will be successful or not. Beyond Patisiran, Alnylam's pipeline depends largely on the capability of their GalNAc-siRNA conjugate platform. Commercial success will only be realized if the gene-silencing therapeutic approach can lead to meaningful improvements in patient outcomes. Also, there are high expectations for a biotechnology company with a $3.5 billion market capitalization and much of their pipeline at early stages of clinical trials.
There are a couple of factors that lead to an optimistic investment thesis on Alnylam. Across the company's pipeline, Alnylam's technology shows a consistent ability to genetically silence the production of target proteins, and doing so with dose-dependent profiles. Results from Patisiran's Phase III trial will set a precedent for how well this genetic knockdown approach translates into improving patient outcomes. Perhaps Alnylam's most valuable asset is the sugar-based delivery system, which may provide a platform for growing a pipeline of RNAi therapies the company has been aggressively pursuing with their 5x15 program.
Whether or not this venture will be successful is unpredictable, but there is one thing that is certain: Alnylam will be a very interesting stock to follow over the next few years.
Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.