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Alnylam Presents New Pre-clinical Data on RNAi Therapeutics Targeting Transthyretin (TTR) for the Treatment of TTR-Mediated Amyloidosis (ATTR)

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  • TTR Knockdown Shown to be Highly Correlated with Regression of TTR Deposits in Mouse Disease Model
  • Comparative Studies Exhibit Superior Activity of RNAi Over Stabilizers Toward Regression of TTR Deposits in Mouse Disease Model
  • Comparative Studies Establish Greater TTR Knockdown with Over 100-Fold Lower Tissue Exposure for RNAi Therapeutics versus Antisense Oligonucleotides (ASO)

April 29, 2014

Alnylam Pharmaceuticals, Inc., a leading RNAi therapeutics company, announced today the presentation of new pre-clinical data on RNAi therapeutics targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR). These data were presented at the International Symposium on Amyloidosis (ISA) held April 27 – May 1, 2014 in Indianapolis, Indiana. In a poster titled “Preclinical Evaluation of RNAi Therapeutics for the Treatment of ATTR: An Update,” Alnylam scientists presented data confirming that the degree of TTR knockdown in a mouse disease model was highly correlated with regression of TTR tissue deposits. Further, comparative studies were performed with the TTR stabilizer tafamidis and a TTR-specific antisense oligonucleotide (ASO). In these pre-clinical studies, RNAi therapeutics targeting TTR were shown to have superior pharmacologic profiles.

“We believe that these new pre-clinical data highlight the potential for RNAi therapeutics targeting TTR to emerge as the optimal approach for the treatment of ATTR. First, in a mouse model of ATTR, we’ve demonstrated that the degree of TTR suppression at steady state knockdown is highly correlated with regression of TTR deposits in multiple tissues. These data suggest that the 80% TTR knockdown target level achieved with patisiran and ALN-TTRsc could facilitate a reduced pathogenic accumulation of TTR amyloid and possibly even a regression of TTR amyloid in patients with ATTR,” said Rachel Meyers, Ph.D., Vice President, Research and RNAi Lead Development at Alnylam. “Moreover, our scientists and collaborators presented comparative studies of RNAi therapeutics with a TTR stabilizer and an antisense oligonucleotide (ASO). In a mouse model of ATTR, treatment with the TTR stabilizer tafamidis resulted in a trend for regression of TTR deposits in a limited number of tissues, while administration of an RNAi therapeutic led to a statistically significant regression in all tissues evaluated. Additional comparative studies were performed with a TTR-specific ASO and showed that RNAi therapeutics achieve a more rapid, potent, and robust knockdown of TTR than the ASO, with an over 100-fold lower drug exposure in liver and ‘bystander’ tissues such as kidney. We believe that the ability of RNAi therapeutics to achieve potent TTR knockdown with lower tissue exposure could result in a more favorable efficacy and tolerability profile.”

New data presented at ISA are based on studies performed in transgenic mice expressing the amyloidogenic mutant human V30M TTR. These mice exhibit deposition of TTR at greater than 12 months of age in similar target organs to those seen in ATTR human disease, including dorsal root ganglion (DRG), sciatic nerve, duodenum, esophagus, stomach, and colon. Animals at greater than 14 months of age, where there is established tissue deposition of TTR, were treated with increasing doses of siTTRsc, a GalNAc-siRNA conjugate specific for TTR. Results showed that the degree of TTR reduction at steady state knockdown was highly correlated in a linear relationship with regression of TTR deposits (p<0.01 in each tissue). Specifically, regression of TTR deposits was greater with every additional level of plasma TTR knockdown, and was most pronounced at the highest dose of siTTRsc tested, which achieved over 95% TTR knockdown. Also, even at a dose that resulted in only about 50% TTR knockdown, TTR tissue deposits were shown to be significantly reduced compared with PBS-treated control animals. These results confirm that TTR knockdown of greater than 50% can lead to regression of TTR tissue deposits, but that the highest levels of TTR knockdown achievable remains the therapeutic objective for RNAi therapeutics.

Additional pre-clinical studies were performed to compare the pharmacologic properties of RNAi therapeutics with those of the TTR stabilizer tafamidis and an ASO targeting TTR. First, studies in the V30M transgenic mouse were performed comparing LNP-siTTR, a lipid nanoparticle-formulated TTR-specific siRNA, with tafamidis. LNP-siTTR was administered at a dose that achieved a robust knockdown of serum TTR by greater than 95%, while tafamidis was administered at a dose that provided a greater than 100% increase in TTR tetramer stabilization, similar to that achieved at clinical doses. Results with LNP-siTTR showed that TTR deposition in all affected tissues (esophagus, stomach, duodenum, colon, DRG, and sciatic nerve) was reduced by mean levels greater than 75% and maximum levels of greater than 95% as compared to controls (p<0.0001 by ANOVA). In contrast, tafamidis administration resulted in only modest TTR deposit regression in only the DRG and sciatic nerve (mean levels of 35% and 64%, respectively), with only the latter achieving statistical significance relative to control. Finally, a study was performed comparing ALN-TTRsc with a TTR-specific ASO; both RNA therapeutics were administered with identical subcutaneous dosing regimens. ALN-TTRsc achieved greater than 90% knockdown of TTR by day 3 at a dose of 10 mg/kg and by day 10 at a dose of 2.5 mg/kg, with resulting liver and kidney concentrations of 1 and 0.6 µg/g, respectively, 24 hours after the final dose. In contrast, 10 mg/kg doses of the ASO achieved nadir of only about 70% knockdown by day 24, with no knockdown effect observed at 2.5 mg/kg. At the 10 mg/kg ASO dose, the corresponding liver and kidney concentrations were 151 and 420 µg/g, respectively. These results demonstrate that ALN-TTRsc achieves more rapid and greater TTR knockdown at 100-fold lower target tissue exposure as compared with an ASO. Taken together, these comparative pharmacologic results demonstrate a favorable profile for RNAi therapeutics as compared with a TTR stabilizer and an ASO.

Alnylam is currently advancing patisiran (ALN-TTR02), an intravenously delivered RNAi therapeutic targeting TTR for the treatment of ATTR in patients with familial amyloidotic polyneuropathy (FAP), in the Phase 3 APOLLO trial in patients with FAP. In addition, the company is advancing ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting TTR for the treatment of ATTR in patients with TTR cardiac amyloidosis, in a Phase 2 trial in patients with familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA). The company is also evaluating additional cohorts in the Phase 1 study of ALN-TTRsc to confirm a fixed dose regimen for further development. The company plans to initiate a Phase 3 trial for ALN-TTRsc in patients with TTR cardiac amyloidosis by the end of 2014.

About Transthyretin-Mediated Amyloidosis

Transthyretin (TTR)-mediated amyloidosis (ATTR) is an inherited, progressively debilitating, and fatal disease caused by mutations in the TTR gene. TTR protein is produced primarily in the liver and is normally a carrier for retinol binding protein. Mutations in TTR cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy. ATTR represents a major unmet medical need with significant morbidity and mortality; familial amyloidotic polyneuropathy (FAP) affects approximately 10,000 people worldwide and familial amyloidotic cardiomyopathy (FAC) affects at least 40,000 people worldwide. FAP patients have a life expectancy of five to 15 years from symptom onset, and the only approved treatment options for early stage disease are liver transplantation, and tafamidis (approved in Europe). The mean survival for FAC patients is approximately 2.5 years, and there are no approved therapies. Senile systemic amyloidosis (SSA) is a non-hereditary form of TTR cardiac amyloidosis caused by idiopathic deposition of wild-type TTR; its prevalence is generally unknown, but is associated with advanced age. There is a significant need for novel therapeutics to treat patients with TTR amyloid polyneuropathy and/or cardiomyopathy.

About LNP Technology

Alnylam has licenses to Tekmira LNP intellectual property for use in RNAi therapeutic products using LNP technology.

About GalNAc Conjugates

GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Research findings demonstrate potent and durable target gene silencing, as well as a wide therapeutic index, with subcutaneously administered GalNAc-siRNAs from multiple “Alnylam 5×15″ programs.

About RNAi

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. RNAi 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 RNA (siRNA), 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.

About the Genzyme Collaboration

In January 2014, Alnylam and Genzyme, a Sanofi company, formed an alliance to accelerate and expand the development and commercialization of RNAi therapeutics across the world. The alliance is structured as a multi-product geographic alliance in the field of rare diseases. Alnylam retains product rights in North America and Western Europe, while Genzyme obtains the right to access Alnylam’s current “5x15” and future genetic medicines pipeline in the rest of the world (ROW), including co-development/co-commercialization and/or global product rights for certain programs. In the case of patisiran, Alnylam will advance the product in North America and Western Europe, while Genzyme will advance the product in the ROW. In the case of ALN-TTRsc, Alnylam and Genzyme are co-developing and co-commercializing the product in North America and Western Europe, while Genzyme will advance the product in the ROW.

About Alnylam Pharmaceuticals

Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is leading the translation of RNAi as a new class of innovative medicines with a core focus on RNAi therapeutics as genetic medicines, including programs as part of the company’s “Alnylam 5x15TM” product strategy. Alnylam’s genetic medicine programs are RNAi therapeutics directed toward genetically defined targets for the treatment of serious, life-threatening diseases with limited treatment options for patients and their caregivers. These include: patisiran (ALN-TTR02), an intravenously delivered RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting TTR for the treatment of ATTR in patients with TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver disease; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG, an RNAi therapeutic targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; and other programs yet to be disclosed. As part of its “Alnylam 5x15” strategy, as updated in early 2014, the company expects to have six to seven genetic medicine product candidates in clinical development – including at least two programs in Phase 3 and five to six programs with human proof of concept – by the end of 2015. The company’s demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, The Medicines Company, and Genzyme, a Sanofi company. In March 2014, Alnylam acquired Sirna Therapeutics, a wholly owned subsidiary of Merck. In addition, Alnylam holds an equity position in Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 200 peer-reviewed papers, including many in the world’s top scientific journals such as NatureNature MedicineNature BiotechnologyCell, the New England Journal of Medicine, and The Lancet. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com.

About “Alnylam 5x15™” and Genetic Medicines

The “Alnylam 5x15” strategy, launched in January 2011, establishes a path for development and commercialization of novel RNAi therapeutics as genetic medicines. Alnylam’s genetic medicine programs are RNAi therapeutics directed toward genetically defined targets for the treatment of diseases with high unmet medical need. These programs share several key characteristics including: a genetically defined target and disease expressed in the liver; the potential to have a major impact in a high unmet need population; the ability to leverage the existing Alnylam RNAi platform with clinically proven delivery to the liver; the opportunity to monitor an early biomarker in Phase 1 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. As updated in early 2014, the company expects to have six to seven genetic medicine product candidates in clinical development – including at least two programs in Phase 3 and five to six programs with human proof of concept – by the end of 2015. The “Alnylam 5x15” programs include: patisiran (ALN-TTR02), an intravenously delivered RNAi therapeutic targeting transthyretin (TTR) in development for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting TTR in development for the treatment of ATTR in patients with TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) in development for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5, an RNAi therapeutic targeting complement component C5 in development for the treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) in development for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 in development for the treatment of hypercholesterolemia; ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver disease; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 in development for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG, an RNAi therapeutic targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; and other programs yet to be disclosed. In 2014, Alnylam and Genzyme, a Sanofi company, formed a multi-product geographic alliance on Alnylam’s genetic medicine programs. Specifically, Alnylam will lead development and commercialization of programs in North America and Europe, while Genzyme will develop and commercialize products in the rest of world. In addition, Alnylam and Genzyme will co-develop and co-commercialize ALN-TTRsc in North America and Europe.

Comments

  1. Sam Hopes

    The new pre-clinical data were presented in a Late-Breaking Abstract Session at Digestive Disease Week, held 3 May to 6 May 2014 in Chicago, Illinois. With this the company now plans to initiate IND-enabling studies with the goal of filing an IND or IND equivalent for ALN-AAT in mid-2015.

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