Alnylam Files Clinical Trial Application (CTA) for ALN-AAT, an Investigational RNAi Therapeutic for the Treatment of Alpha-1 Antitrypsin Deficiency-Associated Liver Disease (Alpha-1 Liver Disease)
- Company Guides that it Plans to Initiate Phase 1/2 Trial in Late 2015 and Report Initial Clinical Results in Early 2016 -
- New Pre-Clinical Data with ALN-AAT Presented at Digestive Disease Week (DDW) Meeting, Showing Robust Knockdown of Serum AAT of Up to 93% with Monthly Subcutaneous Dosing in Non-Human Primates and a Wide Therapeutic Index -
"We believe ALN-AAT holds considerable promise as a novel therapeutic
approach for the treatment of alpha-1 liver disease, an increasingly
recognized clinical manifestation of alpha-1-antitrypsin deficiency
where there is a significant unmet need and where liver transplantation
is the only available treatment option. Our pre-clinical results,
including new data presented at this year's DDW meeting, demonstrate
that monthly subcutaneous doses of ALN-AAT achieves robust knockdown of
serum AAT - the disease-causing protein - of up to 93% in NHPs, with
highly durable effects and a wide therapeutic index. In earlier reported
and recently updated studies, we've demonstrated that ALN-AAT can reduce
liver levels of mutant AAT, improve histopathology associated with
mutant AAT expression, and reduce liver fibrosis and the incidence of
tumor formation in a mouse model of alpha-1 liver disease," said
"Alpha-1 liver disease is caused by expression of the mutant ‘Z allele' of the AAT gene and misfolding of the Z-AAT protein, which then accumulates in liver cells and causes cellular damage. Individuals who are homozygous for the mutant Z allele make up approximately 95% of all people with AAT deficiency liver disease. These individuals have a lifetime risk of liver disease of 10% to 50%, which can manifest as cholestatic disease, chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Severe liver disease can occur in both children and adults and is currently managed with supportive care, or in the case of liver failure, with liver transplantation. Clearly, there is a very high unmet need for novel therapies for alpha-1 liver disease," said Jeffrey Teckman, M.D., Professor in the Department of Pediatrics and Director of Pediatric Gastroenterology and Hepatology at Saint Louis University School of Medicine. "I am encouraged by the pre-clinical data with ALN-AAT, and if these results extend in clinical studies, I believe that this investigational RNAi therapeutic has the potential to become an important treatment option for the management of alpha-1 liver disease. I am also pleased with Alnylam's commitment to advance this candidate to clinical stages, bringing a new potential treatment option forward for patients."
ALN-AAT is a subcutaneously administered investigational RNAi therapeutic that utilizes Alnylam's proprietary ESC-GalNAc-siRNA conjugate delivery technology. ESC-GalNAc-siRNA conjugates are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor, and enable subcutaneous dosing with increased potency and durability and a wide therapeutic index. As per the filed CTA, the Phase 1/2 trial of ALN-AAT will be a randomized, single-blind, placebo-controlled study conducted in three parts. Parts A and B will be single-dose (Part A) and multi-dose (Part B), dose-escalation studies, designed to enroll up to a total of 48 healthy adult volunteers. Part C will be a multi-dose study in adults with the PiZZ mutation in their AAT gene and with mild-to-moderate liver fibrosis. The primary objective of the study is to evaluate safety and tolerability of single and multiple subcutaneous doses of ALN-AAT. Secondary objectives include evaluation of pharmacokinetics of ALN-AAT and clinical activity for ALN-AAT as measured by knockdown of serum AAT. In addition, biopsies will be obtained from subjects with alpha-1 liver disease to quantify the effects of treatment on levels of periodic acid-Schiff (PAS)-stained globules, a measure of AAT misfolding observed in the livers of alpha-1 liver disease patients.
In an oral presentation at DDW, Alnylam scientists presented new data demonstrating an up to 93% knockdown of serum AAT (mean 90 ± 2%) following monthly subcutaneous dosing with ALN-AAT in NHPs at a dose of 3 mg/kg. This level of knockdown was highly durable, lasting for greater than 30 days following the final dose. Further, ALN-AAT was found to have a wide therapeutic index based on results from GLP toxicology studies. Specifically, 13-week studies were performed in the rat and NHP with q2W doses and showed No Adverse Effect Levels (NOAELs) of greater than or equal to 50 mg/kg and 150 mg/kg, respectively; these dose levels were the top doses in both studies. In addition, study results were reported from a transgenic mouse model of alpha-1 liver disease, where mice overexpress the human Z-AAT protein. A single subcutaneous dose of ALN-AAT led to dose-dependent, durable and reversible knockdown of Z-AAT, with an ED50 of ~0.5 mg/kg, with mean Z-AAT knockdown of greater than 90% achieved following a single subcutaneous dose of 3mg/kg. As previously presented, sustained reduction of Z-AAT in aged transgenic mice with established liver disease led to improvement in tissue pathology, decrease in fibrosis, decrease in number of proliferating hepatocytes, and reduction in tumor burden as measured by both number and size of tumors.
"We applaud Alnylam for its efforts to develop a therapeutic for Alphas with liver disease, as there are few options available for them today. The Alpha-1 community is in clear need of a treatment option to improve the disease course and quality of life for both children and adults with Alpha-1 liver disease," said John Walsh, CEO and co-founder of the Alpha-1 Foundation. "We are all pleased with Alnylam's progress to date with ALN-AAT, including the filing of this CTA, and we look forward to following the progress of this program through the course of its clinical development."
About Alpha-1 Antitrypsin (AAT), AAT Deficiency, and Alpha-1 Liver Disease
Alpha-1 antitrypsin deficiency is an autosomal disorder that results in disease of the lungs and liver. AAT is a liver-produced serine proteinase inhibitor with the primary function of protecting the lungs from neutrophil elastase and other irritants that cause inflammation. About 95% of people with alpha-1 antitrypsin deficiency are homozygous and carry two copies of the abnormal Z allele (PiZZ) which expresses the Z-AAT protein. In the liver, misfolding of the mutant Z-AAT protein hinders its normal release into the blood thereby causing it to aggregate in hepatocytes, leading to liver injury, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). There are estimated to be approximately 120,000 individuals with the PiZZ mutation in the U.S. and major European countries, and of these, about 10% have an associated liver pathology (alpha-1 liver disease) caused by the misfolded Z-AAT protein. The only treatment options presently available for alpha-1 liver disease patients are supportive care and, in the case of advanced cirrhosis, liver transplantation. RNAi-mediated inhibition of AAT in people with alpha-1 liver disease may represent a promising new way to treat this rare disease.
Mission statement: The Alpha-1 Project will work with patients, academia, pharmaceutical and biotech companies, and public health organizations in the relentless pursuit of cures and therapies for COPD and liver disease caused by Alpha-1 Antitrypsin Deficiency. For more information, visit www.thealpha-1project.com. The Alpha-1 Project is a wholly-owned for-profit subsidiary of the Alpha-1 Foundation. For more information on the Foundation, visit www.alpha-1foundation.org.
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.
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. Alnylam's
pipeline of investigational RNAi therapeutics is focused in 3 Strategic
Therapeutic Areas (STArs): Genetic Medicines, with a broad pipeline of
RNAi therapeutics for the treatment of rare diseases; Cardio-Metabolic
Disease, with a pipeline of RNAi therapeutics toward genetically
validated, liver-expressed disease targets for unmet needs in
cardiovascular and metabolic diseases; and Hepatic Infectious Disease,
with a pipeline of RNAi therapeutics that address the major global
health challenges of hepatic infectious diseases. In early 2015, Alnylam
launched its "Alnylam 2020" guidance for the advancement and
commercialization of RNAi therapeutics as a whole new class of
innovative medicines. Specifically, by the end of 2020, Alnylam expects
to achieve a company profile with 3 marketed products, 10 RNAi
therapeutic clinical programs - including 4 in late stages of
development - across its 3 STArs. The company's demonstrated commitment
to RNAi therapeutics has enabled it to form major alliances with leading
companies including Merck, Medtronic, Novartis, Biogen, Roche,
Alnylam Forward-Looking Statements
Various statements in this release concerning Alnylam's future
expectations, plans and prospects, including without limitation,
Alnylam's views with respect to the potential for RNAi therapeutics,
including ALN-AAT for the treatment of AAT deficiency-associated liver
disease, its expectations regarding the reporting of initial data from
its ALN-AAT Phase 1 clinical study, its expectations regarding the
potential market opportunity for ALN-AAT, its expectations regarding its
STAr pipeline growth strategy, and its plans regarding commercialization
of RNAi therapeutics, constitute forward-looking statements for the
purposes of the safe harbor provisions under
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