Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, presented new pre-clinical data from its ALN-TTR program at the XII International Symposium on Amyloidosis in Rome on April 18 - 21, 2010. ALN-TTR01 is a systemically delivered RNAi therapeutic being developed for the treatment of transthyretin (TTR)-mediated amyloidosis (ATTR), including familial amyloidotic polyneuropathy (FAP) and familial amyloidotic cardiomyopathy (FAC). These new pre-clinical data demonstrate - for the first time - that treatment with an RNAi therapeutic can result in regression of pre-existing pathogenic TTR deposits in peripheral tissues. Additional pre-clinical data presented at the meeting demonstrated the potential application of TTR-specific siRNA for the treatment of ocular disease in ATTR.
“Indeed, the ability to see regression of TTR deposits in a transgenic mouse model suggests that treatment with ALN-TTR01 in patients could potentially reverse complications of established disease. Accordingly, I am excited about the translation of this promising new agent into clinical trials.”
ATTR is caused by mutations in the TTR gene, which is expressed predominantly in the liver, that result in the accumulation of pathogenic deposits of mutant and wild-type TTR protein in several tissues, including nerves, heart, and the gastrointestinal tract. There are more than 100 mutations that have been identified in the TTR gene. ALN-TTR targets a conserved region of the TTR gene in wild-type and all known mutant forms of TTR, and therefore, has potential as a therapeutic for all patients with FAP and FAC. TTR is also expressed in the eye by retinal pigment epithelial (RPE) cells, and mutations in TTR can lead to ocular complications in ATTR patients including blindness.
"We are very encouraged by these important new pre-clinical data from our ALN-TTR program which we believe point to the breakthrough potential of an RNAi therapeutic strategy in ATTR. Importantly, we have demonstrated for the first time the ability of achieving regression of pathogenic TTR deposits in tissues when ALN-TTR01 is administered in a treatment paradigm," said Rene Alvarez, Ph.D., Associate Director of Research at Alnylam. "These new data significantly extend our previous results showing that ALN-TTR01 can prevent TTR deposition when administered in a prophylactic regimen. We are also encouraged by our initial pre-clinical data using siRNAs targeting TTR for the treatment of ocular amyloidosis. Expression of mutant TTR in retinal cells can lead to blindness in ATTR patients, and an intraocular injection approach with our TTR-specific siRNA could be advanced as a Direct RNAi therapeutic strategy."
The new pre-clinical studies, performed in collaboration with Dr. Maria Saraiva at the Institute for Molecular and Cellular Biology in Portugal, used a transgenic mouse model where the mutant human V30M TTR gene is over-expressed. Specifically, the new data demonstrated that administration of ALN-TTR01 in mature transgenic mice resulted in the regression of existing pathogenic mutant human V30M TTR deposits in tissues, including: dorsal root ganglia, sciatic nerve, stomach, and intestines. These effects in diseased tissues were mediated through silencing of the mutant human TTR expressed in the liver, resulting in regression of established peripheral TTR deposits. ALN-TTR01 administration resulted in a greater than 90% regression of measurable TTR deposits as compared with control-treated animals.
"It is quite encouraging to see these types of results with a novel RNAi therapeutic for the treatment of ATTR, as there are currently very limited options for patients suffering from this devastating disease," said Maria Joao Saraiva, Ph.D., Professor of Biochemistry, Molecular Neurobiology Group, Institute for Molecular and Cellular Biology in Portugal. "Indeed, the ability to see regression of TTR deposits in a transgenic mouse model suggests that treatment with ALN-TTR01 in patients could potentially reverse complications of established disease. Accordingly, I am excited about the translation of this promising new agent into clinical trials."
In addition, new pre-clinical studies were performed with TTR-specific siRNA in a rat model of ocular amyloidosis in collaboration with Dr. Yukio Ando at Kumamoto University in Japan. As compared with control siRNA, intraocular administration of TTR-specific siRNA was found to silence endogenous rat TTR expression by greater than 50%. In a transgenic human V30M TTR rat model, intraocular administration of TTR-specific siRNA resulted in a similar reduction in expression of the human V30M mutant protein. In aggregate, these studies validate the potential application of RNAi therapeutics for the treatment of ocular amyloidosis in ATTR patients.
"The potential for ALN-TTR01 to effect regression of TTR amyloid deposits is an important pre-clinical finding as it relates to the clinical development plan for this RNAi therapeutic, including the nature of clinical endpoints in later-stage studies," said Akshay Vaishnaw, M.D., Ph.D., Senior Vice President, Clinical Research at Alnylam. "Further, the new data in a model of ocular amyloidosis reveal additional potential clinical indications in our overall ALN-TTR program. As we obtain final regulatory and ethics committee approvals, we look forward to initiating our Phase I study with ALN-TTR01 in ATTR patients, which remains on track to start in the next few months."
Previous pre-clinical studies reported by Alnylam have demonstrated the ability of TTR-specific RNAi therapeutics to mediate potent and durable silencing of both wild-type and mutant forms of the TTR gene in rodents and non-human primates. In the first half of 2010, Alnylam expects to initiate a Phase I clinical trial with ALN-TTR01 in patients with ATTR. ALN-TTR01 is being advanced using stable nucleic acid-lipid particles (SNALP) delivery technology developed in collaboration with Tekmira Pharmaceuticals Corporation. In parallel, Alnylam is also advancing ALN-TTR02 utilizing second generation lipid nanoparticles.