alnylam pharmaceuticals inc (ALNY) Key Developments
Alnylam Pharmaceuticals, Inc. Presents New Pre-Clinical Data on ALN-AT3, an RNAi Therapeutic Targeting Antithrombin (AT) for the Treatment of Hemophilia and Rare Bleeding Disorders
Dec 10 13
Alnylam Pharmaceuticals, Inc. announced that it has presented new pre-clinical data with ALN-AT3, a subcutaneously administered RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD), at the 55(th) Annual Meeting of the American Society of Hematology (ASH) held December 7 -- 10, 2013 in New Orleans. In these new studies, repeat administration of ALN-AT3 was found to be well tolerated in Hemophilia A (HA) mice, with no adverse findings up to dose levels 200 times greater than levels required to achieve 50% AT knockdown. Further, the new studies demonstrated that ALN-AT3 administration achieves complete correction of the activated Partial Thromboplastin Time (aPTT) -- an ex vivo measure of blood coagulation that is significantly prolonged in hemophilia -- in HA mice. ALN-AT3 is a key program in the company's ‘Alnylam 5x15’ product strategy, which is aimed at advancing five RNAi therapeutic programs directed toward genetically validated disease targets into clinical development, including programs in advanced stages, by the end of 2015. In a presentation titled 'Expanded Therapeutic Index of Antithrombin Silencing and Correction of APTT in a Hemophilia A Mouse Model,' Alnylam scientists presented data demonstrating that, in contrast to wild type (WT) mice, repeat administration of ALN-AT3 was very well tolerated in HA mice. Specifically, HA mice treated with ALN-AT3 exhibited no adverse events up to 100 mg/kg -- a dose that is 200-fold greater than the mouse ED(50) and that essentially ablates AT protein levels in blood. In fact, 100% of the treated HA mice survived, with no adverse clinical signs or changes to body weight parameters. In WT mice (with intact coagulation systems), repeat administration of over 10 mg/kg ALN-AT3 led to greater than 90% knockdown of plasma AT, and resulted in the expected procoagulant phenotype and poor tolerability. This result was expected since AT knockout in mice and homozygous AT deficiency in humans are known to be embryonic lethal (J. Clin. Invest. (2000) 106:873-878; Blood (2008) 112:19-27). To evaluate the potential reversal of ALN-AT3 efficacy, WT mice treated with 100 mg/kg ALN-AT3 were also treated with exogenous human AT protein. Co-administration of human AT conferred complete protection from prothrombotic adverse events observed in WT mice receiving ALN-AT3 alone, demonstrating that human AT protein could serve as a potential reversal agent for ALN-AT3, if needed. In addition, HA mice treated with ALN-AT3 exhibited significant reductions in aPTT relative to control HA mice. Specifically, the aPTT in HA mice, which is significantly prolonged, was corrected back to aPTT values observed in WT mice. Collectively, these data suggest a substantially expanded therapeutic index of AT knockdown in the hemophilia disease condition, and confirm the active effects for ALN-AT3 that are expected to reset insufficient thrombin generation in people with hemophilia. Alnylam remains on track to begin a Phase I trial with ALN-AT3 early in 2014. Alnylam announced that it has received CTA approval from the MHRA for the initiation of the Phase I clinical study. The study will be conducted in the U.K. as a single- and multi-dose, dose-escalation study consisting of two parts. The first part will be a randomized, single-blind, placebo-controlled, single-dose, dose-escalation study, enrolling up to 24 healthy volunteer subjects. Only low doses of ALN-AT3 will be administered in this part of the study with stopping rules at greater than 40% AT knockdown, which is believed to be a well tolerated level of AT knockdown based on pre-clinical studies, in addition to data from people with heterozygous AT deficiency. The primary objective of the first part of the study is to evaluate the safety and tolerability of a single dose of subcutaneously administered ALN-AT3. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels. The second part of the study will be an open-label, multi-dose, dose-escalation study enrolling up to 18 people with moderate to severe hemophilia A or B. The primary objective of this part of the study is to evaluate the safety and tolerability of multiple doses of subcutaneously administered ALN-AT3 in hemophilia subjects. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels and increase in ex vivo thrombin generation.
Alnylam Pharmaceuticals, Inc. Announces Pre-Clinical Results on ALN-CC5
Dec 9 13
Alnylam Pharmaceuticals, Inc. announced that it has presented new pre-clinical data with ALN-CC5, a subcutaneously administered RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases. Alnylam believes that ALN-CC5 -- part of the company's "Alnylam 5x15" product strategy - represents a novel approach for the treatment of complement-mediated diseases, with a potentially competitive profile compared with intravenously administered anti-C5 monoclonal antibody therapy. In addition, Alnylam presented two separate posters with new pre-clinical data on ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders. In a presentation titled "Development of RNAi Therapeutics Targeting the Complement Pathway" Alnylam scientists presented data showing robust, dose-dependent, and durable knockdown of serum C5 in NHPs. Multiple doses of ALN-CC5 at 2.5 or 5.0 mg/kg led to rapid and dose-dependent knockdown of serum C5 of up to 97.8%, with mean knockdown at nadir of 97.5% (p<0.001) at the top dose. Knockdown of C5 was durable, with greater than 90% knockdown sustained for up to three weeks after the final dose. Further, subcutaneous administration resulted in a consistent greater than 80% knockdown of C5 during the treatment period. The results are consistent with published literature that shows an hepatic origin for the vast majority of circulating C5, and confirms that the serum component of locally produced C5 is minimal at best. In addition, multi-dose administration of ALN-CC5 resulted in robust and durable inhibition of hemolytic activity. At the top dose of 5.0 mg/kg, an up to 94% inhibition of hemolytic activity was observed, with a mean nadir reduction of 92% (p<0.01). Inhibition of hemolytic activity was sustained for at least two weeks after the final dose. Further, inhibition of hemolytic activity was shown to be highly correlated with serum levels of C5 (r(2) =0.93, p<10(-15)). Importantly, a greater than 80% inhibition in hemolytic activity has been previously validated in studies of eculizumab, an intravenously administered monoclonal antibody targeting C5, in patients with PNH as being associated with clinical benefit (N. Engl. J. Med. (2004) 350:552-559; N. Engl. J. Med. (2006) 355:1233-1243). In addition, in two posters titled "ALN-TMP: A subcutaneously administered RNAi therapeutic targeting Tmprss6 for the treatment of -Thalassemia" and "An RNAi-Therapeutic Targeting Tmprss6, in Conjunction With Oral Chelator Therapy, Ameliorates Anemia and Additively Diminishes Secondary Iron Overload In a Mouse Model Of -Thalassemia Intermedia," Alnylam scientists presented new pre-clinical data from the company's ALN-TMP program. The new study showed that weekly subcutaneous administration of ALN-TMP resulted in robust knockdown of TMPRSS6 mRNA in mice, with about 90% knockdown (p<0.0001) at a dose of 1.0 mg/kg. This level of knockdown was associated with a two-fold increase in hepcidin levels (p<0.05), and a greater than 50% decrease in transferrin saturation (p<0.001). The data also demonstrated a linear relationship between TMPRSS6 mRNA silencing and transferrin saturation, suggesting that ALN-TMP can modulate iron restriction in a predictable manner. In addition, studies in a mouse model of -thalassemia intermedia (Hbb(th3/+) mice) were conducted to explore the effects of ALN-TMP in combination with the iron chelator deferiprone compared to either treatment alone. Administration of ALN-TMP, but not deferiprone, was shown to ameliorate anemia and extramedullary hematopoiesis, including increases in hemoglobin, decreases in serum erythropoietin, and reduction in splenomegaly. On the other hand, ALN-TMP and deferiprone were found to act in an additive manner toward reducing serum and liver iron levels. These new findings suggest that combined ALN-TMP and iron chelation therapy may provide improved management of secondary iron overload in -thalassemia, including thalassemia major, and also support the potential for ALN-TMP as a therapeutic option in a broader range of iron overload disorders.
Alnylam Pharmaceuticals, Inc. Presents at 25th Annual Piper Jaffray Healthcare Conference 2013, Dec-04-2013 11:00 AM
Nov 25 13
Alnylam Pharmaceuticals, Inc. Presents at 25th Annual Piper Jaffray Healthcare Conference 2013, Dec-04-2013 11:00 AM. Venue: The New York Palace Hotel, 455 Madison Avenue, New York, NY 10022, United States.
Alnylam Pharmaceuticals, Inc. Receives Fast Track Designation for Patisiran (ALN-TTR02) from U.S. Food and Drug Administration
Nov 11 13
Alnylam Pharmaceuticals, Inc. announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to patisiran (ALN-TTR02) for the treatment of transthyretin (TTR)-familial amyloid polyneuropathy (FAP).
Alnylam Pharmaceuticals, Inc. Reports Positive Phase II Data for Patisiran (ALN-TTR02), an RNAi Therapeutic Targeting Transthyretin (TTR) for the Treatment of TTR-Mediated Amyloidosis (ATTR), and Initiates Phase III Trial
Nov 10 13
Alnylam Pharmaceuticals, Inc. announced the achievement of positive clinical results from its Phase II trial of patisiran (ALN-TTR02), an RNAi therapeutic targeting the transthyretin (TTR) gene for the treatment of TTR-mediated amyloidosis (ATTR). Results showed that multiple doses of patisiran led to robust and statistically significant knockdown of serum TTR protein levels of up to 96%, with mean levels of TTR knockdown exceeding 85%. Knockdown of TTR, the disease-causing protein in ATTR, was found to be rapid, dose dependent, and durable, and similar activity was observed toward both wild-type and mutant protein. In addition, patisiran was found to be generally safe and well tolerated in this study. The Phase II study with patisiran in ATTR polyneuropathy patients (n=29) was an open-label, multi-center, multi-dose, dose-escalation trial to evaluate the safety and tolerability of two doses of patisiran and to demonstrate clinical activity based on serial measurement of circulating serum levels of wild-type and mutant TTR. Patients received two doses of patisiran in 5 cohorts with doses ranging from 0.01 to 0.30 mg/kg, using either a once-every-four-week or once-every-three-week dosing regimen. The international study included 10 sites in Portugal, France, Sweden, Germany, Spain, Brazil, and the U.S. Interim results from the Phase II study were presented at the 2013 Biennial Meeting of the Peripheral Nerve Society, held June 29 - July 3. The new data from 28 patients enrolled and currently analyzed showed that multiple doses of patisiran resulted in rapid, dose-dependent, and durable knockdown of serum TTR levels. As compared with the lowest dose group of 0.01 mg/kg, there was a statistically significant knockdown of serum TTR at doses of 0.15 mg/kg (p<0.05) and 0.30 mg/kg (p<0.001). The study results support further evaluation of patisiran at the 0.30 mg/kg dose administered once every three weeks. With this dose and regimen, mean TTR knockdown at nadir of 83.8% and 86.7% was observed following the first and second doses, respectively, with maximum TTR knockdown of up to 96.0%.
Alnylam also announced that it has initiated the APOLLO Phase III study of patisiran. The APOLLO Phase III trial is a randomized, double-blind, placebo-controlled, global study designed to evaluate the efficacy and safety of patisiran in ATTR patients with FAP. The primary endpoint of the study is the difference in the change in mNIS+7 between patisiran and placebo at 18 months. Secondary endpoints include: the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) score; NIS-weakness; modified BMI; timed 10-meter walk; and the COMPASS-31 autonomic symptom score. The trial is designed to enroll up to 200 FAP patients with a baseline NIS in the range of 10 to 100, which represents patients with Stage 1 or Stage 2 disease. Patients will be randomized 2:1, patisiran:placebo, with patisiran administered at 0.30 mg/kg once every three weeks for 18 months. The study was designed with 90% power to conservatively detect as little as a 37.5% difference in change in mNIS+7 between treatment groups, with a two-sided alpha of 0.05. The placebo mNIS+7 progression rate was derived from an Alnylam analysis of natural history data from 283 FAP patients. Alnylam has obtained protocol assistance for the patisiran Phase III study from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) and has completed its End-of-Phase II meeting with the U.S. Food and Drug Administration (FDA). All patients completing the APOLLO Phase III study will be eligible to enroll in a Phase III OLE study.