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We reported new data from our Phase 1 study with the newly named fitusiran (ALN-AT3), an investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders. Interim results – presented at the American Society of Hematology (ASH) 2015 Annual Meeting, held December 5 – 8, 2015 – showed that monthly, subcutaneous administration of fitusiran achieved potent and dose-dependent lowering of AT of up to 88% in patients with hemophilia. This AT lowering was associated with statistically significant increases in thrombin generation and an 85% reduction in estimated median annualized bleeding rates (ABR) in all evaluable cohorts. The observed bleeding rates are comparable to those reported for prophylactic intravenous infusions of replacement factors in patients with hemophilia. Fitusiran was found to be generally well tolerated to date, including no thromboembolic events or clinically significant increases in D-dimer, a biomarker of excessive clot formation. [spotlight-link icon="release" href="http://investors.alnylam.com/releasedetail.cfm?ReleaseID=945893" type=" "]Read our press release[/spotlight-link] [spotlight-link icon="presentation" href="http://www.alnylam.com/web/assets/ASH-2015_fitusiran_010715.pdf" type="(1.0 MB PDF)"]View the fitusiran Phase 1 presentation[/spotlight-link]

We reported new data from our ongoing Phase 1/2 clinical study with ALN-CC5, an investigational RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases. Data were presented at the American Society of Hematology (ASH) 2015 Annual Meeting, held December 5 – 8, 2015.  Results showed that administration of ALN-CC5 achieved up to 99% knockdown of serum C5 and up to 98% inhibition of serum hemolytic activity, an assay for complement activity.  Further, ALN-CC5 administration resulted in low levels of residual C5, which – based on comparisons from separate studies – were at or below the estimated levels of free C5 observed at therapeutic doses of eculizumab, an approved anti-C5 monoclonal antibody. The effects were also found to be highly durable, with C5 knockdown and complement inhibition results supporting a once monthly and possibly a once quarterly subcutaneous dose regimen.  Importantly, ALN-CC5 was shown to be generally well tolerated, with no clinically significant, drug-related adverse events to date. [spotlight-link icon="release" href="http://investors.alnylam.com/releasedetail.cfm?ReleaseID=945752" type=" "]Read our press release[/spotlight-link] [spotlight-link icon="presentation" href="http://www.alnylam.com/web/assets/ASH-2015_CC5_Hill_Poster_010615.pdf" type="(0.6 MB PDF)"]View the poster[/spotlight-link] [spotlight-link icon="presentation" href="http://www.alnylam.com/web/assets/ASH-2015_CC5_Hill_Presentation_010615.pdf" type="(1.3 MB PDF)"]View the presentation[/spotlight-link]

We presented new pre-clinical data with ALN-HBV, an investigational RNAi therapeutic targeting the Hepatitis B Virus (HBV) genome for the treatment of HBV infection. The ALN-HBV siRNA targets a highly conserved site across genotypes A-J, mapping to the X open reading frame, which is downstream from the most prevalent integration hotspot targeted by siRNAs from other developers. ALN-HBV is thus expected to achieve potent knockdown of HBV surface antigen (HBsAg) expressed by both covalently closed circular DNA (cccDNA) and integrated HBV DNA. Pre-clinical study results in rodent HBV models showed that subcutaneous administration of ALN-HBV led to potent and durable knockdown of HBsAg. Single doses of ALN-HBV in mice resulted in an up to 3.6 log10 and a mean of 1.6 log10 reduction of HBsAg 15 days after a single dose. Further, multiple doses of ALN-HBV in rats showed highly durable knockdown, with effects lasting up to 4 months following three weekly doses of ALN-HBV at 3 mg/kg. In addition, ALN-HBV was generally well tolerated in all rodent models. [spotlight-link icon="presentation" href="http://www.alnylam.com/web/assets/ALN-HBV_AASLD_111515.pdf" type="(1.3 MB PDF)"]View the presentation[/spotlight-link]  

Alnylam and The Medicines Company reported updated positive results from the ongoing Phase 1 clinical trial with ALN-PCSsc, an investigational RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia.  We had previously reported that subcutaneous administration of ALN-PCSsc resulted in an up to 83 percent lowering of LDL-C, with an up to 64 ± 5 percent mean maximum reduction. In new results, the effects of ALN-PCSsc were also found to be highly durable, with clinically significant and clamped reductions in LDL-C that now confirm the potential for a bi-annual subcutaneous dose regimen. An up to 53 percent maximal and 47 percent least squares mean reduction in LDL-C was achieved at day 180 after a single, low volume injection. In addition, ALN-PCSsc was shown to reduce a number of atherogenic lipids, including lipoprotein (a), and total cholesterol, which are associated with increased risk of cardiovascular disease. Importantly, ALN-PCSsc was generally well tolerated with no clinically significant drug-related adverse events to date. [spotlight-link icon="release" href="http://investors.alnylam.com/releasedetail.cfm?ReleaseID=942203" type=" "]Read our press release[/spotlight-link] [spotlight-link icon="presentation" href="http://www.alnylam.com/web/assets/AHA_PCS-Ph-1_111115.pdf" type="(1.1 MB PDF)"]View the presentation[/spotlight-link]

We reported data from our ongoing Phase 2 open-label extension (OLE) studies with patisiran and revusiran, investigational RNAi therapeutics targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR amyloidosis). [spotlight-link icon="release" href="http://investors.alnylam.com/releasedetail.cfm?ReleaseID=939975" type=" "]Read our press release[/spotlight-link] [spotlight-link icon="presentation" href="http://www.alnylam.com/web/assets/Patisiran-Ph-2-OLE-18-Month_EC-ATTR_110315.pdf" type="(720 KB PDF)"]View the initial 18-month patisiran Phase 2 OLE data presentation[/spotlight-link] [spotlight-link icon="presentation" href="http://www.alnylam.com/web/assets/Revusiran-Ph-2-OLE-6-Month_EC-ATTR_110315.pdf" type="(550 KB PDF)"]View the initial 6-month revusiran Phase 2 OLE data presentation[/spotlight-link] [spotlight-link icon="presentation" href="http://www.alnylam.com/web/assets/DISCOVERY_EC-ATTR_110215.pdf" type="(350 KB PDF)"]View the DISCOVERY screening study presentation[/spotlight-link] [spotlight-link icon="presentation" href="http://www.alnylam.com/web/assets/SSA-NH_EC-ATTR_110215.pdf" type="(670 KB PDF)"]View the SSA Natural History study presentation[/spotlight-link]

We presented pre-clinical data with ALN-TTRsc02, an investigational RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR amyloidosis).  In pre-clinical studies, including those in non-human primates (NHPs), ALN-TTRsc02 achieved potent and highly durable knockdown of serum TTR of up to 99% with multi-month durability achieved after just a single dose, supportive of a potentially once quarterly dose regimen. Results from studies comparing TTR knockdown activity of ALN-TTRsc02 to that of revusiran showed that ALN-TTRsc02 has a markedly superior TTR knockdown profile.  Further, in initial rat toxicology studies, ALN-TTRsc02 was found to be generally well tolerated with no significant adverse events at doses as high as 100 mg/kg. [spotlight-link icon="release" href="http://investors.alnylam.com/releasedetail.cfm?ReleaseID=936518" type=" "]Read our press release[/spotlight-link] [spotlight-link icon="presentation" href="http://www.alnylam.com/web/assets/ALN-TTRsc02_OTS_101415.pdf" type="(1.1 MB PDF)"]View the presentation[/spotlight-link]

We announced advancement of innovations in RNAi therapeutics with presentation of scientific data on two new platform technologies: Bis-RNAiTM and ReversirTM.  The Bis-RNAi platform enables simultaneous knockdown of two distinct disease genes using a single, subcutaneously administered molecular entity consisting of two linked siRNAs conjugated to a GalNAc moiety. The Reversir platform enables tailored control of RNAi pharmacology with rapid reversal of target gene silencing effects using GalNAc-conjugated, single-stranded oligonucleotide constructs that are designed to recognize and bind to the complimentary RISC-bound antisense strand of an siRNA. [spotlight-link icon="release" href="http://investors.alnylam.com/releasedetail.cfm?ReleaseID=936348" type=" "]Read our press release[/spotlight-link] [spotlight-link icon="presentation" href="http://www.alnylam.com/web/assets/Bis-RNAi_OTS_101315.pdf" type="(1.0 MB PDF)"]View the Bis-RNAi poster[/spotlight-link] [spotlight-link icon="presentation" href="http://www.alnylam.com/web/assets/Reversir_OTS_101315.pdf" type="(0.9 MB PDF)"]View the Reversir presentation[/spotlight-link]

We reported data from our ongoing Phase 2 open-label extension (OLE) study of patisiran, an investigational RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR amyloidosis) patients with familial amyloidotic polyneuropathy (FAP). Alnylam scientists and collaborators from The Scripps Research Institute and Misfolding Diagnostics, Inc. were able to measure the effects of patisiran on pathogenic, misfolded TTR monomers and oligomers in FAP patients. Results showed a rapid and sustained reduction in serum non-native conformations of TTR (NNTTR) of approximately 90%. Since NNTTR is pathogenic in ATTR amyloidosis and the level of NNTTR reduction correlated with total TTR knockdown, these results provide direct mechanistic evidence supporting the therapeutic hypothesis that TTR knockdown has the potential to result in clinical benefit. Furthermore, complete 12-month data from all 27 patients that enrolled in the patisiran Phase 2 OLE study showed sustained mean maximum reductions in total serum TTR of 91% for over 18 months and a mean 3.1-point decrease in mNIS+7 at 12 months, which compares favorably to an estimated increase in mNIS+7 of 13 to 18 points at 12 months based upon analysis of historical data sets in untreated FAP patients with similar baseline characteristics. Importantly, patisiran administration continues to be generally well tolerated out to 21 months of treatment. [spotlight-link icon="release" href="http://investors.alnylam.com/releasedetail.cfm?ReleaseID=933351" type=" "]Read our press release[/spotlight-link] [spotlight-link icon="presentation" href="http://www.alnylam.com/web/assets/Patisiran-Ph-2-OLE_Poster_ANA_09282015.pdf" type="(480 KB PDF)"]View the non-native TTR poster[/spotlight-link] [spotlight-link icon="presentation" href="http://www.alnylam.com/web/assets/Patisiran-Complete-12mo-Ph-2-OLE_ANA_09282015.pdf" type="(620 KB PDF)"]View the complete 12-month patisiran Phase 2 OLE data presentation[/spotlight-link]

We reported positive initial results from our ongoing Phase 1 clinical trial with ALN-AS1, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias. Study results showed that single subcutaneous doses of ALN-AS1 resulted in an up to 82% lowering of ALA and an up to 93% lowering of PBG in asymptomatic “high excreter” (ASHE) patients, who carry the genetic mutation of acute intermittent porphyria (AIP) and have elevated levels of aminolevulinic acid (ALA) and porphobilinogen (PBG), the toxic heme intermediates that mediate porphyria attacks. Furthermore, analysis of exosomal mRNA preparations from serum and urine revealed that treatment resulted in potent, dose-dependent, and durable silencing of liver ALAS1 mRNA.  Importantly, ALN-AS1 was found to be generally well tolerated with no clinically significant drug-related adverse events to date. These data provide human proof-of-concept for ALN-AS1 as a potential therapy for AIP and other acute hepatic porphyrias. [spotlight-link icon="release" href="http://investors.alnylam.com/releasedetail.cfm?ReleaseID=931607" type=" "]Read our press release[/spotlight-link] [spotlight-link icon="presentation" href="http://www.alnylam.com/web/assets/ALN-AS1_ICPP_Interim-Ph1_09152015.pdf" type="(420 KB PDF)"]View the ALN-AS1 Phase 1 clinical data presentation[/spotlight-link]

We presented data on DMPK and safety of GalNAc-siRNA conjugates at the DIA/FDA Oligonucleotide-Based Therapeutic Conference, held September 9 – 11, 2015, in Washington, D.C.   [spotlight-link icon="presentation" href="http://www.alnylam.com/web/assets/DIA_DMPK_09092015.pdf" type="(2.1 MB PDF)"]View the DMPK presentation[/spotlight-link] [spotlight-link icon="presentation" href="http://www.alnylam.com/web/assets/DIA_Safety_09092015.pdf" type="(2.1 MB PDF)"]View the Toxicology/Safety presentation[/spotlight-link]  

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