During initial development candidate selection, a subset of chemically-modified siRNAs conjugated to trivalent GalNAc does not pass the stringent safety criteria for nonclinical evaluation due to rat hepatotoxicity. This body of work provides evidence that the observed hepatotoxicity is largely attributed to unintended base-pairing of the seed region of the siRNA antisense strand with off-target mRNAs, with little or no contribution from chemical modifications or the perturbation of RNAi pathways. Changing the sequence of the seed region or introducing thermally destabilizing modifications, such as glycol nucleic acid (GNA), in that region mitigated hepatotoxicity. Introduction of seed GNA has the potential to minimize the occurrence of hepatotoxic siRNAs across species without compromising on-target activity. This approach, among others, provides the opportunity to expand the number of initial candidates for nonclinical testing and to streamline the process of development candidate selection for RNAi therapeutics.

We presented new data for fitusiran and givosiran at the American Society of Hematology 59th Annual Meeting & Exposition in Atlanta. Sardh et al. - "EXPLORE: A Prospective, Multinational Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks" Negrier et al. - "Perioperative Management in Patients with Hemophilia Receiving Fitusiran, an Investigational RNAi Therapeutic Targeting Antithrombin for the Treatment of Hemophilia" Sridharan et al. – “In silico Modeling of the Coagulation Cascade and Thrombin Generation: Simulating Antithrombin (AT) Lowering in Hemophilia and Rare Bleeding Disorders (RBDs)”

We presented positive complete results from the APOLLO Phase 3 study of patisiran, an investigational RNAi therapeutic being developed for patients with hereditary ATTR (hATTR) amyloidosis with polyneuropathy, at the 1st European ATTR Amyloidosis Meeting for Patients and Doctors, held November 2-3, 2017 in Paris, France. Adams et al. – “Patisiran, an Investigational RNAi Therapeutic for the Treatment of Hereditary ATTR Amyloidosis with Polyneuropathy: Results from the Phase 3 APOLLO Study” Berk et al. – “Long-Term, Open-Label Clinical Experience with Patisiran, an Investigational RNAi Therapeutic for Patients with Hereditary Transthyretin-Mediated (hATTR) Amyloidosis with Polyneuropathy”

We and our collaborators presented new pre-clinical data highlighting our next generation “Enhanced Stabilization Chemistry Plus” (ESC+) GalNAc-siRNA conjugate platform, and additional data demonstrating our leadership in RNAi technologies, at the 13th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS), held September 24 – 27, 2017 in Bordeaux, France. Brown et al. – “Mechanistic Insights and Progress on the GalNAc-siRNA Platform for Targeted Delivery of RNAi Therapeutics to the Liver” Jadhav et al. – “REVERSIRTM Platform for Rapid and Potent Reversal of RNAi-Mediated Silencing Activity” Knight et al. - "Investigational RNAi Mediated Oxalate Reduction Therapy" Maier et al. – “Impact of Enhanced Metabolic Stability on In Vivo Performance of GalNAc-siRNA Conjugates” Milstein et al. – “Preclinical Development of an RNAi Therapeutic Drug Candidate Targeting Hepatitis B Virus” Schlegel et al. – “Improved Specificity and Therapeutic Index with ESC+ siRNA Conjugates Utilizing Seed-Pairing Destabilization via Novel Chemical Modifications” Schlegel et al. – “Impact of Glycol Nucleic Acid (GNA) on siRNA Structure and Function”

We hosted a series of online "RNAi Roundtables" in August and September, at which Arian Ebank scientists, clinical collaborators, and patients or patient advocates reviewed recent progress in many of the company's late-stage pipeline programs and discussed the related disease areas.


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