17 May, 2018 Nonclinical Research Published in Nature Biotechnology Describing REVERSIR Platform for Potent and Rapid Reversal of siRNA Activity for Tailored Control of RNAi Pharmacology

One of the main features of our ESC GalNAc-siRNA conjugates platform is potent and durable target knockdown in the liver sustained for several months in humans. In some cases, RNAi therapeutics may benefit from a technology that enables reversal of target mRNA knockdown and provides finer control over pharmacology, a desired attribute for therapeutic entities. REVERSIR^TM molecules are GalNAc-conjugated, short, single-stranded, high affinity oligonucleotide constructs designed to recognize and bind to the complementary, RISC-bound antisense strand of siRNAs, thereby leading to rapid and complete reversal of RNAi-mediated target gene silencing activity in vivo.

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09 May, 2018 Nonclinical Safety Evaluation of GalNAc-siRNA Conjugates

We presented a nonclinical safety evaluation of GalNAc-siRNA conjugates at the 8th Annual Biologics Symposium, being held May 8-9, 2018 in Plainsboro, NJ.

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08 May, 2018 New Preclinical Data Demonstrating CNS Delivery of RNAi Therapeutics

We presented initial data demonstrating delivery of nove small interfering RNA (siRNA) conjugates to the central nervous system (CNS) at the TIDES: Oligonucleotides and Peptide Therapeutics 2018 Annual Meeting, being held May 7-10, 2018 in Boston, MA.

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24 Apr, 2018 New Positive Clinical Results for Patisiran at AAN

We presented new positive results from the APOLLO Phase 3 study of patisiran, an investigational RNAi therapeutic for the treatment of hereditary ATTR (hATTR) amyloidosis, at the American Academy of Neurology (AAN) 2018 Annual Meeting, being held April 21-27, 2018 in Los Angeles.

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Adams et al. – “Patisiran, an Investigational RNAi Therapeutic for Patients with Hereditary Transthyretin-Mediated (hATTR) Amyloidosis: Results from the Phase 3 APOLLO Study”

Adams et al. – “Evaluation of Quality of Life and Disability in Patients with Hereditary Transthyretin-Mediated (hATTR) Amyloidosis with Polyneuropathy Following Treatment with Patisiran, an Investigational RNAi Therapeutic: Results from the Phase 3 APOLLO Study”

Mora et al. – “Utility of Genetic Testing to Identify Individuals Suspected of Having Hereditary ATTR (hATTR) Amyloidosis”

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14 Apr, 2018 New Positive Clinical Results for Givosiran at EASL

We presented new positive results from the Phase 1, Phase 1/2, and EXPLORE natural history studies of givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias (AHPs), at the European Association for the Study of the Liver (EASL) 53^rd Annual International Liver Congress, being held April 11-15, 2018 in Paris, France.

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Sardh et al. – “Phase 1/2, Randomized, Placebo Controlled and Open Label Extension Studies of Givosiran, an Investigational RNA Interference (RNAi) Therapeutic, in Patients with Acute Intermittent Porphyria”

Gouya et al. – “EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyrias (AHPs) with Recurrent Attacks”

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28 Mar, 2018 New Clinical Results from APOLLO Phase 3 Study of Patisiran at ISA

We presented additional results from the APOLLO Phase 3 study of patisiran, an investigational RNAi therapeutic for the treatment of hereditary ATTR (hATTR) amyloidosis, at the 16^th International Symposium on Amyloidosis (ISA), held March 26-29, 2018 in Kumamoto, Japan.

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Kristen et al. – “APOLLO, a Phase 3 Study of Patisiran for the Treatment of Hereditary Transthyretin-Mediated Amyloidosis: 18-Month Safety and Efficacy in Subgroup of Patients with Cardiac Involvement”

Coelho et al. – “Patisiran, an Investigational RNAi Therapeutic for Patients with Hereditary Transthyretin-Mediated Amyloidosis: Regional and Genotypic Subgroup Analyses from the APOLLO Study”

Schmidt et al. – “Impact of Hereditary Transthyretin-Mediated Amyloidosis on Use of Health Care Services: An Analysis of the APOLLO Study”

Polydefkis et al. – “Relationship Between Transthyretin Knockdown and Change in mNIS+7: Findings from the Patisiran Phase 2 Open-Label Extension and Phase 3 APOLLO Studies for Patients with Hereditary Transthyretin-Mediated Amyloidosis”

Gonzalez-Duarte et al. – “Changes in Neuropathy Stage in Patients with Hereditary Transthyretin-Mediated Amyloidosis Following Treatment with Patisiran, an Investigational RNAi Therapeutic: An Analysis from the Phase 3 APOLLO Study”

Suhr et al. – “Long-Term Use of Patisiran, an Investigational RNAi Therapeutic, in Patients with Hereditary Transthyretin-Mediated Amyloidosis: Baseline Demographics and Interim Data from Global Open Label Extension Study”

Gillmore et al. – “Home Infusion Administration of Patisiran, an Investigational RNAi Therapeutic in Patients with Hereditary Transthyretin-Mediated Amyloidosis: An Analysis of Safety and Adherence”

Berk et al. – “Impact of Hereditary Transthyretin-Mediated Amyloidosis on Daily Living and Work Productivity: Baseline Results from APOLLO”

Yamashita et al. – “Patisiran, an Investigational RNAi Therapeutic for Patients with Hereditary Transthyretin-Mediated (hATTR) Amyloidosis: Phase 3 APOLLO Study Sub-Analysis of Japanese Patients”

In addition, we presented new data from the Phase 1 study of ALN-TTRsc02, an investigational, subcutaneously administered RNAi therapeutic for the treatment of ATTR amyloidosis.

Vest et al. – “Phase 1 Study of ALN-TTRsc02, a Subcutaneously Administered Investigational RNAi Therapeutic for the Treatment of Transthyretin-Mediated Amyloidosis”

19 Feb, 2018 Nonclinical research published in Nature Communications describing optimization of GalNAc-siRNA conjugates to minimize off-target potential and maximize therapeutic index

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.

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