Capella

Capella—the Online Voice of Progress in RNAi

Alnylam welcomes you to Capella, the destination for updates on our progress in translating the science of RNAi into innovative medicines. For Alnylam, Capella is our online voice for communicating the scientific progress we are making as we work to develop innovative medicines for patients.

To view our corporate presentation, click here.

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. REVERSIRTM 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.

Read article in Nature Biotech

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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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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) 53rd 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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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 16th 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”

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.

Read article in Nature Communications

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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)”

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We presented positive preliminary data from the ongoing Phase 1/2 study with lumasiran (formerly known as ALN-GO1), an investigational RNAi therapeutic targeting glycolate oxidase (GO) for the treatment of Primary Hyperoxaluria Type 1 (PH1) at the American Society of Nephrology (ASN) Kidney Week 2017 Annual Meeting in New Orleans.

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View the presentation

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