Therapy Areas: Cardiovascular
Alnylam Presents New Clinical Research Findings at the Second European Meeting of ATTR Amyloidosis for Doctors and Patients
6 September 2019 - - US-based RNAi therapeutics company Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY) shared new findings at the Second European Meeting of ATTR Amyloidosis (EU-ATTR) for Doctors and Patients, being held September 2-3, in Berlin, Germany, the company said.
The company and collaborators presented results from a proteome-wide biomarker analysis of samples from the APOLLO Phase 3 study of ONPATTRO (patisiran), an RNAi therapeutic for the treatment of the polyneuropathy of hereditary ATTR (hATTR) amyloidosis in adults.
In addition, results were presented from an analysis of the UK Biobank a prospective cohort study with genetic, physical, and health data on approximately 500,000 individuals across the United Kingdom on clinical outcomes and medical history of individuals with the non-pathogenic transthyretin "stabilizing" T119M variant.
A comprehensive proteomics analysis on plasma samples from patients in the APOLLO Phase 3 study was conducted to interrogate system-wide changes in the proteome in response to treatment and to identify potential biomarkers for early detection of disease.
Across greater than 1000 proteins screened, a significant change was observed in the levels of 66 proteins following patisiran treatment (p less than 4.18×10–5).
Neurofilament light chain a well-described biomarker of neuroaxonal damage was identified as having the greatest statistical significance (p equals 3.95×10–21) for change relative to placebo over the 18-month study period.
A correlation between changes in NfL levels and polyneuropathy, as determined by the mNIS+7 score, indicated that decreasing levels of NfL are associated with improvements in measures of polyneuropathy.
Thus, these data support further evaluation of NfL as a potential biomarker for hATTR amyloidosis that may facilitate earlier diagnosis of polyneuropathy and enable monitoring of disease progression and/or regression over time, with or without treatment.
Moreover, upon further evaluation, NfL may also offer an easy and convenient blood test to detect polyneuropathy in patients with mutations that predominantly cause cardiomyopathy, e.g., V122I, but where underlying nerve damage often occurs and can be overlooked.
Results were also presented of an analysis from the UK Biobank characterizing the association of the T119M genotype with mortality and vascular disease.
The T119M variant encodes a thermodynamically and kinetically stabilized TTR protein that increases the stability of wild type and mutant TTR tetramers by slowing tetramer dissociation a mechanism that established the therapeutic rationale for small-molecule TTR tetramer stabilisers.
People with the T119M variant have higher plasma levels of TTR.
A previous Scandinavian study of 68,602 subjects and 321 carriers found an association of the T119M variant with extended lifespan and reduced vascular disease.
Accordingly, the potential effect of the TTR T119M variant on vascular disease and mortality was investigated in the UK Biobank cohort, representing 337,148 subjects and 2,502 carriers of the variant. The analysis showed that carriers of the TTR T119M variant were not protected against vascular, cardiovascular, or cerebrovascular disease, or death.
Furthermore, no difference was seen between T119M carriers and non-carriers in their time to death following a diagnosis of vascular disease. These findings suggest that stabilization of the TTR tetramer and/or higher plasma levels of TTR do not confer protection against vascular disease or death in a general population setting.
Infusion-related reactions have been observed in patients treated with ONPATTRO.
In a controlled clinical study, 19% of ONPATTRO-treated patients experienced IRRs, compared to 9% of placebo-treated patients. The most common symptoms of IRRs with ONPATTRO were flushing, back pain, nausea, abdominal pain, dyspnea, and headache.
To reduce the risk of IRRs, patients should receive premedication with a corticosteroid, paracetamol, and antihistamines (H1 and H2 blockers) at least 60 minutes prior to ONPATTRO infusion. Monitor patients during the infusion for signs and symptoms of IRRs.
If an IRR occurs, consider slowing or interrupting the infusion and instituting medical management as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed.
ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking ONPATTRO. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum levels do not reflect the total vitamin A in the body.
Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g. night blindness).
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