Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study
Open accessAbstract
BACKGROUND: Transthyretin-mediated amyloidosis is an inherited, progressively debilitating disease caused by mutations in the transthyretin gene. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of patisiran (ALN-TTR02), a small interfering RNA encapsulated within lipid nanoparticles, in patients with transthyretin-mediated familial amyloid polyneuropathy (FAP). METHODS: In this phase II study, patients with FAP were administered 2 intravenous infusions of patisiran at one of the following doses: 0.01 (n = 4), 0.05 (n = 3), 0.15 (n = 3), or 0.3 (n = 7) mg/kg every 4 weeks (Q4W), or 0.3 mg/kg (n = 12) every 3 weeks (Q3W). RESULTS: Of 29 patients in the intent-to-treat population, 26 completed the study. Administration of patisiran led to rapid, dose-dependent, and durable knockdown of transthyretin, with the maximum effect seen with patisiran 0.3 mg/kg; levels of mutant and wild-type transthyretin were reduced to a similar extent in Val30Met patients. A mean level of knockdown exceeding 85 % after the second dose, with maximum knockdown of 96 %, was observed for the Q3W dose. The most common treatment-related adverse event (AE) was mild-to-moderate infusion-related reactions in 10.3 % of patients. Four serious AEs (SAEs) were reported in 1 patient administered 0.3 mg/kg Q3W (urinary tract infection, sepsis, nausea, vomiting), and 1 patient administered 0.3 mg/kg Q4W had 1 SAE (extravasation-related cellulitis). CONCLUSIONS: Patisiran was generally well tolerated and resulted in significant dose-dependent knockdown of transthyretin protein in patients with FAP. Patisiran 0.3 mg/kg Q3W is currently in phase III development. TRIAL REGISTRATION NUMBER: NCT01617967 .
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The combined functionality of Patisiran's RNAi technique and LNPs enables robust reduction in expression of the hATTR disease-linked gene, providing a therapeutic treatment for the genetic disease.
“The combined functionality of Patisiran’s RNAi technique coupled with the use of LNPs as a delivery vehicle enables a robust reduction in the expression of the hATTR disease-linked gene, ultimately providing a therapeutic treatment for the genetic disease.[56, 57]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [56]
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- [31]Suhr O, Adams D, Coelho T, Conceicao I, Waddington CM, Schmidt H, et al. Further analysis of phase II trial of patisiran, a novel RNAi therapeutic for the treatment of familial amyloidotic polyneuropathy. XIVth International Symposium on Amyloidosis (ISA), Indianapolis, IN, USA; April 27–May 1, 2014: Abstract OP-72.
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- Authors
- Suhr, O. B., Coelho, T., Buades, J., Pouget, J., Conceicao, I., Berk, J., Schmidt, H., Waddington-Cruz, M., Campistol, J. M., Bettencourt, B. R., Vaishnaw, A., Gollob, J., & Adams, D.
- Affiliations
- Umeå University (SE)
- Hospital de Santo António (PT)
- Hospital Son Llatzer (ES)
- Hôpital de la Timone (FR)
- Boston University (US)
- University Hospital Münster (DE)
- Hospital Clínic de Barcelona (ES)
- Alnylam Pharmaceuticals (United States) (US)
- Inserm (FR)
- Corresponding author
- Suhr, Ole B
- ORCID
- Venue
- Orphanet Journal of Rare Diseases
- Published
- 2015-09-04
- Volume
- 10
- Issue
- 1
- Pages
- 109-109
- ISSN
- 1750-1172 (ISSN-L)
- PMC
- PMC4559363
- OpenAlex
- W1808439685
- Cited by
- 321
- References
- 33
- Citations by year
- 2026: 6 · 2025: 19 · 2024: 40 · 2023: 21 · 2022: 30 · 2021: 29 · 2020: 47 · 2019: 46 · 2018: 38 · 2017: 34 · 2016: 10 · 2015: 1
- FWCI
- 12.02
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Orphanet Journal of Rare Diseases (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Hispana (submittedVersion, cc-by)
- Docusalut (Conselleria de Salut i Consum del Govern de les Illes Balears) (submittedVersion, cc-by)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- Funders
- Alnylam Pharmaceuticals
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Amyloidosis: Diagnosis, Treatment, Outcomes
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- patisiran, hereditary transthyretin amyloidosis, siRNA, lipid nanoparticles, dose-dependent efficacy, infusion reactions, safety and tolerability, pharmacokinetics, pharmacodynamics
- MeSH terms
- Aged, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Amyloid Neuropathies, Familial, RNA, Small Interfering
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