Vutrisiran: a new drug in the treatment landscape of hereditary transthyretin amyloid polyneuropathy

Figures & data

Table 1. Main phase III clinical trials of gene silencing drugs in ATTRv-PN.

Drug	Trial name	Design	Endpoints
Inotersen	Neuro-TTR	ATTRv-PN stage 1 or 2 Inotersen vs placebo 2:1 ratio	Primary: change in the mNIS + 7 and change in the Norfolk QOL-DN score at month 15*.
Patisiran	APOLLO	ATTRv-PN score ≤ IIIB Patisiran vs placebo 2:1 ratio	Primary: change in the mNIS + 7 at month 18*. Secondary: At months 9 and 18: change in the Norfolk QOL-DN score*, NIS-weakness*, R-ODS*, 10-meter walk test*, and COMPASS 31*. At weeks 3,6, 12, 15 and 18: change in mBMI*.
Vutrisiran	HELIOS-A	ATTRv-PN score ≤ IIIB Vutrisiran vs patisiran 3:1 ratio + APOLLO external placebo	Primary: change in the mNIS + 7 compared to external placebo group at month 9*. Secondary: - vs external placebo group: At months 9 and 18: change in the Norfolk QOL-DN score*, the 10-m walk test*. At month 18: change in the mNIS + 7*, R-ODS*, mBMI*. - vs patisiran group: non-inferiority in serum TTR level percent reduction at month 18*.
Eplontersen	Neuro-TTRansform	ATTRv-PN stage 1 or 2 Eplontersen vs inotersen 6:1 ratio + Neuro-TTR external placebo	Primary: vs external placebo group, change in serum TTR concentration, the mNIS + 7 and the Norfolk QOL-DN score at month 15*. Secondary: vs external placebo group, change in the NSC score at months 8 and 15*, SF-36 PCS score*, PND score* and mBMI* at month 15.

Endpoints marked with an * indicate statistically significant results.

The following staging system of the PN were used as inclusion criteria:

Coutinho’s or Familial Amyloid Neuropathy (FAP) stages: ranging from 0 (= Asymptomatic) to 3 (= Wheelchair-bound or bedridden).

Polyneuropathy Disability (mPND) score comprised of 6 stages: 0 (= Asymptomatic), I, II, IIIA, IIIB (= Walking with bilateral aid), IV (= Wheelchair-bound or bedridden) [52].

The scores and scales used as endpoints [32] were:

mNIS +7 (modified Neuropathy Impairment Score): neuropathy score with higher score indicating poorer function, comprised of 5 domains: muscle weakness assessed in 24 muscle groups, reflexes assessed in 5 muscle groups, sensation including quantative sensation testing (QST), in up to 10 sites, autonomic and nerve conduction studies (3 motor and 2 sensory nerves) [52].

Norfolk QOL-DN (Quality of Life-Diabetic Neuropathy): higher scores indicating poorer quality of life, comprised of 35 items grouped into five domains: physical functioning/large-fiber neuropathy, activities of daily living, symptoms, small-fiber neuropathy, and autonomic neuropathy.

R-ODS: functional score, range 0 to 48, with lower score indicating more disability.

COMPASS 31: COMPosite Autonomic Symptom Score with 31 patient-reported questions divided into 6 domains: orthostatic intolerance, vasomotor, secremotor, gastrointestinal, bladder, and pupillomotor. Higher score indicated worse autonomic dysfunction.

NSC: Neuropathy Symptom and Change score [51].

mBMI: modified body mass index, vs: versus.

Table 2. Prescription guidelines and most frequent adverse effects of main commercialized drugs for ATTRv-PN.

Drug	Indication^+	Posology	Frequency	Admin	Associated instructions	Adverse effects*
Tafamidis	PN stage 1	20 mg	Daily	Oral	None	Urinary tract infection
Inotersen	PN stage 1 & 2	300 mg	Weekly	SC	Vitamin A supp Monitoring: Platelet count every 2 weeks, Renal function every 3 months	Headache, Anemia, Fatigue, Diarrhea, Constipation, Nausea, Pyrexia, Vomiting, Chills, Peripheral edema, Myalgia, Arthralgia, Thrombocytopenia, Glomerulonephritis
Patisiran	PN stage 1 & 2	0.3 mg/kg	Every 3 weeks	IV	Vitamin A supp Premedication: IV Corticosteroid, H1 & H2 Blocker, Oral Paracetamol	Peripheral edema Nasopharyngitis Infusion related reactions
Vutrisiran	PN stage 1 & 2	25 mg	Quarterly	SC	Vitamin A supp	Pain in extremity Arthralgia

⁺Indications are the current in place in France; this information may differ between countries. The mentioned PN stages are according to the Coutinho staging system.

*Adverse effects are mentioned if they were found to be more frequent in the drug group compared to the placebo group in the trials with a 2% difference cut-off.

Admin= administration route, SC= subcutaneous, IV= intravenous, Supp= supplementation.

Figure 1. Mechanisms of action of gene silencing therapies in ATTRv.

ASO are shown on the right side of the Figure (c). SiRNAs are shown on the left side of the Figure (a. patisiran and b. vutrisiran). SiRNA drug development focused on three characteristics to improve pharmacokinetics and pharmacodynamics: stability (1) of the molecules which are large, hydrophilic, and negatively charged, delivery (2) to the right organ (the liver) and intracellular diffusion and specificity (3) to correctly activate the RISC while avoiding any off-target effect [26,27]. siRNA: small interfering ribonucleic acid, ASO: antisens oligonucleotid, mRNA: messenger ribonucleic acid, DNA: deoxyribonucleic acid, LNP: lipid nanoparticles, ApoE: apolipoprotein E, GalNAc: N-acetylgalactosamin, ASGPR: asialoglycoprotein receptor, LDL-Rc: low-density lipoprotein receptor, RISC: RNA-induced silencing complex, RNase H: ribonuclease H.

Dyck PJB, González-Duarte A, Obici L, et al. Development of measures of polyneuropathy impairment in hATTR amyloidosis: from NIS to mNIS + 7. J Neurol Sci. 2019;405:116424. doi: 10.1016/j.jns.2019.116424

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Adams D, Gonzalez-Duarte A, O’Riordan WD, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):11–21. doi: 10.1056/NEJMoa1716153

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Coelho T, Marques W, Dasgupta NR, et al. Eplontersen for hereditary transthyretin amyloidosis with polyneuropathy. JAMA. 2023;330(15):1448. doi: 10.1001/jama.2023.18688

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