Study of WVE-003 in Patients With Huntington's Disease

• SAD: 30mg WVE-003 (Drug): Single ascending dose of 30mg WVE-003, an allele-selective stereopure antisense oligonucleotide (ASO)
• SAD: 60mg WVE-003 (Drug): Single ascending dose of 60mg WVE-003, an allele-selective stereopure antisense oligonucleotide (ASO)
• SAD: 90mg WVE-003 (Drug): Single ascending dose of 90mg WVE-003, an allele-selective stereopure antisense oligonucleotide (ASO)
• SAD: Pooled Placebo (Drug): Single dose of placebo
• MD: 30mg WVE-003 (Drug): Three doses of 30mg WVE-003 Q8WK an allele-selective stereopure, antisense oligonucleotide (ASO)
• MD: Placebo (Drug): Three doses of placebo Q8WK

Primary outcomes

• Safety: Proportion of Patients With Treatment Emergent Adverse Events (TEAEs) Related to Study Drug [Day 1 through Week 24 (single ascending dose Period 1); Day 1 through Week 28 (multi dose Period 2)]: The primary outcome for this study was safety and is reported as the proportion of patients with TEAEs related to study drug.

Secondary outcomes

• Pharmacokinetics of WVE-003 in Plasma [Day 1 (single ascending dose Period 1); Day 1 and Day 113 (multi dose Period 2)]: Parameter analyzed: AUC0-6 = area under the concentration-time curve from time 0 to 6 hrs
• Pharmacokinetics of WVE-003 in Plasma [Day 1 (single ascending dose Period 1); Day 1 and Day 113 (multi dose Period 2)]: Parameter analyzed: Cmax = maximum observed concentration.
• Concentration of WVE-003 in Cerebrospinal Fluid (CSF) [28 days post-dose during Period 1 (P1:Day29); 28 days post last dose during Period 2 (P2: Day141)]: WVE-003 concentration in cerebrospinal fluid (CSF) is reported in ng/mL.

Sex: All, ages: 25 Years to 60 Years

Inclusion Criteria:

1. Presence of the A variant of SNP3 on the same allele as the pathogenic CAG triplet expansion
2. Ambulatory, male or female patients aged ≥25 to ≤60 years
3. Clinical diagnostic motor features of HD, defined as Unified Huntington's Disease Rating Scale (UHDRS) Diagnostic Confidence Score = 4
4. UHDRS Total Functional Capacity Scores ≥9 and ≤13

Exclusion Criteria:

1. Malignancy or received treatment for malignancy, other than treated basal cell or squamous cell carcinoma of the skin, within the previous 5 years
2. Received any other study drug, including an investigational oligonucleotide, within the past 1 year or 5 half-lives of the drug, whichever is longer, with the exception of the following:

   a. Received WVE-120101 or WVE-120102 within the last 3 months
3. Implantable CNS device that may interfere with ability to administer study drug via lumbar puncture or undergo MRI scan
4. Inability to undergo brain MRI (with or without sedation)
5. Bone, spine, bleeding, or other disorder that exposes the patient to risk of injury or unsuccessful lumbar puncture
6. Previously received tominersen

Participant flow

Outcome results

• Safety: Proportion of Patients With Treatment Emergent Adverse Events (TEAEs) Related to Study Drug (Primary), Count of participants, Participants: SAD: Pooled Placebo 2; SAD: 30mg WVE-003 1; SAD: 60mg WVE-003 3; SAD: 90mg WVE-003 3; MD: Placebo 0; MD: 30mg WVE-003 8
• Pharmacokinetics of WVE-003 in Plasma (Secondary), Mean, AUC 0-6 (hr*ng/mL): SAD: 30mg WVE-003 1000 +/- 702; SAD: 60mg WVE-003 2310 +/- 3090; SAD: 90mg WVE-003 3890 +/- 2900; MD: 30mg WVE-003 822 +/- 409
• Pharmacokinetics of WVE-003 in Plasma (Secondary), Mean, Cmax (ng/mL): SAD: 30mg WVE-003 240 +/- 168; SAD: 60mg WVE-003 601 +/- 774; SAD: 90mg WVE-003 1061 +/- 942; MD: 30mg WVE-003 186 +/- 106
• Concentration of WVE-003 in Cerebrospinal Fluid (CSF) (Secondary), Mean, ng/mL: SAD: 30mg WVE-003 3.6405 +/- 1.6133; SAD: 60mg WVE-003 5.5346 +/- 2.8402; SAD: 90mg WVE-003 7.0983 +/- 3.1335; MD: 30mg WVE-003 4.2903 +/- 1.9722

Adverse events

Time frame: Day 1 through Week 24 (single ascending dose Period 1); Day 1 through Week 28 (multi dose Period 2)

Serious adverse events by term

Other adverse events by term

26 more terms not shown.

• Results publication: Iwamoto N, Liu Y, Frank-Kamenetsky M, Maguire A, Tseng WC, Taborn K, Kothari N, Akhtar A, Bowman K, Shelke JD, Lamattina A, Hu XS, Jang HG, Kandasamy P, Liu F, Longo K, Looby R, Meena, Metterville J, Pan Q, Purcell-Estabrook E, Shimizu M, Prakasha PS, Standley S, Upadhyay H, Yang H, Yin Y, Zhao A, Francis C, Byrne M, Dale E, Verdine GL, Vargeese C. Preclinical evaluation of stereopure antisense oligonucleotides for allele-selective lowering of mutant HTT. Mol Ther Nucleic Acids. 2024 Jun 11;35(3):102246. doi: 10.1016/j.omtn.2024.102246. eCollection 2024 Sep 10. PMID 39027419
• Results publication: Estevez-Fraga C, Tabrizi SJ, Wild EJ. Huntington's Disease Clinical Trials Corner: November 2022. J Huntingtons Dis. 2022;11(4):351-367. doi: 10.3233/JHD-229006. PMID 36463457

• Study Protocol and Statistical Analysis Plan (PDF, 2022-12-26)

• Medical Director, MD, Study director, Wave Life Sciences