Name: SKY-0515 in Huntington's disease: Pharmacodynamics
Published: 2026-09-16T18:00:43-04:00

Preclinical pharmacology: human cells and Hu97/18 mice

“In vitro pharmacology studies demonstrated that SKY-0515 promotes HTT mRNA and protein lowering in cultured human lymphocytes, with a limited number of off-target genes” (opens the source at this quote in a new tab)
“In Hu97/18 mice treated with SKY-0515 at 1, 3, 10 and 30 mg/kg once daily (QD) for 30 days, a concurrent and comparable dose-dependent decrease of mHTT protein compared to vehicle controls occurred in brain and peripheral blood” (opens the source at this quote in a new tab)

Healthy volunteers: blood HTT mRNA reduction

“SKY-0515 produced dose-dependent reductions in HTT mRNA, with maximum decreases of 67% after a single 16 mg dose and 72% after 14 days of 9 mg daily dosing.” (opens the source at this quote in a new tab)

Participants with HD: blood mRNA and mHTT protein at day 84

“HTT and PMS1 mRNAs in blood were lowered by 62% and 26%, respectively, at the high treatment dose (9mg). Similarly, levels of mHTT protein in blood were lowered by 62% in patients receiving the 9mg dose, and 29% in patients receiving the 3mg dose.” (opens the source at this quote in a new tab)

Participants with HD: blood mHTT and total HTT protein through 12 months

“In Part Cii, increasing reductions in blood mHTT and total HTT (tHTT) proteins were observed at months 1, 2 and 3, reaching mean reductions of up to ~62% and ~65%, respectively, at the 9 mg dose at month 3.” (opens the source at this quote in a new tab)
“Over the following 9 months in Part Cii Extension, the reduction of mHTT and tHTT stabilized, with a maximum mean reduction at the 9mg dose of ~69% for both mHTT and tHTT, supporting the preservation of ~30% of WT HTT protein.” (opens the source at this quote in a new tab)

Participants with HD: biomarker reductions through 15 months

“SKY-0515 has shown consistent average reductions of more than 60% mutant huntingtin protein (mHTT) and 25% PMS1 mRNA in patients at the 9 mg dose throughout the study.” (opens the source at this quote in a new tab)

Neurofilament light chain

“Across all arms, NfL levels remained generally stable from baseline through Day 270 (Month 9), with no consistent dose-related increases observed.” (opens the source at this quote in a new tab)

“Plasma NfL (up to 12 months) and CSF NfL (up to 9 month) has been generally stable.” (opens the source at this quote in a new tab)

CSF markers of neuroinflammation and neuronal injury

“Ten CSF protein markers of neuroinflammation and neuronal injury were measured at Day 1 and Month 9 by NULISA” (opens the source at this quote in a new tab)
“All 10 markers remained stable, including: YKL-40/CHI3L1 (astrocyte activation; p=0.85), CSF NfL/NEFL (axonal injury; p=0.11), S100B (glial injury; p=0.39), MAPT (neurodegeneration; p=0.53), CCL2/MCP-1 (monocyte recruitment; p=0.17), and five pro-inflammatory cytokines (IL-6, IL-8, IL-1B, IL-17A, TNF; all p>0.23).” (opens the source at this quote in a new tab)

Caudate volume and volumetric MRI results

No evidence found.