Pepinemab antibody blockade of SEMA4D in early Huntington's disease : a randomized, placebo-controlled, phase 2 trial
© 2022. The Author(s)..
SIGNAL is a multicenter, randomized, double-blind, placebo-controlled phase 2 study (no. NCT02481674) established to evaluate pepinemab, a semaphorin 4D (SEMA4D)-blocking antibody, for treatment of Huntington's disease (HD). The trial enrolled a total of 265 HD gene expansion carriers with either early manifest (EM, n = 179) or late prodromal (LP, n = 86) HD, randomized (1:1) to receive 18 monthly infusions of pepinemab (n = 91 EM, 41 LP) or placebo (n = 88 EM, 45 LP). Pepinemab was generally well tolerated, with a relatively low frequency of serious treatment-emergent adverse events of 5% with pepinemab compared to 9% with placebo, including both EM and LP participants. Coprimary efficacy outcome measures consisted of assessments within the EM cohort of (1) a two-item HD cognitive assessment family comprising one-touch stockings of Cambridge (OTS) and paced tapping (PTAP) and (2) clinical global impression of change (CGIC). The differences between pepinemab and placebo in mean change (95% confidence interval) from baseline at month 17 for OTS were -1.98 (-4.00, 0.05) (one-sided P = 0.028), and for PTAP 1.43 (-0.37, 3.23) (one-sided P = 0.06). Similarly, because a significant treatment effect was not observed for CGIC, the coprimary endpoint, the study did not meet its prespecified primary outcomes. Nevertheless, a number of other positive outcomes and post hoc subgroup analyses-including additional cognitive measures and volumetric magnetic resonance imaging and fluorodeoxyglucose-positron-emission tomography imaging assessments-provide rationale and direction for the design of a phase 3 study and encourage the continued development of pepinemab in patients diagnosed with EM HD.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:28 |
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| Enthalten in: |
Nature medicine - 28(2022), 10 vom: 08. Okt., Seite 2183-2193 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Feigin, Andrew [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 30.03.2023 Date Revised 20.02.2024 published: Print-Electronic ClinicalTrials.gov: NCT02481674 ErratumIn: Nat Med. 2022 Oct 4;:. - PMID 36195687 Citation Status MEDLINE |
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| doi: |
10.1038/s41591-022-01919-8 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 245 | 1 | 0 | |a Pepinemab antibody blockade of SEMA4D in early Huntington's disease |b a randomized, placebo-controlled, phase 2 trial |
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| 500 | |a ErratumIn: Nat Med. 2022 Oct 4;:. - PMID 36195687 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. The Author(s). | ||
| 520 | |a SIGNAL is a multicenter, randomized, double-blind, placebo-controlled phase 2 study (no. NCT02481674) established to evaluate pepinemab, a semaphorin 4D (SEMA4D)-blocking antibody, for treatment of Huntington's disease (HD). The trial enrolled a total of 265 HD gene expansion carriers with either early manifest (EM, n = 179) or late prodromal (LP, n = 86) HD, randomized (1:1) to receive 18 monthly infusions of pepinemab (n = 91 EM, 41 LP) or placebo (n = 88 EM, 45 LP). Pepinemab was generally well tolerated, with a relatively low frequency of serious treatment-emergent adverse events of 5% with pepinemab compared to 9% with placebo, including both EM and LP participants. Coprimary efficacy outcome measures consisted of assessments within the EM cohort of (1) a two-item HD cognitive assessment family comprising one-touch stockings of Cambridge (OTS) and paced tapping (PTAP) and (2) clinical global impression of change (CGIC). The differences between pepinemab and placebo in mean change (95% confidence interval) from baseline at month 17 for OTS were -1.98 (-4.00, 0.05) (one-sided P = 0.028), and for PTAP 1.43 (-0.37, 3.23) (one-sided P = 0.06). Similarly, because a significant treatment effect was not observed for CGIC, the coprimary endpoint, the study did not meet its prespecified primary outcomes. Nevertheless, a number of other positive outcomes and post hoc subgroup analyses-including additional cognitive measures and volumetric magnetic resonance imaging and fluorodeoxyglucose-positron-emission tomography imaging assessments-provide rationale and direction for the design of a phase 3 study and encourage the continued development of pepinemab in patients diagnosed with EM HD | ||
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| 700 | 1 | |a Smith, Ernest S |e verfasserin |4 aut | |
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| 700 | 1 | |a Suchowersky, Oksana |e investigator |4 oth | |
| 700 | 1 | |a Testa, Claudia |e investigator |4 oth | |
| 700 | 1 | |a Anderson, Karen |e investigator |4 oth | |
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