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Safety, pharmacokinetics and pharmacodynamics of SBT‐020 in patients with early stage Huntington's disease, a 2‐part study
Author(s) -
Diemen Marcus P.J.,
Hart Ellen P.,
Abbruscato Anthony,
Mead Liz,
Beelen Ilse,
Bergheanu Sandrin C.,
Hameeteman Pieter W.,
Coppen Emma,
Winder Jessica Y.,
Moerland Matthijs,
Kan Hermien,
Grond Jeroen,
Webb Andrew,
Roos Raymund A.C.,
Groeneveld Geert Jan
Publication year - 2021
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.14656
Subject(s) - pharmacodynamics , pharmacokinetics , medicine , huntington's disease , mitochondrion , placebo , pharmacology , peripheral blood mononuclear cell , adverse effect , population , bioenergetics , amyotrophic lateral sclerosis , pathology , gastroenterology , disease , biology , biochemistry , in vitro , alternative medicine , environmental health
Aims Huntington's disease (HD) is a neurodegenerative disease with cognitive, motor and psychiatric symptoms. Toxic accumulation of misfolded mutant huntingtin protein induces mitochondrial dysfunction, leading to a bioenergetic insufficiency in neuronal and muscle cells. We evaluated the safety, pharmacokinetics and pharmacodynamics of SBT‐020, a novel compound to improve mitochondrial function, in a 2‐part study in early stage HD patients. Methods Part 1 consisted of 7‐day multiple ascending dose study to select the highest tolerable dose for Part 2, a 28‐day multiple dose study. Mitochondrial function was measured in the visual cortex and calf muscle, using phosphorous magnetic resonance spectroscopy, and in circulating peripheral blood mononuclear cells. Results Treatment‐emergent adverse events were mild and more present in the SBT‐020 group. Injection site reactions occurred in 91% in Part 1 and 97% in Part 2. Mitochondrial function in calf muscle, peripheral blood mononuclear cells or visual cortex was not changed overall due to treatment with SBT‐020. In a posthoc analysis, patients with a higher degree of mitochondrial dysfunction (below the median [∆Ψ m < 3412 and τPCr > 42.5 s]) showed more improvement than patients with a relatively lower level of mitochondrial dysfunction. Conclusion SBT‐020 was safe at all doses, but no significant differences in any of the pharmacodynamic measurements between the treatment groups and placebo group could be demonstrated. The data suggest that the better than expected mitochondrial function in our patient population at baseline might explain the lack of effect of SBT‐020.