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Purpose <p>Synaptic density is strongly correlated with cognitive function in many neurological disorders. All synapses contain synaptic vesicle glycoprotein 2&#xa0;A (SV2A), making it a potential therapeutic target for neurodecline. ABBV-552, a high-affinity positive SV2A modulator, increases neurotransmitter release, improving synaptic efficiency. This Phase 1, open-label, mass balance study examined ABBV-552 safety, pharmacokinetics, metabolism, and elimination.</p> Methods <p>Eight healthy males were orally administered 15 mg [<sup>14</sup>C]-ABBV-552. Safety was assessed via treatment-emergent adverse event (TEAE), vital sign, electrocardiogram, and laboratory value monitoring. Serial blood, urine, and fecal samples were collected pre-dose, Days 1–14, and daily until discharge. Sample radioactivity was measured with HPLC and metabolites characterized with mass spectrometry.</p> Results <p>Eight participants (30–49 years old) received 15 mg [<sup>14</sup>C]-ABBV-552 (~ 100 µCi) and were included in analyses (3 prematurely withdrew [personal reasons]). All TEAEs were Grade 1 in severity; euphoria (25.0%), dizziness (25.0%), and muscular weakness (12.5%) were deemed possibly-related to ABBV-552. No meaningful changes in laboratory values, vital signs, or ECGs were observed. Mean radioactive recovery was 78.8% (urine: 70.9%, feces: 7.83%), with &lt; 1% parent drug in excreta. Parent and one metabolite (M2, mono-oxidized parent) accounted for 84% and 13%, respectively, of circulating drug-related material. M5, M9, and M33 were most prominent in urine (~ 13%, ~ 17%, ~ 11% of dose, respectively); M2/M36 (coeluted; 1.4% of dose) in feces.</p> Conclusions <p>Orally-administered ABBV-552 was well absorbed and primarily recovered in urine as metabolites. M2 was the only major circulating metabolite. Therefore, ABBV-552 is primarily hepatically metabolized and metabolites are renally eliminated. These findings support further investigation of ABBV-552 in neurodegenerative disorders.</p> Clinical trial registration <p>ClinicalTrials.gov (NCT06278766)</p> <p>Date of registration: 26 February 2024</p>

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Mass balance study of [14C]-ABBV-552, a synaptic vesicle glycoprotein 2A positive modulator, in healthy male participants following single oral dose administration

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月21日

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  • Nick Miles,
  • Brian McNamee,
  • Sharif I. Soleman,
  • Cindy Zadikoff,
  • Joey Boiser,
  • Loic Laplanche,
  • Richard Burton,
  • Mohamad Shebley,
  • Ramesh R. Boinpally

摘要

Purpose

Synaptic density is strongly correlated with cognitive function in many neurological disorders. All synapses contain synaptic vesicle glycoprotein 2 A (SV2A), making it a potential therapeutic target for neurodecline. ABBV-552, a high-affinity positive SV2A modulator, increases neurotransmitter release, improving synaptic efficiency. This Phase 1, open-label, mass balance study examined ABBV-552 safety, pharmacokinetics, metabolism, and elimination.

Methods

Eight healthy males were orally administered 15 mg [14C]-ABBV-552. Safety was assessed via treatment-emergent adverse event (TEAE), vital sign, electrocardiogram, and laboratory value monitoring. Serial blood, urine, and fecal samples were collected pre-dose, Days 1–14, and daily until discharge. Sample radioactivity was measured with HPLC and metabolites characterized with mass spectrometry.

Results

Eight participants (30–49 years old) received 15 mg [14C]-ABBV-552 (~ 100 µCi) and were included in analyses (3 prematurely withdrew [personal reasons]). All TEAEs were Grade 1 in severity; euphoria (25.0%), dizziness (25.0%), and muscular weakness (12.5%) were deemed possibly-related to ABBV-552. No meaningful changes in laboratory values, vital signs, or ECGs were observed. Mean radioactive recovery was 78.8% (urine: 70.9%, feces: 7.83%), with < 1% parent drug in excreta. Parent and one metabolite (M2, mono-oxidized parent) accounted for 84% and 13%, respectively, of circulating drug-related material. M5, M9, and M33 were most prominent in urine (~ 13%, ~ 17%, ~ 11% of dose, respectively); M2/M36 (coeluted; 1.4% of dose) in feces.

Conclusions

Orally-administered ABBV-552 was well absorbed and primarily recovered in urine as metabolites. M2 was the only major circulating metabolite. Therefore, ABBV-552 is primarily hepatically metabolized and metabolites are renally eliminated. These findings support further investigation of ABBV-552 in neurodegenerative disorders.

Clinical trial registration

ClinicalTrials.gov (NCT06278766)

Date of registration: 26 February 2024