Therapeutics

UCB0022

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Overview

Name: UCB0022
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 2)
Company: UCB S.A.

Background

This oral small molecule is a positive allosteric modulator of dopamine receptor type 1, which enhances the receptor's signaling in the presence of endogenous dopamine. It binds outside the dopamine site on the receptor, and has no intrinsic receptor-activating potential. UCB0022 is intended to reduce the need for escalating dopamine doses in people with Parkinson’s disease, and to prevent side effects like dyskinesis that arise due to excess signaling through the dopamine type 2 receptor.

The company has shown preclinical data at meetings (e.g. Vermeiren et al., 2022), claiming nanomolar affinity and selectivity and allosteric effects of UCB0022 in cell-based and in vitro assays. The compound reportedly enhances the potency of dopamine to activate D1Rs up to 10-fold, with no effect on other dopamine receptor subtypes. In an MTPT toxin model of Parkinson’s in nonhuman primates, UCB0022 had a longer duration of benefit on motor symptoms, less dyskinesia, and extended ON time compared to levodopa.

UCB has patented a series of tetrahydroisoquinoline derivative D1 positive allosteric modulators. Lilly has taken its D1 PAM, Mevidalen, through Phase 2.

Findings

In April 2021, Phase 1 began with a safety and pharmacokinetic study of single and multiple ascending doses in healthy people and people with Parkinson’s. A total of 100 volunteers were exposed to drug, against a primary endpoint of treatment-emergent adverse events. According to data presented at the March 2024 AD/PD conference, all side effects were mild or moderate. The most common were insomnia, dizziness, and decreased appetite. Higher doses transiently increased heart rate and blood pressure in healthy participants. All adverse events were reduced by dose titration. In Parkinson’s patients, blood pressure did not increase. There were no new neurological findings, deaths, or severe treatment-emergent adverse events.

In November 2023, a Phase 2 study called ATLANTIS began evaluating UCB0022 as an adjunct to levodopa in people with advanced PD. The trial is recruiting 189 patients, to be randomized to one of two doses or placebo. The primary outcome is fluctuation in motor function, measured as the average number of patient-reported OFF hours per day. Secondary outcomes are incidence of side effects, trial withdrawal, and drug levels in blood. The trial, at 40 sites in the U.S., is expected to finish in December 2024.

For details on UCB0022 trials, see clinicaltrials.gov.

Last Updated: 03 May 2024

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References

Therapeutics Citations

  1. Mevidalen

External Citations

  1. clinicaltrials.gov
  2. Vermeiren et al., 2022
  3. patented

Further Reading

Papers

  1. Svensson KA, Hao J, Bruns RF. Positive allosteric modulators of the dopamine D1 receptor: A new mechanism for the treatment of neuropsychiatric disorders. Adv Pharmacol. 2019;86:273-305. Epub 2019 Jul 13 PubMed.
  2. Hao J, Beck JP, Schaus JM, Krushinski JH, Chen Q, Beadle CD, Vidal P, Reinhard MR, Dressman BA, Massey SM, Boulet SL, Cohen MP, Watson BM, Tupper D, Gardinier KM, Myers J, Johansson AM, Richardson J, Richards DS, Hembre EJ, Remick DM, Coates DA, Bhardwaj RM, Diseroad BA, Bender D, Stephenson G, Wolfangel CD, Diaz N, Getman BG, Wang XS, Heinz BA, Cramer JW, Zhou X, Maren DL, Falcone JF, Wright RA, Mitchell SN, Carter G, Yang CR, Bruns RF, Svensson KA. Synthesis and Pharmacological Characterization of 2-(2,6-Dichlorophenyl)-1-((1S,3R)-5-(3-hydroxy-3-methylbutyl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (LY3154207), a Potent, Subtype Selective, and Orally Available Positive . J Med Chem. 2019 Oct 10;62(19):8711-8732. Epub 2019 Sep 30 PubMed.