Levodopa-Enhancing Activity Observed With Bezisterim in Phase 2A Study of Parkinson Disease

Joseph Palumbo

Recently announced data from a phase 2a study showed that as an adjunctive therapy to levodopa, bezisterim (BioVie) may hold promise in ameliorating specific non-motor symptoms of Parkinson disease (PD), particularly issues with fatigue and restlessness of the legs. Patients aged less than 70 years treated with bezisterim and carbidopa/levodopa (C/L) experienced the greatest improvement with treatment in comparison to the overall cohort, which featured patients aged up to 80 years old.^1,2

The trial featured 46 patients with PD who had a history of motor fluctuations, bradykinesia, and motor response to levodopa who were randomly assigned 1:1 to either bezisterim 20 mg twice a day (BID) with immediate-release (IR) C/L or placebo plus IR C/L for 27 days. Bezisterim is an oral, blood-brain barrier-permeable molecule that binds extracellular signal-regulated kinase (ERK) and has anti-inflammatory and insulin-sensitizing activities via inhibition of inflammatory (but not homeostatic) ERK and NF-kB activation and tumor necrosis factor-alpha signaling.

In the bezisterim + C/L group, investigators observed changes of –18.6 and –15.6 on Movement Disorder Society-Unified Parkinson’s Disease Rating Scale-Part III at hours 2 and 3, respectively, in comparison to –16.2 and –12.8 with levodopa alone. These improvements were even greater among those aged less than 70 years old (bezisterim + levodopa: –20.2 and –17.0; levodopa: –16.3 and –12.3). For context, around 50% of the total patient population was less than 70 years old.

Additional findings showed that more bezisterim-levodopa combination treated patients who experienced an OFF state at baseline experienced a morning ON state prior to dosing on day 28. All told, 6 of the 20 (30%) of those on the combination approach had ON state vs 0 of 19 placebo-treated patients (0%). This difference was considered statistically significant (P = .02).

Within the bezisterim group, patients saw a –2.4 change (improvement) in Non-Motor Symptom Scale (NMSS) Sleep/Fatigue domain score, in comparison with those on placebo, who worsened by 1.0 points (P = .0159; cohen’s d = –0.5). Notably, sleep/fatigue domain improvements significantly correlated with motor score improvements (r = .51; P = .0259).

"These full dataset findings suggest that bezisterim as adjunct therapy to levodopa may hold promise in ameliorating specific non-motor symptoms of Parkinson Disease, particularly in sleep/fatigue and restlessness of the legs,” Joseph Palumbo, chief medical officer at BioVie, said in a statement.¹ "These findings extend previously reported improvement in motor symptoms with bezisterim and demonstrate potential intrinsic and levodopa-enhancing activity of bezisterim that is consistent with data from animal models and support further clinical investigation of bezisterim in late-phase trials."

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Results from the study showed significant improvement in fatigue/lack of energy (Q4), as well as urge to move legs/restlessness in legs (Q6) among bezisterim-treated patients but not placebo. Among all patients, those on bezisterim showed changes of –0.87 (90% CI, –1.24 to –0.50; P = .0005; Cohen’s d = –0.26) for fatigue/lack of energy vs –0.39 (90% CI, –79 to –0.02) for those on placebo. In a separate group of patients with symptoms at baseline, the bezisterim group (n = 8) showed changes of –2.25 (90% CI, –3.73 to –0.77; P = .0267; Cohen’s d = –0.15) in comparison with changes of –1.86 (90% CI, –3.44 to –0.27; P = .0759) for placebo.

Using NMSS to assess urge to move legs/restlessness in legs, patients in the overall cohort showed score changes of –0.89 (90% CI, –1.81 to 0.03; P = .01215) with bezisterim whereas those on placebo saw worsening of 0.99 (90% CI, –0.01 to 1.99; P = .1141). For those with symptoms at baseline, bezisterim-treated patients had changes of –2.91 (90% CI, –4.31 to –1.50; P = .0036; Cohen’s d = –0.81) vs placebo, which had changes of –0.71 (90% CI, –2.48 to 1.05; P = .5141).

Bezisterim is also being currently assessed as a therapeutic for patients with Alzheimer disease (AD). In a recently presented randomized, placebo-controlled trial, treatment with the agent demonstrated potential to restore homeostasis and decrease biological aging in a small per-protocol sample of patients. All told bezisterim-treated patients displayed –4.77 years advantage on the Inflammation Age Clock (P = .022), –5.0 years advantage on the Hannum Age Clock (P = .006), –1.92 years advantage on the GrimAge Clock (P = .068), and –3.71 years on the PhenoAge Clock (P = .081). In addition, this group had a –3.68-year advantage on SkinBlood Clock (P = .017), a previously published finding.

Overall, decreased age acceleration found in bezisterim was correlated with improvements in neurologic assessments, including CDR-SB (Pearson r = 0.413; P = .099), ADAS-Cog12 (Pearson r = .455; P = .067), Mini-Mental State Exam (MMSE; Pearson r = –0.580; P = .015), Alzheimer’s Disease Assessment Scale (ADCOMS; Pearson r = .469; P = .058), and Alzheimer’s Disease Composite Score-Clinical Global Impression of Change (ADCS-CGIC; Pearson r = .467; P = .059). In comparison, there were no correlations with neurologic assessments for placebo.³

REFERENCES
1. BioVie’s bezisterim demonstrates potential improvement in sleep/fatigue and restless leg symptoms for Parkinson’s disease patients. News release. BioVie. May 22, 2024. Accessed June 7, 2024. https://finance.yahoo.com/news/biovie-bezisterim-demonstrates-potential-improvements-120000796.html
2. Palumbo J, Reading CL, Ahlem C, et al. Improvement of motor and non-motor symptoms with bezisterim adjunctive to carbidopa/levodopa in patients with Parkinson’s disease: a phase 2a, placebo-controlled study. Presented at: World Congress on Parkinson’s Disease and Related Disorders; Lisbon, Portugal. May 19-22; 2024.
3. Reading CL, Yan J, Testa MA, et al. Clinical outcomes and biomarker findings from a randomized, placebo-controlled trial of bezisterim in subjects with mild to moderate probable Alzheimer’s disease. Presented at: 12th Annual Alzheimer’s and Parkinson’s Drug Development Summit; April 23-25; Boston, MA.