Hybridopa Shows Motor, Nonmotor Gains in Phase 2a Parkinson Disease Trial

A small randomized controlled pilot study published in Brain Communications has shown that a 3-week smartphone-based multimodal digital therapeutic, DopApp (Remepy Inc.), significantly improved motor and nonmotor outcomes in levodopa-treated patients with Parkinson disease (PD) compared with a placebo app, while also producing measurable changes in thalamocortical functional connectivity on resting-state functional MRI (rs-fMRI).¹ The findings, described as preliminary and proof-of-concept in nature, suggest that digitally delivered behavioral interventions may augment the effects of standard dopaminergic pharmacotherapy by engaging brain circuits not fully addressed by levodopa alone.

Forty-two adults with PD on stable levodopa regimens were randomly assigned 1:1 to either DopApp or a placebo app for 21 days. Thirty-nine participants completed the study per protocol (DopApp: n = 20; placebo: n = 19). The DopApp intervention incorporated adaptive daily training modules spanning fine motor exercises, sensorimotor-deprivation tasks using spatial memory games, physiotherapy, speech therapy, and psychological strategies including elements of cognitive behavioral therapy, acceptance and commitment therapy, mindfulness-based approaches, and guided imagery—delivered in approximately 30-minute daily sessions without therapist involvement. The placebo app provided Parkinson disease–related educational content of comparable format and delivery but without therapeutic components.

The primary outcome measure was change from baseline in the Movement Disorder Society–Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score (Parts I, II, and III combined). The DopApp group demonstrated a mean ± SD improvement of −9.7 ± 7.03 points from baseline compared with −1.95 ± 5.57 points in the placebo group—a between-group difference of 7.75 points that was statistically significant (P = .0005; d = 1.22). Notably, 65% of DopApp participants exceeded the established minimally important clinical difference (MCID) of 6.7 points on the MDS-UPDRS total score, compared with 15.8% in the placebo group. Improvements were observed across both MDS-UPDRS Part III motor examination scores (between-group difference: 6.46 points; P = .0009; d = 1.16) and Part II motor experiences of daily living scores (between-group difference: 1.49 points; P = .039; d = 0.68). Depressive symptoms as measured by the Beck Depression Inventory–II also improved significantly in the DopApp group (3.5 ± 5.02 points) versus a negligible change in the placebo group (+0.05 ± 4.31; P = .023; d = 0.76), though baseline BDI-II scores were low in both groups, limiting conclusions about effects on clinically significant depression.

On rs-fMRI, a neuroimaging sub-study was conducted in 31 participants (DopApp: n=17; placebo: n=14). Seed-based connectivity analyses revealed 2 distinct, parallel thalamocortical pathways differentially modulated by the intervention. In the motor pathway, increased resting-state functional connectivity (rsFC) was observed between the right ventral lateral posterior (VLp) thalamic nucleus and bilateral primary motor cortex (M1) in the DopApp group relative to placebo (PFDR < .05), and this connectivity increase correlated with improvements in MDS-UPDRS Part III scores (r = −0.72 and −0.64; P < .001 and P < .005 for right and left M1 clusters, respectively). In the limbic pathway, increased rsFC was observed between the left anteroventral thalamic nucleus (AV) and default mode network nodes—including medial prefrontal cortex, posterior cingulate cortex, and angular gyrus—as well as bilateral hippocampal and parahippocampal regions (PFDR < .05). Connectivity changes within this pathway correlated with reductions in BDI-II scores (r = −0.65; P < .005) and improvements in MDS-UPDRS Part II (r = −0.66; P < .01).

“These results represent an important milestone in Remepy’s journey of bringing a first-in-class Hybrid Drug for Parkinson’s disease to market, demonstrating how combining pharmacological drugs with personalized AI-driven digital protocols can improve the quality of life for people living with Parkinson’s disease,” Or Shoval, the coCEO of Remepy, said in a press release.² “The findings provide clinical validation that integrating pharmacologic treatment with adaptive digital protocols can amplify therapeutic response. Building on these results, we are advancing Hybridopa toward a pivotal phase 3 clinical program. The study will evaluate the therapy’s efficacy and safety across a broader Parkinson disease population. We are looking forward to initiating the phase 3 study later this year, which will be the most advanced drug–software combination program in clinical development.”

Engagement metrics derived from app usage logs suggested dose-response relationships between specific content types and domain-specific clinical and neural outcomes.¹ Greater daily exposure to sensorimotor-deprivation tasks correlated with increased rsFC between the right VLp seed and both the M1 (r = 0.81; P < .001) and supplementary motor cortex (SMC) (r = 0.82; P < .001). Furthermore, higher self-initiated engagement with emotion regulation content correlated with left AV–medial prefrontal cortex connectivity increases (r = 0.82; P < .001).

“[T]his study provides preliminary clinical and neurobiological evidence that a targeted, digital therapeutic can augment standard dopaminergic treatment in Parkinson disease,” first author Merav Catalogna, PhD, director of neuroscience at Remepy, and colleagues concluded in the paper’s Discussion section.¹ “By engaging multidimensional digital activities, DopApp improved motor function, mood and daily living while modulating thalamocortical connectivity in motor and limbic circuits. Dose–response relationships between engagement and outcomes suggest that adaptive, task-specific digital tools may drive circuit-selective plasticity. These findings support the potential of scalable, adjunctive digital interventions and their integration into precision, drug-digital treatment strategies for neurodegenerative diseases. Furthermore, they represent an early step towards the development of hybrid digital-drug interventions that may personalize care, enhance pharmacological efficacy and extend therapeutic reach beyond the traditional clinical setting.”

REFERENCES
1. Catalogna M, Saporta N, Tamir T, et al. Neural correlates of Parkinson’s improvements after combined digital-levodopa therapy: a pilot study. Brain Communications. 2026;8(3):fcag148. doi: 10.1093/braincomms/fcag148
2. Remepy reports strong clinical phase IIa results for Hybridopa™, a first-in-class hybrid drug for Parkinson's disease. News release. Remepy. May 20, 2026. Accessed May 21, 2026. https://www.remepy.com/news/remepy-reports-strong-clinical-phase-iia-results-for-hybridopa-tm-a-first-in-class-hybrid-drug-for-parkinsons-disease