GAD-Related Parkinson Gene Therapy AAV-GAD Demonstrates Efficacy in Topline Findings

Ali Rezai, MD

(Credit: West Virginia University)

Topline data from MeiraGTx’s clinical bridging MGT-GAD-025 study (NCT05603312) assessing its investigational gene therapy showed that over a 26-week period, patients with Parkinson disease (PD) treated with the agent displayed significant improvement in motor function. The therapy, an adeno-associated virus (AAV)-mediated delivery of glutamic acid decarboxylase (GAD) gene transfer into the subthalamic nuclei (STN), demonstrated significant effects in high doses.¹

Among all the participants in the trial (n = 14), the high-dose AAV-GAD group (n = 5) had a statistically significant 18-point average improvement from baseline in the Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3 “OFF” medication score (P = .03) at week 26, with no significant changes observed by researchers in the sham or low-dose groups (n = 4; n = 5; respectively). Notably, investigators also reported that AAV-GAD demonstrated safety and was well tolerated, with no serious adverse events (SAEs) related to the treatment observed among the participants.

“These safety and outcome results are excellent. The extent of motor score improvements in patients who received the high dose treatment combined with significant quality of life improvement measures are very encouraging for both patients and physicians,” principal investigator Ali Rezai, MD, executive chair of the Rockefeller Neuroscience Institute at West Virginia University, said in a statement.¹

MGT-GAD-025 is a 6-month, 3-arm, randomized, double-blind, sham-controlled study investigating AAV-GAD among participants who had idiopathic PD, a history of levodopa responsiveness for at least 12 months, and a UPDRS Part 3 score of at least 25 points in the "OFF" state. Participants were randomized to receive either AAV-GAD infused bilaterally into the STN (low dose group, 7.0×1010 vg; high dose group, 21×1010 vg or a sham procedure in a blinded fashion.

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In the trial, the primary objective was to assess the safety and tolerability of the gene therapy while exploratory efficacy end points included the mean change in MDS-UPDRS Part 3 scores in the “OFF” state and the Parkinson’s Disease Questionnaire (PDQ-39) score. Participants who completed this trial could enroll in a long-term follow-up study (NCT05894343), where they will be monitored for a total of 5 years post-treatment.

“We are excited about these impressive clinical data in Parkinson’s disease,” Alexandria Forbes, PhD, president and chief executive officer of MeiraGTx, said in a statement.¹ “With material made using our proprietary production process at commercial scale, we have demonstrated that AAV-GAD is safe at all doses studied, including a higher dose than previously tested. We have now treated a total of 58 patients in this development program in 3 independent multicenter clinical studies and have seen no SAEs related to AAV-GAD treatment.”

In the high dose AAV-GAD group, researchers reported that the PDQ-39 score among participants improved by 8 points from baseline (P = .02), the low dose group improved by 6 points from baseline (P = .04), and there was a 0.2-point worsening observed in the sham surgery group that was not statistically significant. Additionally, investigators observed a dose response in PDQ-39 score, with 100% of patients in the high dose group, 60% of patients in the low dose group, and 25% of those in the sham surgery group who reported an improvement. For the PDQ-39 score, researchers noted a trend to significance between the high dose and sham surgery groups at 6 months (evaluable per group, n = 4).

Forbes continued in the statement, “With the completion of this randomized, double-blinded bridging study, we have also demonstrated with even very small numbers of subjects that AAV-GAD treatment results in significant and clinically meaningful changes in key efficacy endpoints in Parkinson’s disease. For the UPDRS Part 3 in the ‘off’ state, a change of 5 to 10 points is considered clinically meaningful. The 18-point change observed in the high dose arm in this study underscores the very substantial impact of AAV-GAD treatment in these Parkinson’s patients. Similarly, for the PDQ-39, where a 2 to 4-point change is considered clinically meaningful, the 8-point and 6-point changes observed in the high and low dose groups, respectively, again indicate a substantial and clinically meaningful impact of AAV-GAD treatment.”¹

“These data demonstrate the impact of using highly targeted local delivery of gene-based therapy to correct the aberrant circuitry that results from the depletion of dopamine in the brain of idiopathic Parkinson’s patients as the disease progresses. AAV-GAD treatment is designed to normalize circuit function in all forms of Parkinson’s disease with its potential benefit not limited to any single type of Parkinson’s,” Forbes added in the statement.¹ “The significant, substantial, and clinically meaningful changes observed in this small, sham-controlled study provide us with a clear path forward in our clinical development strategy and underpin our discussions with regulators in the US, Europe, and Japan with the goal of initiating a Phase 3 study to support approval of this disease-modifying treatment globally.”

REFERENCES
1. MeiraGTx Announces Positive Data from Randomized, Sham-controlled Clinical Bridging Study of AAV-GAD for the Treatment of Parkinson’s Disease. News Release. MeiraGTx. Published October 15, 2024. Accessed November 13, 2024. https://investors.meiragtx.com/news-releases/news-release-details/meiragtx-announces-positive-data-randomized-sham-controlled