Bayer AG and Asklepios BioPharmaceutical, Inc. presented results from the 18-month Phase Ib clinical trial for AB-1005, an investigational gene therapy for treating patients with Parkinson?s disease (PD).1,2 The data were presented at the American Academy of Neurology 2024 Annual Meeting in Denver, Colorado, USA. The study met its primary objective, which was to evaluate the safety of a one-time bilateral delivery of AB-1005 directly to the putamen. Eleven patients were enrolled into two cohorts, Mild stage PD (6 patients) and Moderate stage PD (5 patients), based on timing from PD clinical diagnosis and the severity of PD symptoms at trial screening.

As of November 3, 2023, 57 nonserious adverse events (AEs) and 6 serious adverse events (SAEs) were reported. Most AEs were transient and were expected perioperative events (<1 month from treatment). These included headache, tremor, dyskinesia, arthralgia, musculoskeletal chest pain, fatigue, COVID-19, and magnetic resonance imaging (MRI) abnormalities.

The 6 SAEs reported in 3 patients (n = 1 in the Mild Cohort and n = 2 in the Moderate Cohort) were all assessed as unrelated to the treatment by the Investigator and the Sponsor. Bilateral infusions of AB-1005 within the putamen (up to 1.8 mL) were well tolerated, with no SAEs associated with the investigational gene therapy or contrast agent. Neurosurgical delivery of AB-1005 resulted in putamen coverage of 63% ± 2%, exceeding the goal of greater than 50% coverage with AB-1005.

Scheduled 6-month postoperative MRIs revealed findings of asymptomatic unilateral T1 hypointensity adjacent to 3 of the putaminal infusion trajectories. Clinical follow-up for up to 5 years post administration is ongoing. The Movement Disorder Society-Unified Parkinson?s Disease Rating Scale (MDS-UPDRS) is an internationally recognized tool used to assess the severity of PD symptoms, including motor symptoms. The Mild Cohort (n = 6) demonstrated relative stability from baseline to 18 months for both MDS-UPDRS Part II patient-reported Activities of Daily Living scores and Part III clinician-rated Motor Examination scores in ?ON?

and ?OFF? medication states. Patient-reported PD Motor Diaries provide a tool for assessing patient motor state over an extended 3-day period and then normalized to a 16-hour waking day.

The Mild Cohort (n = 5) showed a -1.3 hour reduction in ?Good ON? time, a 0.2 hour increase in ?ON? time with troublesome dyskinesia, and a 1.1 hour increase in ?OFF?

time. One patient in the Mild Cohort declined to complete the diary after dosing, while troublesome dyskinesia and increased ?OFF? state time in this cohort were driven by another subject with a genetic defect of unknown pathological significance.

These factors are believed to have contributed to worsening of "Good ON? state time and ?OFF? state time over 18 months for the Mild Cohort.

Levodopa Equivalent Daily Dose (LEDD) is a summary measure of all anti-parkinsonian medications taken over a 24-hour period. The Mild Cohort had a lower LEDD at baseline than the Moderate Cohort and demonstrated further stability of LEDD over 18 months. MDS-UPDRS scores for the Moderate Cohort (n = 5) demonstrated a Part II Activities of Daily Living mean (standard error) improvement of -3.8 (3.5) points from baseline, and Part III Motor Examination improvements of ?20.4 (4.5) points ?OFF?

medication, and ?10.6 (3.6) points ?ON? medication compared to baseline. Most PD patients can sense a 3-point reduction of MDS-UPDRS Part III, and the 20.4-point improvement seen in the ?OFF?

state in the Moderate Cohort is considered to represent a large clinical effect. Motor Diaries for the Moderate Cohort reported a 2.2-hour improvement in ?Good ON? state time, which was clinically meaningful; a 0.5-hour reduction in ?ON?

state with troublesome dyskinesia; and a 1.7-hour reduction in ?OFF? state time. This equates to a 23.6% ± 11.8% increase in ?Good ON?

state time and a 33.1% ± 17.4% decrease in ?OFF? state time in the Moderate Cohort at 18 months. The Moderate Cohort demonstrated a progressive reduction of dopaminergic medications post-treatment, with a mean 258 ± 162 mg LEDD reduction from baseline.

Notably, the motor improvements demonstrated were in the setting of a reduced levodopa requirement. These outcomes demonstrate that most patients in the Mild Cohort achieved overall clinical stability with little change in MDS-UPDRS and PD Motor Diary outcomes and that participants in the Moderate Cohort achieved clinical motor improvement at 18 months. AskBio is planning to publish 18-month study results later this year.

Based on the top-line 18-month safety and clinical effects results presented, a Phase II trial (REGENERATE PD) has been developed and is expected to begin enrolling patients later this year in the U.S., EU, and UK.