Bayer AG and Asklepios BioPharmaceutical, Inc. (AskBio), a gene therapy company wholly owned and independently operated as a subsidiary of Bayer AG, on Sunday April 14 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.(1)

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.(2)

"These early findings are encouraging and show AB-1005 to be well tolerated in this study in patients with mild to moderate Parkinson's disease," said Krystof Bankiewicz, MD, PhD, Scientific Chair, Parkinson’s and MSA, AskBio. "Further, they highlight areas of potential future exploration in our upcoming Phase II REGENERATE PD trial, which will look more closely at the potential efficacy of AB-1005 in the treatment of Parkinson's disease."

Patients also completed 18-month neurological assessments and self-reported questionnaires at regular intervals to evaluate the severity of motor and non-motor symptoms associated with PD.(1)

Mild Cohort

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 2OFF" 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.

Moderate Cohort

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.

"We are excited to see AskBio’s investigational gene therapy for Parkinson's disease reach significant milestones in clinical development and look forward to moving into Phase II later this year," said Christian Rommel, PhD, Head of Research and Development at Bayer's Pharmaceuticals Division. "While much remains to be done, we recognize with increasing confidence the potential of AB-1005 to provide a transformative impact for patients in the future."

About AB-1005

AB-1005 is an investigational gene therapy based on adeno-associated viral vector serotype 2 (AAV2) containing the human glial cell line-derived neurotrophic factor (GDNF) transgene, which allows for stable and continuous expression of GDNF in localized regions of the brain after direct neurosurgical injection with magnetic resonance imaging (MRI)-monitored convection enhanced delivery.(3,4) GDNF is a homodimer that is a distantly related member of the transforming growth factor-β superfamily. In midbrain neuronal cell cultures, recombinant human GDNF promoted the survival and morphological differentiation of dopaminergic neurons and increased their high-affinity dopamine uptake. GDNF has long been evaluated as a potential treatment for diseases, such as Parkinson’s, marked by progressive degeneration of midbrain dopaminergic neurons.(5)

About the AB-1005 Phase Ib trial

In this Phase Ib, multi-center, multi-site, parallel assignment, non-randomized trial, 11 patients were administered AB-1005 to the putamen via one-time bilateral convection-enhanced delivery. Patients were enrolled into two cohorts, Mild (6 patients) and Moderate (5 patients), based upon the duration and stage of their PD. The objective of this investigation was to evaluate the safety and potential clinical effect of AB-1005 delivered to the putamen in patients with either a recent or a long-standing diagnosis of PD. The outcomes assessed at 18 months were incidence of Treatment-Emergent Adverse Events (TEAEs) as reported by the patients or assessed clinically by physical and neurological examinations, motor symptoms as reported via the Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and PD Motor Diary self-assessments, and non-motor symptoms of PD and brain dopaminergic network integrity as measured by DaTSCAN.(1) These assessments will continue for up to five years.