First Patient Dosed in Phase 1 Trial of Gene Therapy AB-1005 in Multiple System Atrophy-Parkinsonian Type


The double-blind, placebo-controlled study is expected to include 9 patients aged 35-75 years old with MSA-parkinsonian type who will be randomized 2:1 to either investigational AB-1005 or sham surgery.

Nicolas M. Phielipp, MD, neurologist at the University of California Irvine

Nicolas M. Phielipp, MD

According to an announcement from AskBio, the first patient has been dosed in its phase 1 REGENERATE MSA-101 study (NCT04680065) assessing AB-1005, an adeno-associated viral vector serotype 2 (AAV2) gene therapy in development for patients with multiple system atrophy (MSA)-parkinsonian type (MSA-P).1

The first dosing took place at the Ohio State Wexner Medical Center while other institutions such as the University of California Irvine and the Quest Research Institute are expected to have patients as well. AB-1005, also known as AAV2-GDNF, is designed to encode the human glial cell line-derived neurotrophic factor (GDNF) transgene that is delivered to the putamen. In midbrain cultures, recombinant human GDNF has been shown to promote the survival and morphological differentiation of dopaminergic neurons and increased their high-affinity dopamine uptake.

"It means a lot to the MSA community to know that the first patient has been enrolled in the Phase 1 REGENERATE MSA-101 trial," Philip M. Fortier, MA, president and executive director at Defeat MSA Alliance, said in a statement. "There is no cure for MSA, and there are currently no treatments to stop or slow the progression of the disease. This makes it especially hard for patients, given the rapid decline many will experience. Today's milestone hopefully brings us one step closer to potentially changing the outcome for MSA patients."

REGENERATE MSA-101, a randomized, double-blind, placebo-controlled study, is expected to include 9 patients aged between 35-75 years with a clinical diagnosis of MSA-P. Each of these individuals has less than 5 years from their diagnosis, are on stable anti-parkinsonian medication regimen, and can walk a distance of 25 feet with or without an assistive device. On the day of surgery, patients will be randomized to either AB-1005 or a control surgery, with the primary outcome of safety, as measured by treatment-emergent adverse events (AEs) and serious AEs.2

The trial will assess a number of secondary outcomes as well, including MSA symptoms and signs, through the Unified Multiple System Atrophy Rating Scale (UMSARS), and change in striatal dopamine transporter (DaT) binding, using Single Photon Emission Computed Tomography DaT imaging. Additionally, investigators will observe changes in quality of life using the Multiple System Atrophy Quality of Life assessment, a self-reported questionnaire of 40 items.

"In those with MSA-P, the loss of dopamine producing neurons leads to markedly disabling symptoms, such as profound motor impairment throughout the hands, legs, and trunk," principal investigator Nicolas M. Phielipp, MD, neurologist at the University of California Irvine, said in a statement. "Previous experience with a similar approach in a population of Parkinson's disease patients has been very encouraging and supported the consideration of this approach in MSA-P. The intent is for GDNF levels in the brain to help preserve dopamine neurotransmission, which is noticeably reduced in MSA-P."

He added, "We're including a genetic sequence in the AAV2 vector that codes for the GDNF protein and are delivering this to the putamen. In this way, we're targeting local brain cells and adjacent brain tissue that can benefit from the protein's growth properties. This trial marks the first step toward understanding the potential that GDNF gene therapy might have for patients with MSA-P."

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Earlier this year, at the AD/PD 2023 Advances in Science & Therapy Conference, AskBio presented preliminary results from a phase 1b study assessing AB-1005 in patients with mild to moderate PD. The analysis featured 6 early-stage (<5 years; MDS-UPDRS: <32) and 5 moderate-stage (>4 years; MDS-UPDRS III: 33-60) patients who were administered up to 1.8 mL of AAV2-GDNF (3.3E12 vg/mL)/gadoteridol (2 mm) co-infusions per putamen. All told, the therapy was found to be well tolerated, with all patients completing 9-18 months of clinical follow-up.3

The preliminary findings suggested stabilization in the mild cohort, with 0.75% (±25) change in the OFF-medication state on MDS-UPDRS-III and a modest –0.9 (±0.9) hour decrease in good ON time without troublesome dyskinesias at 12 months, according to self-reported motor diaries. For those with moderate PD, investigators observed 12-month improvements of ­–43.7% (±9.9) in MDS-UPDRS-III or OFF state. Motor diary good ON time improved by 2.2 (±0.2) hours, –0.5 (±0.5) hours with troublesome dyskinesias, and –1.8 (±0.5) hours less OFF-medication time.

Additional findings from the study showed a puntaminal coverage of 63% (±2%) that was comparable between both cohorts. No serious adverse events (AEs) associated with the treatment were detected, and all reported AEs primarily occurred peri-operatively or were related to a patient’s underlying condition. All 11 patients tolerated the procedure and 10 remained on the treatment for more than 12 months.

"Enrolling the first patient in our REGENERATE MSA-101 trial is an important step in AskBio's ongoing work to advance GDNF gene therapy," Krystof Bankiewicz, MD, PhD, scientific chair, Parkinson’s and MSA at AskBio, said in a statement.1 "The clinical advancement of AB-1005 for the treatment of MSA-P comes as we are gathering the results of our Phase 1 programs in Parkinson's. Taken together we expect the outcomes of these trials to meaningfully contribute to the body of scientific knowledge related to the potential of GDNF gene therapy in the treatment of these debilitating central nervous system diseases. We believe these data, combined with our exploration of AAV-based intracranial gene delivery and our close collaborations with clinical neurosurgical centers of excellence, will support our goal of successfully developing and eventually delivering to patients these much-needed treatments."

1. AskBio announces first patient randomized in phase 1 trial of AB-1005 (AAV2-GDNF) gene therapy for multiple system atrophy-parkinsonian type (MSA-P). News release. AskBio. November 17, 2023. Accessed November 20, 2023.
2. GDNF Gene therapy for multiple system atrophy. Updated November 16, 2023. Accessed November 19, 2023.
3. Van Laar AD, Christine CW, Merola A, et al. A clinical phase 1b safety and preliminary efficacy gene therapy study investigating AAV2-GDNF for the treatment of Parkinsons disease. Presented at: AD/PD Conference; March 28-April 1, 2023. Gothenburg, Sweden.
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