Phase 1b Trial of VY-AADC01 Gene Therapy for Advanced Parkinson’s Disease Shows Positive Results

An ongoing Phase 1b trial of VY-AADC01, a gene therapy for the treatment of advanced Parkinson’s disease (PD), is showing positive results, including improvement of motor function and activities of daily living, durable clinical effects, and good tolerability.

The announcement was made by Voyager Therapeutics, the gene therapy company specialized in neurological diseases that is leading the trial.

In data previously presented at the 2017 Annual Meeting of the American Academy of Neurology (AAN) and at the American Association of Neurological Surgeons (AANS) Annual Scientific Meeting, Voyager described the motivations behind the development of the gene therapy, as well as initial results.

VY-AADC01 was developed to directly deliver and promote the expression of the enzyme aromatic L-amino acid decarboxylase (AADC), which is responsible for the transformation of levodopa into dopamine. VY-AADC01 works by promoting the expression of AADC in a specific brain region called the putamen.

The therapy is based on the assumption that because patients with advanced PD don’t show degeneration of the dopamine-responsive neurons in this brain region, promoting putamen neurons to transform levodopa to dopamine could potentially reduce PD’s motor symptoms after a single administration.

Following the positive results of a Phase 1a clinical trial (NCT01973543) presented at AAN and AANS, the results of the new Phase 1b trial (NCT03065192) are similarly promising.

Overall, results demonstrated durable, dose-dependent, and time-dependent improvement across several measures of motor function after a single administration of VY-AADC01. Measures included patient reports, PD rating scales, and activities of daily living.

The Phase 1b study included 15 patients with advanced PD and disabling motor fluctuations who were treated with a single dose of VY-AADC01.

The primary objective is to assess the safety and distribution of the gene therapy administered under magnetic resonance imaging (MRI) guidance to the putamen brain region.

Secondary goals include measures of AADC expression and activity in the putamen, as measured by positron emission tomography (PET) scans, and assessments of motor function and daily activities, as measured by the Unified Parkinson’s Disease Rating Scale (a measurement of PD severity), quality of life, and a patient-completed diary.

Patients were divided into three groups of five, with each group receiving ascending doses of VY-AADC01. Data were collected at 24 months for group one, 12 months for group two, and six months for group three.

Following are some of the observations:

• VY-AADC01 improved multiple measures of patients’ motor function and activities of daily living in groups two and three.
• VY-AADC01 increased mean putaminal AADC enzyme activity by 13% in group one, 56% in group two, and 79% in group three at six months relative to baseline. Coverage of the putamen and AADC enzyme activity were found to be highly correlated.
• VY-AADC01 resulted in reduced daily doses of oral levodopa (and related medications) to achieve optimal motor control, suggesting that patients could make more dopamine with lower doses of oral levodopa.
• Parkinson’s medications were reduced by an average of 208 mg (14%), 553 mg (34%) and 618 mg (42%) for groups one, two, and three, respectively, at six months, compared to baseline.
• Moreover, VY-AADC01 was found to increase patients’ “on-time” without dyskinesia (impairment of voluntary movement) from 10.5 hours to 13.5 hours, and to reduce “off-time,” as self-reported in their diaries.
• All 15 patients had successful VY-AADC01 infusions that were well-tolerated, with no vector-related serious adverse events (SAEs).
• Fourteen of the 15 patients were discharged from the hospital within two days following surgery. As previously reported, one patient experienced two adverse events: a pulmonary embolism, or blood clot in the lungs, and related heart arrhythmia, or irregular heartbeat.
• Consequently, deep vein thrombosis prophylaxis was added to the protocol and no subsequent events were observed.

“We are very pleased with the updated results from our dose-escalation trial. By six months in Cohort 3, patients achieved the clinically meaningful improvements in motor symptoms that were observed in Cohort 2 and with even lower doses of their oral Parkinson’s medications, including levodopa,” Bernard Ravina, MD, MS, Voyager’s chief medical officer, said in a press release.

“These encouraging results continue to de-risk the program and support the use of either dose of VY-AADC01 administered in Cohort 2 or Cohort 3 for our planned pivotal trial. We continue to be impressed with the Cohort 2 data out to 12 months, namely, the increase in diary on-time of four hours without dyskinesia, decrease in off-time of 54%, supported by a 56% reduction in UPDRS-III motor scores while on medication,” said Steven Paul, MD, Voyager’s president and chief executive officer.

“In addition, preliminary results from our posterior delivery trial suggest that even greater coverage of the putamen, the brain region we are targeting, can be achieved and with shorter administration times. We are excited to continue to follow the patients in this Phase 1b trial, particularly patients in Cohort 3 from six to 12 months, and those in the posterior delivery trial, as we approach the start of the pivotal Phase 2-3 program later this year,” Paul added.

The positive results support the continuation of the clinical program into Phase 2/3 trials, which are on track to begin in late 2017 and to dose the first patient in the first half of 2018.