Neurologix has announced positive interim results of its landmark gene therapy clinical trial for patients with Parkinson's disease. Neurologix's 12-patient, dose-escalating Phase I trial is the world's first study to use a viral vector (the non-pathogenic adeno-associated virus, or AAV) for the treatment of an adult neurological disease.
In the Neurologix-funded trial, the vector was injected into a specific target site in the brain in order to transfer a gene to treat Parkinson's disease. The gene encodes glutamic acid decarboxylase (GAD), an enzyme which synthesizes the major inhibitory neurotransmitter in the brain, (gamma)-aminobutyric acid (GABA).
Under the FDA-sanctioned trial protocol, patients with advanced Parkinson's disease received unilateral (one side of the brain) infusion of AAV-GAD via a hair-thin catheter into the subthalamic nucleus (STN), a deep brain structure known to function abnormally in Parkinson's patients. According to the interim findings, Neurologix's STN AAV-GAD treatment appears to be safe and well-tolerated in advanced Parkinson's disease, with no evidence of adverse effects or immunologic reaction related to the study treatment. Furthermore, patients in the trial, at one year, exhibited a statistically significant improvement (27%, p = .04) in motor function on the side of their body correlating to the treated part of the brain, as measured by the Unified Parkinson Disease Rating Scale (UPDRS). In contrast, the untreated side evidenced no significant improvement in the UPDRS score. Also, activities of daily living (ADL), another standard measure of Parkinson's severity which is recorded by the patients themselves, showed a strong trend toward statistical improvement (p= .06).
In addition, fluorodeoxyglucose (FDG)-PET scans at one year revealed that the treated side of the brain exhibited a statistically significant decrease in abnormal metabolism, while the untreated side showed a further increase in abnormal metabolism. The imaging results were considered similar to those achieved with STN Deep Brain Stimulation, an FDA-approved treatment which currently represents the preferred surgical approach for advanced Parkinson's disease. This data provides solid biological support for the observed clinical improvements.
Twelve subjects in total have undergone gene transfer, four in each of three dose cohorts. Seven of the eight patients representing the low and mid-dose cohorts have now been evaluated one year following treatment. Three of the remaining five subjects have been followed for six months and the remaining two for more than four months.
The trial results were presented by Andrew Feigin, M.D., Associate Director, Movement Disorders Center of the North Shore - Long Island Jewish Health System at the 19th Annual Symposia on the Etiology, Pathogenesis and Treatment of Parkinson's Disease and Other Movement Disorders. Dr. Feigin and his colleague David Eidelberg, M.D., Head of the Neurosciences Research Center at North Shore, have been responsible for monitoring, evaluating and conducting neurological reviews of the trial participants before and for one year following treatment.
The gene therapy procedures were performed at NewYork-Presbyterian Hospital/Weill Cornell Medical Center by Michael G. Kaplitt, M.D., Ph.D., the Tara and Victor Menezes Clinical Scholar in Neurosurgery at Weill Cornell Medical College and Director of Stereotactic and Functional Neurosurgery at NewYork-Presbyterian/Weill Cornell, and Dr. Matthew J. During, Professor of Molecular Medicine at the University of Auckland. Drs. Kaplitt and During are the co-founders of Neurologix and are consultants to the company. In a joint statement, Drs. Kaplitt and During commented: "While the primary objective of any Phase I trial is to demonstrate safety, the FDA's requirement of unilateral infusion of AAV-GAD allowed us the unique opportunity to compare treated and untreated sides of the brain. In essence, the untreated side acted as a control. The combined clinical and imaging data provide powerful evidence that this treatment appears to be efficacious, as well as safe, at the current dose levels."
This Phase I trial is the culmination of more than 10 years of basic research. In 1994, Dr. Kaplitt was the first author of a paper published in Nature Genetics, along with Dr. During as senior author, which demonstrated, for the first time in a preclinical model, that AAV could be a safe and effective vehicle for gene therapy in the brain. Most importantly, AAV has never been associated with any human disease.
According to Drs. Kaplitt and During, "The goal of this research is to determine whether we can 're-set' a specific group of cells that have become overactive, causing the characteristic impaired movements associated with Parkinson's disease. The interim UPDRS scores are highly promising and, if they are borne out with additional data, would be comparable to results seen with STN Deep Brain Stimulation. Unlike deep brain stimulation, however, our gene therapy approach is much simpler, can be carried out entirely under local anesthesia, and avoids leaving any devices in the body. We look forward to the completion of the patient evaluations and the final analysis of these findings." Under the clinical protocols, the last cohort of patients was treated this past spring and will complete evaluations by mid-2006. Pending the final results, Neurologix intends to formulate and submit to the FDA a pivotal trial protocol for the use of STN AAV-GAD in the treatment of Parkinson's disease.
"The results of the trial are highly encouraging, in terms of both safety and efficacy," stated Eric J. Nestler, M.D., Ph.D., member of the Neurologix Scientific Advisory Board and Professor and Chairman, Lou and Ellen McGinley Distinguished Chair in Psychiatric Research, The University of Texas Southwestern Medical Center at Dallas. "These are very exciting findings. If the efficacy demonstrated here is replicated in a definitive trial, it would represent a fundamentally new platform for the treatment, not only of Parkinson's disease, but of a large number of neurological and psychiatric disorders as well. Such a replication would make viral-mediated gene therapy for brain diseases a reality."
Dr. Paul Greengard, Nobel Laureate, Vincent Astor Professor and Head of the Laboratory of Molecular and Cellular Neuroscience at Rockefeller University, and Chairman of the Neurologix Scientific Advisory Board, commented, "The initial results of the trial are very encouraging. To achieve, in a phase I study, statistically significant improvement in both motor scores and PET scans at one year is impressive, particularly given the absence of these changes on the untreated side of the brain. We look forward, now, to a pivotal trial to even more vigorously test and corroborate these important results."
The Phase I trial, which is the first FDA-approved clinical trial to test gene therapy to treat Parkinson's disease, is an open-label dose-escalation study with four patients in each of three escalating dose cohorts. The third cohort of four patients received 10 times the dose of the first cohort. The 12 patients participating in the trial were diagnosed with severe Parkinson's disease of at least five years' duration and no longer adequately responded to current medical therapies.
Following treatment, patients were evaluated at 1, 3, 6 and 12 months. These evaluations included scoring via the UPDRS, neuropsychological testing, videotaped examinations and timed motor tasks. PET scans were also taken at baseline, 6 and 12 months.
The surgery entailed a stereotactic neurosurgical procedure performed under local anesthesia with the patient awake. First, MRI was used to image the target subthalamic nucleus (STN) region of the brain. The STN was mapped using microelectrodes by recording from single neurons as the electrode was slowly moved towards the STN. Once a signature firing pattern was obtained confirming that the electrode was in the STN, the fine-wire electrode was removed, leaving only the microelectrode sheath through which a hair-thin (165 micron) hollow tube was inserted. Thirty-five microliters containing 3.5, 10 or 35 billion particles (depending upon dose cohort) of the AAV (adeno-associated virus) viral vector with a human GAD gene (cDNA) were then infused at 0.5 microliters/minute, together with 15 microliters of 25% mannitol. After the 100-minute infusion period, the delivery catheter was withdrawn and the incision closed. No hardware was left behind following this procedure, and all patients were discharged within 48 hours of the procedure.