Neurologix, Inc. (OTC Bulletin Board: NRGX),today announced positive results in a Phase 2 trial of its investigational gene therapy for advanced Parkinson's disease (PD), NLX-P101. Study participants who received NLX-P101 experienced statistically significant and clinically meaningful improvements in off-medication motor scores compared to control subjects who received sham surgery. In the trial, this benefit was seen at one month and continued virtually unchanged throughout the six month blinded study period. The results also demonstrated a positive safety profile for NLX-P101, with no serious adverse events related to the gene therapy or surgical procedure reported. Patients enrolled in the trial had moderate to advanced PD and were not adequately responsive to current therapies.

Neurologix, Inc., is a clinical-stage biotechnology company dedicated to the discovery, development and commercialization of gene therapies for serious disorders of the brain and central nervous system (CNS). Neurologix's investigational AAV(adeno-associated virus) vector gene therapy, NLX-P101, is a novel,non-dopaminergic approach that uses an inhibitory gene (glutamic acid decarboxylase or "GAD") to selectively alter the neural circuitry affected in PD and, thereby, normalize brain physiology. Neurologix's technology is the only gene therapy strategy currently in development which bypasses the dopamine system.

"We are extremely pleased that years of research by our group with AAV vector gene transfer technology has led to the unprecedented milestone of a statistically significant improvement in a double-blind, placebo-controlled trial of gene therapy for any neurological disorder," said Michael G. Kaplitt,MD, PhD, scientific co-founder of Neurologix, Inc., neurosurgeon, NewYork-Presbyterian Hospital/Weill Cornell Medical Center and Associate Professor and Vice Chairman for Research, Department of Neurological Surgery, Weill Cornell Medical College. "We now have solid scientific evidence to support NLX-P101 as an important, potential treatment for this devastating disease."

Matthew J. During, MD, DSc,Professor of Molecular Virology, Immunology and Medical Genetics,Neuroscience and Neurological Surgery, The Ohio State Medical School,and Professor of Molecular Medicine and Pathology, University of Auckland, New Zealand, and Michael G. Kaplitt, MD, PhD, are the scientific founders of Neurologix, Inc., and have been at the forefront of gene therapy research since 1989. This Phase 2 trial is the result of more than 15 years of progress with their work in AAV gene transfer technology. They were the first to demonstrate that AAV could be an effective gene therapy agent in the brain, which they reported in their landmark Nature Genetics paper in 1994. Drs. During, Kaplitt and colleagues subsequently published additional research demonstrating the beneficial effects of AAV-GAD gene therapy for Parkinson's disease in the journal Science in 2002. Today's findings build upon earlier positive results from the NLX-P101 Phase 1 trial, which was the first ever clinical gene therapy trial for Parkinson's disease. Results oft hat study appeared in 2007 as a cover article in The Lancet and in a second article in the Proceedings of the National Academy of Sciences.

Neurologix and Gene Therapy A Novel Approach to Parkinson's Disease

In Parkinson's disease, patients lose dopamine-producing brain cells,resulting in substantial reductions in the activity and amount of GABA(gamma-aminobutyric acid), the major inhibitory neurotransmitter in the brain. This contributes to an abnormal increase in activity of the subthalamic nucleus (STN) of the brain, a key regulatory center for movement, and causes a dysfunction in brain circuitry responsible for coordinating movement. GABA is made by a gene called glutamic acid decarboxylase, or GAD.

Neurologix's gene therapy approach to PD aims to reset the overactive brain cells to inhibit electrical activity and return brain network activity to more normal levels. The strategy involves restoring GABA and thus improving the patient's motor control by using an AAV vector (a disabled, non-pathogenic virus) to deliver the GAD gene back into the STN. Increasing GAD causes more GABA to be synthesized, thus helping to calm the STN over-activity.

NLX-P101is delivered to the brain through a standard, minimally-invasive surgical procedure that uses similar techniques to those currently employed in traditional surgery for PD. The Neurologix gene therapy procedure, however, does not require general anesthesia nor implantation of a permanent medical device in the brain.

"While dopamine clearly plays a role in Parkinson's disease, dopamine levels in the brain are inherently difficult to control, resulting in sub-optimal treatment outcomes for patients. We believe that by altering chemical targets further downstream in the brain's network that regulates movement, we have the potential to help improve outcomes and restore motor function for patients with advanced Parkinson's disease," added Matthew J. During, MD, DSc, scientific co-founder of Neurologix, Inc.

"Based on this data, we are confident that NLX-P101 has great potential to advance the treatment paradigm for Parkinson's patients, and to eventually offer an important, new therapy for patients with this debilitating disease. The study investigators continue to further evaluate the detailed data and we look forward to its publication or presentation," said Clark A. Johnson, President and Chief Executive Officer of the Company. "Today's news is also important validation for our ongoing development of other technologies for neurological and psychiatric diseases, including our advanced pre-clinical program in epilepsy. Given these results, we would look to pursue a strategic transaction which will maximize value for the Company."

Study Details

This double-blind, multi-center, randomized,sham-procedure-controlled Phase 2 study was designed to evaluate the safety and efficacy of NLX-P101 in patients with moderate to advanced PD who were not well-controlled on available medical therapy. Trial participants were randomized to receive either an infusion of NLX-P101 bilaterally into each subthalamic nucleus, or a sham infusion of a sterile saline solution. Each procedure was carried out under local anesthesia.

The primary measure of efficacy in the study was the difference in off-medication motor scores between the treated and sham groups on the Unified Parkinson's Disease Rating Scale (UPDRS) Part 3(Motor section), which has long been the standard for clinical assessment in Parkinson's disease. All subjects were evaluated at baseline as well as one, three and six months after undergoing surgery.

The trial also showed that NLX-P101 was well-tolerated with no serious adverse events related to the drug or procedure reported. All treated subjects will continue to be monitored for safety for a 12-month period following their surgical procedure.

By Paul Francuch

Chicago and Montreal researchers studying thelowly lamprey eel have identified an overlooked nervous system pathwayrunning parallel to known brainstem locomotor command circuitry invertebrates such as birds, fishes and mammals.

The finding isreported in Nature Neuroscience, online May 16, and highlighted in themagazine's "news and views" section.

Simon Alford, University ofIllinois at Chicago professor of biological sciences and the article'scorresponding author, said the role of a neurotransmitter associatedwith this parallel pathway may also suggest new research directions fortreating Parkinson's disease.

Alford, along with his formergraduate student and lead author Roy Smetana, now a University ofPittsburgh resident in psychiatry, worked with Universit de Montraland Universit de Qubec Montral neurobiologist Rjean Dubuc and hispost-doctoral researcher Laurent Juvin in trying to sort out how theneurotransmitter analog muscarine modifies sensory information going tothe brain.

Their work determined that muscarine stimulated neuralactivity, leading to locomotion in the laboratory lampreys.

Thegroup focused its attention on a collection of brainstem neurons thattell the spinal cord to generate motor output that enables walking andother locomotion.

"We started looking at this group of neurons,which in the lamprey are conveniently very large, so they're easy toplant electrodes and record from," said Alford. "We discovered themuscarinic excitation was not working on these cells, but on apreviously unknown group of cells within the brainstem."

What'smore, these newly discovered brainstem neurons showed what Alford calleda "very odd response" to the muscarine.

"Instead of just turningon -- like a synapse turns on a neuron and makes it fire -- when youput muscarine on these cells, they turn on and stay on" for a minute orlonger which he said for a neurological reaction can be a very longtime.

The researchers discovered the actual brainneurotransmitter that activates muscarine receptors -- another chemical,acetylcholine -- sends a signal to these newly discovered brainstemneurons, switching them on for the lengthy minute or so durations.

Alfordsaid the finding opens up new insights into animal locomotion.

"It'sa system for turning on your locomotor system and making you walk orrun in a very coordinated, straight-line fashion sustaining locomotionfor a considerable time," he said. "This simply was not known to existbefore we discovered it."

The role of the neurotransmitteracetylcholine may ultimately suggest new Parkinson's disease treatments.While a key Parkinson's symptom is tremor, an advanced stage symptom isthe inability to start a movement, such as walking. Symptoms associatedwith Parkinson's can be helped by reducing acetylcholine-mediatedneurotransmission in the brain, but little work has focused on brainstemmuscarine receptors in this disease.

"This may be a backdoorfinding into a secondary effect of Parkinson's disease that's not wellstudied because most research emphasis has been on dopamine and thebasal ganglia, a different neurotransmitter and region of the brain,"Alford said.

Major funding for the research came from theNational Institute of Neurological Disorders and Stroke, and theCanadian Institutes of Health Research.

Megan Brooks

In a randomized, multicenter study of advancedParkinson's disease (PD) patients, those treated with deep brainstimulation (DBS) of the subthalamic nucleus combined with best medicaltherapy had better self-reported quality of life at 1 year than thosetreated with best medical therapy alone.

The surgery groupreported greater improvement in mobility and activities of daily livingafter 1 year and required a third less daily dopaminergic drugs than thecontrol group, according to an article published online in the April 29issue of The Lancet.

The differences noted were "clinicallymeaningful," the study team, with senior study author Keith Wheatley,DPhil, professor of medical statistics, Cancer Research UK ClinicalTrials Unit, University of Birmingham, United Kingdom, concludes in thearticle, "but surgery is not without risk, and targeting of patientsmost likely to benefit might be warranted."

Self-Evaluation ofFunctional Status

The results are from the ongoing PD-SURG trial,a randomized, open-label trial.

The study involved 366well-matched patients with advanced PD for whom current medical therapywas not providing adequate symptom control; 183 were randomly allocatedto DBS plus best medical therapy (178 underwent DBS) and 183 to bestmedical therapy alone. In 174 of the surgery patients, the subthalamicnucleus was the surgical target and 176 procedures were bilateral.

Medicaltherapy could include apomorphine infusion according to local practice,other dopamine agonists, monoamine oxidase type B inhibitors,catechol-O-methyltransferase inhibitors, amantadine, or other drugs forPD symptoms.

The primary endpoint was the patients'self-evaluation of their functional status on the 39-item PDquestionnaire (PDQ-39).

According to the investigators, the meanchange from baseline to 1 year on the PDQ-39 summary index was 5.0points in the surgery group and 0.3 point in the medical therapy group(difference, 4.7 points; 95% confidence interval [CI], 7.6 to 1.8; P =.01).

"The sample size for the trial was based on detecting a10-point difference in the quality of life scale," Dr. Wheatley noted inan email to Medscape Neurology. "Of course, we would have liked alarger benefit, but the observed 5-point benefit is worthwhile forpatients."

Significant differences favoring surgery were alsoseen in the mean change in the PDQ-39 score for mobility (8.9; 95% CI,13.8 to 4.0; P = .0004), activities of daily living (12.4; 95% CI,17.3 to 7.5; P < .0001), and bodily discomfort (7.5; 95% CI, 12.6to 2.4; P = .004). Between-group differences in all other domains ofthe PDQ-39 (eg, social support, cognition and communication) were notsignificant.

Verbal Fluency and Vocabulary

However, in aneditorial published with the study, Maria C. Rodriguez-Oroz, MD, fromUniversity of Navarra in Pamplona, Spain, notes that a more detailedneuropsychological analysis of a subgroup of patients showed a declinein verbal fluency and vocabulary in the DBS group.

Still, at 1year, patients who had the surgery were "better able to get about andperform their normal daily activities," Dr. Wheatley told MedscapeNeurology, "and they needed a lot less medication than the patients inthe medical therapy arm."

Patients in the surgery group weretaking a mean levodopa equivalent dose of 894 mg/day (SD, 568 mg/day) at1 year, whereas those in the medical group were on 1347 mg/day (SD, 585mg/day; P < .0001), a difference of 453 mg/day (95% CI, 328 580),which represents a 34% reduction in mean daily dopaminergic drugrequirement in the surgery group.

At baseline, 45 patients ineach group were taking apomorphine. By 1 year, this had decreased to 13in the surgery group and had increased to 63 in the medical therapygroup.

The findings on the PDQ-39, the study team reports, "weremirrored by clinically meaningful differences on the United Parkinson'sDisease Rating Scale (UPDRS), including the patient-rated UPDRS part IV,which showed substantial benefits of surgery in the time and severityof dyskinesia and off periods the most common reasons for patients tobe considered for surgery."

At 1 year, 75 patients in the surgerygroup vs 21 in the control group reported no waking day dyskinesia and45 and 5, respectively, reported no off time (P < .0001 for both).

Asexpected, DBS was not without risk; 36 (19%) of 178 surgery patientshad 43 surgery-related serious adverse events, most commonly infection.There was 1 unsuccessful suicide attempt after DBS in a patient who had aprevious suicide attempt before the study. There was 1 surgery-relateddeath due to hemorrhage.

Trial Differences, Advantages,Limitations

Dr. Rodriguez-Oroz says 3 aspects of this trial makeit different from previous DBS trials in PD patients: "the trialincludes a larger number of patients, has a longer follow-up, andpermits treatment of patients in both groups with continuous infusion ofapomorphine," which is increasingly being used for PD.

One majorlimitation of the trial, recognized by Dr. Rodriguez-Oroz and the studyteam, is that evaluators were not blinded to treatment allocation.Another, according to Dr. Rodriguez-Oroz, is that reports ofimprovements in dyskinesias and off periods were based on the UPDRScomplications of therapy subsection rather than a "more reliablesource," such as diaries, in which patients could note changes in motorabilities more immediately is another limitation.

A thirdlimitation is that a standard definition of the on state was notspecified; "instead, assessment of whether a patient was in the on statewas left to the judgment of neurologists at each center."

"Anexcellent aspect of this trial is that follow-up will continue to 9years," Dr. Rodriguez-Oroz notes. "This will provide invaluableinformation about the long-term benefit of surgery, especially indifferent subgroups of patients (eg, according to age, disease severity,disease duration, and reason for surgery)."

The study wassupported by funding from the UK Medical Research Council andParkinson's UK. One of the study investigators discloses having receivedtravel grants from Medtronic, and another received reimbursement feesfrom Medtronic for time spent collecting and analyzing data as a memberof the ad hoc adverse event committee for another DBS study. The otherstudy authors have disclosed no relevant financial relationships. Dr.Rodriguez-Oroz discloses that she is on the advisory board of UCB Spain;receives payment for lectures and travel for scientific meetings fromGlaxoSmithKline, UCB, Lundbeck, and Medtronic; and has received paymentfrom Medtronic for teaching.