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Neurologix Inc.'s Phase II victory last week with NLX-P101 brought a much-needed credibility boost for gene therapy in Parkinson's disease and closely followed good news at the same clinical stage in advanced heart failure from Celladon Corp. with partner Targeted Genetics Corp.

Is woebegone gene therapy finally gaining respect - and efficacy? Nobody's jumping up and down just yet, except for these firms' investors. Even they are not jumping too high, although the news helped Neurologix's sub-dollar stock (OTC BB:NRGX) to rise more than 50 percent, putting shares at $1.15 at the close of trading on the day results were made public.

"It's not a coincidence that these things are happening when they are," said Michael G. Kaplitt, scientific co-founder of Neurologix Inc., who is also a neurosurgeon. Celladon also uses an approach similar to Neurologix's, under a patent held by Kaplitt, his father (a heart surgeon) and another person. "These technologies we worked on 15 years ago are now bearing fruit," Kaplitt told BioWorld Insight.

NLX-P101, the only gene therapy in the works that bypasses the dopamine system, is an adeno-associated virus approach that deploys glutamic acid decarboxylase to alter neural circuitry. Neurologix reported eye-opening improvements in off-medication motor scores compared to control PD subjects given sham surgery in the Phase II trial that involved 45 subjects, with benefit clear at one month and continuing through the six-month blinded study period in patients who hadn't been responsive to treatment otherwise. No serious adverse events turned up.

"We have to eventually deal with treating the control patients, which is part of the original design, and we have to digest all the data, which are still coming in," Kaplitt said. Regulatory steps are unclear. "The FDA has never really had to deal with this issue before," he noted. Except for Neurologix and Celladon, companies have never gotten past a randomized blinded study.

Neurologix's method delivers NLX-P101 to the brain by way of standard, minimally invasive surgery that doesn't require general anesthesia or implanting a permanent medical device. Kaplitt and colleagues were the first to prove that an AAV strategy could help the brain, as reported in a Nature Genetics paper in 1994 and eight years later in the journal Science. The firm's Phase I trial became the first ever in PD, with results published first on the cover in The Lancet and later in the Proceedings of the National Academy of Sciences.

Since PD patients lose dopamine-producing brain cells, which causes a drop in gamma-aminobutyric acid and makes the brain's subthalamic nucleus more active, Neurologix scientists figured they could "reset" overactive brain cells by restoring GABA through an AAV vector that puts the GAD gene back into the subthalamic nucleus, effectively calming it and helping the patient regain motor control. The current standard treatment is L-dopa, a dopamine precursor that hikes dopamine levels, but does not halt the course of the disease.

Gene therapy in PD is hardly unheard of. Also last week, the Michael J. Fox Foundation for Parkinson's Research granted to Ceregene Inc., of San Diego, $2.5 million to support Phase II testing of CERE-120, a gene therapy that brings neurturin to dying dopamine brain neurons. The Fox group gave another $2.1 million to bolster a collaborative effort between Biovail Laboratories International srl, a subsidiary of Toronto-based Biovail Corp., and MedGenesis Therapeutix Inc., of Victoria, British Columbia, that aims to develop a glial cell line-derived neurotrophic factor.

In mid-June, Oxford BioMedica plc, of Oxford, UK, reported new data from its ongoing Phase I/II trial with ProSavin, with data showing benefit after two years. Two out of three patients in the initial low-dose group showed sustained improvement in motor function of 30 percent at two years, compared to 28.5 percent at one year. ProSavin, designed to carry genes for three enzymes needed for dopamine synthesis directly into the brain, was safe and well tolerated. The company was still shopping for a partner.

The happy gene therapy news from Seattle-based Targeted Genetics Corp. and Celladon Corp., of La Jolla, Calif., came at the start of the month, when they offered the first Phase II trial with Mydicar for the treatment of advanced heart failure. The smallish study - 39 patients - met its primary safety and efficacy endpoints for high dose drug vs. placebo, with the composite primary endpoint taking in the simultaneous assessment of patients' clinical outcomes, exercise tolerance, heart failure symptoms, biomarkers and cardiac function. Targeted Genetics' stock (OTC PK:TGEN) jumped more than 28 percent on the news, unveiled at a meeting of the Heart Failure Association of the European Society of Cardiology. Celladon uses Targeted Genetics' AAV method to directly infuse therapy to congestively failing hearts.

Over the six-month study period, patients given high-dose Mydicar stayed an average of 0.2 days in the hospital, compared with 2.1 days for those on placebo, and those who completed the six-minute walk test were able to walk one extra meter after six months of Mydicar, compared with an 87-meter drop in walking distance for those on placebo. Blood biomarkers suggested improvement after six months vs. placebo, and on questionnaires patients described feeling better.

Gene therapy efforts are still mostly associated with oncology. "In cancer, while people make hypotheses about single genes, the relevance of animal models can be much more difficult to ascertain," Kaplitt said, thanks to the variability between patients.

Further complicating the picture is the fact that incipient tumor cells spread far and wide in the body. "If it's so focal, you could probably take that cancer out surgically," he said. Making certain gene therapy gets to all the cells that could reactivate amounts to a powerful challenge. "The biology of cancer remains poorly understood," Kaplitt said. "It's a lot better than it used to be, but it's still very imperfect."

Neurologix chose its disease area, including not only PD but epilepsy and depression, because they're all large unmet needs with well-known biology, can be studied relatively easily in animals, and involve a clear target in the brain, although "you have to know that spot and how to get there safely," Kaplitt said.

Though the FDA has yet to approve any drugs from the gene-therapy space, promising noises have been made by federal agencies, including word from the National Institutes of Health and the FDA that they are coming up with ways to push gene therapies through the regulatory process. Margaret Hamburg, head of the FDA, and Francis Collins, director of the NIH, this month teamed authorship of an article in the online New England Journal of Medicine. The two agencies will find "a more integrated pathway that connects all the steps," their leaders vowed, but the piece was low on specifics.

Meanwhile, failures stack up. In the spring, Gaithersburg, Md.-based GenVec Inc. stopped its Phase III trial of pancreatic cancer gene therapy TNFerade when an interim analysis failed to show efficacy, and Ark Therapeutics Group plc, of London, gave up on its European marketing application for Cerepro, a gene therapy for glioma, after regulators questioned its clinical benefit and said they wanted another Phase III trial. This month, GenVec said it has engaged Wells Fargo Securities LLC to look at strategic alternatives. Ark said it was going ahead with recruiting patients in the U.S. Phase III trial of Trinam, a locally delivered gene therapy for preventing restenosis in vascular access grafts, and has smaller academic trials of other adenoviral vector gene therapies in such areas as refractory angina, peripheral arterial disease and fetal growth retardation.

Neurologix continues on strong. Marc Panoff, chief financial officer, said the firm has retained MTS Health Partners LP, a merchant bank, to investigate ways to get financing. Kaplitt declined to say more. "I don't think it's a good idea to speculate in public on what our next step might be," he said, but partnering and other options are being explored.

"Data analysis [from the Phase II trial] is also actively happening," Kaplitt said last week, adding that he had "spoken just yesterday with principal investigators, and both agree they want to try to get the data out in a publication as soon as possible," possibly at the end of summer or start of fall, though the date is hard to specify given deadlines and lead times for journals.

Regarding gene therapy in general, "a lot of fields have gone through some of these difficulties early on," Kaplitt said, positing an oft-made comparison with monoclonal antibodies. "There was a period of time where it was thought that [area of research] was dead," he said. "The problem is that early enthusiasm [for new approaches] is a little premature and maybe excessive, and then the reaction becomes premature and excessive in the negative."

Gene-therapy research soldiered on, though, sometimes foiled by trial design or procedures. "Some other things were showing promise in different areas," Kaplitt said. "After the initial concern about using retroviruses as gene therapy in some pediatric immune deficiency syndromes, a lot of those problems got slowly resolved and there have been reports in the last year or so of what looks like some real successes." Ocular gene therapy, too, is making strides. But there's been particular interest in the Phase II results reported by Neurologix and Celladon. "These two events, in my view, are watershed events for the future of the field," Kaplitt said.