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BioWorld Insight: Parkinson’s Update: Disease Pipeline Running the Gamut

April 12, 2022

By Brian Orelli, Contributing Writer

There were roughly 40 million Americans over the age of 65 in 2010, but as the baby boomer generation continues to reach the monumental age, the number of Americans in that class is expected to increase to 70 million in 2030.

In addition to being the typical retirement age, 65 also marks an increased risk of developing Parkinson’s disease.

Put those two together, and it’s likely to see a substantial increase in the number of Parkinson’s patients in the future.

Parkinson’s is a neurodegenerative disease, which affects the part of the brain that controls movement, both voluntary and involuntary. “As those cells die, dopamine becomes unavailable and creates a number of difficulties for patients over a progressive period of time,” explained Anthony Giovinazzo, president and CEO of Cynapsus Therapeutics Inc.

Most of the new medications have focused on increasing the level of dopamine, either directly or indirectly. Rather than slowing down the disease, the drugs only treat the symptoms of Parkinson’s. The current treatments also tend to wear off over time. As patients develop resistance to the drugs, they experience an increasing number of “off states,” where their muscle control shuts down.

Companies are taking a variety of approaches to solve the current treatment difficulties, from the high-risk strategy of gene therapy to the lower-risk approach of developing extended release versions of drugs that have already proven successful.

New! Exciting! Risky?

Neurologix Inc. is taking a somewhat radical approach to treating Parkinson’s disease through gene therapy. NLX-P101 is designed to act downstream of the dopamine signal, delivering a gene for glutamic acid decarboxylase, an enzyme that controls the synthesis of the inhibitory neurotransmitter GABA.

NLX-P101 attempts to replicate the data seen with deep brain stimulation, which is effective in restoring the signal to the subthalamic nucleus in Parkinson’s disease patients. But deep brain stimulation requires a complicated surgery, and patients have to carry around a battery pack, making the treatment not amenable to most patients.

The results of a Phase II trial testing NLX-P101 against a sham-operated control were published last month in Lancet Neurology. The Fort Lee, N.J.-based company demonstrated a more than 23 percent increase in a motor symptoms score, significantly better than the approximate 13 percent improvement seen in the control group. (See BioWorld Today, March 17, 2011.)

“We feel good that we passed a threshold that is very hard to pass,” said Matthew During, co-founder of Neurologix, of the proof-of-concept study.

The next step is a Phase III study. While the exact protocol hasn’t been worked out with the FDA yet, During expects that the trial will be significantly larger than the Phase II with 10 or more international centers recruiting 100-120 patients per arm.

Gene therapy is certainly more risky than more conventional approaches, but During said the risk is justified by going after the 15 percent to 20 percent of patients that are not doing well on current therapies. “The new drugs aren’t good for patients that have severe fluctuations,” During said.

The Road Traveled Before

Rather than reinventing the wheel, many companies are tripping out the steering wheel of classic drugs.

Toronto-based Cynapsus is developing APL 130277, a sublingual thin film strip containing apomorphine that dissolves much like the breath mint strips. The dopamine agonist has proven highly successful at helping patients get unstuck from the off state quickly, but the drug is highly irritating when injected.

Other have tried to change apomorphine into a more tolerable form, including tablets that dissolve in the buccal cavity, patches, rectal suppositories, nasal drops and liquid under the tongue. But they were all fraught with problems.

“They did teach somewhat on what the problems were and allowed us to focus in on how to solve those problems, using this thin film strip system,” Cynapsus’ Giovinazzo said.

Cynapsus has validated the new delivery system in an animal model and expects to start a Phase I trial shortly. By applying for FDA approval through the 505(b)(2) program, Cynapsus expects it can to complete all the required studies and apply to the FDA by 2013 at a dirt-cheap price of $20 million.

Civitas Therapeutics Inc., a Chelsea, Mass.-based spinout of Alkermes Inc., also is working on changing the mode of delivery for Parkinson’s drugs. The company is using Alkermes’s AIR technology to develop an inhaled product for Parkinson’s disease patients. The start-up hasn’t disclosed which molecule it’s working on, but Cynapsus’ Giovinazzo said it’s either levadopa or apomorphine. (See BioWorld Today, Jan. 10, 2011 .)

Last month, Impax Pharmaceuticals, the branded products division of Hayward, Calif.-based Impax Laboratories, Inc., reported that IPX066, an extended-release carbidopa-levodopa product, met the primary endpoint in its Phase III trial, ADVANCE-PD. IPX066 significantly reduced the percentage of off time in Parkinson’s disease patients compared to immediate-release carbidopa-levodopa. The data, combined with an earlier Phase III trial, APEX-PD, will allow the company to fi le a new drug application in the fourth quarter of this year.

Depomed Inc. also is working on an extended-release formulation of levodopa-carbidopa called DM-1992. In a Phase I trial, Depomed was able to show that it could maintain therapeutic blood levels of levodopa over 24 hours in a twice-daily formulation.

“If you take levodopa immediate-release you need to take four to six doses – some patients even go up to eight times a day – because it gets absorbed immediately in the gut,” said Georg Yu, director of corporate development at Menlo Park, Calif.-based Depomed.

In addition to improving convenience, the extended release technology is expected to reduce side effects that are caused by the fl uctuations in dopamine levels.

Hugging the Middle

In between the companies developing therapies at the extremes of the novelty spectrum, are companies developing new chemical entities that target the dopamine pathway.

Xenoport Inc., of Santa Clara, Calif., is developing a transported prodrug of levodopa, XP21279, that it believes will limit the peaks and troughs of drug blood levels seen with orally administered levodpa. The company started a Phase II trial at the end of last year comparing of XP21279 to Sinemet, a combination of carbidopa and levodopa.

Ligand Pharmaceuticals Inc. is looking for a partner to bring its partial dopamine agonist aplindore into Phase III development. The San Diego-based company gained control of the drug through its 2009-acquisition of Neurogen Corp., which had previously demonstrated promising results in a Phase IIa trial. (See BioWorld Today, Oct. 15, 2008.)

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