A handful of drugs to treat the symptoms of Parkinson’s disease are edging closer to market, creating compelling new commercial opportunities for drug makers even as truly novel disease-modifying drugs remain out of reach – for now.

Important catalysts have unfolded for Parkinson’s disease drug developers like Civitas Therapeutics Inc., Cynapsus Therapeutics Inc. and NeuroDerm Ltd. in the last two months alone, fueling momentum behind new treatments for the devastating neurodegenerative disease. New therapeutics will be important to patients and physicians, maybe even payers, too, given that the standard of care for Parkinson’s disease, the catecholamine precursor levodopa, is more than 40 years old and carries troublesome side effects.

Nonetheless, the mid- to late-stage drugs in clinical development are largely designed to improve the delivery of levodopa or other long-marketed drugs. The effort is around two primary enhancements: the development of a rescue medication for acute use when background therapy fails and the development of more continuous drug delivery to reduce or eliminate the peaks and troughs patients currently experience due to levodopa’s short half-life.

Farther out on the horizon is the hope that truly novel disease-modifying medications could alter the progressive nature of the condition. Early research is mainly focused on two potential genetic targets of the disease, alpha synuclein, a protein found in the brain in Parkinson’s patients, and the leucine-rich repeat kinase 2 (LRRK2) gene, the greatest known genetic contributor to Parkinson’s. Potential therapeutics based on these emerging areas of research are just now in preclinical or early clinical testing.

“I have seen much more activity from biotech and pharma in Parkinson’s disease in the last two to three years,” MJFF’s Sherer said.

For now, the focus is on developing drugs to address the troubling symptoms of the disease, which include motor symptoms like bradykinesia (loss of spontaneous and voluntary movement), rigidity and resting tremors, and non-motor symptoms like cognitive impairment, mood disorders and sleeplessness.

“One of the things that has the greatest potential is to better deliver the best drug, and that is levodopa,” researcher Jeffrey Kordower, Rush University Medical Center, said during an interview at the Michael J. Fox Foundation’s Parkinson’s Disease Therapeutics Conference in October. His comments were specifically about drugs in development for motor symptoms, although his research focuses largely on cell therapy and gene therapy for potential disease-modifying options.

Drugs In Development For Motor Symptoms Of Parkinson’s Disease
Drug & Developer	How It Works	Phase of Development
IntecPharma’s Accordion Pill	Levodopa/carbidopa in an accordion-shaped pill that unfolds in the stomach for up to 12 hours	Phase II
AbbVie’s Duodopa	Levodopa/carbidopa intestinal gel	Pending at FDA with action expected in early 2015; approved in Europe
Neuroderm’s ND0612L and ND0612H	Levodopa/carbidopa continuous subcutaneous liquid formulation	Phase II
Impax’s Rytary	Levodopa/carbidopa extended-release capsule	Pending at FDA with Jan. 5 PDUFA date (delayed since 2013 due to manufacturing issues)
Acorda’s CVT-301	Levodopa/carbidopa inhalable formulation for acute rescue treatment	Phase II
Cynapsus’ APL-130277	Apomorphine sublingual filmstrip for acute rescue treatment	Phase II
Source: interviews and company filings

A Generic Market With Room For Improvement

Levodopa and carbidopa, which is generally co-administered with levodopa to prevent its breakdown before it reaches the brain, are available generically, as are dopamine agonists.

Both mechanisms are designed to address one of the leading causes of motor symptoms in Parkinson’s disease – lack of dopamine in the brain – and help reduce muscle rigidity, improve speed and lessen tremor. But while levodopa is considered the most effective option and can help some Parkinson’s patients live relatively normal lives for some period of time, the window of efficacy eventually declines. The drug also presents troubling side effects when used long term, particularly the involuntary movements and tics known as dyskinesia, as well as hallucinations and illusions.

Despite the high level of generic penetration in the market, which could present commercial challenges to new treatments for motor symptoms, the need for advancement is also well recognized. Patients treated with the existing oral levodopa eventually see their symptoms re-emerge over time and are left in a continuous cycle of “on” and “off” episodes. Drugs that can fill that therapeutic gap could have significant commercial potential.

The Michael J. Fox Foundation for Parkinson's Research, which invests in some 200 to 300 research projects each year, has been pivotal in providing early financing for some promising but risky pipeline bets in the hopes of encouraging industry or outside investors to invest down the line as the drugs advance. One of the non-profit’s areas of focus has been on new drug delivery options with an eye on therapeutic advances that could help patients in the near-term.

“We at the Fox Foundation had gotten involved in some projects focused on improving the delivery of levodopa, which could have a big impact for patients who suffer from these on/off episodes,” CEO Todd Sherer said in an interview.

“Levodopa is still the most effective treatment we have for motor symptoms of Parkinson’s, especially the slowness of movement,” he said. “One of the challenges that happens is that over time the drug loses its effectiveness.”

Big Catalysts For Biotechs

The MJFF provided early financial support to Civitas Therapeutics for the development of an inhalable dry-powder formulation of levodopa for acute treatment of “off” episodes. The organization also helped to finance Phase II clinical trials for NeuroDerm’s continuous, subcutaneous liquid dose of levodopa/carbidopa, a product that could supplant oral levodopa/carbidopa in moderate to severe patients by offering steadier therapeutic dosing and fewer “off” episodes as a result.

Both companies have reached pivotal catalysts recently. In September, Civitas was acquired by Acorda Therapeutics Inc. for $525 million, six months after reporting promising Phase IIb data on the inhaled drug CVT-301.

NeuroDerm, taking a different route, launched an initial public offering Nov. 3 after releasing positive Phase II data on its lead candidate, ND0612L, at the MJFF Parkinson’s meeting in October. The Phase II data demonstrated that treatment with ND0612L resulted in a clinically significant reduction in fluctuations of plasma levodopa concentrations, a two-hour reduction over placebo in “off” time, improved sleep and global clinical improvement without an increase in dyskinesia.

NeuroDerm netted $41.5 million through the sale of 4.5 million ordinary shares at $10, below the company’s expected $13-16 range, but enough, according to the company, to run pivotal trials on both of its Parkinson’s candidates, the low dose ND0612L for moderate Parkinson’s disease and a high-dose version, ND0612H, for severe Parkinson’s disease [See Deal].

“Following the IPO, we have the funding required to give us the flexibility to carry out our plans,” NeuroDerm CEO Oded Lieberman said. That includes several “big ticket” clinical trials in 2015, he added.

Acorda intends to move CVT-301 into Phase III testing in early 2015, with an NDA targeted for 2016. The specialty pharma believes CVT-301 could be a $500 million peak sales opportunity.

“We looked at a lot of things along the way, and this stood out pretty quickly as being special,” Acorda CEO Ron Cohen said of CVT-301.

The company sees significant commercial potential for the drug because more than 70% of the 1 million people with Parkinson’s in the U.S. are treated with levodopa and about half of them experience “off” episodes within five years of starting treatment, the firm said.

“The problem with levodopa when you take it by mouth is it is very poorly absorbed,” Cohen said. “You never know when it is going to fail.”

CVT-301 was developed with Civitas’ ARCUS pulmonary drug-delivery technology, which was originally studied for the development of inhaled insulin by Eli Lilly & Co but scuttled. The inhaled version of levodopa is not intended to replace oral levodopa as the standard of care, but rather be added to existing treatment regimens as an acute therapy when “off” episodes emerge.

Data from three human trials showed CVT-301 quickly and reliably treated “off” episodes, according to Acorda. Data from the Phase IIb study of 86 patients met the primary endpoint of mean improvements in the unified Parkinson’s disease ratings scale (UPDRS) Part III motor score versus placebo at time points ranging from 10 minutes to 60 minutes post-administration.

A Competitive Race For Acute Therapy

Acorda could face competition in the acute treatment market, however. Cynapsus Therapeutics is similarly developing an acute treatment for “off” episodes, only the company’s technology is a thin sublingual filmstrip formulation of the dopamine agonist apomorphine, which has been marketed in the U.S. since 2004 as Apokyn. It is currently sold by Britannia Pharmaceuticals Ltd.

Apomorphine is the only dopamine agonist approved for acute symptoms, but the currently marketed drug has limitations. It is delivered as a subcutaneous injection, which is particularly burdensome to Parkinson’s patients in the midst of an episode. It also causes severe nausea in some patients and is maintained in a highly acidic state, which can cause painful injection site reactions.

As a result, its current use is quite limited. Only about 3,000 to 4,000 patients in the U.S. are using the injected form, according to Cynapsus CEO Anthony Giovinazzo.

“Its delivery is inconvenient and its delivery can be painful, especially if you are injecting three or four times a day,” he said. Cynapsus believes its sublingual formulation addresses the drawbacks of the current drug.

The company reported positive results from a small dose-ranging Phase II study Nov. 22, showing that of 16 treated patients, 14 were able to convert from “off” to “on” following treatment with the drug, APL-130277. The onset of clinically meaningful improvement was seen in as early as 10 minutes and lasted up to 90 minutes, while the mean time to “on” was 22 minutes.

Cynapsus believes that it has successfully found a way to reduce the high acidity and limit irritation as well. No irritation was reported in a study in healthy volunteers who have taken the drug or in the Phase II study, but FDA has still requested the company run a study to evaluate irritation in Parkinson’s patients. Following the most recent study results, Cynapsus said it plans to move forward with a pivotal study, which will form the basis of a regulatory filing via the 505(b)(2) pathway in 2016.

The firm is hoping to eventually sign a commercial partner for APL-130277 and Giovinazzo said Cynapsus has confidentiality agreements signed with several potential partners.

The Chronic Market

NeuroDerm’s 24-hour continuous liquid formula of levodopa/carbidopa could be more impactful, however, if it demonstrates more consistent efficacy versus the oral combination without increasing side effects in a larger clinical trial.

“The opportunity for the past few decades has been continuity in levodopa penetration. People tried everything imaginable and it was clear that the oral route was not a good route and other routes should be explored, primarily continuous administration,” Lieberman said.

Both the company’s low-dose ND0612L and high-dose ND0612H are drug-device combinations. NDO612L is administered subcutaneously through a fixed-dose belt pump that operates 24 hours a day and can be preprogramed to the desired delivery profile. ND0612H is administered through a similar device, but one that delivers the drug through two insertion points.

ND0612H is designed to be an alternative to surgical interventions for severe patients who no longer respond to oral therapy or ND0612L. These patients usually have limited treatment options other than surgical interventions, including deep brain stimulation, in which an electrode is implanted in the brain, a procedure fraught with risk, or potentially treatment with AbbVie Inc.’s Duodopa, a gel formulation of levodopa/carbidopa that is delivered directly to the duodenum or upper area of the small intestine via a surgically placed pump and tube.

Duodopa is approved in Europe but has not yet been approved by FDA. The company received a “complete response” letter for the drug initially, refiled and expects action in early 2015.

Non-Motor Symptoms: An Underappreciated Opportunity

Aside from motor symptoms there are other drugs in development for the non-motor symptoms of Parkinson’s disease, like Acadia Pharmaceuticals Inc.’s Nuplazid (pimavanserin), a selective serotonin inverse agonist targeting 5-HT2A receptors, in development for Parkinson’s psychosis. The company is targeting a regulatory submission for the drug in the first quarter of 2015. Acadia persevered testing the drug in the clinic using novel endpoints. It had to change its study design after an initial failure, but emerged with positive Phase III data in 2013 Also see "Acadia’s Persistence With Pimavanserin In Parkinson’s Psychosis Pays Off" - Pink Sheet, 16 April, 2013..

Nuplazid would be the first drug on the market specifically for Parkinson’s psychosis, an overlooked segment of the market, according to the MJFF. Atypical antipsychotics used to treat the general patient population aren’t suitable for Parkinson’s patients because they interfere with the dopamine receptors. Nuplazid has received “breakthrough therapy” designation from FDA.

New drugs still have a long road to go until they reach the market, but the activity signals increased investment in Parkinson’s disease on the part of the pharmaceutical industry. More significant investment will be required to discover biomarkers of the disease and potential disease-modifying drugs.

“I have seen much more activity from biotech and pharma in Parkinson’s disease in the last two to three years,” MJFF’s Sherer said. “If I could wave my magic wand I would hope that [industry] would not be as fickle. It seems like people bounce in and out of Parkinson’s. I think if we could make a long-term commitment, we would make a lot more progress more quickly.”

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