If Alzheimer's disease (AD) has been a graveyard for drug development over the past 10 years, Parkinson's disease (PD) has been on life support, limping along with mostly lackluster reformulations and extended-release versions of levodopa (L-dopa). The dopamine precursor became a clinically relevant treatment in the late 1960s based on research conducted by George Cotzias and colleagues, garnering Cotzias the 1969 Lasker Prize.

But instead of becoming the starting point to treat PD, L-dopa – often paired with other drugs to control specific symptoms or enhance its effect – has been the mainstay, crossing the blood-brain barrier and bathing the brain with dopamine. The drug has helped to alleviate motor symptoms associated with the disease in many patients but, potentially, at the cost of exacerbated cognitive and behavioral symptoms, now recognized as nearly equal contributors to the physical decline associated with PD.

Efforts to move beyond the L-dopa premise encountered multiple obstacles, from failures in the lab to funding shortfalls. Of nearly 1,800 drug trials in which PD was the primary indication, only 200 were phase III studies, according to Cortellis Clinical Trials Intelligence. In more than 960, the phase was not specified. Although some of those were large observational studies, most enrolled 60 or fewer patients and only 70 percent were completed.

Of approximately 300 PD drug candidates cited by Cortellis Competitive Intelligence (CI), only 36 were launched, with two more registered and two in pre-registration.

"I've been working in Parkinson's disease my whole adult life," said Bernard Ravina, vice president of clinical development at Voyager Therapeutics Inc., of Cambridge, Mass., and former medical director in clinical development at Biogen Idec Inc. He added, diplomatically, "The last decade or so has not yielded what people were hoping for."

Michael Jakowec, associate professor in the department of neurology at the University of Southern California and a member of the Society for Neuroscience, was more direct.

"Overall, it's been pretty disappointing over the last 10 years," Jakowec told BioWorld Insight. "I think there have been a lot of unimaginative approaches, reflecting a lack of novelty in the field."

Jakowec ascribed some of the shortfall to research cuts in PD at big pharma, leading "high-risk, exciting, cutting-edge targets to fall by the wayside."

'RENEWED ADVANCES' IN PD DRUG DEVELOPMENT

But Cortellis numbers also suggest the field may have turned a corner. Half of the PD drug candidates cited by Cortellis CI remain in discovery, suggesting a robust pipeline of assets. Moreover, drugmakers are moving beyond L-dopa. Although dopamine receptor agonists still represent the largest categories of PD drugs in development, biopharmas are producing compounds using mechanisms that provide more elegant symptom management and, increasingly, target the underlying disease.

"There are renewed advances in Parkinson's drug development, with a lot of focus on new targets and new innovation," said Todd Sherer, CEO of the Michael J. Fox Foundation for Parkinson's Research (MJFF).

He characterized those efforts as falling into three distinct buckets, beginning with iterative improvements in formulations for dopamine-based therapies that address motor control. Two of those drugs already crossed the finish line in 2015. Rytary (formerly IPX066), an extended-release oral capsule formulation of carbidopa/L-dopa developed by Impax Pharmaceuticals, of Hayward, Calif., and Abbvie Inc.'s Duopa, a carbidopa/L-dopa enteral suspension, both were green-lighted by the FDA in January.

Other companies are nearing the finish line with improved formulations. Prominent among those is Acorda Therapeutics Inc., thanks to its $525 million buyout of Civitas Therapeutics Inc. and phase III-ready CVT-301, an inhaled L-dopa formulation designed to treat motor fluctuations, or "off" episodes. The acquisition garnered a nomination for this year's Allicense Breakthrough Deal Awards. (See BioWorld Today, Sept. 25, 2014, and March 2, 2015.)

Among the others is Neuroderm Ltd., of Rehovot, Israel, which is going head to head with Duopa with continuous, subcutaneous delivery of liquid L-dopa/carbidopa combination candidates ND0612H for severe PD cases and ND0612L for moderate cases. (See BioWorld Today, Dec. 31, 2014.)

The next group of candidates, Sherer said, is emerging from companies addressing other neuro-receptor targets, not just for motor but also for nonmotor symptoms associated with PD. He counted among those Northera (droxidopa), which last year won a long-sought FDA approval for Chelsea Therapeutics International Ltd., of Charlotte, N.C., to treat neurogenic orthostatic hypotension, or NOH, associated with the disorder. (See BioWorld Today, Feb. 19, 2014.)

"There's a lot of work on serotonin receptors, glutamate receptors and other targets within the brain that may impact motor and nonmotor symptoms," Sherer told BioWorld Insight.

Indeed, scores of such targets are being explored, according to Cortellis CI, among them glial cell neurotrophic factor ligands, orphan nuclear receptor NURR1 agonists, NMDA receptor antagonists and sodium channel inhibitors.

And companies entering the space are nearly as numerous. In January, 2011 start-up Lysosomal Therapeutics Inc., of Cambridge, Mass., closed a $20 million series A round less than a year after securing a $4.8 million seed round. The company is testing a small-molecule glucocerebrosidase, or GCase, activator in Gaucher patients before broadening its approach to patients with Parkinson's who have GBA1 mutations. (See BioWorld Today, May 13, 2014.)

Last month, Merck Serono spinoff Prexton Therapeutics SA, of Geneva, raised €8.7 million (US$10 million) to move a metabotropic glutamate receptor 4, or mGluR4, agonist development program into trials in PD. (See BioWorld Today, Feb. 25, 2015.)

And a year ago, Neurophage Pharmaceuticals Inc. moved one step closer to initiating human studies for lead candidate NPT088, with the completion of a $17 million series D. In January, Neurophage added $10 million to the round and said it will move NPT088, which uses the company's general amyloid interaction motif, or GAIM, technology to target misfolded proteins, into clinical studies by the end of the year. (See BioWorld Today, March 26, 2014.)

Others include Neurolixis Inc., of San Diego, which is advancing the serotoninergic compound NLX-112, licensed from Pierre Fabre Medicament, of Castres, France, to treat L-dopa-induced dyskinesia, and Eboo Pharmaceuticals Inc., of Durham, N.C., which received a grant from the MJFF to advance cellular delta receptor agents in PD and depression.

Just last week, consumer testing firm 23andme Inc. set the PD world abuzz by disclosing the launch of a therapeutics group headed by former Genentech executive Richard Scheller, whose research interests address the rapid release of neurotransmitters.

23andme has a broad partnership with New York-based Pfizer Inc. and a narrower arrangement with Genentech, a unit of Basel, Switzerland-based Roche AG, looking specifically at fully sequencing a subset of the 11,000 individuals with PD who have submitted phenotypic and genetic information to the company. (See BioWorld Today, March 13, 2015.)

The next near-term success in that area could come from Newron Pharmaceuticals SpA, of Milan, Italy, and neighboring partner Zambon SpA, which resubmitted the new drug application for Xadago (safinamide) to the FDA at the end of 2014. The move came one week after the EMA recommended the PD treatment for approval, putting the company on course for EU and U.S. launches this year. (See BioWorld Today, Dec. 30, 2014.)

Xadago was the first new chemical entity in 10 years to get a positive opinion from the EMA in Parkinson's. The once-daily, orally available monoamine oxidase-B, or MAO-B, inhibitor blocks a key enzyme involved in the breakdown of dopamine and has been shown to have an effect on symptoms both in combination with dopamine agonists in the early stages of the disease and in combination with L-dopa at more advanced stages.

SYMPTOM MANAGEMENT SEEKS TO EXTEND 'HONEYMOON PERIOD'

Perhaps the most exciting work is occurring in disease modifying drugs, Sherer said, with the first two candidates targeting gene modification finally reaching the clinic.

PD is characterized by the death of dopamine-containing neurons that leads to motor deficits. Anatomically, the dying neurons contain clumps of protein known as Lewy bodies, composed of misfolded alpha-synuclein (alpha-syn). Inhibiting alpha-syn is the therapeutic approach pursued by Affiris AG, of Vienna, and Prothena Corp. plc, of Dublin, which are off to a running start with their immunotherapy approaches, now in phase I studies.

"Those are leading the edge in this area," Sherer said.

The PD space has high hopes for those candidates, and that enthusiasm is shared by big pharma. In 2013, Prothena inked a pact with Roche worth up to $600 million in up-front and milestone payments for its anti-alpha-syn antibody, PRX002. (See BioWorld Today, Dec. 12, 2013.)

In January, Neuropore Therapies Inc., of San Diego, also inked a potential $480 million global collaboration with UCB SA, of Brussels, to develop therapies aimed at slowing the progression of PD, although its NPT200-11 is a small molecule that targets pathogenic alpha-syn. That candidate is in preclinical development but expected to enter clinical trials this year.

Others within the gene therapy space include Uniqure BV, of Amsterdam, which made headlines in 2013 when CEO Jörn Aldag personally assisted in the surgery in which the gene for glial cell line-derived neurotrophic factor, together with its adeno-associated viral vector (AAV), was administered directly into the brain. Recruitment into the phase I study is expected to be completed this year. (See BioWorld Today, July 30, 2013.)

Oxford Biomedica plc, of Oxford, UK, has a PD gene therapy program in the clinic, and Sangamo Biosciences Inc., of Richmond, Calif., picked up Ceregene Inc.'s gene therapy assets in a 2013 buyout of the San Diego company. (See BioWorld Today, Aug. 28, 2013.)

Voyager is one of the newest entrants in gene therapy, but the company is backing into the area slowly, Ravina said, using its AAV platform to demonstrate proof of concept with lead program VY-AADC01 by seeking to replace aromatic L-amino acid decarboxylase, or AADC, and maintain lower required doses of L-dopa for patients while still providing reliable symptom management as the disease progresses. Lessons learned along the way will help the company direct its delivery of gene therapy.

"A number of attempts in the past were around trophic factors," such as neurturin and GDNF, Ravina explained. "They're clearly important for the development and maintenance of dopaminergic neurons, so the thinking in the past was that it was sufficient to deliver those proteins to the affected areas."

The problem, he continued, was that "very little of what was delivered actually got to affected tissues, and whatever got there didn't distribute very far." Although additional efforts have been made to deliver neurotrophic factors, the key takeaway from early failures was that "when you try to deliver things that will make neurons sprout but you deliver them late in the course of the disease, there's not much left to grow and sprout," Ravina said. "There's a fundamental principal of exposure in all of drug development. We have to be able to do that well, and if we do that well, it will open the window into more obvious disease-modifying approaches."

But frustration borne of the failure to develop disease-modifying approaches actually heightened efforts to improve symptom management in PD, according to Ravina, a scientific advisor to the MJFF.

"New formulations and even approaches such as levodopa infusions are actually pretty attractive," he told BioWorld Insight. "If you could get terrific symptomatic control that was durable, disease modification becomes less important. If you've got well-established, known pharmacology, can you make it work better later in the disease? If you can extend that honeymoon period, where patients usually do very nicely, even when they're 10 years in to the disease, that would be a nice accomplishment."

'GOOD, HEALTHY MIX' OF COLLABORATION, COMPETITION

One handicap to the PD field has been lack of funding, with much of the capital infusion coming from the MJFF and other nonprofits. Deals for PD assets involving stem cell and other cell therapies have been virtually nonexistent over the past eight years, according to Laura Vitez, principal business analyst with Thomson Reuters Recap, and deal volume in general did not gain traction over that period.

"The low-hanging fruit in stem cell therapy has been picked already," Jakowec agreed. "I think great advances are being made in stem cells in a lot of indications – diabetes, bone marrow and cardiac issues, for instance – but in terms of the brain, it's been very disappointing."

Neurology deals, in general, have been flat over the past five years, according to Recap's Vitez. Although that trend may be driven by bigger failures in AD and mixed messages from the FDA about pain medicines, "perhaps lack of progress in PD contributed, as well," she told BioWorld Insight.

But aversion to the inherently complex PD space also may be changing. Data tracked by the MJFF showed that approximately $23 million in initial funding from the foundation led to $2.285 billion in potential follow-ons, with $1.7 billion of that targeting symptomatic treatments in development, $562 million targeting disease-modifying therapies for alpha-synuclein and the rest going to disease-modifying therapies against other targets.

More PD programs are finding partners as well. For example, in 2013, Proteostasis Therapeutics Inc., of Cambridge, Mass., partnered with Biogen Idec to find drug candidates based on inhibition of Usp14 – implicated in diseases caused by aggregation-prone proteins, including PD – in a deal worth upward of $200 million. (See BioWorld Today, Dec. 10, 2013.)

Voyager, which closed its $45 million Third Rock-led series A in 2014, landed a potential $845 million deal just one year later with Genzyme, a unit of Sanofi SA, that includes the development of gene therapies across a range of indications, including programs for PD, Friedreich's ataxia, Huntington's disease and other central nervous system disorders. (See BioWorld Today, Feb. 12, 2014, and Feb. 12, 2015.)

More players mean more competition, but "we find there's a great balance in Parkinson's between collaboration and competition," Sherer observed, noting that big pharmas are collaborating with researchers, with biotechs and with each other to move the field along.

"I like to see collaboration around some of the fundamental issues," he added, "but I also like to see healthy competition so the science can advance more quickly. I feel like there's a good, healthy mix of both in the Parkinson's landscape."

'WE NEED TO HAVE BIOMARKERS' TO ASSESS TREATMENTS

One notable missing link to moving better PD drugs to market is a dearth of reliable biomarkers. Less than three years ago, the Parkinson's Disease Foundation funded 13 projects, with grants totaling $1.35 million. They included an enzyme-linked immunosorbant assay emerging from research conducted at Harvard Medical School and Brigham and Women's Hospital that could test blood samples to detect subtle differences in the shape of assembled alpha-syn protein.

The MJFF and the National Institute of Neurological Disorders and Stroke (NINDS) at the NIH also launched a collaboration called BioFIND, a multisite study focused on identifying PD biomarkers and designed to complement the MJFF's $45 million biomarkers study known as the Parkinson's Progression Markers Initiative and the Parkinson's Disease Biomarkers Program, a NINDS consortium. BioFIND is designed to build a clinical dataset and biologic sample set that scientists and clinicians can use for their own biomarker discovery research. (See BioWorld Today, Dec. 3, 2012.)

But those efforts are all for naught if the FDA squashes biomarker development like a bug on the floor. A report released last week by the Manhattan Institute for Policy Research concluded the agency has approved only four biomarkers since 2008, with two more under review. Meanwhile, 20 biomarker qualification packages stalled at the consultation and advice stage, according to Paul Howard, senior fellow at the institute and co-author of the report, who maintained that hundreds of potential biomarkers could be used to enrich clinical trials, serve as surrogate endpoints and pinpoint safety concerns. (See BioWorld Today, March 12, 2015.)

"There's definitely been a huge focus and sense of urgency around developing Parkinson's biomarkers," Sherer said, in large part due to the identification of new genetic targets. "We need to have biomarkers to assess those potential treatments."

The MJFF has worked, in collaboration with other organizations, to develop a process to measure alpha-syn in spinal fluid, and work is under way to develop an alpha-syn-based imaging agent.

"The genetic understanding of Parkinson's has pointed to potential biomarkers," Sherer said. "There's still a lot of work to be done in that area, and the need has become more urgent because of how quickly the therapeutic field is advancing."

Biomarkers that can identify PD at the earliest stages are "critical" to future drug development, Voyager's Ravina agreed.

"The thinking really is analogous to what's been seen with Alzheimer's disease and what's been seen with clear, monogenic disorders like Huntington's disease," he said. "We know from different kinds of studies in both of those indications that the disease process starts many years prior to the traditional diagnosis. It's easier to unpack the issue in something like Alzheimer's because we have an amyloid tracer and tau tracers now, so you can look at their relative progression compared to the clinical manifestations. In Parkinson's, we don't yet have an alpha-synuclein brain imaging tool."

'TO PROTECT NEURONS, WE CAN'T WAIT UNTIL THEY'RE ALL GONE'

Researchers also now understand that some of the characteristics once deemed risk factors for PD – mood, sleep disorders and impairments in smell, for instance – are more likely early manifestations of the disease, Ravina said. By the time most PD patients see a physician and are diagnosed, they're missing as many as 70 percent of their dopamine terminals and up to 30 percent of the actual cells. Researchers now are seeking to understand the time frame for the onset of PD and the correlation to more traditional motor manifestations.

"That earlier window, which is analogous to mild cognitive impairment, is going to be very important," Ravina predicted. "If we're going to protect neurons, we can't wait until they're all gone."

Many neuroscientists now believe that the ultimate treatment for PD consists of more than simply replacing neurotransmitters, Jakowec added.

"That's not going to cure the disease," he maintained. "It's a disease of the system and of the circuitry. When you lose circuitry, you have to start figuring out ways to put back those circuits. The brain does a very good job of that in early postnatal life, which is a very complex and challenging developmental stage, and consequently we get these behaviors that we hold onto for a long period of time. Parkinson's disease can't be looked at as one little Lego in the structure that can be replaced efficiently and prompt the system to fix itself. I think we've convinced ourselves that's not going to happen."

Recognizing that other manifestations, such as cognitive decline, are more than side effects of PD also may lead to better drug development, according to Jakowec, who is a staunch advocate of approaching PD holistically. He called the impact of diet and exercise alongside drug therapy "underappreciated" in PD.

"You can pick up cognitive issues very early in the disease, even before patients know they have them," Jakowec said. "One thing that's exciting about that is that you can begin to intervene earlier. If you think you have a potential new therapeutic target, you should be able to start going after it, and there's a lot of evidence to suggest that we can do that."

Understanding the presentation of the disease and its underlying causes also may allow researchers and drug developers to better differentiate PD patient populations when enrolling clinical trials and to target therapies more appropriately to patient subtypes, Sherer suggested.

Jakowec agreed. "The potential for data mining is important," he said. "We have a very poor grasp of gene environment and epigenetic interactions, and genetic profiles can be over-interpreted. We are more than just our genes."

Only about a dozen genes have so far been directly implicated in PD, but hundreds more are involved in neuroplasticity, "and there are probably thousands of genes that contribute to maladaptive phenomena," Jakowec pointed out. By keeping one eye on the role of environmental factors rather than targeting the expression of a single gene of interest, "we could get a lot of benefit across a spectrum of risk factors, which could be a huge contribution," he suggested.

Whatever the sweet spot, rapidly increasing understanding of the genetic underpinning of PD will continue to open new targets that may progress into drug development, experts agreed.

"What's really exciting is that, for the first time, we have the potential for treatments that might be targeting the true, underlying disease process in Parkinson's," Sherer said. "I'm very optimistic about the next 10 years."