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In the Pipeline: Therapeutic Agents

Phase I:

  • AAV2-hAADC. A gene therapy that works by allowing cells in the body other than neurons to process levodopa.
  • Donepezil (Aricept®). An Alzheimer’s therapy being tested for dementia and mild cognitive impairment in PD.
  • IPX203. An updated formulation of RytaryTM, this intermediate-release formulation of carbidopa/levodopa is intended to improve upon the existing drug.
  • OXB-102. A gene therapy that modifies neurons so that they produce dopamine.
  • ODM-104. A COMT inhibitor that enhances the effects of levodopa by blocking the COMT enzyme.

Phase II:

  • PF-06649751. A dopamine agonist designed to offer fewer side effects than currently-approved drugs in the class.
  • SYN120. A new class of combination drug (dual antagonist of the 5-HT6 and 5-HT2A receptors) being tested for treatment of cognition and psychosis in PD.

Phase III:

  • APL-130277. A new formulation of an existing PD drug, apomorphine, that is placed under the tongue for rescue from “off” periods in PD.
  • CVT-301. An inhaled form of levodopa used as a rescue for “off” periods.
  • Istradefylline. An A2A receptor antagonist, already approved in Japan, that is designed to reduce “off” time and suppress dyskinesias.
  • NDO612H. A formulation of levodopa delivered through a subcutaneous pump (needle placed just under the skin) to even out symptom fluctuations.
  • Tozadenant. An A2A receptor antagonist designed to reduce “off” time and suppress dyskinesias.
  • Vercise Primary Cell (PC) Deep Brain Stimulation system. A new DBS surgery technology that aims to reduce side effects.

Phase IV:

  • Rivastigmine tartrate (Exelon®). The only medication approved by the FDA to treat dementia in PD; it is now being tested for its potential to treat mild cognitive impairment.

In the Pipeline: Neuroprotective Agents

Phase I:

  • AAV2-GDNF. A gene therapy treatment designed to boost levels of GDNF, a naturally occurring protein that may protect dopamine neurons in the brain.
  • BIIB054. An immunotherapy that clears alpha-synuclein, a protein whose build-up is thought to contribute to PD.
  • NPT200-11. A drug designed to stabilize the brain protein alpha-synuclein, whose misfolding is related to PD.
  • PRX002. An immunotherapy that clears alpha-synuclein, a protein whose build-up is thought to contribute to PD.

Phase II:

  • Nilotinib (Tasigna®). A drug approved for treatment of blood cancers being tested for efficacy and safety due to possible serious side effects.

Phase III:

  • EGCG. A compound found in green tea that works by stopping alpha-synuclein clumps from forming in the brain.
  • Isradipine (Prescal®). A calcium channel blocker that is approved for treatment of high blood pressure.
  • Inosine. A nutritional supplement that converts to urate, a natural antioxidant found in the body. A phase III trial recently completed enrollment.

Phase IV:

  • None.

What's in the PD Pipeline?

When will newer and better medications be available for people with Parkinson’s disease (PD)? How will they help you or a loved one who lives with PD?

We cannot know these answers for sure, but we can observe the possibilities by looking at the research pipeline — the process by which researchers find and test new treatments.

Currently, scientists are focusing on two major categories: therapies that aim to ease the symptoms of PD, and those that show promise to slow or stop its progression. Treatments in both categories are making their way through the pipeline. While it is difficult to predict which ones will come to market next, we can look at trends to see where we are now and where we might be in the future.

The Drug Development Process

Scientists typically identify new medicines in one of two ways. One is to test compounds that are already approved by the US Food and Drug Administration (FDA) for use in treating other diseases to see whether they might also work for Parkinson’s disease. The other is to theorize a new pathway that may be applicable to Parkinson’s disease, and then to find a compound that can be developed to target it.

Under both approaches, the therapy must travel through a multi-step process before it can be approved for the market, and reach the people who live with PD.

Basic/preclinical research. In this phase, scientists look at the building blocks of PD (the brain, neurons and chemical reactions) seeking clues to help us better understand the disease. They identify new compounds that have potential to treat PD, and test them — first in simple PD models, such as cells in a Petri dish; later, in more complex models, like yeast and fruit flies; and then, in complex models, such as rats.

Clinical trials. Once a potential new drug has been “validated” through animal testing, it may move to the phase where it needs to be tested on humans, called clinical trials. Clinical trials typically proceed through four phases.

  • Phase I: A drug is tested in 10 to 30 people for safety.
  • Phase II: A drug is tested in a group of 50 to 150 people for safety and efficacy in treating PD.
  • Phase III: A drug is tested, typically in a group of 300 people (but as many as 3,000) at multiple locations. This is the definitive study which determines whether a drug is both safe and effective — and therefore deserves FDA approval — or whether it falls by the wayside.
  • Phase IV: A drug, after it has been approved, may be monitored in a “post-market” trial to find out more about how it works or if it has additional uses.

(To view a larger image of the pipeline, click here.)

Recent Successes & Disappointments

In less than two years, three new PD therapies have emerged from the pipeline and received FDA approval. Two provide new ways to deliver carbidopa/levodopa, the gold standard medication for PD, while a third addresses symptoms of Parkinson’s disease psychosis.

  • Carbidopa/Levodopa Extended-release Capsules (RytaryTM). This extended-release formulation of carbidopa/levodopa aims to reduce “off” time for people who experience this difficulty when taking other levodopa-based PD therapy.
  • Carbidopa/Levodopa Enteral Suspension (DuopaTM). This gel form of the drug is pumped directly into the intestines to provide continuous therapy and avoid wearing-off. It requires the surgical placement, in the stomach, of a tube through which the drug is delivered.
  • Pimavanserin (NuplazidTM). This is the first drug to be approved for treatment of PD-related symptoms of psychosis, such as hallucinations and delusions.

In addition to the approval of new Parkinson’s treatments, we have seen the approval of new uses for an existing treatment. Deep brain stimulation (DBS) surgery, which was originally approved for advanced PD in 2002, has now been approved for earlier stages of Parkinson’s disease. The surgery is available to people who have lived with PD for at least four years, and who are experiencing either (i) recent onset of motor complications, or (ii) motor complications for a longer duration that have not been adequately controlled by medications.

By contrast, take a look at the following medications. What do they have in common? The answer is that each of them showed promise in the early stages of research, but in later-stage trials, were shown to be ineffective.

  • AFQ056
  • Cere-120
  • Cogane
  • Coenzyme Q10
  • Creatine
  • Preladenant
  • PYM50028
  • Ubiquinone

It is disappointing that these drugs didn’t prove effective in treating PD, but it is important to know that the work done to test them is helping to inform new research.

Pipeline Trends: Therapies to Watch

After a drug has been shown to be safe and effective in a phase III clinical trial, its sponsors must submit a New Drug Application (NDA) to the FDA. If the FDA approves the application, the drug can be marketed and sold in the US. Right now there is one NDA pending review by the FDA. Look for news about this drug soon.

  • Safinamide (Xadago®). An add-on drug taken with levodopa to extend “on” time. It is approved in Europe.

Pipeline Trends: Therapeutic Agents

Currently, there are many therapies on the market that help to ease the movement symptoms of Parkinson’s disease. In the therapeutic pipeline (see first box at right, top of page), scientists are testing new medications and new formulations of existing medications to help better control Parkinson’s movement symptoms, lessen side effects, or treat symptoms for which effective medications do not exist (e.g., cognitive issues).

For example, most people with Parkinson’s are familiar with carbidopa/levodopa, the gold-standard medication for PD that is often prescribed as Sinemet®. Sinemet affects the dopamine system in the brain. Two therapies in the pipeline test new ways of taking the drug (for example, with an inhaler) with the goal of overcoming challenges like “wearing off.”

Meanwhile, a new class of Parkinson’s drugs called A2A antagonists have been working their way through the pipeline as well. Unlike other PD drugs, A2A antagonists do not affect the dopamine system. Thus, many in the Parkinson’s community are hoping the drugs may help to improve PD symptoms and enhance the effects of levodopa, without worsening dyskinesia.

In addition, gene therapies for PD continue to be tested. In this type of treatment, a harmless virus carries new genes into the brain cells affected by PD to either promote dopamine production (to help treat symptoms) or boost levels of substances that protect brain cells (to potentially stop the disease).

Another approach to finding more effective Parkinson’s therapies is finding ways to improve deep brain stimulation surgery. Researchers are testing DBS devices that may better focus electrical stimulation on specific points in the brain, or target new areas of the brain altogether. The goals of these approaches are to reduce side effects and address symptoms like gait and balance difficulties.

Pipeline Trends: Neuroprotective Compounds

People with Parkinson’s know all too well that we urgently need therapies that can slow or halt disease progression. Although to date, none have been proven to do this, some new approaches are working their way into early clinical studies (see second box at right, beginning halfway through the page).

Several of the potentially neuroprotective compounds in the PD pipeline focus on alpha-synuclein, the protein that forms toxic clumps in the brain cells of people with PD. Potential therapies would harness the immune system to clear alpha-synuclein or use vaccines to prevent or halt alpha-synuclein build-up. In addition, a few others — for example, isradipine — have been used for years to treat other health conditions.

A Look Ahead

It is difficult to predict which potential therapies will work and which will not. For every potential therapy that enters the process, one in a thousand will end up being approved for PD. While we can’t know exactly what’s next, we can be optimistic at the level and type of research ongoing for Parkinson’s, all of which aims to improve and more importantly, reverse the course of Parkinson’s for all of those living with the disease.

Questions?

Do you have more questions about the PD pipeline? Ask the experts your questions via email or call our HelpLine at (800) 457-6676.