Why should dopamine reduction work for Parkinson's?

While I've discussed before, I've been asked by several readers to explain why dopamine reduction should work for Parkinson's.

Feeling better with dopaminergic therapy. At least at first.

Most people with Parkinson's recall the impact when they were first treated with levodopa or a dopamine agonist. There was a noticeable and prompt improvement in movement, which seems to prove that Parkinson's is a disease of dopamine deficiency.

In a prior post, the reason for this initial benefit of dopaminergic therapy is explained. In short, the improvement is due to the way a drug affects the dopamine receptors whether dopamine levels are high or low rather than the day a drug allows normal biologic function to return by removing a toxin. Randomized, controlled, clinical trials show that dopaminergic therapy improves quality of life compared to placebo - but these studies only show the effects last for ~9 months. And they show that in many cases, the benefit starts to wear off by 6 months.

There are no data showing that any dopaminergic therapies slow, halt or reverse the worsening of disease. We need to reevaluate how we treat Parkinson's if we want to discover a way to improve function and reverse the disease.

Dopamine-reduction therapy could conquer the disease.

As shared in a prior post, dopamine reduction therapy with a drug called RB-190 reverses disease pathology in each of the 9 research models of Parkinson's where it was tested. That's an impressive set of data, and coupled with the drug's established safety record (it was FDA-approved for treating a rare cancer) led the FDA to agree that the next step is a clinical trial enrolling people with Parkinson's.

How could dopamine reduction work?

In the article we published in the Journal of Neurology, we detail the scientific evidence showing how dopamine and its metabolites cause toxicity for the dopaminergic neurons - the brain cells that control movement.

We also detail how RB-190 reverses pathology in 9 models of Parkinson's. These data with RB-190 therapy show benefits in 2 ways: (1) reduced alpha-synuclein accumulating in the neurons and (2) brain cells prevented from being killed. Together these would stop or reverse progression of disease. In addition, the data suggest that RB-190 could restore mitochondrial function - which would restore normal function of these critical brain cells and reverse motor dysfunction.

How will we show that ?

Upon successful fundraising, we will launch a Phase 2A clinical trial and then treat a small group of people with Parkinson's. We plan to enroll people in the first clinical trial who have not received dopaminergic therapy and subsequently those who are receiving treatment, with focus on those with mild disease.

And while we are not moving as quickly as we'd like, we are making progress. We recently secured our first investor. We are making progress and getting closer to launch drug manufacturing.

What can you do to help?

If you try to discuss this with your doctor, they will likely tell you that reducing dopamine does not make sense for someone with Parkinson's disease. That is a reasonable way for an expert to respond to the idea. Keep in mind that your doctor has been studying and treating Parkinson's for anywhere from 5 to 30 years from the point of view that the disease is caused by dopamine insufficiency. While I'm willing to bet that most Parkinson's doctors have not read the scientific studies that show the promise of dopamine reduction therapy (by inhibiting the enzyme tyrosine hydroxylase with RB-190), you should not present this approach as being the solution - yet. Until we generate data in people that proves dopamine reduction is the best approach, let's not move past asking your doctor's opinion and risk seeming confrontational. You need this relationship.

Instead, let's consider the groups whose mission is finding a cure, or more fairly worded, a way to conquer and/or control Parkinson's and restore normal function. Should such an foundation, government agency or professional society be anchored in the traditional way of treating the disease when it is not working? Or should novel approaches - even those seeming inconsistent with current understanding of the disease - be given extra attention? What are the best ways to foster innovation and look for breakthroughs?

These are the questions I ask gently and respectfully when I engage with such groups. And I'll continue to ask such questions when speaking with experts at the International Movement Disorder Society meeting in Philadelphia later this month and the Michael J. Fox Foundation Therapeutics Conference next month. That's where I believe energy needs to be directed to create an environment where potential breakthroughs can be evaluated rigorously and quickly rather than needing to navigate extra barriers.

I should admit that I do not know that dopamine reduction therapy will conquer Parkinson's, but I do know that the current approaches continue to fail to do so. I also know that it is an uphill battle to convince the Parkinson's community that the approach we advocate (dopamine reduction) is reasonable to pursue. It doesn't help that I am a cardiologist with no formal training in neurosciences. That makes me an outsider - another hill to climb.

We need the funding environment to be more welcoming of potential breakthroughs. Ask your favorite foundation how they foster the evaluation and development of such therapies. Let's find a way to move this project forward as an test case of such a possibility, which may prove how to conquer the disease.