What would you do if...
You discovered a transformative way to treat Parkinson's Disease?
Tackling Parkinson's Disease
with focus on halting and/or reversing disease progression
One of my favorite people suffers with Parkinson's Disease (PD). So as a doctor and friend, I began to study PD to help him navigate the disease and the health care system. PD is a horrible disease; after it gradually takes away your ability to move and care for yourself, it starts to affect your ability to communicate, understand or think normally.
But then something happened I did not expect. As I dug deeply into the scientific literature, I started to see the disease differently. Perhaps that should not be a surprise, as I learned long ago that doctrine is not always right, and that looking at diseases from different perspectives can bring unique insights. For example, I learned decades ago as a cardiologist that a person's experience with a treatment can be completely different when looking at the effects after a dose or two compared to what the treatment does weeks or months later.
What happened? I discovered a new way to treat Parkinson's Disease (PD).
The standard teaching (since the 1970s) is that patients with PD suffer because a deficiency of dopamine, and therefore, that dopamine (in the form of levodopa) should be supplemented or stimulated. However, studies show that the individual neurons vital for our ability to move any muscle are producing near-normal amounts of dopamine even in the end stages of PD. At the same time, these neurons cannot protect themselves from dopamine-related toxicity as can normal neurons, so the small number of living neurons to control movement become more dysfunctional and die because of the dopamine they are producing.
With diseases having similar cell physiology and pathology, we've learned that the best long-term outcome is realized when the average levels of the neurotransmitter (in this case dopamine) are reduced while still allowing for temporary increases as activity requires.
I figured out how to control dopamine levels according to this model, which will protect the critical and delicate neurons deep in the brain responsible for the disease, and allow them to function better so people can function better.
Perceptions and Possibilities
Levodopa is a seductive therapy. The drug typically produces dramatic benefit for patients with PD, allowing those who cannot move to move. But the research over the past 40+ years shows without doubt that levodopa and drugs that act similarly are palliative. The disease progresses and eventually the drug benefit wanes or it produces intolerable side effects.
As I read the early publications, including significant work written in German, I began to see the disease differently. The standard teaching is that PD patients suffer from dopamine deficiency and therefore require therapies that increase dopamine. And these early papers showed that the critical region of the brain that controls movement had only 10% of the usual amount of dopamine by the time people died with end-stage PD. The studies also showed that the cells that were most critical - the dopaminergic neurons of the basal ganglia - were only sparsely present, and many were not able to make dopamine. So that meant that on a per cell basis, these cells were making near-normal amounts of dopamine.
If there are fewer cells making dopamine, and each producing only normal amounts, it makes sense to augment dopamine, except for two critical facts.
First, dopamine is toxic to the very neuronal cells that synthesize it. And in PD, the cells are less able to protect themselves from the toxic effects of dopamine, leading to cell dysfunction and death. Normal amounts of dopamine are more than the cells can tolerate in PD.
Second, what makes sense immediately does not always prove beneficial long-term. Cardiologists understand this, particularly those focused on congestive heart failure, a disease with normal and pathologic cell biology that parallels PD. Consider beta-blockers - from the 1960s through the 1990s, they were contraindicated for patients with heart failure due to established risks when administering them at standard (full) doses as well as because when beta-agonists were administered, patients could get up and walk around with less shortness of breath. I led the first phase 2 clinical trial of the beta-blocker carvedilol (Coreg) that challenged this paradigm and eventually proved beta-blockers can be administered so they don't cause problems early while over the long-term, halt and/or reverse progression of heart failure. One needs to be willing to look beyond the initial effects to understand the potential impact on the biology of disease over long-term, and this is so in PD as much as in heart failure.
Thus, I saw a different model of disease, taking a page from other diseases where immediate and long-term impact of therapies are discordant. In this model, dopamine is the bad-actor, and reducing - instead of augmenting - its levels within key neurons is the goal, forgoing early reversal of symptoms to realize long-term benefit.
Proof of Principle and Path Forward
How could I leverage my experience in heart failure to PD?
After studying the cellular pathologies of both diseases, I sought a way to understand how antagonizing dopamine could affect patients with PD. In PD, this is possible by blocking the enzyme that neurons use to synthesize dopamine. As with heart failure, cells bathed by high levels of a toxic neurotransmitter (norepinephrine in heart failure and dopamine in PD) will suffer progressive dysfunction and eventually death. However, these cells do need to retain the capacity to release the neurotransmitter at levels that produce a response. This can be thought of as lowering basal levels while incompletely blocking synthesis, release and receptor binding.
In the late 1970s, a compound was developed and eventually approved by the FDA for treating a complication of a rare cancer that appeared to be an ideal therapeutic for treating PD. The drug alpha-methyl-p-tyrosine (AMPT) seemed ideal - it blocked the synthesis of dopamine in neurons. Its pharmacology and safety were known, it was on the market since 1979 and it reduced but did not shut off dopamine synthesis in the brain. Scientific studies showed that it protected dopaminergic neurons in two animal models and one cell model, providing lab evidence of "Proof of Principle."
How could I recruit PD experts to test my approach/treatment?
It's not easy to get experts to admit they might be mistaken in their assumptions. PD experts have been teaching and treating on the premise that more dopamine is optimal, when data support my view that less dopamine is optimal.
I expected difficulty finding PD experts who were open to such a contrarian idea. But I quickly found several bright, accomplished, respected PD experts who are excited to pursue this path in clinical trials.
How could I leverage my insights from working within the FDA?
With this repurposed drug, I approached regulators and received informal feedback that identified time and cost efficient paths to market, and specifically that would allow for initiation of clinical trials within months of starting the process. I connected with several PD experts who were excited about conducting the initial clinical trials. And I used my expertise in designing and executing clinical trials to develop a study protocol and detailed financial models.
What was left to put in place? Funding.
In the 1990s, scientists started to publish clinical studies suggesting that an old drug for treating high blood pressure in adults could be useful for treating ADHD in children. By the early 2000s, Shire started its development program for this drug (guanfacine) and launched in 2009. At the time, there was no patent protection for the drug and there were companies selling it as a generic. Following approval, Shire had exclusivity for 3 years and at peak, earned over $500MM annually.
Different from Shire, I filed a Method of Use patent and am currently working on a manufacturing process to allow for AMPT to be administered once daily instead of the current version that is administered 4 times a day. As Shire did, I expect to pursue FDA approval under the 505(b)(2) pathway and secure 3 years of exclusivity. With over a million suffering from PD in the US and another million in the EU, a dramatic and transformative impact is possible for those suffering from PD (translated for investors, the market opportunity is significant).
Pitching Is Not About Your Batting Average
When I look back, presumably after the drug is on the market helping people with PD, there will be three things I am doing now that will make me proud.
Number 3 is the key. I am not trying to get into the Hall of Fame by having a stellar batting average. My mission is to get the critical hit that enables the mission to advance. If my batting average were 0.003, and I were able to launch the first clinical trial because I got the one "yes" that provided the funding needed to start clinical trials, then I would consider the project astoundingly successful.
Does it matter that the proposal has not yet been embraced by two billionaires, a couple of foundations, tens of VC firms, countless Angel investors and a handful of strategics? No. Have they heard the last of me? Absolutely not. Should my friend give up on me? Never.
The stakes are too high to give up or worry about how many rejections I must endure. For this mission, I only need one "yes."