Mechanisms of Action

For any drug, we want to understand how it works - the mechanism or action. As doctors, that's reasonable because it influences the drug's use; determining when the drug is most important, anticipating the timing of the effects (good and bad) and predicting interactions with other drugs, amongst other important questions.

But the reality is that while we believe we know the mechanism of action for the drugs we prescribe or test, it may be more belief than proven certainty that we know the actual mechanism of action - as opposed to having proof a drug has a specific action inside the body but not having proof that that action is responsible for the benefit of that drug.

Consider statins as an example. We "know" that they reduce blood levels of the bad cholesterol (LDL) and presume that to be their mechanism of benefit. However, within years of the drugs being approved and widely used, it became evident that they did more than lower bad cholesterol levels, including anti-inflammatory effects and reducing the likelihood of blood clot formation. We know statins cause these three actions (and others), but we don't know which is the reason they work - or if only one of these actions is the reason.

Apologies that I focus on cardiology medicines, but the same is true with the medicines to lower blood pressure called ACE inhibitors. Is their benefit because they lower the production of a hormone called Angiotensin II? This hormone causes our arteries to narrow and thereby raises the pressure within them, and reducing its amount does the opposite. The indirect effect is to reduce another substance, norepinephrine, and by doing so, also lower blood pressure. In addition, this type of drug reduces the breakdown of bradykinin. More bradykinin relaxes the arteries, widening them and lowering the pressure within them. Then there are the beneficial effects of the drugs on the chemical composition of the walls of the arteries. Some of us are old enough to recall the description of the blood vessels in people with high blood pressure as "hardening of the arteries." ACE inhibitors reverse this.

Starting to get the picture? No one knows if one of these mechanisms or some combination of these mechanisms are why drugs work. But it remains important to understand the relevant mechanisms of action - rather than a simple description of a mechanism of action, or as the FDA requires, identification of a putative mechanism of action.

RB-190's Mechanisms of Action

In laboratory studies (also labeled as pre-clinical studies) show at least

RB-190 blocks cell death - by at least three different biological pathways, reverses lysosomal function, blocks alpha-synuclein deposition, preserves axon density and reduces oxidative stress (summarized here). Do I know which of these are going to be the most important in people? No. Do I expect to learn which is most important in the clinical studies? No. There are no methods to allow measurement of any of these parameters in people. So we may never know which is the reason the drugs would work.

I don't believe this lack of knowledge will be a problem for doctors or patients because it is not as important to understand how a drug works as it is to understand how the clinical effects of a drug are manifest. By that I refer to this scenario. RB-190 can lower blood pressure and is most likely to do this maximally about 1.5-2 hours after taking a dose. If a person feels dizzy when standing up about 1-5-2 hours after taking a dose, then we "know" that the drug is causing that effect and adjustments need to be made to eliminate this side effect. That's what we need to know to help clinicians and patients.

People with Parkinson's understand this too well. Many of you take levodopa-containing medicines and you can feel when the medicines are kicking in and when they are wearing off. That enables you to learn how frequently and in what settings you may need to take another dose of the medicine.

The Message

When I am asked how RB-190 works, my answer has two parts. (1) We discovered that the key brain cells that control movement experience Parkinson's as a disease of dopamine excess, and therefore toxicity. (2) RB-190 prevents the dysfunction and death of these key brain cells, which would be the explanation if clinical data were to show that the drug reverses disease progression and improves movement.

We're excited for the discoveries we anticipate over the next 2-4 years. Though we also feel as though we are moving too slowly despite how much we are accomplishing. Stay tuned.