Craig Lindsley, PhD, Director of the Warren Center for Neuroscience Drug Discovery talks about a new drug that may lengthen the time Parkinson’s patients have relief from their symptoms.
Interview conducted by Ivanhoe Broadcast News in 2022.
How is this new Parkinson’s drug different than other drugs that are currently available?
LINDSLEY: There’s been little innovation in Parkinson’s in the last 50 years since L-dopa and dopamine replacement therapies entered the market. This is fundamentally different. With some of the advances we’ve seen in deep brain stimulation and modulation of this pathway called the indirect pathway, where the Parkinsonian tremors are due to too much brake and not enough gas. This circuit, which is in a delicate balance, is dysregulated, which is why when people try to do purposeful movement, they get shaking because the brake is being applied as they’re trying to apply the gas. Through a lot of research over almost 20 years, we identified a receptor in this indirect pathway that is over activated. We can potentiate or activate a receptor at this circuit. It dampens that overactive signaling and this is the mGlu4 receptor. We’re potentiating with a positive allosteric modulator. This is different because it’s not dopamine replacement therapy. We’re targeting this overactive synapse and bringing that gas and brake back into balance.
How effective is this drug on that receptor?
LINDSLEY: Pre-clinically, it’s very effective. It’s a very potent molecule that gives significant potentiation to the receptor. We can see this in electrophysiology and native systems. We can see this in behavioral models of Parkinson’s disease, whether we look at haloperidol-induced catalepsy or 6-hydroxydopamine lesion rats. Those are two of the early gold standard models. Very robust efficacy and we’re very excited that this is now in phase one clinical trials and doing very well.
Has the trial started?
LINDSLEY: Yes. The phase one has started. We have done what’s called the single ascending dose where we gradually increase doses in healthy volunteer cohorts. We’re now, in the multiple ascending dose phase of that where we’re giving healthy volunteers the same drug dose for 14 days to look at safety, tolerability, as well as some biomarkers, looking at drug levels in the CSF. As soon as that is complete and we submit that to the FDA, we’ll be able to do a pilot phase one B trial in symptomatic Parkinson’s patients.
Where is the trial happening and how many patients are involved?
LINDSLEY: The phase one trials have been going on at worldwide clinical trials, a clinical trial CRO and that’s in San Antonio, Texas. This program has been in development since the center started in 2003.The Michael J. Fox Foundation and NIH funded it. We’d partnered with a couple of different pharmaceutical companies. What we see, a lot of times, is the market changes. There’re leadership changes and one of the first groups we worked with, their head of research exited. The new head of research, the first thing they did was decide to exit neuroscience. The project came back to us. One of the things I think is really great about Vanderbilt is when the project came back, it had so much potential, we didn’t want to partner with another big pharma that may change direction. So, they allowed us to do a startup. It was one of the first Vanderbilt spin out companies named Appello Pharmaceuticals. It’s based here in Nashville, and they’re the ones overseeing and executing the clinical trials. It’s great for us because the scientific leadership of the center is intimately involved with the company. We get to make sure that the drug is going to get into patients. A lot of companies are based in various parts of the country, but the big clinical CROs are in different regions. For phase one trials, for safety and tolerability, we just go with the best phase one unit.
Do you have any details on how many patients are currently in there?
LINDSLEY: It’s off the top my head, but 16 to 20 volunteers in the SAD and probably 20 to 30 in the MAD, the multiple ascending dose arm.
How long has the trial been going on?
LINDSLEY: Its’s been going on for about a year now. When you’re doing the safety tolerability to make sure that the compound that we’ve already shown in pre-clinical in animals in the GLB toxicology is safe and well tolerated, we have to do a lot of studies starting off with very low doses and increasing it to make sure it’s going to be safe and tolerable in humans. We also make sure we’re not going to do any harm to them by giving them the drug before we go into patients who already have some problems and we don’t want to exacerbate any issues. Phase one is typically done in healthy males. We don’t have to worry about any kind of reproductive issues. We do start taking in people anywhere in the ages from 18 to 50 just to get the pharmacokinetics and the exposure. We ask, “Does the drug have high enough exposure to engage the target and still be safe and well tolerated?”
What are the next steps after this?
LINDSLEY: We’re in the multiple ascending dose arm, right now, and we’re getting safety tolerability as well as some biomarkers that show us, we’re having good target engagement. As soon as we complete that, probably in the first quarter of next year, we submit those results to the FDA and request permission to proceed into the Phase one B where now we’re going to go into symptomatic Parkinson patients and see if the compound is efficacious.
Would you imagine it being in people with early-stage symptoms or moderate to late stages?
LINDSLEY: It’s going to be early and moderate. It’s going to be patients that are currently responsive to L-dopa therapy because for our compound, it should have standalone efficacy. But then, it should also allow us to be L-dopa sparing and to go on top of a lower dose of L-dopa. Because one of the big issues we have in Parkinson’s is as people are on L-dopa for a long period of time, it starts to lose efficacy. They start to have this bad on and off time. Even if our compound can just be L-dopa sparing, people can be on L-dopa therapy for a much longer period of time without the adverse events. We’re probably going to patients that are responsive to L-dopa, at least to begin with.
Will this help with the L-dopa making it more effective?
LINDSLEY: Yes, patients have a longer time span on it before it becomes ineffective, but also standalone therapy as well.
What impact do you think this will have for the patients and their families?
LINDSLEY: I think it’s huge because as L-dopa’s effectiveness starts to wane, they start to have uncontrolled movements and bradykinesia. But then, with long-term dopamine replacement therapy, you can induce a state of hyperdopaminergia, which is very similar to schizophrenia. Advanced stage Parkinson’s patients start to have hallucinations, delusions, disorganized behavior, sleep deficits. So, there’s a whole host of non-motor symptoms that can be the result of prolonged dopamine replacement therapy treatment. This would give us an option that is not dopamine based.
Is the drug called AP472?
LINDSLEY: Correct.
Is this drug supposed to be oral or through IV?
LINDSLEY: It is an oral drug. Everything for Parkinson’s patients, especially, you want to have a once-a-day oral drug. So far, the human pharmacokinetics we’re seeing is going to be supportive of once-a-day oral dosing.
How far away are you all from the clinical one B trial?
LINDSLEY: We are hopefully going to do that next summer, the second quarter. Then, if that looks positive, then we still have the potential to run the phase two trial in 2023 as well.
Is there anything else you feel is important for people to know?
LINDSLEY: I think one of the most important things to know is that I think some of the discoveries that are happening at Vanderbilt are things that could only happen in an academic environment. A lot of us came from Big Pharma, and in Big Pharma, because of timelines, we would typically have at the most, two years to start a novel project, novel target and get to a clinical candidate. We would not have the time to really understand the target completely and the complex biology as well as what a clinical candidate should look like for that target. We’re just kind of sprinting. In the academic and drug discovery environment, you can take time with grants and things from the Fox Foundation and NIH. With those five or ten years, the mechanism and all the caveats, so that when we do move it into a drug discovery situation, we know what a candidate should look like. It’s a very thoughtful and informed process that isn’t solely beholden to timelines. It may take us a little bit longer, but I think the compounds we produce really have the legs to move through clinical development without hiccups and hopefully impact patients.
END OF INTERVIEW
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