MDS 2022 | IkT-148009 as a potential disease-modifying therapy in Parkinson’s disease

So IkT-148009 was developed in-house. It’s a highly selective brain penetrant inhibitor of a class of enzymes called the Abelson tyrosine kinases. We frequently refer to them as c-Abl inhibitors. It’s quite unique in this class. There are a number of drugs that target mutant forms of c-Abl to treat certain types of cancer, the most famous of which is a drug called Gleevec or imatinib. But the problem is with all of those drugs that they have high toxicities, and those toxicities emerge from the fact that they inhibit all of the members of the Abelson tyrosine kinase family. 148009 is unique in that it only inhibits what are known as the non-receptor tyrosine kinases, those that are involved in signaling pathways that are driving the defects associated with Parkinson’s disease in our view.

Well, we just completed what has been known as the 101 trial. It was a Phase I and Ib study in 88 healthy subjects of the same age range as Parkinson’s patients and 14 Parkinson’s patients who had mild to moderate disease that also were still on all their symptomatic medications. And the purpose of that trial was to measure safety, pharmacokinetics like drug concentration as a function of dose, and tolerability. Drugs in this class, this Abelson tyrosine kinase class, usually cause a lot of problems, GI problem. So you have nausea, diarrhea, vomiting in half of everybody that they just have to put up with. Usually you see a lot of anemia. You see other disturbances in blood cell parameters. 148009 had none of these problems. That was in part by design, the ability to limit. The selectivity of the enzymes that 148009 inhibits also meant it did not inhibit collateral enzymes that could give rise to these bad side effects.

So all of a sudden we could give that drug orally once daily. You had very large concentrations in the bloodstream. No meaningful side effects were observed either in patients or in healthy subjects up to a large dose. And because what are known is the exposure, so a measure of the overall spread of the drug in your body, were so high, we were worried that this would give rise to long-term side effects. But we’ve recently completed long-term safety and tolerability studies separately from the clinic, and those studies also say not much to worry about or nothing to worry about so far. So we began then with the 201 trial that began in late May of this year with our opening the first site. It’s a three-month dosing trial.

The reason we’re using three months instead of something much longer, which many investigators have often used, is because in a three-month trial, we can get safety data on long-term dosing of this drug at a high concentration, which we need to justify going into a year-long dosing trial. And we’ve also learned from our animal models, again, thinking back, what was the basis of doing this work, we could see this functional recovery in the brain or other organs in the body in under two months. So three-month dosing may not be as successful as it was in the animals. We can’t know this.

But we should see the beginnings of many of the Parkinson’s-related disease assessments we make, starting to head in the direction of resolution, how much resolution we see, how successful it’ll be. We don’t have any idea, but we’re very encouraged because everything thus far has matched our expectation because we did all of this underlying scientific discovery work that gave us a better foothold on saying, “I’m going to go in the clinic and spend millions of dollars, and I’m not going to fail just because I didn’t know whether this thing would be successful in first place.” Highly validated mechanism of action, well understood class of medication in human beings. That gives us a better chance of success in our view. And we’re encouraged.