Extended Dosing Improves Safety of IkT-148009, Animal Studies Show

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by Steve Bryson, PhD |

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The safety profile of IkT-148009, an investigational oral medication for Parkinson’s disease, improved the longer the drug was dosed, demonstrating target selectivity, according to interim three-month animal data.

The ongoing toxicology studies, conducted by the therapy’s developer, Inhibikase Therapeutics, were designed to meet regulatory requirements for regular dosing in humans, including daily administration in rats for six months and non-human primates for nine months.

Following a review of these results by the U.S. Food and Drug Administration (FDA), the company said it expects to initiate a Phase 2a study in 2022 to evaluate IkT-148009 in up to 120 Parkinson’s patients over three months.

“These learnings, coupled with the absence of clinically significant adverse events in our Phase 1 study, add to our growing confidence in the safety and tolerability of IkT-148009,” Milton H. Werner, PhD, president and CEO of Inhibikase said in a press release.

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IkT-148009 blocks c-Abl kinase, an enzyme that plays a role in Parkinson’s progression. The therapy has been designed to selectively target c-Abl kinase without blocking similar enzymes, thus avoiding unwanted side effects.

Its goal, according to Inhibikase’s website, is to halt disease progression and reverse functional loss in Parkinson’s. Clinical development is expected to proceed through 2024, the company said.

“As a highly selective kinase inhibitor, IkT-148009 has demonstrated it is distinct in its ability to discriminate against the target enzyme, c-Abl, without engaging other targets in the Abelson enzyme family,” Werner said. “We believe this property may enable IkT-148009 to offer best-in-class safety, avoiding the most harmful side-effects commonly associated with c-Abl inhibitors the longer they are dosed in patients.”

“We are pleased to share interim data from ongoing chronic toxicology studies that support this hypothesis, indicating a more favorable profile in rats and non-human primates given extended treatment with IkT-148009,” Werner added.

Before initiating its ongoing Phase 1 trial (NCT04350177) — which is testing the medicine in healthy volunteers — Inhibikase submitted to the FDA 14 days of toxicology data in rats and non-human primates.

The No Adverse Event Level or NOAEL, a measure of drug safety in animals, was determined to be 31.2 mg in non-human primates. However, the NOAEL in rats could not be measured over the two weeks.

After three months of dosing, the NOAEL in non-human primates was 75 mg, a 2.4-fold increase in the tolerable dose. The NOAEL in rats was established at 50 mg.

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The Phase 1 study, launched in February, is testing single and multiple ascending doses of IkT-148009 versus a placebo in older healthy adults (males and females ages 55 to 70) for up to seven days. In addition to safety and tolerability, how the medicine moves into, through, and out of the body — called pharmacokinetics — also is being examined.

Doses ranging from 12.5 to 100 mg have been administered so far, which achieved sufficient levels of the medicine in the body with no relevant side effects.

Based on these results, the FDA recently gave Inhibikase clearance to extend the study to a Phase 1b trial to include patients with Parkinson’s disease. Safety, tolerability, and pharmacokinetics of IkT-148009 for up to 14 days will be evaluated, as will efficacy outcomes of cognition, motor function, and gut motility. The impact on alpha-synuclein aggregates — a hallmark of Parkinson’s — also will be measured in multiple tissues and fluids.

In addition to the animal toxicology requirements, the company has added three-month dosing to groups of rats and non-human primates to support three months of dosing in Parkinson’s patients in its upcoming Phase 2a trial. This trial will assess the same efficacy outcomes as the Phase 1b study.

According to Werner, the results of the animal studies, “taken together with efficacy signals observed preclinically,” have bolstered Inhibikase’s confidence in the safety and tolerability profile of its medication candidate.

“We look forward to evaluating IkT-148009 in a planned Phase 2a study, subject to FDA agreements, to see how this profile translates into patients with Parkinson’s disease,” Werner said.