Anle138b Seen as Safe and Moving to Patient Trial With MJFF Support

The small molecule anle138b has shown “excellent” safety and tolerability profiles in a first study in healthy volunteers, and reached therapeutic dose levels in the blood, according to its developer Modag.

These results enabled Modag to secure an additional $1.4 million in funding from the Michael J. Fox Foundation (MJFF), which will support a first study in patients of anle138b as a potential treatment for Parkinson’s disease. This trial is expected to begin by year’s end.

The company is also planning to initiate two long-term clinical trials assessing the safety and efficacy of anle138b in Parkinson’s and multiple system atrophy (MSA) in late 2021.

“The reviewers of The Michael J. Fox Foundation are among the world’s leading experts on Parkinson’s disease, so the funding for this study from this highly recognized organization adds further validation to our approach and its potential,” Johannes Levin, chief medical officer of Modag, said in a press release.

“In my clinical work with MSA and Parkinson’s patients, I am confronted with the urgent need for disease-modifying treatments on a daily basis. Thus, I am pleased that we have made such rapid progress towards the first potential tests in patients,” Levin added.

A hallmark of many neurodegenerative disorders, including Parkinson’s and MSA, is a buildup of the protein alpha-synuclein in the brain, which forms clumps known as Lewy bodies that are thought to contribute to neurodegeneration in patients.

These alpha-synuclein clumps contain fibrous oligomeric conformations, or structures that have repeating molecular patterns, which are considered toxic and can disrupt the working of cells in the brain.

Anle138b is designed to dissolve these toxic oligomeric structures and prevent new ones from forming, with the goal of alleviating neurodegenerative symptoms. Unlike antibodies targeting these toxic protein aggregates, which require intravenous (into-the-bloodstream) infusions and are often too large to cross the brain’s blood vessels, as a small molecule anle138b can is taken by mouth and the compound easily enters the brain.

The medication was initially developed to treat MSA, but has potential therapeutic value for all synucleinopathies, or diseases that feature alpha-synuclein aggregates.

“Anle138b is a small molecule that specifically binds to toxic oligomeric structures of alpha-synuclein, the core aggregating protein in Parkinson’s disease,” said Armin Giese, chief scientific officer of MODAG. “This prevents the formation of new oligomers and thereby blocks the disease-specific aggregation process from advancing.”

The compound was seen to reduce the buildup of these toxic clumps and delay disease progression in models of MSA, Parkinson’s, and Alzheimer’s disease. Moreover, anle138b was found to reverse Parkinson’s-related motor symptoms in mice models of the neurodegenerative disorder.

This preclinical research was supported by a $1.26 million MJFF research grant given in 2015, which also enabled MODAG to develop a biomarker test to determine anle138b levels in the body, and to identify a therapeutic dose in animal models.

The completed Phase 1 clinical trial (NCT04208152) evaluated the effects of anle138b capsules in healthy volunteers, with a focus on the treatment’s safety, tolerability, and pharmacokinetics (the movement of a drug into, through, and out of the body).

It involved 68 people and was performed in three parts.

In the first and second parts, participants received ascending doses of anle138b, or a placebo, for comparison. A single day treatment was given in part 1, while the assigned treatment in part 2 was taken daily for seven days.

The third part investigated that impact of food on the uptake of anle138b. Here, participants were asked to take a single dose of the medication before breakfast (while fasting), or after eating a high-fat breakfast in two different periods.

No side effects associated with anle138b were reported at any dosage level, with the treatment safe and well tolerated even at the highest dose (300 mg) given.

However, a dose of 100 mg was enough for the treatment to reach blood levels above the therapeutic dose previously determined in animal studies.

The research also showed that the molecule’s overall half-life  — the time taken for its plasma concentration to reduce to half its peak value — is about 12 hours, and uptake is not affected by food.

“The successful completion of our first clinical trial with anle138b is an important step toward beginning further evaluation in neurodegenerative diseases and underscores our expertise in drug development,” said Torsten Matthias, CEO of Modag.