AIT-101 clears toxic protein clumps, early data show
The Phase 2a clinical trial of AIT-101 also met its goals of safety, tolerability
AI Therapeutics‘ experimental therapy AIT-101 led to reductions in levels of toxic proteins in people with amyotrophic lateral sclerosis (ALS) associated with mutations in the C9ORF72 gene, according to data from a clinical trial.
The Phase 2a clinical trial also met its main goals of showing that AIT-101 had an acceptable safety and tolerability profile, and that the therapy’s active ingredients were able to reach participants’ brains.
“This study provides early clinical evidence of AIT-101’s ability to clear the toxic protein aggregates that may contribute to the adverse pathology of ALS and provides a strong rationale for further clinical studies,” Murat Gunel, MD, said in a press release. Gunel is a member of AI Therapeutics’ board of directors and chair of the company’s scientific advisory board.
“This is exciting progress toward a new treatment for ALS,” added Gunel, a professor at Yale University in Connecticut.
Although the exact molecular mechanisms that cause ALS are not completely understood, abnormal clumps of proteins have been identified in nerve cells in virtually all cases of ALS. These clumps are thought to be toxic and contribute to nerve cell death and dysfunction in the disease.
AIT-101 is designed to activate the autophagy lysosomal pathway, a set of cellular recycling machinery that breaks down proteins and other complex molecules that are faulty or no longer needed.
The experimental therapy specifically acts by targeting a protein called PIKfyve, which activates the transcription factor TFEB and results in a greater production of lysosomes — the structures where the cellular recycling takes place. By activating this pathway, AIT-101 aims to help clear toxic disease-driving protein clumps.
AI Therapeutics recently announced new preclinical data showing that AIT-101 was effective in a mouse model of ALS driven by mutations in the gene coding for the TDP-43 protein. AIT-101 also is known as LAM-002A.
“AIT-101 belongs to a new class of experimental therapeutics that directly target the clearance of toxic protein aggregates in motor neurons, which is a hallmark of ALS,” said Suma Babu, a physician scientist at Massachusetts General Hospital and professor at Harvard Medical School.
AI Therapeutics sponsored a Phase 2a clinical trial (NCT05163886) to evaluate AIT-101 in people with ALS caused by mutations in the C9ORF72 gene, the most common type of ALS-associated mutation. Mutations in this gene normally result in a hexanucleotide repeat region, where a sequence of six nucleotides (the building blocks of DNA) is repeated an excessive number of times.
This causes the production of abnormally long proteins, including the poly(GP) protein, which may contribute to abnormal protein clumping in nerve cells.
The trial enrolled 15 adults with C9ORF72-associated ALS. For the first 12 weeks (about three months), participants were assigned randomly to take oral capsules of AIT-101 or a placebo twice daily. Then, for the next 12 weeks, all participants were treated with AIT-101.
Biomarker analyses showed that after 12 weeks of treatment with AIT-101 levels of toxic poly(GP) clumps decreased by 73%. There also was a significant increase in levels of a biomarker called sGPNMB in AIT-101-treated patients, which suggests the therapy is affecting the PIKfyve protein as expected, according to AI Therapeutics.
“The positive results of this trial are encouraging for further development of AIT-101 in ALS. … This data may have broad implications for all ALS individuals, not only for C9ORF72 ALS individuals tested in this trial,” said Babu, the trial’s principal investigator.
“We are encouraged by the results of this initial study of AIT-101, our first-in-class PIKfyve kinase inhibitor. In particular, we are impressed with the speed and magnitude of reduction of toxic protein aggregates as measured by poly(GP),” added Brigette Roberts MD, CEO of AI Therapeutics.
After the 24-week study, participants had the option to continue into a long-term extension study where they can continue to receive the experimental treatment.
“This patient-centric, biomarker-driven, Phase 2a ALS clinical trial was able to efficiently inform us about the biological efficacy and [central nervous system] drug delivery of AIT-101 in C9ORF72 ALS individuals, using a relatively small sample size, short placebo exposure duration and short trial duration overall, while also providing trial completers with the option of long term expanded access to AIT-101,” Babu said.
“We thank all the patients and investigators who participated in this study; the dedication of so many towards this and other clinical studies offers inspiration and hope for patients suffering from this devastating disease,” Roberts said.