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OrphAI Therapeutics&#8217; experimental therapy <a href="https://www.orphai-therapeutics.com/ait-101-product-page">AIT-101</a> has been awarded orphan drug status in the European Union for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), following a similar designation granted in the U.S. last year.
In Europe, orphan drug status is given to medicines designed to treat life-threatening or chronically debilitating conditions affecting fewer than five in every 10,000 people. It provides companies with a range of benefits, including assistance with trial protocols, reduced regulatory fees, and 10 years of market exclusivity if the treatment is ultimately approved.
Similar benefits are awarded in the U.S., where the therapy received such a designation last June from the U.S. Food and Drug Administration (FDA), though the market exclusivity period is seven years.
“OrphAI Therapeutics now has orphan designation for AIT-101 both in the US and the EU for the treatment of ALS, an important step toward bringing the drug to patients suffering from this neurodegenerative disorder,” Brigette Roberts, MD, <a href="https://www.orphai-therapeutics.com/">OrphAI</a>’s CEO and director, said in a <a href="https://www.globenewswire.com/news-release/2024/02/15/2830145/0/en/OrphAI-Therapeutics-receives-Orphan-Drug-Designation-for-AIT-101-as-a-treatment-for-amyotrophic-lateral-sclerosis-in-the-European-Union.html">company press release</a>.
“We look forward to moving AIT-101 into the next stage of clinical development,&#8221; Roberts added.
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<h3>AIT-101 awarded orphan drug status in US last year</h3>
The molecular mechanisms that <a href="https://alsnewstoday.com/causes-of-als/">cause ALS</a> are not fully understood, but most cases of the progressive disease are marked by the accumulation of toxic TDP-43 clumps in motor neurons — the nerve cells that control voluntary movements and are lost in ALS. These clumps trigger a number of stress responses in cells that ultimately contribute to motor neuron dysfunction and death.
AIT-101, also called LAM-002A or apilimod, is an experimental oral therapy that&#8217;s designed to activate cells&#8217; waste disposal systems. Included in those systems are lysosomes — membrane-bound organelles containing enzymes that break down cellular waste — and autophagy, a cellular process that involves the degradation and recycling of larger cell components that are no longer needed.
By activating these two processes, AIT-101 is expected to help clear the misfolded proteins and toxic protein clumps that contribute to disease progression. The therapy works by inhibiting, or blocking, a protein called PIKfyve.
In preclinical studies, AIT-101 was shown to clear toxic protein clumps and <a href="https://www.nature.com/articles/nm.4490">improve the survival of motor neurons</a> derived from ALS patients. Moreover, the therapy was effective at <a href="https://www.biorxiv.org/content/10.1101/685800v1.full">improving functional deficits</a> in a mouse model of ALS.
Its use &#8220;in relevant animal models has been shown to reverse the pathological [disease-causing] and functional consequences of &#8230; toxic aggregates,&#8221; or clumps, OrphAI notes on its webpage.
AIT-101 was investigated in a recently completed <a href="https://clinicaltrials.gov/study/NCT05163886">Phase 2a clinical trial (NCT05163886)</a> involving 15 adults with ALS caused by mutations in the C9orf72 gene. Such mutations are the most common genetic cause of ALS; the C9orf72 gene carries instructions for a protein of the same name, necessary for the production of lysosomes.
In the trial, participants were randomly assigned to take oral capsules of AIT-101 or a placebo, twice daily, for 12 weeks, or about three months. Then, for the next 12 weeks, all participants received AIT-101.
The trial <a href="https://alsnewstoday.com/news/ait-101-clears-toxic-protein-clumps-early-clinical-trial-als/">met its main goal</a> of showing that AIT-101 was generally safe and well tolerated, and was able to reach the patients’ brains. Moreover, the therapy significantly reduced the levels of toxic protein clumps derived from the mutated C9orf72 gene by 73%, and increased the levels of another marker suggesting the therapy was affecting the PIKfyve protein as expected.
According to the company, AIT-101 is &#8220;the most clinically advanced PIKfyve inhibitor in development.&#8221;

OrphAI’s AIT-101 granted orphan drug status in Europe for ALS

<a href="https://www.ai-therapeutics.com/">AI Therapeutics</a>&#8216; experimental therapy AIT-101 led to reductions in levels of toxic proteins in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (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&#8217;s active ingredients were able to reach participants&#8217; brains.
&#8220;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,&#8221; Murat Gunel, MD, said in a <a href="https://www.globenewswire.com/news-release/2023/04/05/2641635/0/en/AI-Therapeutics-Announces-Positive-Results-from-Phase-2a-Biomarker-driven-Trial-of-AIT-101-in-Patients-with-C9ORF72-Amyotrophic-Lateral-Sclerosis-ALS.html">press release</a>. Gunel is a member of AI Therapeutics’ board of directors and chair of the company&#8217;s scientific advisory board.
&#8220;This is exciting progress toward a new treatment for ALS,&#8221; added Gunel, a professor at Yale University in Connecticut.
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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 <a href="https://alsnewstoday.com/news/phase-2-trial-oral-ait-101-enrolling-adults-c9orf72-mutations-us/">greater production of lysosomes</a> — 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.
&#8220;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,&#8221; said Suma Babu, a physician scientist at Massachusetts General Hospital and professor at Harvard Medical School.
AI Therapeutics sponsored a <a href="https://clinicaltrials.gov/ct2/show/NCT05163886?term=NCT05163886&amp;draw=2&amp;rank=1">Phase 2a clinical trial (NCT05163886)</a> 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.
<h3>Study design</h3>
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.
&#8220;The positive results of this trial are encouraging for further development of AIT-101 in ALS. &#8230; This data may have broad implications for all ALS individuals, not only for C9ORF72 ALS individuals tested in this trial,&#8221; said Babu, the trial&#8217;s principal investigator.
<h3>Encouraging results</h3>
&#8220;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),&#8221; 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.
&#8220;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,&#8221; Babu said.
&#8220;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,&#8221; Roberts said.

Tag: AIT-101

OrphAI’s AIT-101 granted orphan drug status in Europe for ALS

AIT-101 clears toxic protein clumps, early data show