Historically, it has been difficult to incentivize companies to develop therapies for rare or “orphan” conditions. The National Conference of State Legislatures (NCSL) explains that “orphan” conditions are:

neglected conditions whose treatments are often not considered profitable due to their cost to develop and limited patient population.

Across the globe, policymakers have worked to overcome these obstacles by implementing various legislation and initiatives to advance drug development in this sphere. One such initiative is the Orphan Drug designation. Drugs granted orphan status often earn benefits for the drug developer, such as fee waivers, regulatory assistance, and market exclusivity—though these incentives might differ slightly based on the country in which designation is granted. 

According to Dr. Andrea Lobo in ALS News Today, the European Union (EU) granted Orphan Drug status to AIT-101, an experimental therapy designed for people living with amyotrophic lateral sclerosis (ALS). AIT-101 has also received Orphan Drug designation in the United States in 2023. 

What is AIT-101?

Developed by OrphAI Therapeutics, AIT-101 is described as 

a proprietary, oral disintegrating formulation of a potent and highly selective PIKfyve kinase inhibitor. Inhibition of PIKfyve kinase by AIT-101 leads to the activation of the transcription factor TFEB, which…leads to increased lysosomal and autophagosomal activity responsible for clearing misfolded proteins from cells.

Essentially, AIT-101 activates TFEB. This helps to clear cellular waste from cells and contributes to autophagy, or the clearance of cell components that aren’t needed any more. In ALS, TDP-43 accumulates in motor neurons. These TDP-43 clumps are toxic and lead to motor neuron death and dysfunction. OrphAI wants to see whether AIT-101 could potentially remove these toxic buildups and misfolded proteins, reducing or stopping disease progression. 

So far, researchers have evaluated AIT-101 in both preclinical and clinical studies. Preclinical data suggests that AIT-101 was effective in clearing TDP-43 clumps, protecting motor neurons, and improving functional defects in murine models. A Phase 2a study with 15 adults living with ALS found that AIT-101 was safe, well-tolerated, able to reach the brain, and effective in reducing TDP-43 clumps by 73%.

What is Amyotrophic Lateral Sclerosis (ALS)? 

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that affects nerve cells called motor neurons in the brain and spinal cord. These motor neurons help the brain and body communicate. When these motor neurons degenerate and die, the muscles weaken and waste away. ALS can affect people of all ages, backgrounds, and ethnicities. However, it is more common in males (particularly white males) and those who are older in age. 

ALS leads to the loss of voluntary muscle control, which can cause multiple symptoms include: 

• Gradually worsening muscle weakness in the arms, legs, and hands 
• Difficulty with small movements, holding objects, and walking
• Slow or slurred speech
• Muscle cramping or twitching
• Frequent tripping and/or falling 
• Poor posture and/or balance
• Difficulty speaking and/or swallowing
• Eventual inability to move muscles throughout the entire body
• Psychological distress 
• Respiratory/ventilatory failure 

There is currently no cure for ALS.