Actus Begins Gene Therapy Trial for Pompe Disease

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Actus Therapeutics of Chapel Hill has dosed the first patient in a phase 1/2 clinical study of its gene therapy in patients with Pompe disease, a rare genetic disorder that often leads to premature death in children and adults.

The study will assess safety, bioactivity and immune responses following treatment with a single infusion of the therapy, called ACTUS-101.

“This is an exciting milestone for our company but most importantly, if ACTUS-101 is successful, it could have a meaningful impact on the quality of life for those who suffer from Pompe disease,” said Sheila Mikhail, J.D., chairman and chief executive officer of AskBio, a gene therapy platform company that spun out Actus Therapeutics in 2017.

Mikhail said ACTUS 101 could be “a groundbreaking metabolic treatment” that replaces the current treatment for Pompe, enzyme-replacement therapy every other week. 

It is delivered by intravenous injection and causes liver cells to produce a continuous supply of acid α-glucosidase (GAA), an enzyme that is either missing or in low quantities in patients with Pompe disease. GAA breaks down glycogen, a complex sugar, in the body. Insufficient GAA causes a progressive buildup of glycogen in organs and tissues, especially skeletal and cardiac muscle, impairing their ability to function normally. 

All study participants in the open-label trial will receive ACTUS-101 while maintaining their current enzyme-replacement therapy (ERT) with alglucosidase alfa. As the trial progresses, subjects who meet specified criteria for safety, transgene expression and motor function will be eligible to suspend treatment with ERT. 

“Our strategy at AskBio is to create transformative medicines for people with serious diseases through focusing on validated targets that address causal human biology,” Mikhail said. “ACTUS-101 is a next-generation gene therapy.”

Duke scientists instrumental to therapy

Two experts in Pompe disease at Duke University, Dwight Koeberl, M.D., Ph.D. and Priya Kishnani, M.D., have played key roles in developing ACTUS-101. Both have equity stakes in Actus Therapeutics.

“Preclinical data suggest that this gene therapy product may prove to continuously produce the GAA they (Pompe patients) are lacking,” Koeberl said. “If enough GAA is produced, patients may be able to stop ERT entirely. This would improve their overall quality of life by eliminating the need for weekly or bi-weekly ERT treatments while also strengthening their outlook for living with Pompe.” 

Kishnani, who has treated Pompe disease patients for over 20 years and was instrumental in Duke’s ERT trials in 1999 that led to FDA approval of IV alglucosidase alfa in 2006, said if ACTUS-101 is successful it will bring a renewed sense of hope to the Pompe disease community.

“This has the potential to not only be life-changing for our patients with Pompe disease but also could impact how we approach other inherited metabolic disorders,” she said. “It is an exciting time in the field, with gene therapy treatment as a potential therapeutic approach for many conditions for which there is no treatment or as a way to enhance treatment outcomes.” 

Current therapy has limitations

While GAA enzyme-replacement therapy with alglucosidase alfa has shown benefit, many patients have persistent muscle weakness. In addition, some patients develop anti-GAA antibodies that limit efficacy.

Currently there is no cure for Pompe disease, which affects about one in 40,000 people worldwide.  

Preclinical models have shown that liver-directed gene therapy for GAA has the potential to overcome the limitations of ERT by delivering sustained and efficacious GAA plasma levels. The U.S. Food and Drug Administration recently granted Fast Track Designation for Actus-101 for the treatment of patients with Pompe disease. 

Patient recruitment for the Phase 1/2 clinical study began in November, and AskBio also has a follow-on program in late-stage preclinical development.

ACTUS-101 uses adeno-associated virus (AAV) vectors to deliver genetic information that codes for the production of the missing or deficient GAA enzyme in Pompe disease. AAV offers the advantages of no pathogenicity, efficient long-term gene expression, ease of genetic manipulation, and the property of low or, in many cases, absent immune response. 

The proprietary vectors are a key differentiator for the company. They were developed by pioneers in the field including Richard Jude Samulski, Ph.D., a co-founder of AskBio. 

Legacy support from NCBiotech

Samulski was recruited to the University of North Carolina School of Medicine from the University of Pittsburgh in 1993 with the help of about $250,000 in grant funding from the North Carolina Biotechnology Center. He directed the Gene Therapy Center at UNC-Chapel Hill for many years.

Several grants and loans from the Biotech Center have supported the development of Samulski’s academic research and commercial technologies respectively.

Samulski and Mikhail founded AskBio in 2003 to commercialize AAV gene therapies. AskBio subsequently spun out three gene therapy companies prior to Actus:

  • NanoCor Therapeutics, developing treatments for cardiovascular disease.
  • Chatham Therapeutics, developing treatments for hemophilia. Chatham was sold to Baxter International (now Shire) in 2014 for $70 million.
  • Bamboo Therapeutics, developing treatments for rare neuromuscular diseases. Bamboo was sold to Pfizer in 2016 for $150 million in a deal that could be worth as much as $645 million if certain milestones are met. 
Barry Teater, NCBiotech Writer
Tue, 01/29/2019 - 16:03