Agilis Biotherapeutics, LLC (Agilis), a biotechnology company, and T-TOP Clinical Research Co, Ltd. (T-TOP), have entered into an exclusive agreement to advance the clinical development of Agilis’ innovative treatment of Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency using gene therapy.

In January, Agilis announced an exclusive, worldwide license with National Taiwan University (NTU) for AADC gene therapy developed by Dr. Paul Hwu, Professor of Paediatrics at NTU Children’s Hospital.

The AADC gene therapy programme is, to the company’s knowledge, the most advanced CNS gene therapy programme in the world, with the most patients treated to date and follow-up data extending for more than five years in some cases.

Under the agreement, T-TOP will provide clinical, database, regulatory and strategic management services for prior and current AADC clinical studies. In collaboration with National Taiwan University, Agilis and T-TOP will advance current clinical evaluations and a phase IIb study to build upon the clinical data developed to date. Agilis is evaluating potential early-opportunity registration pathways for the AADC gene therapy in territories around the world, potentially positioning it to be the first CNS gene therapy to seek registration.

“We are excited to embark on the next stage of development for the AADC gene therapy programme in collaboration with Dr. Hwu and T-TOP to bring this potentially impactful treatment to patients with this devastating disease,” stated Christopher Silber, M.D., Agilis chief medical officer, noted.

“Dr. Hwu’s pioneering studies in the treatment of AADC Deficiency using gene therapy have shown encouraging progress in treating this disorder, and represent a seminal step for CNS gene therapy. Given the devastating clinical course of disease for patients with severe AADC deficiency and refractoriness to standard therapy, a gene therapy treatment that could improve the most severe forms of this disorder represents a critical advance for these patients and their families. Having a premier, local partner in Taiwan for ongoing clinical development in the AADC gene therapy programme provides enabling capabilities as we seek to position this programme for registration.”

Minhsuing Kao, chairman of T-TOP, noted, “We are pleased to collaborate with Agilis to ensure high quality and rigor in the clinical development of AADC gene therapy, provide expertise in the clinical trial and data management activities required for successful development, and help shepherd the programme through the next stages of development toward approval. T-TOP has worked with Dr. Hwu on the AADC programme for some time and is familiar with the full requirements of the study protocols for this exciting, innovative potential therapeutic. We look forward to working with Agilis, Dr. Hwu and NTU in bringing AADC gene therapy to patients in need.”

In its profound forms, AADC deficiency causes severe developmental delays, extreme muscle strength and control deficits, and frequent hospitalisations often culminating in premature death within the first decade of life. Dr. Hwu’s team has successfully treated 18 subjects in two prospective clinical treatment groups with a single administration of the AADC gene therapy. Treated subjects exhibited substantial gains in motor function and cognitive scales over multiple years following the single gene therapy treatment, as well as evidence of de novo dopamine production by F-DOPA PET imaging and the emergence of dopamine metabolites. In contrast, untreated patients routinely showed continued deterioration as the disease progresses, as observed in natural history cases.

Dr. Hwu commented, “Clinical studies continue to support strong safety and promising efficacy to date, with patients showing persistent improvements in functional, biomarker and imaging measures. Collectively, the data from our studies represent the first time gene therapy has been demonstrated as a potential durable treatment for AADC deficiency, and we are encouraged to advance development and bring this important therapy to patients.”

Dr. Mark Pykett, Agilis president and CEO, stated, “The AADC gene therapy programme continues to be an important catalyst for Agilis and a landmark in the development of gene therapy treatments for CNS disorders. Given our commitment to this program and our focus on its successful development, we believe it has the potential to be the first CNS gene therapy product approved anywhere in the world. We have been impressed with T-TOP’s clinical-regulatory development and their insights and experience in the AADC gene therapy programme, as well as the tremendous quality of clinical research being performed in Taiwan. We are thrilled that we can enhance our development efforts with people and organisations as skilled and committed as T-TOP, Dr. Hwu and NTU.”

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic condition resulting from deficits in the enzyme, AADC, which is responsible for the final step in the synthesis of the neurotransmitters dopamine (a precursor of norepinephrine and epinephrine) and serotonin (a precursor of melatonin). AADC deficiency arises from mutations in the dopa decarboxylase (DDC) gene. In its profound forms, AADC Deficiency results in severe developmental failures, global muscular hypotonia and dystonia, severe, long-lasting seizures known as oculo-gyric crises, frequent hospitalizations (including prolonged stays in intensive care), and the need for life-long care. Symptoms and severity vary depending on the type of underlying genetic mutation which abrogates AADC enzyme function. Severe forms of the disease can arise from specific DNA mutations. Patients with severe forms usually die before the age of 6-7 years due to profound motor dysfunction, autonomic abnormalities, and secondary complications such as choking, hypoxia, and pneumonia. No treatment options other than palliative care currently exist for patients with severe AADC deficiency.