FDA Issues Guidance for Developers Targeting Therapies for Single Enzyme Defect Diseases

The FDA recently released guidance to sponsors on the best practices for gathering evidence to demonstrate the effectiveness of replacement or corrective therapies intended for slowly progressive, low-prevalence rare diseases associated with substrate deposition and are caused by single enzyme defects

Drug effectiveness can be challenging to demonstrate for these types of rare diseases for several reasons:

• Research could take years or even decades due to slow disease progression.
• Extreme rarity of a specific disease combined with geographical distribution of patients could also make disease-specific instruments and endpoints to assess clinical response not feasible for development.
• Clinical trials in general are difficult to conduct for rare cases due to extremely low number of patients with a specific disease.
• Multiple therapies being investigated at once can also reduce the number of subjects available.

The guidance suggested certain areas to take into consideration when developing an approach to drug development for these diseases, including the analysis of enzyme activity as well as the performance of replacement enzymes. Some non-substrate biomarkers are closely linked to the pathophysiology of a disease. Sponsors can use these changes in biomarker levels for dose selection and they can serve as an early demonstration of drug activity. However, this analysis cannot replace the demonstration of substrate reduction.

“When the pathophysiology of a disease is well understood and the mechanism of action of the drug/biologic is well characterized, specific drug-induced substrate reduction in relevant tissue or tissues can have a reasonable likelihood of predicting clinical effectiveness,” the FDA noted.

The FDA said developers could use several strategies for treating these diseases, including administering enzyme replacement therapy; using a pharmacologic chaperone to bind to the mutant enzyme; reducing the rate of substrate synthesis; diverting substrates to an alternative metabolic pathway; and using viral vectors to introduce the wild type gene into somatic cells.

The guidance also contains recommendations for conducting both animal and human studies to support accelerated approval of a new drug.

Disease-specific animal models are important to look at for drug development in rare diseases and the evaluation of the toxicological profile in animals is crucial for all drug development programs.

The FDA recommended the testing enzyme replacement therapies in healthy subjects could pose a potential risk of inducing an immune response or a deficient state in such subjects. This may leave nonhuman data from animals the only way to estimate a safe starting human dose and establish initial estimates of dose-response relationships.

The FDA also suggested that sponsors should look at 2 or more dose levels.

When assessing efficacy or safety in clinical trials it is extremely critical to take into account that most rare diseases are pediatric diseases or have onset of manifestation in childhood. The FDA recommends that sponsors address ethical considerations for conducting investigations in addition to getting parental consent for pediatric subjects.