LSIPR 50: Daniela Verthelyi—Safety first

According to Daniela Verthelyi of the US Food and Drug Administration (FDA), the development of therapeutic proteins and peptides has improved the lives of countless patients, but there are still numerous challenges ahead, including those relating to bioavailability and immunogenicity.

Verthelyi, who is chief of the immunology laboratory at the FDA, works with researchers, reviewers and research-reviewers to address questions of product immunogenicity for the Office of Biotechnology Products and other areas of the FDA.

She also helps develop new approaches to address immunogenicity risk for peptides, heparins, and other complex products, as well as contributing to the writing of industry guidance documents that outline the FDA’s current thinking.

An important part of Verthelyi’s team’s work is to improve understanding of what product attributes can induce adverse effects by “modulating the immune system”.

She explains: “In terms of research, I lead a group of scientists who are focused on developing a better understanding of immunology and inflammation, and applying the information gained to respond to emergent public health and regulatory issues, and support the scientific-based regulation of therapeutic products.

“For some products, targeting the immune system is their mechanism of action, but other products can induce unwanted immune responses that reduce their safety and efficacy,” she adds.

Better products

Verthelyi believes that the main achievement of her team is bringing together a group of scientists who are committed to using their skills to develop tools that improve the development and regulation of therapeutic products.

“Over the past ten years we have worked very closely with industry and academia to improve our understanding of the factors that govern the interaction of therapeutic proteins, peptides, and other complex products with the immune system, and to develop strategies that improve product safety and efficacy,” she says.

Verthelyi adds that the assessment of product immunogenicity has become an integral part of product development.

In terms of challenges in her research field, Verthelyi explains that product immunogenicity can render life-saving products ineffective and cause severe adverse effects.

“While substantial progress has been made in identifying and mitigating risk factors for product immunogenicity, challenging questions remain with respect to predicting whether a biologic or naturally derived complex drug product will
be immunogenic, what subset of patients
will be affected, and how the immune response will impact the clinical outcome,” she says.

According to Verthelyi, the way her team addresses these challenges is by having scientists who are focused on understanding the molecular mechanisms of immune-mediated drug hypersensitivity, while others focus on the impact of product of impurities and developing tools to improve risk assessment and mitigation.

“In recent years we have seen a surge of emerging viral infections that have caused global threats and require immediate development of therapeutics,” she says.

Verthelyi explains how the regulatory assessment of these products in real time is particularly challenging.

“In response, we have researchers developing in vitro and in vivo models that can be used to assess potency and model safety and efficacy for products aimed at emerging and neglected infectious diseases,” she adds.

Tailor-made treatment

The team’s current challenge is to improve understanding of the interactions between drug products and individual patients so that in the near future treatment can be tailored to the patient. This will reduce safety concerns, improving efficacy, and helping physicians make the best decision for their patients.

“New discoveries in innate immunity, regulation of the microbiome, and genetics, paired with improved bioanalytical characterisation of therapeutic products, should help address some of the remaining questions, but detailed studies linking product and patient parameters will be critical to make real improvements,” she says.

While clinical trials are a powerful tool in assessing product safety, sporadic safety signals can be hard to interpret, she says.

“We hope to develop better tools to characterise therapeutics in order to reduce residual uncertainty when assessing the immunogenicity risk of therapeutic products.

“The hope is that a thorough understanding of the mechanism of action and off-target activities of the product paired with improved bioanalytical characterisation will ultimately reduce uncertainty, allowing for more streamlined product development.”

The key to success in her field, Verthelyi believes, is to work hard and remember that the focus is on improving the outcome for patients as well as protecting public health.

“We need therapies that are safe, effective and available,” she adds.