They play pivotal roles in creating effective therapies for conditions like cancer, autoimmune diseases, and hormonal disorders. However, the complexity and potential risks associated with HPAPIs necessitate a deep understanding and careful handling.
In this Q&A, Xiaoxia Li, a seasoned toxicologist, walks OSP through the landscape of HPAPIs—elucidating their applications, potential risks, and regulatory considerations. Xiaoxia also provides a glimpse into the future of HPAPIs, particularly in personalized medicine and targeted therapies.
OSP: What common uses and applications exist in drug design and development for high-potency active pharmaceutical ingredients (HPAPIs)?
XL: HPAPIs have wide-ranging applications in pharmaceutical development. Their development strategies often depend on the class of molecules—e.g., small or large molecules—but they are primarily used in medications intended to treat diseases that require a potent response when other forms of treatment have proven less effective. Specifically, HPAPIs treat cancer, hormonal disorders, and autoimmune diseases—utilized across various medical fields, but oncology is the most common area.
OSP: What are the most common risks associated with HPAPIs?
XL: High potency drugs present numerous opportunities for improved drug selectivity, efficacy and safety profiles. Although this class of molecule offers numerous benefits to patients, they require particular care and attention when ensuring the safety of those involved in their manufacture and handling, in addition to their inherent complexity. HPAPIs can be likened to a sharp knife—they’re effective but can also be dangerous. They can cause toxicities at low doses due to their high potency. However, they are often more specific to their target, meaning that off-target toxicity might be reduced compared to traditional drugs. Yet, when they miss their intended target, their effects can be significantly more robust and potent—this should be monitored and managed closely. From a toxicological evaluation perspective, steep dose response could occur often when conducting nonclinical studies for a HPAPI, therefore designing studies for HPAPIs requires careful considerations.
OSP: What are some examples of HPAPI-based drugs that have made significant impacts?
XL: Gene therapies and CAR-T cell therapies are areas of intense focus. A notable example is the case of Emily Whitehead, the first pediatric patient to receive CAR-T cell therapy. This highly potent and personalized treatment effectively saved her life, and she’s now a teenager, having survived for more than ten years since her treatment. This therapy received U.S. FDA approval in 2017.
Another example involves oligonucleotides, which are often high-potency APIs. Oligos are short, single strands of synthetic DNA or RNA that serve as the starting point for many molecular biology and synthetic biology applications. They’re intermediate in size—they are bigger than small molecules but smaller than biologics, like peptides and proteins—demonstrating that unique consideration needs to be taken while evaluating oligo’s safety profile. Another promising area is immuno-oncology. This field has seen significant developments recently, and indeed, both the CAR-T therapy Emily Whitehead received and oligos can be considered a product of immuno-oncology.
OSP: How do HPAPIs contribute to personalized medicine, and how might that role evolve as personalized medicine becomes more commonplace?
XL: Personalized medicine is a field that’s becoming increasingly important as we understand more about the unique genetic makeup of individuals. We’ve learned from advancements in biology and pharmacology that treatments can be very individualized. A treatment like CAR-T cell therapy, which saved Emily’s life, may not work for everyone because it’s so personalized.
This is particularly true for drugs targeting specific mutations in certain diseases, which must be tailored to the individual. Let’s take CAR-T cell products as an example. These are considered personalized because they’re based on research that identifies specific proteins on the surface of cancer cells of a particular patient. These proteins serve as new antigens, and antibodies are created to target them. But these antibodies are made from T cells harvested from that specific patient.
These T cells are modified and then reintroduced into the patient’s body. They can effectively combat cancer if they work as intended in that specific patient. This is why treatments need to be individualized and personalized. This approach is also immuno-oncology. It involves using a patient’s own T cells, manipulating them, and modifying them to target specific proteins on the surface of that patient’s specific cancer cells.
OSP: How does the US FDA regulate HPAPIs?
XL: We typically don’t categorize drugs as “high-potency APIs” when a nonclinical toxicology program is designed. We usually refer to drugs by their specific category or classify them as large or small molecules. And then they are regulated based on the appropriate classification. However, many of these drugs, like CAR-T cell therapies or certain small molecules, are high-potency APIs because they’re extremely effective at much smaller dosage.
In terms of regulatory perspective, when we evaluate the safety profile of a novel drug including HPAPIs, the relevant regulatory guidelines need to be followed. However, there are no regulatory guidelines that specifically address nonclinical testing of some new modalities that are HPAPIs.
For example, antibody-drug conjugates (ADCs) are biopharmaceutical molecules consisting of a cytotoxic small molecule covalently linked to a targeted protein carrier via a stable cleavable or non-cleavable linker. The process of conjugation yields a highly complex molecule with biochemical properties that are distinct from those of the unconjugated components. The impact of these biochemical differences on the safety and pharmacokinetic profile of the conjugate must be considered when determining the types of nonclinical safety studies required to support clinical development of ADCs. The hybrid nature of ADCs underscores the need for a science-based approach to safety assessment that incorporates relevant aspects of small and large molecule testing paradigms. Nonclinical testing strategies need to be well established with a good understanding of regulatory expectations and ADC-mediated toxicity that can be used to guide the types of nonclinical safety studies needed to support ADC clinical development.
OSP: What safety concerns or considerations should drug developers and sponsors keep in mind when working with HPAPIs?
XL: Special precautions need to be taken to ensure all personnel are well protected during handling the HPAPIs. This requires the use of the right personal protective equipment (PPE) when needed. For example, technicians may use standard masks and other protective measures when working with a regular protein drug that isn’t highly potent. But when dealing with a highly potent API, the technicians need to dress appropriately to protect themselves from exposure to the drug.
This protective equipment needs to be used not just during formulation preparation but also during analytical work. This includes the analysis of formulation concentrations and the handling of plasma or serum samples. In all these situations, technicians need to be well-protected.
OSP: What are some things drug sponsors and developers should consider when choosing a laboratory testing partner?
XL: The laboratory testing partner’s expertise and experience should be prioritized over any other factor. To illustrate this, let’s consider the example of designing a toxicology program for an ADC. As mentioned above, ADCs’ hybrid nature makes predicting their potential toxicity a challenging task. Additionally, in the absence of specific regulatory guideline for ADCs, scientific support and technical expertise from the laboratory testing partner become critical to ensure nonclinical program can be successfully conducted.
OSP: What does the future of HPAPIs look like?
XL: [HPAPIs] certainly have a promising future. The era of personalized medicine is already upon us and, as we discussed, HPAPIs have a significant role to play in that field. But also, cancer drugs, targeted therapies, immuno-oncology drugs—they can all benefit from further development of HPAPIs.
The most significant advantage of these drugs is that they can achieve life-changing pharmacological effects with smaller dosage and/or less frequent doses. This is particularly beneficial for patients, as it may mean less frequent dosing. Imagine a patient who is used to one dose per month—for certain oligonucleotides—being able to reduce those uncomfortable instances to a dose every three or six months.
Joining WuXi AppTec with more than 15 years of preclinical drug development experience, Xiaoxia Li provides scientific support to our clients and will enhance the quick response rate for technical questions. She began her career at a preclinical contract research organization (CRO), BOZO (Biology and Zoology) in Tokyo, and then spent more than 13 years working as a Study Director at ITR Laboratories in Montreal, Canada. Afterwards, she worked as a Scientific Leader in nonclinical development for a pharmaceutical company in Toronto, Canada, before starting her own consulting firm, Sunrise IDD Inc. Dr. Xiaoxia Li is a Diplomate of the American Board of Toxicology (DABT). She completed her PhD in Pharmacology in Japan and received her MD and MSc in China.
