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Development Differences: Biopharmaceuticals and Small Molecules

Scott E Boley at MPI Research discusses the nonclinical development of biopharmaceuticals in comparison with small molecules

The only thing certain is change. This axiom holds true for many aspects of today’s world, but it is a central tenet for drug development. Fifteen years ago, small molecules (chemically synthesised molecules designed to interact with a specific cellular receptor) represented the majority of pharmaceuticals under development. During the past 10 years, however, the number of therapies being developed that fall into the broad category of biopharmaceuticals has exploded, and there are predictions that the majority of therapies developed in the next 10 years will fall into this class.

For the purposes of this article, the term biopharmaceutical is used interchangeably with the terms biotechnology-derived pharmaceutical, large molecule, biologic or biotherapeutic. In the most general sense, the term biopharmaceutical can be used to refer to anything that was produced by a living cell (bacterial, yeast, mammalian, insect or plant) and may include antibodies, peptides, intact proteins, oligonucleotides, vaccines and stem cells. The nonclinical safety programme used to support the development of a biopharmaceutical can differ significantly from that used to support the development of traditional small molecules.

This article will discuss some of the differences that apply to the nonclinical development of a biopharmaceutical compared with a small molecule, with the understanding that there are exceptions to every rule and, in drug development, there is typically more than one exception.

While the nonclinical development of small molecules is not a straightforward task, the nonclinical development of biopharmaceuticals is even more complicated, due to the nature of the test articles involved. For a small molecule, companies would follow a ‘standard’ nonclinical approach consisting of rodent and non-rodent general toxicology studies (including carcinogenicity studies), rodent and rabbit reproductive toxicology studies, safety pharmacology studies and genetic toxicology studies. In many cases, the rodent and non-rodent species are selected based on the in vitro metabolism profile of the small molecule in a variety of species (including humans). The selected species would be those that best represent the profile expected for humans.

PHARMACOLOGICAL EFFECTS

As biopharmaceuticals are not metabolised through the same mechanisms as small molecules (for the most part they are catabolised into naturally occurring constituents), the approach required to support clinical development is markedly different. It is important to understand the pharmacology of the compound and whether it would be expected to produce a pharmacological effect in a nonclinical species. For the development of biopharmaceuticals, regulatory bodies allow the animal studies needed to support the clinical trials to be conducted in a single species. If the biopharmaceutical is active in both rodent and non-rodent species, both species are used during development of the biopharmaceutical similar to the approach used in the development of small molecules. However, if the biopharmaceutical is active only in non-human primates (NHP), due to the homology between the targets in humans and in NHP, there is the option of conducting the nonclinical studies only in NHP (typically cynomolgus or rhesus monkeys). If it is not known whether there is pharmacological activity in a particular species, it is best to conduct literature searches to investigate the level of homology for the target in various species, followed by cell-based assays with pharmacodynamic endpoints to provide preliminary data on the activity profile of the compound. While some view the need for NHP studies as increasing the cost of the nonclinical development portion of the process, it should be recognised that this can be offset by the possible removal of rodent studies from the nonclinical programme.

MEASURING THE IMMUNE SYSTEM RESPONSE

Another common characteristic of biopharmaceuticals is their propensity to elicit an immune response in the test system being utilised. This can be due to the inherent immunogenicity of the biopharmaceutical itself, or perhaps to a contaminant derived from the host cell that is present in the bulk drug being produced. Small molecules do not typically elicit a response from the immune system because of their diminutive size, whereas biopharmaceuticals are much larger and can be recognised by the immune system as a potentially foreign substance. It is often desirable to measure the levels of anti-drug antibodies (ADAs) formed in response to biopharmaceutical administration as a means of assessing the immune response against the test article. ADAs may have no effect on the activity of the test article; conversely they can cause inactivation.

A functional assay is needed to determine if the biopharmaceutical bound to the ADA is still active. This requires specialised analytical techniques and expertise that are uniquely different from that used in the development of small molecules. A recently proposed change in the guidance document ICH S6 R1 would allow the quantification of ADAs to be postponed until after the exposure data are obtained and any effects on the immune system have been determined. If the exposure toxicity profile is well understood, it is accepted that even if ADAs are present, they do not have an impact on the interpretation of the study, and therefore the ADA levels might not need to be assessed. If, however, it is found that the exposure profile decreases with time, it would be necessary to analyse the ADA samples to determine if this decrease was due to an immune-mediated clearance.

In the case of small molecules, a standard battery of separate safety pharmacology studies is conducted, where the potential for the test article to affect the major physiological systems (such as the central nervous, cardiovascular and respiratory systems) is examined. This is due to the nature of the small molecules and their ability to interact with specific cell surface receptors. The safety pharmacology studies are designed to determine the possibility of off-target interactions affecting these essential physiological systems. This can be done for biopharmaceuticals as well, but they are not typically conducted as standalone studies. Regulatory bodies allow safety pharmacology endpoints to be included in the design of the general toxicology studies as a means to reduce the number of animals used in the development of a therapeutic. If a particular class of biopharmaceuticals is known to have potential risks for any of the major systems, standalone safety pharmacology studies would still be warranted.

REPRODUCTIVE TOXICOLOGY

The approach taken with regard to reproductive toxicology for biopharmaceuticals is also different from that for small molecules. For small molecules, the standard approach is to conduct reproductive toxicity testing in rats and rabbits at various points during the drug development timeline. As with the general toxicology studies, if there is pharmacological activity of the biopharmaceutical only in NHP, reproductive toxicology studies can be conducted solely in NHP. The rationale is that if there is no pharmacological activity of the test article in a particular species, conducting reproductive toxicology studies in that species would not provide meaningful data for clinical trials. A single-species approach can involve a single study that covers the period from gestation day 20 to birth and can involve only a single dose group in addition to a control group. However, the size and duration of these studies are significant, because the average female gives birth to a single offspring, and the typical gestation period is approximately 180 days. To complicate matters further, the success rate of mating can be as low as 40 per cent, adding more time to the front-end of the study. If the biopharmaceutical is active in rodents, however, a standard reproductive toxicology plan can be followed for that test article.

DOSING & DELIVERY

The procedures for preparing dosing solutions used for nonclinical safety studies with biopharmaceuticals may differ from those used for small molecules. For example, biopharmaceuticals are more prone to ‘adhesion’ than small molecules and may, therefore, require specific materials during their formulation (for example, glass is used instead of plastic, and so on). In addition, the vigorous homogenisation procedures that are often used during preparation of small molecule suspensions are seldom consistent with the preparation of biopharmaceuticals because of the propensity of homogenisation to create bubbles that can denature a biopharmaceutical protein. In addition, the methods used in the analysis of the dosing formulation for small molecules can be different from those used for biopharmaceuticals. Small molecules are generally analysed by LC-MS/MS, but for biopharmaceuticals, analysis of the dosing formulation is not so straightforward. Some can be analysed using procedures that are identical to those used for small molecules, while others may require more sophisticated approaches (for example, ELISAs for monoclonal antibodies). It is critical that laboratories conducting studies with biopharmaceuticals have sufficient knowledge of and experience with the handling and analysis of biopharmaceuticals to prevent issues that may affect the integrity of the formulations being used to dose the animals.

The delivery of biopharmaceuticals presents its own challenges. Biopharmaceuticals cannot be administered orally because they would be broken down in the acidic environment of the stomach before they had an opportunity to become systemically available. Therefore, the common routes of administration are parenteral (subcutaneous, intravenous, intraperitoneal and intramuscular). While these routes are also utilised in the administration of small molecules and are common in many laboratories, intravenous infusion requires both specialised equipment to ensure the constant rate of administration and technical expertise to monitor the equipment.

CONCLUSION

As indicated above, the nonclinical studies involved in the development of biopharmaceuticals demonstrate a number of differences compared with those needed for small molecules. For many companies, the required expertise may not be available in-house, requiring that this work be outsourced to a CRO. It is critical that the CRO selected have the experience, expertise and equipment needed to provide a complete study that will be accepted by a regulatory agency.


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Scott E Boley received his doctorate in Biochemistry and Environmental Toxicology from Michigan State University, US. His postdoctoral work involved the use of transgenic mice and molecular biology to examine tumour characteristics common to human tumour formation. He then went to Eli Lilly, and Company, where he developed the nonclinical research strategy for novel oncological and neurological compounds. He joined MPI Research in 2005 as a Study Director and now serves as Senior Director of General Toxicology and Infusion Toxicology at MPI Research. Scott currently works with various teams including a formulation staff experienced with biopharmaceuticals, and a multi-disciplinary toxicology team familiar with biopharmaceutical test articles (including oligonucleotides, antibodies, vaccines and cells). He also works with a reproductive toxicology team that offers NHP reproductive toxicology testing of biopharmaceuticals, and an experienced immunology group known for its assay development to detect ADAs and determine potential effects on the immune system (KLH and immunophenotyping).
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