The complexity of nonclinical safety studies has been increasing in recent years as researchers seek to obtain as much information as possible about the safety and pharmacology of their therapeutics prior to commencing clinical studies. Toxicological testing of pharmaceuticals has been an important part of regulatory drug development for over half a century, and there is now an extensive library of regulations and guidance that researchers must consider when developing new products or new formulations of existing products. As each therapeutic is different, there is deliberate flexibility in much of the guidance to ensure that product-specific considerations are investigated. Navigating this guidance effectively forms a major part of the successful partnership between contract research organizations and their customers.
Nonclinical therapeutic product development is not as straightforward as following a prescriptive list of investigations to satisfy regulators. Studies often contain product-specific measurements, loosely termed “biomarkers,” to assess both off-target effects on normal tissue as well as on-target effects due to the mechanism of the product being developed. Both these on- and off-target effects can have dose-limiting implications on the effective use of a chosen therapeutic.
It should be noted that the objectives of preclinical pharmaceutical development are essentially the same whether you are developing small- or large-molecule therapeutics. The goal is to understand the potential efficacy, bioavailability and safety of your product in a series of in-silico, in-vitro and in-vivo studies before entering the clinic. However, there are some critical differences in how the nonclinical safety testing of biologics has developed, and now some of these approaches are being incorporated into small-molecule drug studies.
A bit about biologics
The term “biologics” refers to newer classes of products that include a wide range of different therapeutic modalities, such as monoclonal antibodies, recombinant proteins, peptides, DNA and RNA oligonucleotides and cell and gene therapies, as well as vaccines. Vaccines have, of course, been successfully used clinically for many years, and new approaches to vaccination are continually being developed—with them comes a need to demonstrate both safety and clinically relevant pharmacology in nonclinical safety studies.
The molecules that make up most, but not all, biologics are amino and nucleic acids. The catabolism of proteins, peptides, DNA and RNA by enzymatic cleavage and subsequent clearance and recycling is well understood, and so the possibility of producing bioactive or toxic metabolites is limited. Hence the general focus of safety studies for biologics is on on-target effects, and more occasionally on non-target tissue effects—in essence, pharmacology. The emphasis is different in small-molecule safety assessment where xenobiotics introduced into the body are cleared by many different mechanisms, all of which can contribute to the toxicity of the product.
Looking at dose-limited effects
It is important to consider whether the exaggerated pharmacological effects of a biopharmaceutical can be dose-limiting. As a consequence, those studying these effects need to assess the pharmacological response within well-designed and well-executed safety studies. Researchers are therefore required to perform safety studies in pharmacologically relevant species, i.e., those nonclinical species in which the therapeutic has a comparable mode of action to that expected in the clinical setting. This means that species selection is essential, and that a series of in-silico, in-vitro and in-vivo investigations are carried out to understand the drug pharmacology in a range of laboratory animals and thus identify the most relevant species.
Small-molecule safety programs typically use a rodent and non-rodent species; however, there is more flexibility in a biologics safety program. The default position is still to identify a rodent and non-rodent species in which the therapeutic is active, but if this is not possible and only one species exists, then a one-species safety program can be conducted. There are also examples where there is no relevant species, as the therapeutic is only active in humans. In this instance, several other options may be explored, such as using a transgenic animal that expresses the human target or developing a surrogate molecule (usually a murine version of the human therapeutic) to generate safety data. With appropriate scientific justification, some standalone studies that are relevant for small-molecule drugs may be combined with other studies when developing biologics, and some studies may be excluded altogether. The essential safety data is still collected, but usually in conjunction with other investigations rather than in separate studies. This has the added benefit of meeting our “3Rs” goals (reduce, refine and replace animal testing) by reducing the total number of animals used in such investigations, but has the knock-on effect of making these studies far more complex.
As with all generalities, there are exceptions. Not all biologics are made up of “naturally occurring” molecules, some have been extensively chemically modified. This can mean that hybrid new chemical entity/biologics approaches are undertaken to assess the safety profile of those modified components. These challenges, including the need to demonstrate clinically relevant pharmacology on studies, mean that the designs of biologics safety programs require a great deal of understanding of the therapeutics’ mode of action.
On differences and similarities
So, whilst some differences exist in the approach taken to assess the nonclinical safety of small- and large-molecule therapeutics, there are increasingly greater similarities. As discussed earlier, there are potential off-target toxicities that need to be investigated for xenobiotics where the selection of a relevant species is just as critical. For example, some drugs produce specific metabolites relevant in the clinical setting that are not reproduced in all nonclinical species. In these instances, the toxicity of the therapeutic may need to be evaluated in species that produce a similar metabolic profile to that in human. If the metabolite is human-specific it may be necessary to also test the safety of that human metabolite in a relevant safety-testing species. Equally, the importance of dose-limiting pharmacology can be a critical investigation, and this may be explored in nonclinical safety studies.
In practice, this means that many product specific biomarkers of drug intervention are now included on safety studies to measure the pharmacology of the drug in addition to traditional safety endpoints. Also, specific safety markers may be included to assist in the selection of safe clinical doses. In all cases a sound understanding of the expected biology of the therapeutic is required in order to design product-specific packages that stand up to regulatory scrutiny and predict clinical safety.
Overcoming the barriers
With an increasing focus on including biomarkers to measure all manner of potential toxicities as well as pharmacodynamics on studies, one of the biggest barriers to being able to support nonclinical product development is the bioanalytical support required on studies. Many of the complex biological responses we measure are focused on specific therapeutic areas, and preclinical contract research organizations (CROs) are increasing their knowledge and experience across a wide range of therapeutic areas. This knowledge base is becoming integrated into all aspects of the projects the CROs support, and the expertise is being accessed by drug developers.
Drug developers recognize the added value of full-service nonclinical CROs that take a very translational approach to study design and execution. Those that can bring their experience, scientific and technical expertise to bear in developing and optimizing the best possible program for their customer’s molecules have an advantage in the marketplace. From early program design and the identification of relevant biomarkers for use on the project, through to problem-solving as they review the findings from these complex biological systems—that is where CROs can really create value for their customers. CROs that are equipped with the knowledge base and infrastructure to support development in this way play an essential role in product development partnerships.
Lee Coney is the chief scientific officer of Huntingdon Life Sciences’ biologics business; he has been with the company for 10 years following a career working in a number of U.K.-based biotech companies. His experience to date has been spent developing therapies that include vaccines, recombinant proteins, monoclonal antibodies, viral and non-viral gene delivery systems and cell-based therapies.
Changes in store for Huntingdon and Harlan
Late June saw Huntingdon Life Sciences and Harlan Laboratories announce that the combined companies will be called Envigo. The new name and brand will be launched later this year, ushering in, as they say, “a significant milestone for the combined organization, marking great progress in integrating the companies and building on a heritage of more than 80 years.”
The name Envigo is made from a combination of words that reflect the identity of the new company. The letters E and N come from “enhance, enrich and enable—the company aims to help make the world a better place through advancing the research and product development of its customers. As for the “vigo” part, it originates from “vigorous and invigorate,” and the Latin word “vita” meaams “life”—so, being dynamic and strong, imparting vitality, energy and life.
“This is a hugely exciting time for our company. We at Envigo will be united with our customers in the knowledge that the research they conduct, and the products we help them develop, have the potential to enhance life, said CEO Brian Cass. “Our new name and brand will reflect our integrated management structure and the broader product and service offerings of our combined organization.”
Adrian Hardy, chief operating officer, added: “Our customers are looking for partners who understand their goals, take ownership of projects, and deliver high quality products and science. Our goal is to establish Envigo as the number one partner for both customer service and scientific expertise.”