Revisiting Comparative Drug Development

Although there is significant overlap between veterinary and human medical science, collaboration and cross-disciplinary efforts are rarely pursued during drug development. The concept of One Medicine proposes that both humans and their pets can benefit from the incorporation of clinical trials using companion animals with naturally occurring diseases that behave similarly to human diseases into the drug development process. Interest in this approach is rising, but there are many hurdles to overcome before comparative drug development becomes commonplace.

The One Medicine Concept

In light of the push for greater collaboration within the pharmaceutical industry following the global COVID-19 pandemic and the greater awareness of the ways in which animal health can impact humans, it is important to revisit the One Medicine concept, which advocates for collaboration between members of the human and veterinary medical fields.¹

The idea behind One Medicine was initially proposed in the 19^th century by Rudolf Virchow.² His initial belief that human and animal health are linked has been expanded on by many others who have outlined the many ways in which human and veterinary medicine are connected and can benefit from working together. The name One Medicine was formally used for the first tine by Dr. Calvin Schwabe in 1984.

The focus of One Medicine is promotion of collaboration between pharmaceutical and veterinary professionals to drive development of new medicines that can benefit both humans and animals, the latter including companion and industrial animals.^1,2 The concept is based on the fact that, in many species of animals, diseases that are very similar to those that occur in humans occur naturally and spontaneously. Performing parallel clinical studies can thus provide information about the safety and efficacy of novel drug candidates that can be used to benefit both human and animal health.

It is also worth noting that the One Health concept that has become more mainstream following the COVID-19 pandemic simply expands on the earlier One Medicine idea. This initiative emphasizes the interconnectedness of human, animal, and environmental health, as exemplified by the spread of zoonotic diseases and the need for global, multidisciplinary cooperation in the event of future pandemics.¹

The Value of Comparative Drug Development

Although the One Medicine concept has been around for many years, it is more recognized within the veterinary community than the human pharma field. That truth was evident during the COVID-19 pandemic, when the experience that veterinarians and animal vaccine developers have had in dealing with animal coronavirus infections was largely not considered within the public health response.¹

However, there are a variety of professionals and organizations actively promoting the concept today. One of these is the UK’s Humanimal Trust, founded in 2014 by orthopedic–neuro veterinary surgeon Professor Noel Fitzpatrick in response to his frustration with the unfairness inherent in the gulf between animal and human medicine.² Now headed by Chair of Trustees Professor Roberto La Ragione, the Humanimal Trust seeks to remove the barriers that keep that divide in place by establishing a roadmap for collaboration and creating opportunities to realize it, as well as spreading awareness of the benefits of sharing knowledge about human and animal clinical practice, funding and facilitating research, and developing educational program for young children, to medical and veterinary students.

In the larger One Health area, collaboration has focused on solving the problems presented by zoonosis and antibiotic resistance.³ This directed effort is understandable, as zoonotic pathogens, or those that originate in animals, account for approximately 75% of emerging infectious diseases. The benefits of such collaboration were realized long before the One Health concept was formalized; the vaccine against smallpox was discovered following recognition that the human disease resembled cowpox, which led to development of the first vaccine against this deadly disease.

In the One Medicine area, which is generally more closely associated with companion animals,¹ a key driver for collaboration between veterinary and human medicine resides in the recognition that rodent models used in preclinical studies for human drug development often do not provide data that correlate with drug performance in humans.⁴ This poor correlation accounts for the high number of failures when drug candidates move into phase II and phase III studies. The high failure rates contribute greatly to the high cost of drug development.⁵

The reverse translational model encompassed by the One Medicine concept, meanwhile, leverages clinical studies in companion animals with naturally occurring diseases that behave similarly to those in humans.⁴ This model can be used on the level of precision medicine to predict drug side effects and/or efficacy for individual patients using specific single nucleotide polymorphism information, as well as in the much broader application of developing improved predictive capabilities and actual therapies for both people and their pets.

In this approach, clinical data from human patients are used to design clinical trials for animals with spontaneous diseases that model the human disorders.⁴ The data generated from these early studies are used in combination with computational modeling of pharmacokinetic and pharmacodynamic information to predict the safety and efficacy of the drug candidates.

Using animals that live in the real world, are exposed to different environmental hazards, and have spontaneously occurring diseases allows studies in a more natural setting with much greater relevancy than highly inbred, genetically modified rodent models created in a sterile lab setting.⁵

Many Therapeutic Areas Can Benefit

Pet owners today view their pets as family members and are willing to provide high levels of ongoing care, which also contributes to the clinical relevancy of companion animals.⁵ There is consequently a drive to develop more advanced diagnostic technologies and treatment solutions for veterinary applications. Specialties and subspecialities within veterinary medicine are increasing in number, and veterinary schools are establishing collaborations with drug developers to accelerate discovery of new drugs and devices.

The idea of conducting clinical trials in companion animals with naturally occurring diseases was initially proposed in 1929 by Nobel laureate August Krogh. The first such clinical trials were conducted in pet dogs with cancer.⁵ Today, most reverse translational clinical trials with companion animals involve dogs and cats. Horses are also occasionally used, as the dog, cat, and horse genomes have been fully sequenced and annotated.

As with humans, cases of cancer are on the rise in companion animals, particularly dogs.⁵ In this species, it accounts for nearly 50% of pet deaths. Developing cancer treatments using rodent models is nearly impossible owing to the complexity of the disease and its variability of progression. Naturally occurring cancers in dogs are being used, however, to better understand the disease, identify relevant biomarkers, develop new diagnostic tools, and evaluate and predict the safety and efficacy of drug candidates.

Another disease experienced by companion animals with significant similarity is osteoarthritis, a chronic and progressive musculoskeletal disorder.⁵ In this case, unlike rodents, pets have joints with similar architecture that are weight-bearing and thus provide more relevant data. The same is true for spinal cord injury and disorders. Other areas of focus for comparative drug development include brain and neurological diseases, bone and joint diseases, diabetes mellitus, chronic enteropathies (e.g., inflammatory bowel diseases (IBD)), hypertension, congestive heart failure, infectious diseases, and others.^2,4–6

In many of these areas, parallel clinical trials using companion animals have already been conducted.⁵ For instance, Restasis for dry-eye disease was developed for humans after Lifitegrast, a topical immune-modulating agent, was proven efficacious in the treatment of canine keratoconjunctivitis sicca. The tyrosine kinase inhibitor ibrutinib was developed to treat mantle cell lymphoma and chronic lymphocytic leukemia in humans using data from clinical trials in dogs with naturally occurring non-Hodgkin’s lymphoma. Separately, operative techniques to treat human patients with osteosarcoma were established through clinical trials with dogs with the same disease. Treatments based on mesenchymal stem cells for IBD and other chronical inflammatory disorders, such as chronic oral inflammatory diseases, are also being developed using data from clinical trials with dogs and cats. Naturally occurring dog and cat disease models of forms of cardiomyopathy are helping to evaluate viral vector–based gene therapies for both human and veterinary patients.

Comparative Oncology

Comparative oncology is “the study of naturally developing cancers in animals as models for human disease,” as defined by the Comparative Oncology Program (COP) from the NIH’s National Cancer Institute Center for Cancer Research,⁶ which was founded in 2003 to help advance cancer drug development by treating pet animals — primarily cats and dogs — in properly designed clinical trials with naturally occurring cancer. Both animals and people benefit from any newly developed therapeutics that result.

More attention was brought to the field of comparative oncology when at a workshop on the subject hosted by the World Small Animal Veterinary Association’s (WSAVA’s) One Health Committee during its 2019 World Congress, released a manuscript (“Delivering Innovation to Oncology Drug Development through Cancer Drug DISCO (Development Incentive Strategy using Comparative Oncology): Perspectives, Gaps and Solutions”) was published in the Annals of Medical and Clinical Oncology.^7,8 The paper “outlines new commercial perspectives on the value of closer relationships between the human and animal health pharmaceutical and biotech sectors to deliver a ‘win/win’ for successful cancer drug development in humans and dogs.”

More specifically, a new funding strategy was proposed that has been implemented as the drug DISCO initiative.⁸ The goal is to increase the number of animal-based clinical trials for cancers that closely mimic those in humans. In this approach, pharmaceutical companies would license developmental cancer treatments to animal health drug companies for the development of veterinary medicines, allowing the animal health companies to avoid the significant time and cost involved in early R&D. The animal health companies would conduct clinical trials and share the results with the pharmaceutical developers. If successful, the animal health companies can market the drug for veterinary applications. The pharmaceutical companies benefit from leveraging the initial clinical data in highly relevant animal models.

As we reach the end of 2022, comparative oncology continues to attract new research talent. One example is Dr. Jon Kim, who recently joined the University of Florida College of Veterinary Medicine faculty with the intention of applying artificial intelligence (AI) and machine learning (ML) to the development of novel diagnostic and clinical applications.⁹ During his education, Kim realized that in most cases it is impossible to tell human from animal tissue in clinical samples without knowing the sample history. That led him to comparative oncology. He is seeking new ways to use data, particularly data generated by studying naturally occurring cancers in companion animals, to better understand how cancer develops and progresses.

Veterinary informatics –– the combination of veterinary health record day with informatics technologies, such as natural language processing, AI, and ML –– currently finds limited use, largely due to the lack of standardization of veterinary medical data, including imaging, laboratory, genetic, and sensor data.¹⁰ There is significant potential, however, if such data can be accessed, including for zoonotic disease surveillance and reporting, tracking of zoonosis in food animals, the study of antimicrobial resistance in food animal populations, extended outbreak detection, disease outcome prediction, and investigation of environmental effects on pets and people. There are also clinical applications, such as gaining better understanding of disease mechanisms and earlier and more accurate diagnosis leading to improved outcomes. It may also be possible to identify naturally occurring disease models in companion animals that are representative of rare human diseases, enabling the discovery and development of novel treatments.

Notable Acquisition Activity from 2015 to 2020

In 2014–2015, there were a fair number of small biotechs developing specialized veterinary medicines.¹¹ Most have since been acquired by larger animal health companies looking to benefit from already-marketed products and to facilitate the development of others in the pipelines of these emerging players.

Nexvet Biopharma, which was focused on developing species-specific antibody drugs starting with clinically tested human therapies, particularly anti-nerve-growth-factor antibodies for controlling joint pain, was snapped up by Zoetis Inc. (previously the Pfizer animal health business) in July 2017.¹²

Aratana Therapeutics, which applied the human drug development approach to pet medicines (including in-licensing human medicines), had three approved products (GALLIPRANT^® (grapiprant tablets, a first-of-its-kind NSAID for canine osteoarthritis); ENTYCE^® (capromorelin oral solution, for stimulating the appetite in dogs suffering from chronic and acute conditions); and NOCITA^® (bupivacaine liposome injectable suspension, a long-acting local anesthetic for post-operative pain relief)) and several other candidates when it was acquired by Elanco Animal Health in July 2019.^13,14

In July 2021, Elanco acquired TANOVEA^® (rabacfosadine for injection) from VetDC (a spinoff from Colorado State University and its animal cancer research center) shortly after the drug received U.S. Food and Drug Administration (FDA) approval as the first treatment for lymphoma in dogs.¹⁵ Elanco quickly followed that move with the acquisition of Kindred Biosciences, which was developing canine equivalents of such drugs as Orencia, Enbrel, and Xolair, which are expected to be launched as blockbusters through 2025, in August 2021.^16,17

A couple of firms have managed to stay independent. CanFel Therapeutics is a semi-virtual company focused on developing antibody therapies for the treatment of cancer in dogs and cats using its cCSC development platform and cell-based discovery techniques.^11,18

Others are starting with the development of veterinary medicines and considering their later transfer to human patients. Cresilon’s product VETIGEL^® is a hemostatic medical device that arrests severe bleeding in animals in a matter of seconds without manual pressure. Recent fundraising will allow expansion into additional markets and submission of a 510(k) premarket notification to the FDA to enable entry into the human health market.¹⁹ Researchers at the University of Missouri have used click chemistry to enable targeted delivery of drugs to treat tumors in dogs.²⁰ Leah Labs, meanwhile, is developing chimeric antigen receptor (CAR)-T cell therapies to treat cancer in dogs using CRISPR gene-editing tools.²¹ Animol Discovery is using advanced human drug discovery technology in combination with ML approaches to accelerate the discovery of novel veterinary medicines.²²

Many Challenges to Surmount

Despite the fairly obvious benefits of sharing veterinary and human health information and the calls to do so by groups such as the Humanimal Trust, actual collaboration between the two sets of professionals rarely occurs. Numerous barriers to the development of such relationships exist, including the lack of opportunities for veterinarians and physicians to connect, lack of awareness within both groups that the knowledge each has can complement and assist the other, perceptions of “us against them,” and a general view by many in the human medical field that veterinarian medicine has less worth.¹

On a simpler level, regulations exist that permit the use of human drugs for the off-label treatment of companion animals under certain circumstances, removing some of the incentive to develop novel medicines specifically for animals.⁵ Lack of financial incentives for investing in veterinary indications is also often another significant hurdle.

Another challenge is the small number of veterinary clinical trials conducted each year. For instance, in 2015, just over 120 veterinary clinical trials for cancer therapies were listed in the Veterinary Cancer Society’s database vetcancertrials.org, while over 18,000 human trials were noted at clinicaltrials.gov.²³ Part of this discrepancy is due to the lack of regulatory requirements for multi-phase animal clinical trials. Siloed processes for animal and human drug development and approval complicate the situation even further.^8,24

Animal clinical trials also tend to involve fewer patients than human trials and thus generate less data.⁵ Doses are generally much smaller as well.²⁵ Indeed, veterinary clinical trials are seldom designed with the intent of having the data inform human trials and therefore lack certain important characteristics needed to do so. As with human clinical trials, ethical aspects must also be addressed to protect both the pets that participate in clinical trials and their owners.

While these issues can be overcome, others are more challenging to resolve. Perhaps the greatest limitation is the fact that there are many diseases that afflict humans for which there are no similar diseases that are occur naturally in companion animals.⁵ It is also difficult, without sufficient knowledge of comparative anatomy, physiology, pathology, and medicine, to identify appropriate naturally occurring disease models in animals that optimally represent human diseases. In addition, animal models, even those with naturally occurring diseases, still have limitations that must be taken into consideration when using data from animal clinical trials to predict outcomes in humans.

Education is Key

The key to overcoming the various challenges to expanding comparative drug development efforts is increasing the awareness of the benefits of combining veterinary and human clinical research.² “We must ensure that the best research, clinical practice and learning, benefiting both humans and animals, are accessible, funded, encouraged, and promoted,” said Humanimal Trust Chair of Trustees La Ragione. In 2020, the organization formed the Humanimal Hub to address this need. It is a free online platform for all human and animal medical and veterinary professionals to meet, collaborate, and share knowledge.

Others have outlined additional ways to facilitate the needed cross-disciplinary collaboration.⁵ For instance, expert panels comprising physicians, veterinarians, and academic researchers should be formed to identify optimal naturally occurring animal disease models with the greatest potential for accelerating translation. Professional societies, conferences, workshops, and journals dedicated to One Medicine and comparative drug development should be established. Medical and veterinary schools should work together to establish opportunities for students and faculty members from the two fields to interact with one another and participate in cross-teaching and cross-training exercises. Clear mechanisms for financial support of One Medicine projects and clinical research will also be essential.

Some schools are taking the idea of cross-disciplinary training to heart.²⁶ Harvard offers a One Health clinical elective in which medical students spend four-week rotations shadowing veterinarians at the nearby Franklin Park Zoo. UCLA residents and medical students join rounds at the Los Angeles Zoo, while veterinary cardiologists join teaching rounds at UCLA. The Saint Louis Zoo’s Institute for Conservation Medicine welcomes students from colleges, universities, and medical schools to explore challenges that threaten wildlife conservation and public health. At the University of Pennsylvania’s Anatomy Exchange, over 100 medical and veterinary students view cadavers in each other’s labs each fall. Medical and veterinary schools also participate in zoobiquity conferences, with students from both listening to talks by physicians and veterinarians.

Comparative research projects have emerged from these various activities to explore many different types of therapies (small molecules to antibodies to mesenchymal stem cells) to overcome microbial resistance in chronic implant and wound infections and to treat sleep apnea cardiovascular disease, epilepsy, pain, cognitive decline, anxiety, infectious diseases, and more. These projects are hopefully just the beginning of a wave of investment in One Medicine education that will ultimately lead to many novel therapeutics that benefit people and their companion animals.

Animal Experimentation vs. Clinical Medicine

 While there are no specific, binding regulations regarding the implementation of veterinary clinical trials, such studies still very significantly from traditional animal experimentation conducted during preclinical investigations.²³ Preclinical animal studies are performed according to specific laboratory protocols in a laboratory setting with no control groups and are not expected benefit to the animals; in many cases they are sacrificed for further evaluation.

With clinical trials, the safety of the animals is a prime concern, as is generation of quality data with high relevancy to both veterinary and human drug development. Clinical trials with pets, in fact, can help companies meet the 3R goals for human drug development, including reducing the use of genetically engineered laboratory animals, replacing large numbers of lab animals that represent poor disease models with fewer companion animals that are better disease models and can benefit from the administered therapies, and refining the data generated. At the very least, clinical trials in dog and cat patients have the potential to facilitate the transition between preclinical laboratory research using rodent models and human clinical trials and to minimize the risk of drug development.²⁴

References

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