Category: Animal Health

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

1. Tracey A. “The One Medicine concept: its emergence from history as a systematic approach to re-integrate human and veterinary medicine.” Emerg. Top. Life. Sci. 5: 643–654 (2021).
2. Ellis, Danielle. “One Medicine: how human and veterinary medicine can benefit each other.” News-Medical.net. 26 Oct. 2022.
3. De Giusti. Maria et al. “Collaboration between human and veterinary medicine as a tool to solve public health problems.” The Lancet. 3: e64-e65 (2019).
4. Schneider, Benjamin et al. “Model‐Based Reverse Translation Between Veterinary and Human Medicine: The One Health Initiative.” CPT Pharmacometrics Syst. Pharmacol. 7: 65–68 (2018).
5. Kol, Amir et al. “Companion animals: Translational scientist’s new best friends.” Sci. Transl. Med. 7: 308ps21 (2015).
6. “Comparative Oncology Program.” NIH National Cancer Institute Center for Cancer Research. N.d.
7. WSAVA-Supported Oncology Manuscript Highlights Benefits to Humans and Dogs of Collaboration between the Pharmaceutical and Biotech Industries in Drug Development. WSAVA. Jun. 2020.
8. Carrozza, Amanda. “Drug DISCO: How commercial incentives can improve cancer drug development.” DVM360. 20 Aug. 2020.
9. “ Jon Kim: Using AI to revolutionize the field of comparative oncology and help animals and humans in the real world.” University of Florida Health. 4 Oct. 2022.
10. Lustgarten. Jonathan L et al. “Veterinary informatics: forging the future between veterinary medicine. human medicine. and One Health initiatives—a joint paper by the Association for Veterinary Informatics (AVI) and the CTSA One Health Alliance (COHA).” JAMIA Open. 3: 306–317 (2020).
11. Thayer, Ann M. “Pets Are Biotechs’ New Best Friends.” C&E News. 17 Aug. 2015.
12. Zoetis Completes Acquisition of Nexvet Biopharma. 31 Jul. 2017.
13. Aratana Therapeutics to be Acquired by Elanco Animal Health. Aratana Therapeutics. 26 Apr. 2019.
14. Elanco Finalizes Acquisition of Aratana Therapeutics. Elanco. 18 Jul. 2019.
15. TANOVEA® (rabacfosadine for injection) Receives Full FDA Approval as First Treatment for Lymphoma in Dogs; Elanco Acquires Product from VetDC, Inc. 19 Jul. 2021.
16. Elanco Announces Agreement to Acquire Kindred Biosciences. Kindred Bio. 16 Jun. 2021.
17. Elanco Closes Acquisition of Kindred Biosciences. Elanco. 30 2021.
18. “CanFel Therapeutics is an emerging veterinary oncology company.” CanFel Therapeutics. N.d.
19. Vignesh, R. “This biotech just raised $25M to develop plant-based gel that stops traumatic bleeding in seconds.” Tech Funding News. 28 Oct. 2022.
20. ‘Click’ chemistry may help treat dogs with bone cancer, MU study finds. University of Missouri. 7 Nov. 2022.
21. Gilyard, Burl. “LEAH Labs Startup Fetching Fresh Funding for Cancer Treatment for Dogs.” Twin Cities Business. 21 Apr. 2021.
22. Animol Discovery, Inc. announces Series B financing of $34.0 million to advance its pipeline of novel veterinary pharmaceuticals. Animol Discovery. 28 Jul. 2022.
23. Fürdös, Irene, Judit Fazekas, Josef Singer and Erika Jensen-Jarolim. “Translating clinical trials from human to veterinary oncology and back.”  Journal of Translational Medicine. 13: 265 (2015).
24. Grimm, David. “Can clinical trials on dogs and cats help people?” Science. 11 Aug. 2016.
25. Rhodes, Linda. “Terminology Matters: Understanding the Differences in Animal vs Human Drug Development.” Kiasco Research. N.d.
26. Boyle, Patrick. “What medical students can learn about health from animals.” AAMC News. 10 Dec. 2019.

Originally published on PharmasAlmanac.com on November 18, 2022.

There remains a critical unmet need for safe and effective hemostatics for both internal and external use in a wide range of applications, from animal and human surgery to point-of-care treatments for traumatic brain injuries. Cresilon’s Chief Executive Officer and Co-Founder Joe Landolina developed a plant-based adhesive polymer with unique hemostatic properties while experimenting with natural materials in a laboratory as a teenager and partnered with fellow co-founder Isaac Miller to found the Brooklyn-based biotech company Cresilon, Inc. In this Q&A, Joe and Pharma’s Almanac Editor in Chief David Alvaro, Ph.D., discuss Joe’s unique invention, its many potential uses, and the unique company built around a mission to impact and save lives.

David Alvaro (DA): As I understand it, the Cresilon story goes back to an invention you created when you were still a teenager. Can you share that story, including how you found yourself experimenting with plant-based gel technology at the time?

Joe Landolina (JL): I’m an engineer by training, but, long before my training, I was lucky to have had an early start in chemical research. My grandfather had been an executive at Hoffman-LaRoche, and when he retired, he decided to start a vineyard, including a fully stocked laboratory. From the day I learned how to walk, I was allowed into a lab with him, and I spent a lot of time just shadowing him every step along the way.

As a young high school student, I had the opportunity to join a summer research program in tissue engineering at Columbia University. Since kindergarten, I had always wanted to go into a medical field, but through the exposure to tissue engineering in that program, I realized that there was far more to medicine than just going to medical school to become a doctor. The project I got to work on involved chondrocyte regeneration — regrowing cartilage — using a plant-based scaffold that could differentiate stem cells into a target tissue. As a naïve young kid, I decided to go back home and try to make my own scaffold and see whether I could grow a cell on that scaffold. Needless to say, I did not end up with cartilage or anything resembling cartilage.

However, while experimenting with that scaffold, I found a blend of two polymers extracted from algae that would stick to skin and wouldn’t let go until you wanted it to. By then, I was then 17 years old and a freshman in the chemical engineering program at NYU, and the program was having a competition. If you made it through a few stages of the competition, you could attend classes at the business school, and I was really interested in that, because I wanted as well-rounded of an education as possible. I decided to investigate whether my polymer blend, when applied to a bullet wound, would hold the wound together and prevent the patient from bleeding out long enough to get to the next level of care. With that concept, we won the competition.

That experience formed the basis for Cresilon. We realized that we could leverage that same two-polymer system and use it to immediately reassemble local tissue. Today, we have this product commercially available for animal health under the brand Vetigel — a blend of two polymers that will instantly stop anything from the most traumatic bleeds all the way down to the most precise surgical bleeds in a matter of seconds. Perhaps more importantly, it allows the patient to create a durable fibrin patch underneath; if you remove the gel within a matter of minutes, you actually have what looks to be repaired tissue. For example, if you had a lacerated jugular vein — which is a very lethal and difficult-to-treat injury — you can put this on, and not only will the bleeding stop in about two seconds, but, if you peel it away a minute or two later, there will be a fibrin patch underneath, more permanently sealing the wound. The blood vessel will still have blood flowing through it; it’ll still have a pulse, and just the vessel wall will be repaired by the patient.

The company has grown since we founded it back in 2010. We now have about 60 full-time employees and do all our manufacturing in-house in Brooklyn; in fact, we are the only biomanufacturer in the five boroughs of New York. Today, we have sales operations in animal health in both the United States and Europe, and we are eagerly awaiting clearance on a filing with the U.S. FDA for a first-in-human indication for Vetigel.

DA: Today, “plant-based” has become a bit of a positive buzzword across industries. Going way back to the invention and the inception of Cresilon, did you consciously decide to use plant-derived ingredients with that appeal in mind, or was it just kind of happenstance that it aligned with this trend?

JL: It was a bit of both. My parents had wanted to ensure that my laboratory endeavors were safe, and, since they assumed that anything I could grow in nature was inherently safe (which may not always be true!), I was able to play with plant-based materials that way. Besides, I was working out of a winery lab, so I couldn’t exactly call Sigma and order cell culture reagents but had to stick to the food-grade materials that you could procure as a winery at the time. On top of that, plant-based materials tend to be inexpensive, easy to access, and easy to manipulate and purify, which was very helpful for a young engineer.

DA: What were some of the key inflection points the company has gone through since the founding?

JL: We’ve been very lucky that the merits of the technology and our mission have been essentially the same from day one. Our mission has always been saving lives, and the technology has always been about stopping bleeding. Most of what has changed over time has been our ability to execute the mission at different scales.

One major inflection point for us was realizing the value of the animal health market, which was not initially on our radar. It was only through talking to the market — in particular, the scarcity of available animal health treatments in New York in the aftermath of Hurricane Sandy — that we realized that we could broaden our scope outside of just trauma care. That opened up not only animal health but also the surgical market as a focus for Cresilon.

I like serving underserved markets, and while our technology is a gamechanger anywhere, it makes that much more of a difference in a market where 85% of our customers are small business owners. For them, being able to apply top-grade engineering and healthcare solutions to a patient at a price that’s affordable for the average American pet owner is massive. And this is not an insignificant market by any means; there are more than three billion bleeds in pets every year in the United States alone.

DA: You mentioned that the vision has not changed much from the very beginning, but have the technology or the product itself changed much from the early iterations? Are there significant differences in how Vetigel is formulated for animal versus human use?

JL: Yes and no. Vetigel is a blend of two polymers, and since we’ve never been known for this kind of creativity here at Cresilon, we call them A and B. Since day one, Vetigel has always been A plus B plus water. We’ve gotten a lot better at purifying these materials and understanding our supply, because these are natural farmed materials with seasonality and other factors that needed to be worked out.

We ended up with a single master formulation of Vetigel that is used for all the indications that we’re exploring. If you had asked me a decade ago, I would have anticipated a different formulation for each indication. However, it turns out that the master Vetigel formulation that we filed with the FDA for external use will be the same formulation that we’ll apply for military and trauma use and ultimately for surgical use. There are different levels of control involved in different indications, but using essentially the same product for all the indications gives Cresilon tremendous versatility, because we know that all of the data that support the safe, efficacious use of Vetigel are effectively applicable to everything else that we want to be doing.

DA: Can you expand a bit on how the mechanism of action underlying Vetigel?

JL: Our mechanism of actions is simply elegant or elegantly simple, depending on how you want to look at it. We have two long-chain polysaccharides –– incredibly high-molecular weight-materials — that create a viscous gel that can be applied to wound tissue using a syringe. As the gel leaves the syringe, the polymer chains spin slightly and then immediately snap into a mechanical barrier that maintains its own pressure. Unlike other hemostatics on the market that work by absorbing blood and require the application of pressure to form a clot, this material creates its own pressure and will hold strong even in the face of brisk or high-pressure bleeding. It is responsive to pressures that push on it, so increasing pressure increases that resistance.

Another critical property of Vetigel is that it is nonporous, so when a clot forms, it’s no longer attached to the gel and will stay behind if you take the gel off. This allows for much faster action and reduces the risk of rebleeding, because, unlike other hemostatics, it doesn’t rip or create little fractures or tears in the clot as the patient breathes or moves.

DA: Among the huge range of potential human uses, what do you see as the most critical or the biggest unmet need that is not well served by the hemostatics on the market?

JL: Trauma care is a major issue. The best trauma products today offer about an 80% success rate, meaning that they are unable to control the hemorrhage in 20% of cases, which is unacceptable in my mind. Additionally, 91% of battlefield mortality is due to what we call “preventable hemorrhage.” It’s not only that we offer a better product to stop bleeding; we can really save countless lives.

Surgery faces another critical need. Every single second that a patient is on the operating table under anesthesia adds additional risks for that patient, additional blood loss, and additional costs incurred by the hospital system. Orthopedic and spinal procedures are particularly bloody procedures, and a lot of the time in surgery is spent in hemorrhage control. On the basis of some of our animal work, we think that Vetigel can drastically reduce the amount of time that a patient is on the table and enable surgeries that would be too life-threatening to perform otherwise.

DA: Do you foresee a future in which Vetigel is a standard product that consumers have in their homes, in their first aid kits?

JL: I think that we’re in the sweet spot mechanistically and economically: this product can be used in neurosurgery, but it can also live in a first aid cabinet.

DA: What can you tell me about the team that you’ve assembled at Cresilon and the different backgrounds and kinds of expertise you have brought onboard?

JL: What I love about this team is that comprises cross-disciplinary, diverse individuals that come from all backgrounds, walks of life, and disciplines. We have a good mix of younger, less experienced talent that are hungry, creative, and fast-paced and individuals that bring decades of experience and understand how to bring products across the finish line. With a product like this, I find it useful to have a broad range of skill sets, from less experienced all the way up to industry veterans and everything in between.

DA: Speaking of diverse perspectives, can you explain the cooperative R&D agreement that you have signed with the Walter Reed Army Institute of Research and the U.S. Department of Defense to investigate traumatic brain injuries?

JL: The Walter Reed collaboration is one of the most interesting projects we have going on right now. This is the first indication that Cresilon is exploring in a formal capacity that is not purely hemostatic. Walter Reed reached out to us after reading an article about Cresilon, and we started talking about their areas of interest and the deficiencies that they saw in current technologies. Importantly, there is currently no point-of-care solution to treat what is called a penetrating ballistic brain injury — a bullet wound or shrapnel injury to the head that penetrates to the brain.

In a lot of cases of this type of injury, the major risk to the patient isn’t the initial injuries to the brain; it’s the swelling of the brain that occurs in the hours following the injury. And there are very limited ways even to transport a patient with a severe brain injury. The collaboration is looking at using a material like our technology not only to stop the bleeding in this type of injury but to actually function as a neuroprotective, injected into the bullet or shrapnel track of this type of injury to stabilize the brain so that that patient can be moved to the next level of care and be seen by a neurosurgeon.

This may not be the largest market, but the engineer in me is very excited to deal with these types of indications. The work with Walter Reed is in a very early stage; we are preparing to begin studies to evaluate the safety and efficacy in these types of models, something that Cresilon has not had the capabilities to do before, although we have done dermatological work with Vetigel. I’m hoping by early next year that we’ll be able to see some initial results from the collaboration.

DA: Have you begun looking into additional applications for Vetigel that are not strictly hemostatic?

JL: With a material like Vetigel that stays where you want it to, is biocompatible, and works with the body in important ways, there are theoretically applications in wound healing, burn treatment, drug delivery modalities, treatment of nonhealing wounds, cosmetic surgery, and so on, and we’ve had a handful of collaborations in those spaces before.

As Cresilon continues to build our business, we will focus on our core areas of excellence, which is currently hemostasis, but our intention is ultimately to leverage this technology as far as it will go into as many indications as possible.

DA: What’s it like doing biomanufacturing in Brooklyn? Have you seen changes in the sector in NYC since Cresilon was founded?

JL: Cresilon was the first biomanufacturer to come into New York and among the first major biotech tenants to take space in New York City. We had the pleasure of being the first to try to negotiate with developers, landlords, and governmental agencies. New York is not Cambridge — there is not a lot of greenfield in this city, so we have to take the buildings that we’re given and find ways to make biotech work. I think that the key to this is having a good developer partner. But over the last 12 years, we have seen the industry grow around us, and we’re building a community of biotechs here in the city.

As far as picking Brooklyn: I’m a native New Yorker who was not excited by the prospect of commuting to New Jersey every day and really wanted to continue working in my own city. Additionally, in our early days, most of our employees were students, so we needed lab space that was somewhat close to a major campus. Our South Slope building is four subway stops away from NYU’s engineering campus, which made it easy for us to attract talent. By the time that we became large enough both to be able to afford and to consider other options, we were all sold on Brooklyn.

If you’re an engineer that studies in New York and you want to work in a plant doing actual physical manufacturing, you have almost exactly one option — Cresilon — which means that we’re opening entry-level engineering roles. We average 800 resumes for each available position, because there are so many engineers that study in New York but realize during their senior year that jobs in the field that they studied may not exist in the city where they want to live.

DA: Is there anything that merits a mention here about the company’s funding?        

JL: Like much of how we’ve grown this business, our funding has also been somewhat unorthodox: our investors are predominantly private individuals. Cresilon has raised roughly $90 million to date, and I’m very proud of that number, because it’s very difficult to attract funding to build a manufacturing site for a product that hasn’t been proven in the market or even launched yet. Having groups of investors that were willing to support us and see us through that development cycle was massive, and it’s allowed us to do what we do today.

DA: Is there anything you can disclose about what the next few years will bring to Cresilon and what else you have in the works?            

JL: In the coming 12–18 months, we will have several major milestones. First, a full global launch of Vetigel is already underway, which will drive the business to profitability, something I’m very excited about. It’s a great proof of concept, because some of our investors viewed our animal health markets not as a major profit center to the business but as a steppingstone in the path to eventual human access. In the next 12 months, we will prove that Vetigel is here to stay, which will allow Cresilon to be uniquely profitable even without our human markets.

Beyond that, after another 12–18 months, we will likely see our first human clearances. We have a pending submission with the FDA for an external-use medical device under the brand name Cresilon Hemostatic Gel that we filed late last year, and we anticipate gaining clearance soon. We also have a submission that we’re preparing for major trauma, which will be submitted in the next several months. That will allow us to drastically expand our mission, so that we can get this product into the areas where it’s more needed.

Over the next three to five years, we will build out that indication set, so that we can expand to all hemostatic indications in animals and humans and start setting our sights on portfolio expansion. Even if you have the best product in the world, it’s my opinion that a one-product company isn’t really a company. On one hand, the technology behind Vetigel has a lot more to give, and there are many more threads for us to pull, but we can’t put all our eggs into one basket. One of the proudest moments is our history took place in 2017, when we filed our first patent on technology that wasn’t derivative of my invention. It’s great to see our teams starting to make offshoot products, but I unfortunately can’t talk about any of those yet.

DA: Finally, if you look forward well into the future, what do you envision as the ultimate big-picture societal impact of Vetigel?     

JL: Within animal health, one of the things that keeps us going as a team is that we report lives saved or lives impacted figures to our team every Monday morning. Seeing that number increase every single Monday means that every syringe that comes off our line here in Brooklyn is making a difference somewhere in the world. We’ve received calls and emails from customers halfway around the world telling us about how they had a pet owner whose dog was hit by a car and is now walking around because of this product, and nothing else would have been able to stop it but our product.

You can extrapolate that to the fact there are something like 33 billion veterinary surgeries globally every single year, of which about 20% lead to some sort of bleeding event. We can consider the impact that that can have even in animal health — which is not as developed as human health — and extrapolate that into the human side. This is a product that can save countless lives, save countless dollars, and make the average OR visit shorter, without having to be overengineered or specifically designed for each indication. It’s effectively as close to a one-size-fits-all application as you can get in life sciences.

Originally published on PharmasAlmanac.com on November 16, 2022.

On September 1, 2020, TriRx Pharmaceutical Services, a global CDMO serving the biopharmaceutical market, announced its acquisition of a manufacturing site in Segré, France. The agreement between TriRx and Merck includes transfer of ownership and operations of a state-of-the-art facility that includes dedicated offices, production, sampling, warehouse areas, and a world-class staff, delivering products to all major global markets. The acquisition was predicated on an internal strategy to continually add high-demand capabilities, such as sterile injectables and animal health, to an already robust service offering. 

The transaction also facilitated TriRx’s expansion into Europe, by the acquisition of a best-in-class facility from Merck, one of the largest pharmaceutical  companies in the world. This strategic move seamlessly aligns with our overall future plans. The Segré site offers a stable book of business, including a long-term supply agreement with Merck to continue manufacturing the animal health products formerly produced by MSD. 

An Underserved Industry with Substantial Growth Potential

The production of animal health products serves dual segments — pet care and food supply. The global animal health market was valued at $47.1 billion in 2019 and estimated to be expanding at a compound annual growth rate of 5.8% through 2027.¹ Assuring animal health is a critical component to the world’s food supply.

The regulatory rigors of animal health products, while not identical in terms of oversight, are fundamentally consistent with those for human health pharmaceuticals — much of the same regulatory scrutiny and current Good Manufacturing Practices (cGMPs) exist in both spaces. The capabilities at the Segré site supplement those at our Huntsville, Alabama facility. The acquisition of this site allows us to add sterile injectables to our existing capabilities in the liquids, creams, and ointments dosage forms with additional non-sterile liquids. Furthermore, the competencies needed to manufacture animal health products are analogous to those required for human pharmaceuticals, and we estimate that our animal health production will consume roughly 30–40% of our total production at the Segré site, enabling us to broaden our service offering to our existing clients who operate in both the animal and human health industries. 

This site will transition to a worldwide center of contract manufacturing excellence in the fast growing animal health market and will continue to be a significant contributor to the local economy.

Entrance into Europe 

The prospect of adding a centrally located, European facility with a sustained track record of high performance both in regulatory compliance and in delivery, as well as a highly competent, professional staff of around 130 people (we are pleased to have retained 100% of the site staff) that serve the international marketplace was extremely attractive. The facility fits our competitive growth strategy well, as the animal health market is rising at about a 6% compound annual growth rate (CAGR). The Segré site supplies North America, European and International markets, and is licensed to support roughly 120 markets worldwide. With very few of these types of facilities and capabilities currently in the CDMO market, acquiring a sterile injectable facility that specializes in high-quality manufacturing and development for one of the largest pharmaceutical companies in the world — with a history of significant and exceptional performance in both manufacturing and fill-finish — will meet a rapidly growing/underserved market demand.

Future Outlook 

In the next three to five years, TriRx Pharmaceutical Services will continue to take a determined and opportunistic approach to expanding into additional delivery technologies; solid dosage form sterile human health, and biologics capabilities. We will also continue our search for an active pharmaceutical ingredient (API) facility that will facilitate a broad and integrated approach to satisfying market demand for our customers. 

TriRx’s Legacy

Founded and led by a team of pharmaceutical industry executives who have served as both contract service providers and customers, TriRx Pharmaceutical Services has a profound and multifaceted understanding of customer needs. We operate facilities that provide state-of-the-art laboratory, manufacturing, packaging, and warehousing capabilities, with a depth of understanding, commitment, and knowledge to deliver exceptional experiences on every project. 

 

References

1. Animal Health Market Size, Share & Trends Analysis Report By Animal Type (Production, Companion), By End Use, By Product (Pharmaceuticals, Feed Additives, Vaccines), By Distribution Channel, And Segment Forecasts, 2020 – 2027. Rep. Grand View Research. Feb. 2020. Web.

Originally published on PharmasAlmanac.com on December 9, 2020

A recently published study,¹ sponsored by TriRx Pharmaceutical Services and conducted in 2021, explores current challenges, trends, and needs facing animal health organizations, as well as the factors driving the process by which these organizations select contract development and manufacturing organizations (CDMOs) to support their operations.

Industry experts were selected to participate in the survey on the basis of their roles and experience relevant to the investigation of current and future dynamics in the animal health market. All survey respondents held roles in animal health companies, with 58% representing mid-sized, 20% large, and 22% small animal health firms. Most respondents held director or senior director job titles, with 30% primarily working in business development, 20% in drug production and manufacturing, and the remainder split among other roles critical to manufacturing and outsourcing (e.g., supply chain, external manufacturing, purchasing/procurement, and quality assurance / quality control). Respondents were evenly split between North American and European organizations, and the majority had more than five years of experience within the animal health organization. They represent companies that market a range of veterinary medicine dosage forms, with 74% of organizations having recently worked with liquids and semi-solids, 68% with oral solid dose (OSD) drugs, 60% with injectables, and 26% with inhalers or aerosols.

Outsourced manufacturing clearly continues to play a significant role in the animal health market. Overall, 94% reported that their company currently outsources services or operations to CDMOs (or CMOs), with 82% of respondents themselves being part of the decision-making unit at their firm that is involved in CDMO selection, positioning them well to provide insights into both the difficulties facing the animal health supply chain and the priorities such companies have when evaluating CDMOs.

The first question in the survey asked the industry experts to identify which stage in the product life cycle poses the most significant challenges to their organizations. Procurement of raw materials and the related resources required for developing and manufacturing the product was identified as the greatest challenge (34%), followed by manufacturing and packaging (26%); research, development, and clinical stages (18%); storage and transportation (16%), and finally the sell stage of the product to the final consumer (6%).

COVID-19 and the Supply Chain

The ongoing impacts from the COVID-19 pandemic and the industry’s reconsideration of global supply chains continue to add complexity to the veterinary product life cycle. The primary pandemic-related issue experienced by organizations was a shift in resource allocation from non-COVID- to COVID-related products (60%), but a number of others were ranked highly, including supply shortages of APIs and other raw materials (48%) and disruptions in transportation and logistics (42%).

Similarly, when asked to select the five most significant hurdles their organizations face with respect to sourcing and procurement, the highest-ranking response was identifying and sourcing reliable, high-quality raw material suppliers, selected by 52% of respondents. A number of closely related issues also ranked highly: lack of transparency with vendors, including unavailability of past evaluation metrics and vague specifications (46%); establishing reliable, interruption-free, and timely supply channels for materials (44%); and tracking compliance of suppliers with required regulatory standards (20%).

The responses offered with regard to the most difficult issues at the storage or logistics stage of the product life cycle focused more on the challenges of establishing distribution channels across global markets, with those that respondents identified as the most concerning including understanding import/export requirements and navigating disruptions across global markets, as well as establishing reliable storage and logistics channels across finished products, both of which were ranked among the top five by 64% of respondents.

Familiar Development, Manufacturing, and Sales Challenges

Development and manufacturing were identified as the most challenging stages of the product life cycle, and the questions that explore issues that companies face during the development and manufacturing stages of the product life cycle reflect some of the more traditional difficulties faced in these stages rather than the disruptions wrought on the supply chain by the pandemic. This underscores the critical importance of CDMOs in animal health drug development and manufacturing and the companies’ ongoing attempts to evaluate and select effective CDMO partners.

Unsurprisingly, the top-ranking challenge during development was designing an optimal and efficient “time to market” timeline, a traditional development complexity that is only becoming more critical, despite continuous innovations accelerating the path of drugs to market (66%). The other top issues identified were well upstream of the development cycle for individual drugs, including identifying the right products or therapeutic areas for investments (64%), disrupted and unusual future product forecasting (62%), and developing an IP or patent protection strategy (58%).

During manufacturing stages, a diverse set of hurdles was reported as particularly difficult, with tracking compliance of CDMOs with required regulatory standards selected as the most pressing (52%). As always, scaling of manufacturing remains a perpetual struggle, with 48% of respondents identifying scaling up from development or clinical phases to commercial manufacturing and 46% selecting the limited choices of commercial-scale CDMO partners among the more vexing issues at this stage. Other ranking responses revolve around digital and data-related complexities, including addressing IT security threats (48%), establishing robust, data-driven planning and scheduling strategies for manufacturing (46%), and serialization (38%).

Selling drug products to consumers was identified as the least problematic stage of the product lifecycle (6%), and there was little difference among the relative ranking of issues encountered at this stage, including establishing direct-to-consumer/patient/physician channels (92%); establishing a reliable pharmacy benefit manager (PBM), wholesaler, and pharmacy networks (90%); and competing with other, potentially favorable dosage forms (89%), among others.

Solutions

Subsequent questions explored the solutions that each respondent’s organization is currently implementing or planning to implement within the coming 24 months to address the relevant complexities facing the animal health drug supply chain. Consistent with longer-term trends impacting drug manufacturing across categories, consolidating suppliers was a popular solution, identified as a current solution by 36% of respondents and a solution sought over the next two years by 30%. Thirty-two percent of respondents reported that their organizations are currently developing a sustainable serialization strategy, while 28% reported that they were planning to do so over the next 24 months. Similarly, the adoption of new technology — including the Internet of Things (IoT), analytics, machine learning, and artificial intelligence — is a supply chain solution currently deployed in 30% of respondents’ organizations and planned by 28%.

Dosage Forms and Therapeutic Area

A different series of questions explored the therapeutic areas addressed by the respondents’ organizations and the considerations that are involved in selecting the optimal dosage form. The therapeutic area targeted by the most organizations was metabolic diseases (38%), followed by pain management (32%), emesis (30%), cardiology (28%), and parasitic, microbial, and fungal infections (each 26%), which aligns well with the overall markets for animal health drug products.

When identifying the most strategic dosage form (on the basis of sales volume) for drug products with multiple formulations, oral solid dose (OSD) led the pack (38%), followed by semi-solids (32%) and injectables (30%). In a breakdown by volume of current products by therapeutic area and dosage form, anti-emetics were the drugs most formulated as OSD and endoparasiticides the least offered as OSD (36%). Antimicrobials were the drug type most typically formulated as semi-solid liquids, creams, ointments, or lotions (43%), while reproduction control drugs were least commonly formulated as semi-solid products. However, reproduction control drugs were the dominant drugs formulated as sterile injectables (43%), with drugs addressing renal failure representing the smallest relative fraction of sterile liquid drug products.

The survey produced an interesting inverse trend in terms of which dosage forms were considered to be the most difficult to develop and manufacture versus which are the most challenging to package, store, and ship. Semi-solids were identified as the most troublesome to develop and manufacture (40%) but the least to package, store, and ship (26%), while injectables were considered the most straightforward of the three to develop and manufacture (26%) but the most difficult to package and transport (44%).

The survey additionally sought to explore the decision drivers determining the selection of the optimal dosage form for products for which multiple formulations are possible. The most important decision driver was on the level of patient (or owner) centricity: ease of administration (20%). Some more manufacturing-centric factors were also considered important, notably access and availability of excipients and raw materials (16%), the regulatory framework (14%), and cost of manufacturing and/or packaging (14%), while the top development challenge — time to market — was not identified as a particularly significant factor driving dosage form selection (6%).

CDMO Selection Decision Drivers

The survey concluded with a number of questions investigating the factors determining the selection of CDMO partners for animal health drug manufacturing and packaging and the methods employed to evaluate CDMOs.

Here we see some of the distinction between decision drivers in CDMO selection for human versus animal health drug products. While similar surveys exploring the human healthcare market have typically identified quality as the most important decision driver and ranked cost relatively far down the list, the animal health experts in this survey selected cost as the most important driver, followed by reliability and technical competence, with quality ranking in fourth place. Among a large list of specific CDMO attributes that factor into the CDMO selection process, therapeutic experience was the most prominent (82%), followed by safe and secure IT infrastructure (80%), access to the CDMO’s C-suite leadership (78%), and geographic convenience (proximity to the CDMO location) (78%).

Following the selection of a CDMO partner, animal health companies need to continue to evaluate a range of performance attributes of their CDMO partners to determine whether the partnership is successful. The most important performance attribute identified in this survey was communication and transparency, which was ranked as “very important” or “somewhat important” by 90% of respondents. The next most important performance attributes were resource management (80%) and billing practices (78%), although a large number of attributes (e.g., account management, responsiveness, compliance and safety audits, and technical competence, among others) also ranked very highly.

In terms of their biggest frustrations with their existing CDMO partners with regard to manufacturing and packaging, a lack of technical know-how and support was most often selected by respondents as among their top five sources of frustration (54%), followed by cost overruns (50%), and a lack of quality (48%) and on-time delivery (46%).

In total, the survey provides insight into the rapid evolution of the animal health market, highlighting ongoing issues in development, manufacturing, and distribution, including certain situations that were worsened by the disruptions and volatility of the pandemic. Raw material sourcing difficulties, disruptions across global markets, and unusual product forecasting complexities remain topics of particular concern. Simultaneously, the respondents from the animal health sector indicate a limited choice of contract outsourcing partners, particularly those with relevant therapeutic experience and technical know-how who are capable of production scale-up and high-volume commercial manufacturing, with cost remaining a primary underlying concern.

Reference

The Animal Health Product Lifecycle: Challenges, Insights, and Needs. Rep. TriRx Pharmaceutical Services. 2022. 

Originally published on PharmasAlmanac.com on June 21, 2022