Veterinary investigations ultimately lead to interventions from the veterinary or associated armouries. These seek to prevent, overcome, heal and cure maladies that are encountered. Products that are on the shelf or in the dispensary do not "just happen". The paths for a commercial product being available on the shelf are often tortuous, serendipitous or can just be lucky accidents. Nearly always there is a dogged determination by research or commercial leaders to drive an idea to a commercial reality. Very few companies are generating ideas from scratch where a need is identified, chemistry is matched and that product is ultimately commercialised. Three examples may help explain some of these pathways.
Hailed as the first new generation anthelmintic in 40 years, this active was developed by Novartis Animal Health and now is part of the Elanco portfolio. The beginnings were quite humble, an odd positive in in-vitro screens at Nihon Pharma, who were in the business of pursuing and generating new actives for the agrochemical industry, principally fungicides, insecticides and herbicides. Chemical libraries are agnostic to function, so once constructed, have to be assessed in screening programs which may or end up as a product of value. It has been estimated that there are 3x 1062 possible chemical combinations - all with varying characteristics and nuances between and within classes.
Perceptive and diligent medicinal chemists identified the potential of the AAD class through the patent literature and evaluated the class for activity against nematodes of importance in animal health. In the background was a company, interested in livestock and marketing in that space, that perceived the need for new classes of anthelmintics and had the financial resources to back the development. The AAD class was then confirmed as a potent broad spectrum anthelmintic with possible activity for other parasite types. The initial research phase had to provide early evidence of efficacy with monepantel or closely related analogues, that could be formulated, was safe in the target species and for humans, and could be manufactured at scale and at a cost that was acceptable. None of these barriers can be assumed to have been met so large investments are made often with a low chance of success. The costs to develop a product for ruminants anthelmintic is estimated at 100M USD with the final development phase estimated at 20M. A wide range of expertise is required including medicinal, manufacturing and residue chemists, experts in packaging, medicinal animal safety, regulatory affairs, project managers, clinical developers, target and rodent animals modellers, toxicologists, to name a few. There are hundreds of individuals and respective careers involved over 8-10 years. This requires very significant corporate commitment in the face of competing priorities for funding.
Monepantel managed to make it that through the labyrinth of initial discovery, financial and technical risks, technical challenges, having demonstrated novelty and the survived the nuances of company politics to be ultimately marketed. Once done, however, there are challenges of marketing and pricing, lifecycle management and in the face of fierce commercial competition.
This chemistry, now market by Zoetis as Startect (in combination with abamectin), was part of the Pharmacia and Upjohn (P&U) stable that entered by merger into Pfizer. The roots of innovation and discovery in these companies extend back to Italy in 1837 (Pharmacia) and 1886 in the US (Upjohn) and coming together in 1995 before joining into Pfizer in 2003. During periods of mergers and consolidation it is simple for innovation to be misplaced. A team of ruminant enthusiasts in P&U and then Pfizer ultimately recognised the value of a new class of broad spectrum anthelmintic and ensured that derquantel continued on in development despite competing internal priorities. Key to that success was senior leadership support over the long term, strong clinical development leadership so as to regionalise activity (and reduce costs), strong technical skills in toxicology, manufacturing process development, formulation, regulatory affairs and marketing. Importantly, derquantel was combined with abamectin. It is rare for a new chemistry to be marketed in the first instance in combination with what was then generic chemistry, adding to the risks and uncertainties. All of the inherent challenges mentioned above for monepantel are also relevant for derquantel.
So the path for new anthelmintics in ruminants is difficult and full of uncertainty from many different perspectives including discovery, technical and commercial. This adds to the strong argument for very careful use of available products for the medium to long term.
As a change of direction, this chemistry represents novelty, but also serendipity, on behalf of a few key individuals to bring a novel class of pain relief to the companion animal space. This chemistry was initially discovered by a Japanese scientist working for Pfizer. The approach was to discover if the EP4 binding site in the inflammatory pathway could be inhibited so as to improve safety outcomes compared to the current approaches such as the opioids and NSAIDs (that have wider and more diverse binding domains). Targeted in vitro screening discovered galliprant from within internal company libraries. Changing internal company priorities led to the chemistry being licensed to a small group of previous employees (Raqualia). While this company was aiming at human development, a small business (Aratana) in the US identified companion animals as a possible market and began to develop under licence. While this was successful, that company and its products including galliprant was sold to Elanco and now is a global product. This product represents a novel chemistry and mode of action that has come from human development but marketed for the first time in animals. It managed to survive many corporate changes and relied heavily on a small group of diverse individuals to succeed.
Innovative product development in veterinary medicine is a perilous process!