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Timely topic: October 2014

Why does it take so long for new dewormers to become available on the market for small ruminants?


Adriano Vatta, BVSc, MSc, PhD
Veterinary Medicine Research & Development
Zoetis, Kalamazoo, Michigan

Some producers may be wondering: when are the drug companies going to bring out some new dewormers (anthelmintics)?  What is the problem?  Why are we having to rely on “old” drugs that, in many cases, are no longer working as they should?

We know that all the products that are currently available on the market to treat gastrointestinal nematode parasites (such as Haemonchus contortus or barber pole worm, Teladorsagia circumcincta or brown stomach worm or Trichostrongylus colubriformis or bankrupt worm) can be grouped into three classes, the benzimidazoles (e.g. albendazole and fenbendazole), the imidazothiazoles (e.g. levamisole) and the macrocyclic lactones (e.g. ivermectin and moxidectin).  

Although we have seen the release of monepantel (Zolvix®, Novartis Animal Health) and the combination of derquantel and abamectin (Startect®, Zoetis) in some countries in recent years, the situation in the United States has not changed.  There have not been any new classes of anthelmintics for livestock released on the market in the United States since ivermectin was developed more than 30 years ago.

Sometimes individuals or groups, be they rural communities or traditional healers in the developing world, producers, or university researchers, will identify a plant, an extract or some other product that they believe has anthelmintic properties. Reports of efficacy may derive from anecdotal evidence or traditional knowledge passed on from one generation to the other, on the one hand, or from controlled experimental studies, on the other.  However, before such products can be legally marketed and sold, they need to pass through rigorous testing, and as this article attempts to explain, this is a time-consuming and expensive process that has no guarantee of ultimate success.

Finding new drugs with anthelmintic
properties is hard to do

Potential new drugs, or new chemical entities, are difficult to find. Because parasites affecting humans have assumed much lesser importance in the developed world, animal health companies cannot leverage data gained from human drug discovery as they can in other areas such as internal medicine. Some new drugs are derived from discoveries for crop pests, but much of the drug discovery process for anthelmintics has to start from scratch. Generally the starting point is a high-throughput screening method. Compounds are either purchased from outside vendors or are developed by medicinal chemists in-house. Some compounds are derived from natural sources but many are synthesized by chemists in the laboratory. 

Various systems are used to screen the compounds for antiparasitic activity. These screens may be mechanism-based, which means the screen is intended to identify drugs that act on a defined “target” in the parasite, such as an ion channel or metabolic pathway, or the screens may be based on whole organisms, where the screen brings the new chemical entity in contact with the parasite in question. Test plates that contain many tiny wells are generally used for whole organism screens and these wells are filled with different potential new drug compounds. 

Specific stages of the parasites, such as the eggs or the larvae, are then added to the compounds in the wells and the parasites are evaluated after a period of incubation. Eggs might be assessed to see if they have hatched to larvae. Larvae might be assessed for motility, with decreased motility indicating a potential drug effect. Compounds that are then found to have a “hit” will be examined further. Where available, preliminary testing will be done in small animal models for efficacy against parasites (for example, gerbils infected with barber pole worms) and for safety in mammalian hosts. Wider testing of the compounds against other parasites, such as insects or ticks, will be conducted if this has not already been done as part of the screens. 

Eventually, testing will be conducted against the specific parasite(s) in the target livestock species for which a new drug is sought. Typically much of the screening is automated, but it generally requires screening of compounds in the thousands or millions to identify just a few hits. Most of these will be eliminated before they get to the stage of being tested in the target livestock species, for example, because they are as toxic to the host as they are to the parasite or because the efficacy in the test plates does not translate into efficacy in actual animals. The compounds may be sent back to the medicinal chemists for modification to attempt to make the compound less toxic to the host or to improve efficacy against parasites.

If all proceeds well during the initial “discovery” research stages, further exploratory testing will follow.  Because companies are trying to fulfill a market need, companies will attempt to match a potential chemical “lead” with a defined product profile which has been compiled using market research. The product profile will define the parasites that the drug should be effective against and the way in which the product is to be administered (e.g. oral, injectable, pour-on, oral tablets or granules). Chemists will then attempt to formulate a test drug product that will match the requirements for the desired method of delivery, and for efficacy, safety and stability. If a specific device is required to deliver the drug, for example, a bolus preparation, this will be given attention at this stage too.

To inform the development process, data on what is referred to as the pharmacokinetics and pharmacodynamics of the drug will be collected. Pharmacokinetics is concerned with how the drug is absorbed, distributed in the body, metabolized and eliminated, while pharmacodynamics looks at the way in which the drug exerts its effect, or its mechanism of action.  Formulation will affect the pharmacokinetics and pharmacodynamics of the drug and knowledge of these aspects of the drug enable the formulation chemist in turn to make modifications to improve the way in which the drug is delivered to the parts of the body where the parasites are to be found.

Exploratory testing in animals will seek to identify the spectrum of parasites, in this case, gastrointestinal nematodes, that the product might be effective against.  Historically, and for reasons related to the biology of the parasites and their interaction with their hosts, anthelmintics have been developed to target as broad a spectrum of worms as possible. Obviously, certain parasites are more economically important than others. In sheep and goats, the barber pole worm is very important, which is not news to most visitors to this site. In cattle, an anthelmintic would need to be able to kill parasites such as barber pole worm (Haemonchus placei), brown stomach worm (Ostertagia ostertagi) and intestinal worms (Cooperia spp.) and would also need to be effective against the larval stages of the brown stomach worm. As discussed below, cattle parasites are to a large extent the drivers for the anthelmintic market in North America.

Drugs are expensive to develop

In thinking about developing a new product, companies will carefully assess the market needs and weigh up the pros and cons and determine what the return on investment might be.
It will take several million dollars to screen for a new chemical entity and several more million dollars to take the investigational new drug through the full development process. Once a company registers a patent, it has a limited period of time in which to exercise its rights to the exclusive sale of the drug. The actual process of developing the drug may take several years, which means that the actual time available in which to sell the final product may be considerably less than the patent period. This will influence the amount of money a company can expect to earn from the sales of the final product and will, in turn, influence the amount of money a company is willing to invest in the development of the drug.

When new anthelmintics are developed, the cost of producing the active ingredient is an important consideration.  Anthelmintics have typically been sold at relatively cheap prices. The benefits of treating a herd of cattle or a flock of sheep must substantially outweigh the costs of treatment and the costs associated with the handling of the animals to deworm them. In other words, anthelmintics need to be cost effective for producers to want to buy them. The cost of the final active ingredient will have a measurable impact on the cost of the final product and this will in turn influence the decision of the consumer to buy the product. 

There are also the costs of distribution and marketing that must be taken into consideration. In addition to the costs required for development of the product, the FDA is also authorized to levy fees for drug applications, for sponsors, for establishments and for products. While relatively low in comparison with the total costs of developing the actual product, these fees range from several thousand dollars for product fees to several hundred thousand dollars for new animal drug applications.

The small ruminant market is small compared with the cattle market in the United States and to date, the clinical problems resulting from anthelmintic failure due to resistance have not been reported by any measure to the same degree in cattle as they have been in sheep and goats. For example, deaths resulting from haemonchosis and the clinical signs of anemia and bottle jaw that are seen, though reported, are relatively less common in cattle compared with sheep and goats.  Treatment for gastrointestinal parasites in cattle is done in particular to improve production by eliminating the subclinical effects of parasites. 

Anthelmintics are not generally used to prevent clinical disease in cattle while this is commonly the case with sheep and goats, especially under the small-scale farming conditions in the southeastern United States. Clinical disease is, therefore, less commonly noted when anthelmintics start to fail in cattle.  Reductions in weight gain may be seen, but many other factors may impact weight gains and especially where parasitism is subclinical, the reduced efficacy of an anthelmintic may not be immediately identified as a contributing factor to the poor production. As such, the need to develop new drugs for cattle has not appeared to be as urgent as it has been for sheep and goats.


cattle

What may weigh in even heavier on the decision-making process within animal health companies is the fact that the companion animal health market is significantly larger than the livestock market and generally has higher profit margins, which means that products for dogs and cats are more likely to provide greater returns on investment than products intended for cattle, sheep, and goats.  Companies may choose to develop products for dogs and cats rather than for livestock.

Drugs need to meet stringent requirements for efficacy, safety and manufacturing

In addition to consideration of costs, drugs have to pass through extensive testing for efficacy, safety, and manufacturing. In the case of anthelmintics, this process is regulated by the Food and Drug Administration (FDA), which stipulates certain requirements. The regulatory authorities and the animal health industries of the European Union, Japan, and the United States have agreed on guidelines for the efficacy of anthelmintics in a process referred to as the “International Co-operation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products” or “VICH.”  This has streamlined the process by which products may be tested and registered for sale in the different markets, eliminating to a large extent the need for the duplication of certain studies, but there are still stringent requirements that have to be met.

Efficacy
Typical studies that will be conducted are dose determination studies, which, as the name indicates, are studies in which the minimum effective dose is determined. Where the claim is aimed at multiple parasite species, generally one of the parasites, or a stage of a particular parasite, will be less susceptible to the drug and the final dose of the product will then be based on this so-called dose-limiting species.  Once a final dose has been established, dose confirmation studies are conducted. Where a product with a fixed combination of actives is registered, non-interference studies may be required to ensure that none of the individual active ingredients interferes with the efficacy of any of the other actives. 

Safety
Safety studies are required to be conducted in the target animal, for obvious reasons, but where the product is intended to be used in pregnant or nursing animals, further studies in these groups are required. Safety studies are also required to ensure the safety of the animal handler and the consumer. Injectable products carry the risk of the user accidentally injecting the product into themselves. Topical products, such a pour-ons, have the potential of coming into contact with human skin if protective clothing is not worn (e.g. gloves) or if treated animals rub up against a person.  The effects of possible human exposure need to be examined through toxicology testing in laboratory animals.

Where animals are intended for human consumption, studies are conducted to determine the residues that remain in meat after treatment and the duration that such residues are present. This will determine the withdrawal period for slaughter for human consumption that appears on the label.  Where milk is to be consumed, studies are conducted to determine the milk withdrawal period for the product in question. 

A further component of safety evaluation concerns environmental safety. Antiparasitics that are given to animals will be excreted by the animal in the dung or urine. In this way, drugs may end up in the environment and have an effect on insects or fish or other animals. An example here is the effect that the macrocyclic lactones have on dung beetles.  A company will need to demonstrate that the effects of their product on the environment are negligible for their product to be licensed.

Nursing doe

Manufacturing
C
ompanies need to demonstrate that their products are manufactured to certain quality standards and that their manufacturing processes and facilities conform to set standards, known as good manufacturing practice.  Manufacturers need to demonstrate that the active ingredient comes from a reliable source and that the product’s composition does not change from batch to batch.  Products not only have to be effective on the day they are manufactured, but they need to maintain their efficacy for a useful period of time, to allow for distribution and storage of the product. 

The manufacturer needs to demonstrate that the drug product retains its effective concentration of active ingredient within certain limits for a certain period of time. Stability of the drug also needs to be demonstrated within the intended packaging. The concentration of drug should not decrease through, for example, deterioration of the drug nor should the concentration increase through the loss of the more volatile compounds through the packaging.

At any of the stages during the development process, a product may not meet the grade and this will require adjustments to be made to the formulation, the dose, the manufacturing processes, the packaging, etc. and additional testing will be required, increasing the costs of development and increasing the time it takes to get the product to market.

So to return to the question of when we will see new dewormers appear on the US market for use in sheep and goats, the answer remains unknown. Companies will not divulge their development plans, and even if they did, there would be no guarantee of success.  It would be foolish to be overconfident and overoptimistic about any product reaching the market given all the technical and regulatory hurdles that must be crossed before a new drug is licensed.

What can we do in the interim?

The answer is probably obvious to anyone who has visited the website of the American Consortium for Small Ruminant Parasite Control, and for those who are new to the site, an abundance on information is available here. From choice of breed to the proper use of available dewormers to alternative methods of control, the website provides a wealth of guidance on ways in which to improve parasite control through integrated methods.


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