In this article I report about my personal experience and share in the discovery and development of lufenuron (initially known as CGA-184699) and PROGRAM, and a short summary of the evolution of flea control products in the last decades.

In April 1985 I joined the Centre de Recherches Agricoles in St-Aubin (Fribourg, Switzerland), the main research station of Ciba-Geigy Animal Health in those years. It was my first job in the industry after completing my PhD and a few years research in the Swiss Federal Institute of Technology (ETHZ) in Zürich.

My major responsibility was to manage the in-vitro screening for new ectoparasiticides that aimed at discovering new active ingredients with potential for the control of external parasites of livestock and pets.

I was the head of a team of six that tested about 300 new molecules weekly for their efficacy against engorged ticks, mites, adult houseflies and fly larvae. Those compounds that showed efficacy at discriminatory concentrations were selected for further tests to determine their minimal efficient concentrations against a broader spectrum of parasites, including fleas and cockroaches. Another team handled a comparable screening against parasitic worms.

Discovery of CGA-184699

Molecular structure of CGA-184699

Only a few months after I joined the team two compounds caught my attention: CGA-183893 and CGA-184699. CGA was an acronym indicating the origin of the compound, in this case Ciba-Geigy-Agricultural Division. Both compounds were tested within less than one month interval. And both were to be developed to new products that still remain in the Animal Health market today.

CGA-184699 was ineffective in our tick, mite and adult housefly tests, but was highly effective in the larvicidal test against dipteran larvae (Lucilia sericata, Lucilia cuprina and Musca domestica). This was not particularly surprising, because CGA-184699 is a benzoylphenyl-urea (BPU), a family of Chitin Synthesis Inhibitors (CSI) characterized precisely for their efficacy in inhibiting the development of insects: affected larvae cannot complete molting and die. BPUs belong to the broader class of the Insect Growth Regulators (IGRs, also known as Insect Growth Disruptors, Insect Development Inhibitors, etc). CGA-183893 was also an IGR that was to become dicyclanil, the active ingredient of CLiK. If you are interested in the discovery and development of dicyclanil click here.

Molecular structure of DIFLUBENZURON, the first BPU

The potential of BPUs as insect larvicides had been discovered around 10 years earlier. First commercial products with diflubenzuron, its first representative, had been launched in the early 1980s for crop protection. Since than, the chemists in the agricultural division of Ciba-Geigy had regularly synthesized dozens of analogues of diflubenzuron trying to find a better one that was not covered by the original patents, a “strategy” which was and remains the usual practice followed by all multinationals. Among other positive features, all BPUs are characterized by a rather low toxicity to vertebrates, including mammals, because vertebrates do not produce chitin. Low toxicity was rare among parasiticides in those years, and in Ciba-Geigy AH it was perceived as a key benefit for any new product. In the mid 1980s commercial usage of BPUs against veterinary parasites was still completely marginal.

Efficacy of CGA-184699 against dipteran larvae was not particularly exciting for a BPU. But in subsequent tests we found an excellent larvicidal efficacy also against cockroaches and against cat fleas. This was more interesting because in those years Ciba-Geigy AH was highly interested in new products against these two pests. In fact, one of my tasks besides managing the routine screening was to develop new tests against cockroaches and fleas that should help us to discover and characterize the potential of new compounds against these pests faster than in the past.

Characterization of CGA-184699

CGA-184699 proved to be very effective against cockroaches, both after oral and tarsal treatment, i.e. it could be interesting both for a cockroach bait as well as for a product for surface treatment.

Cat fleas (Ctenocephalides felis): adult female (left) and male (right)

Regarding fleas we found out that CGA-184699 also inhibited egg hatching from female fleas that had been fed blood containing the compound. This meant that it was not only adequate for directly treating the environment of pets where flea larvae live (carpets, furniture, lawns, etc.), but could also work when fed to the dogs, i.e. it had systemic effect. And if it was not excreted or metabolized too quickly, keeping sufficiently high blood levels during weeks could be possible.

However, many people in research, including myself, thought that this would only be interesting for dog breeders, not for the usual dog owner. The reason is that fleas infesting a dog or a cat would not be killed at all after a treatment with CGA-184699, which is what most pet owners expect from a flea product. Using such a product as CGA-184699 efficacy as perceived by a pet owner (i.e. "fleas are gone") is only reached through population control, which takes about a month after treating a pet with lufenuron. And this requires a preventative approach, i.e. starting the treatments before the pets become heavily infested.

Further studies revealed that CGA-184699 was also very effective against blowfly larvae on sheep and against housefly larvae, but for these indications we were already working full speed with CGA-183893, which was to become the current Rolls Royce of blowfly strike prevention in sheep worldwide.

A controversial decision

As usual in those years in Ciba-Geigy AH, after extensively exploring the efficacy of a new compound, our Screening Team proposed the management to promote it to the Development Stage. If the proposal was accepted, a so-called New Product Team (NPT) would take it over for the next steps and studies. All the NPTs were based in Basel, the headquarters of Ciba-Geigy AH, not in our research station.

 alt=The decision on starting a New Product Project (NPP) with CGA-184699 against cockroaches was not controversial: everybody agreed.

The decision to start an NPP for flea control was more difficult. Some people in the headquarters shared the previously mentioned estimation that a systemic IGR for flea control had little potential because it was only adequate for dog and cat breeders, not for the normal pet owner. Others, particularly our colleagues from the US thought differently and were highly motivated to push CGA-184699 and to create an NPT for it.

Every year all research and development projects were reviewed, discussed and presented to the management in a so-called New Product Portfolio Review meeting usually hold just before the summer. I remember that to decide upon CGA-184699 for flea control a special meeting was called (probably in 1987) with significantly more participants than for the normal Portfolio Reviews, including several of our US R&D colleagues. It was a rather unusual event, signaling that quite a lot was at steak.

After rather hot discussions, the management decided to promote CGA-184699 to development with highest priority. Two projects were started, one for flea control on dogs and cats, and one for cockroach control, each one with an own New Product Team.

Flea control in the 1980s: an undiscovered El Dorado.

In the 1980s, flea control in dogs and cats had nothing to do with the current situation. The numberless spot-ons and tablets currently available for monthly administration didn’t exist. Most products for on-animal use were OTC products based on synthetic pyrethroids (e.g. permethrin), organophosphates (e.g. diazinon) or carbamates (e.g. carbaryl, propoxur) and were mostly available for spraying, shampooing, powdering or bathing the pets, a rather awkward and unplesant business. The products for flea control were all spin-offs from pesticides previously discovered and used mainly as agricultural and/or livestock insecticides. A few insecticide-impregnated collars were also available. In the previous decades parasite control in dogs and cats had been the last priority within most agrochemical and AH companies, preceeded by pesticides against agricutural, livestock and household pests.

Efficacy of such flea products was often unreliable, party due to increasing flea resistance to these compounds, partly to the fact that spraying and bathing were highly susceptible to incorrect administration. The bottom line was that flea control using on-animal products was mostly poor and certainly insufficient for effectively controlling the flea populations that often developed around chronically infested pets. As a consequence most households remained infected with more o less immature stages that ensured periodic re-infestation of the pets.

For these reasons, treatment of the household environment with more potent means by professional Pest Control Operators was often required, and flea control was a substantial part of their business. However, most PCO products contained the same or similar active ingredients as the on-animal OTC products. Their main advantage was that PCOs were better trained than pet owners and thus their work was more effective. But they were also expensive, and many pet owners couldn’t afford their services. The global result was that flea control could be considered as an unsolved problem, thus an opportunity for whoever came with a better alternative.

Ciba-Geigy had identified such an opportunity and had started investing increasing resources in flea control on pets. Other strategic reasons drove Ciba-Geigy’s increasing interest in pet parasiticides as well. Ciba Geigy AH was virtually absent from the US Animal Health market: pet parasiticides was a good option to strengthen its presence there. In addition pet parasiticides had the highest potential in Europe and Japan as well, two other strategic regions for Ciba-Geigy that had focus its priorities in the so-called TRIAD, i.e. USA, Europe and Japan. And since Ciba-Geigy had virtually no products in this market, whatever new products would mean growth and not replacement or cannibalization of other products. Finally, the data package for registration of pet products is less expensive and can be completed faster than for livestock, because no data on residues have to be generated for non-food animals.

From CGA-184699 to lufenuron and PROGRAM

After its promotion to development, CGA-184699 left our team in the Research Center. But we kept track on what was going on with the flea and the cockroach projects. We ran some studies in our facilities for them and we also met regularly our colleagues from overseas during the yearly New Product Portfolio Review meetings.

In 1991 I left the Research Centre at St-Aubin to join the headquarters in Basle as International Product Manager for livestock ectoparasiticides. In Basel I was able to follow the progress of both projects even closer than before.

As far as I remember both projects progressed well. CGA-184699 became lufenuron, and trade names were selected for both projects. The flea product was to become PROGRAM, and the cockroach product was to become INSTAR. The PROGRAM team decided also to develop two different formulations: a tablet formulation for dogs, with first priority, and an oral suspension formulation for cats.

Very soon, our USA colleagues could show that a single oral dose of lufenuron was enough to reliably kill all offspring of fleas infesting a dog during about one month. Fist studies with artificially infested dogs showing such an efficacy were soon confirmed in simulated home environments after artificial infestations, and finally in field studies with natural infestations. Everything pointed to a monthly flea pill that would reliably prevent the build up of flea populations in the pets’ environments. These positive results obviously pushed the expectations on futures sales.

If I recall correctly the first country where the PROGRAM tablets for dogs became registered and launched was South Africa. By the early 1990s the tablets had been registered in several European countries and Australia as well. Sales were good, but not really spectacular, at least not everywhere. The highest expectations came obviously from the USA, where a highly motivated and enthusiastic team was preparing the launch.

This team had been very successful in the introduction of INTERCEPTOR in the USA, a milbemycin oxime tablet for heartworm prevention and worm control in dogs and cats. INTERCEPTOR was the first direct competitor of Merial’s HEARTGARD, the first monthly pill with ivermectin for heartworm prevention at all, which had created this market and dominated it for years. INTERCEPTOR was a big success for Ciba-Geigy AH in the USA and become very soon its largest and most profitable product.

In the meantime Ciba-Geigy and Sandoz merged to become Novartis, but this didn’t have a significant impact on these projects.

The US team decided to engage in a kind of "big-bang" launch for PROGRAM that included heavy TV-promotion with an advertising budget of about USD 20 million, an unprecedented A&P investment for Ciba-Geigy AH or any other Animal Health company in those years. In fact, the launch of PROGRAM in the USA was the birth of positioning veterinary medicines as consumer products. It was prepared and run under the slogan “Think big”, which conquered the vocabulary and the minds of almost everybody in Novartis AH, including the management.

Success was overwhelming, soon exceeding the USD 100 million sales, completely unprecedented for Novartis AH. PROGRAM was very expensive for users, but it was the first and only product promising effective flea control with a once-a-month treatment, and delivering. A key success factor in the strategy and its success was that PROGRAM was sold only through vets, not OTC, which ensured adequate education of the new users, which had not been possible if sold OTC. Until than, all flea products were sold OTC and most veterinarians were not seriously involved in this business. Consequently PROGRAM had been positioned as a veterinary “medicine”, and not as a “pesticide”, in line with the general corporate strategy of changing our image from an “agrochemical” to a “pharmaceutical” company.

The huge A&P campaign for PROGRAM flooded the vets with many new customers: dog and cat owners that wanted to try the flea pill they have heard about on TV. Since vets had a good margin on their PROGRAM sales, they were enthusiastic: for quite a number of them PROGRAM more than doubled their income. This also strengthened their “loyalty” towards NOVARTIS, making it easier for them to prescribe other NOVARTIS products. This strong involvement and rewarding of veterinarians had been also part of the Novartis’ strategy in the USA and elsewhere, because it had numerous other new veterinary medicines in the pipeline to strengthen its position in the pet market worldwide, e.g. FORTEKOR (with benazepril hydrochloride, for heart and kidney disease), CLOMICALM (clomipramine hydrochloride for separation anxiety) and later also ATOPICA (with ciclosporine against atopic dermatitis). Many Novartis AH competitors were to follow a similar strategy with their new flea products in the following years.

PROGRAM's LOGO as designed by the US teamEnthusiasm about PROGRAM was huge in the headquarters of Ciba-Geigy. And the management decided to repeat the exercise almost everywhere, including those countries where PROGRAM had been already launched with moderate success in the previous years. For the launch in the USA, our colleagues there had not adopted the international design and logo for PROGRAM, nor the packaging concept designed in the headquarters, but had developed an own look for PROGRAM. This in spite of the strong pressure in the company for avoiding local deviations from the international branding concepts. Instead, for this kind of "big-bang" re-launch all the countries had to change to the US branding concept.

Success of this “THINK BIG” re-launch outside the US was not homogeneous. It worked very well in some countries, but in didn’t in other countries, e.g. in most of Latin America, where such an expensive product addressed only the rather small portion of affluent people. But altogether, PROGRAM became number 1 product in the Novartis AH product range.

In the meantime, a full battery of new lufenuron products were in the pipeline:

  • PROGRAM INJECTABLE for cats with an unprecedented protection period of 6 months;
  • SENTINEL (= PROGRAM PLUS), a combination tablet with lufenuron and milbemycin oxime for monthly prevention of both fleas and heartworms.

At that moment, all these products were really new and seemed unique and superior to what was then available. Nothing disturbed the prevailing enthusiasm and optimism.

A key success factor when working with such ambitious A&P campaigns was and remains to ensure enough product supply to satisfy the suddenly increasing demand. Therefore on-time manufacturing of enough active ingredient became an essential factor for commercial success that had to be scheduled many months before the expected sales would become effective. The future demand was estimated based on huge sales of the dog tablets after launch in the USA, which was not considered as the final sales plateau; and extrapolating these sales for the launch of the new products previously mentioned (PROGRAM suspension and injectable for cats and SENTINEL). It was known that some vets were already prescribing the dog tablets for cats as well, but it was assumed that they were a minority and no accurate estimation was available.

A side issue became a quite hot potato inside NOVARTIS. The Agricultural division (which soon after became Syngenta, a later Novartis spin-off) had developed lufenuron for crop protection as well (MATCH). But the Animal Health management thought that the use of lufenuron as a pesticide was a threat for the current success of PROGRAM in the US and elsewhere and tried to stop the introduction of lufenuron for crop protection. They couldn’t, among other reasons because the Agricultural division was still about a factor 10 larger than Animal Health and was obviously more powerful than Animal Health at the corporate level. But the development of the cockroach product with lufenuron was dropped, in spite of the fact that it was almost completed and had shown very promising results against cockroaches and also against termites. This also meant the final drop of any future investments in products for the control of househols pests by Novartis AH.

Nevertheless, in spite of the huge success and the corresponding enthusiasm, PROGRAM had and still has a significant weakness: it does no kill adult fleas, i.e. it needs too long for controlling infestations, and thus has to be used preventatively starting early in the flea season. Initially this was not decisive, because there were no alternative once-a-month treatments with adulticidal effect and as convenient as PROGRAM. But things were to change soon.

Competitors were not sleeping

Obviously, competitors weren’t sleeping. But nobody at Novartis AH (and probably in other companies either) anticipated what was to come.

Already in the early 1990s Rhône-Mérieux, the Animal Health Division of Rhône-Poulenc (a French multinational, now Sanofi), had launched FRONTLINE, a new flea & tick spray for dogs and cats containing fipronil, a new active insecticide, introduced also as an agricultural pesticide. Initially it was not a real threat for PROGRAM. Although it was acknowledged that it worked much better than all previous old-fashioned products, spraying dogs or cats was not really innovative when compared with a monthly pill, and was much less convenient and safe than PROGRAM. And Rhône-Mérieux was perceived by Novartis AH as a minor competitor, unlikely to become a threat elsewhere than in France. And indeed, it did not seem to stop PROGRAM’s success story.

Interestingly, years earlier fipronil had gone through our ectoparasiticide screening in Ciba-Geigy AH and it had been identified as an excellent compound of a new chemical class of insecticides (phenylpyrazoles), effective against numerous insects and ticks. However, it was considered to be too toxic and showed cross-resistance with some organochlorines. In those years Ciba-Geigy AH would have never developed an active ingredient with such a high acute toxicity, substantially higher than most synthetic pyrethroids and numerous organophosphates and carbamates, those insecticides discovered between the 1950s and 1970s that dominated the market in those years.

But unexpectedly, in 1997 Rhône-Mérieux merged with Merck AgVet, the Animal Health Division of Merck & Co, the finders of ivermectin and by then the number 1 Animal Health company worldwide. They became Merial. And more or less at that time Merial introduced FRONTLINE TOP SPOT, the fipronil spot-on formulation as a once-a-month ready-to-use flea & tick killer and preventative for dogs and cats.

This was a completely different threat for PROGRAM than the fipronil spray. Because it was even more convenient to use than PROGRAM's tablets and was also a flea killer: within about 48 hours it would kill all fleas on an infested pet and protect it for about one month. Treatment could start any time during the year, i.e. it could be used both therapeutically and preventatively. And it also controlled ticks, which PROGRAM did not. And Merial was a much powerful compertitor, market leader in the most important countries. Needless to say, MERIAL adopted a similar BIG-BANG launch as the one that Novartis has used for PROGRAM. And the success of FRONTLINE was immediate.

It is useful to know that before the launch of FRONTLINE TOP SPOT there were already a few spot-ons for flea and tick control on dogs in some countries, mainly TIGUVON from Bayer containing fenthion (an organophosphate pesticide), and EXSPOT from Intervet (now Merck Animal Health) containing permethrin (a synthetic pyrethroid). However, neither product had a once-a-month claim, and they were not considered as particularly effective, perhaps because flea resistance to pyrethroids and organophosphates was already widespread. And very important, no significant A&P campaign had been run to boost their sales.

About a year after Merial launched FRONTLINE TOP SPOT, Bayer introduced ADVANTAGE, its new once-a-month flea spot-on for dogs and cats containing imidacloprid, another new active ingredient from a new chemical class of insecticides (neonicotinoids), which they had also introduced for crop protection. ADVANTAGE was also a flea killer, and about as effective as FRONTLINE TOP SPOT, but not effective against ticks. Initial success of ADVANTAGE was not as explosive as FRONTLINE TOP SPOT, but it quickly became no. 2 among the flea control products.

In 1998 I left Novartis to become an independent consultant. Since then I have followed the dramatic development of the flea market from the other side of the fence.

In 1999 Pfizer (now Zoetis) lunched STRONGHOLD (in some countries under the TM REVOLUTION) containing selamectin (a macrocyclic lactone), also a once-a-month spot-on for dogs and cats for the control of fleas and ticks, but also of mites and worms, including heartworm prevention. This sounded as the non-plus-ultra for a pet parasiticide. However, success of STRONGHOLD was not as huge as initially expected, probably because it did not meet the high expectations regarding tick control raised during the launch. But it became well established as an effective flea control alternative, particularly where heartworm prevention was an important indication (Southern USA, Mediterranean regions, etc.).

At the beginning of the new century these three once-a-month flea-spot-ons, FRONTLINE TOP SPOT, ADVANTAGE and STRONGHOLD (REVOLUTION) had already taken over leadership of flea control in the most relevant markets.

A side effect of the successful introduction of all these flea products was that the previous share of PCOs in the flea control market almost disappeared. The new products were so effective that very few pet owners needed their services. And since all these new products were marketed through the vets (for the same strategic reasons than previously mentioned for NOVARTIS), sales of OTC flea products also dropped substantially.

The flea & tick control race

And this was only the beginning of a highly innovative and still running race for a share in the market for flea & tick control in pets.

During the 2000’s Merial successively introduced complementary spot-on formulations combining fipronil with other active ingredients (all veteran generics) to improve FRONTLINE’s efficacy, e.g.:

  • + Methoprene, an Insect Growth Regulator (IGR) to add efficacy against immature stages of fleas;
  • + Amitraz, to strengthen the efficacy against ticks;
  • + Cyphenothrin, a synthetic pyrethroid, to strengthen the efficacy against ticks and fleas.

Bayer followed the same strategy of strengthening its flea control product range introducing successive combinations of imidacloprid with complementary active ingredients (all veteran generics), e.g.:

  • + Pyriproxyfen, another IGR to add efficacy against immature flea stages;
  • + Permethrin, a synthetic pyrethroid to add efficacy against ticks and mosquitoes;
  • + Moxidectin, a macrocyclic lactone to add efficacy against worms, including heartworm prevention.

By the turn of the century flea & tick control in pets had become the largest single Animal Health Market worldwide worth, well over 1 billion USD, and a very lucrative one because margins were and remain significantly higher than in the livestock market.

Already in the 2000's other Animal Health companies eager to get their share on this market successively introduced additional flea & tick control products with new insecticidal active ingredients during the first decade of the 2000s, e.g.

  • Spinosad (COMFORTIS, tablets) by Elanco, a new natural insecticide;
  • Spinetoram (ASSURITY, CHERISTIN, spot-on) by Elanco, a synthetic spinosad derivative;
  • Metaflumizone (PROMERIS, spot-on, now dropped), by Fort Dodge (acquired by Pfizer), a semicarbazone, a new chemical class of insecticides;
  • Indoxacarb (ACTIVIL, spot-on), by Merck AH (formerly Intervet), an oxadiazine, a new chemical class of insecticides;
  • Dinotefuran (VECTRA, spot-on) by CEVA, a neonicotinoid.

Besides the previously mentioned Novartis products, only COMFORTIS is indicated for oral administration, whereas all other new products are spot-ons for topical administration.

After expiry of the patents for fipronil and imidacloprid in the mid 2000’s, hundreds of spot-ons with generic fipronil or imidacloprid flooded the market worldwide. And spot-ons took almost complete control of the pet flea & tick control market.

Novartis reactions

Everybody in Novartis AH was aware that the basic weakness of PROGRAM when compared with all new spot-ons was its lack of adulticidal effect on fleas. But many in Novartis AH thought that being an oral pill or suspension that does not contaminate the hair of dogs or cats, its “safety” advantage towards all insecticidal spot-ons could counterbalance this weakness. A lot was invested in communicating this to users and vets. Also for the launch of the new products containing lufenuron previously mentioned: PROGRAM suspension and injectable for cats, and SENTINEL (combination with milbemycin oxime) for dogs and cats, all for oral or parenteral administration i.e. not for topical administration and thus not contaminating the pets’ hair coat.

It is true, that all these Novartis products are “cleaner” and less contaminating than all the spot-ons. But for most pet owners this was obviously less important than getting rid of the fleas as soon as possible. And the success of the spot-ons could not be stopped: sales of lufenuron products dropped down to a much lower level than initially expected.

Novartis AH reinforced its efforts to discover or license a new flea adulticide. Getting a new systemic one suitable for oral or parenteral administration had first priority. But after years of search nothing was found suitable for a once-a-month pill that would kill fleas quickly and remain effective for about a month. Instead, a super-rapid flea killer was discovered, developed and launched around 1999. It was CAPSTAR, a pill containing nitenpyram, a new neonicotinoid (same chemical class as imidacloprid from Bayer’s ADVANTAGE). It cleans a dog or a cat from fleas within a few hours. But its efficacy lasts only for not much more than 24 hours. It has become well established for cases were immediate relief of fleas is required, but this was and remains a niche market, and CAPSTAR never challenged the leadership of the spot-ons.

Since no suitable systemic flea adulticides were identified, research efforts were soon expanded to topical insecticides as well. These efforts led to the discovery and launch of pyriprole, a new phenylpyrazole, i.e. belonging to the same chemical class as fipronil, the active ingredient of Merial’s FRONTLINE TOP SPOT. Using pyriprole, PRAC-TIC was developed and launched in the mid 2000’s, a once-a-month spot-on for the control of fleas and ticks. Its efficacy is comparable to that of FRONTLINE TOP SPOT but not really superior. And for whatever reasons it was introduced only in the EU and a few other countries, but not in the USA, Australia and several other key countries. And when PRAC-TIC was launched, the flea control market was already crowded with many of the numerous products from other AH companies previously listed. Later on SENTINEL SPECTRUM, another once-a-month pill containing lufenuron, milbemycin oxime and praziquantel (to add efficacy against tapeworms) was also introduced in some countries, but it did not significantly change the global market positions.

The bottom line for Novartis AH was that the huge internal expectations (reaching the USD billion sales by 2000) that PROGRAM had created were not met, resulting in the corresponding huge disappointment. A significant internal side issue around the unmet expectations was the need for disposing of dozens of tons of lufenuron active ingredient that had been manufactured to meet the expected demand and now remained unused after shelf-life expiry. Part of the huge overproduction was due to the fact that after the launch, the use of the dog tablets in cats was substantially underestimated. And the launch of the two new cat formulations (PROGRAM SUSPENSION and PROGRAM INJECTABLE) did not add the expected volumes.

Starting in the late 1990s several scientific papers were published showing efficacy of lufenuron against established fungal infections in dogs and cats. But other papers reported lack of efficacy and the whole issue remains controversial. Even more controversial is the use of lufenuron against Candida infections in humans, so far not based on serious scientific studies. Currently this topic occupies the first places if a Google search is run on lufenuron. However, Novartis never developed an indication of lufenuron as a fungicide for veterinary or human use.

Lufenuron has been also found to be effective against several parasitic lice of fish. And in January 2015 the EU has approved an MRL (maximum residue limit) for lufenuron in Atlantic salmon and rainbow trout, strongly suggesting that a use as a fish lousicide in aquaculture may be approved soon. But if confirmed, this usage will represent a marginal market when compared with flea and tick control in pets.

2015: The race continues

In 2014, shortly before I finished writing this story, three additional players have entered the race for flea & tick control in dogs:

  • NEXGARD from Merial, containing the active ingredient afoxolaner;
  • BRAVECTO from Merck AH, containing fluralaner.
  • SIMPARICA from Zoetis, containing sarolaner
  • CREDELIO from Novartis, containing lotilaner

The active ingredients belong to a new chemical class called isoxazolines discovered by other agrochemical companies. All are tablets for oral administration, not topical spot-ons, i.e. they follow the path opened by Novartis AH with the PROGRAM product range about 25 years ago. All three are flea & tick killers. But whereas NEXGARD and SIMPARICA are once-a-month pills, BRAVECTO is a once-a-quarter pill, i.e. one single treatment protects dogs from fleas and ticks for up to 3 months.

But in the meantime, spot-ons containing generic fipronil or imidacloprid have flooded the market worldwide. Only in Spanish-speaking countries about 75 such spot-ons brands (two thirds with imidacloprid, one third with fipronil) are being marketed in 2015, this besides additional spot-ons with other active ingredients.

It will be interesting to watch whether the new isoxazoline products can capture a significant share of the pet flea & tick control market now in the hands of those hundreds of generic spot-ons. And if they do, which will be the losers.

However, Novartis AH won’t play a role anymore. In 2014 it has been divested by Novartis and acquired by Elanco. And Elanco has recently announced that it has sold its US rights for two lufenuron products, SENTINEL and SENTINEL SPECTRUM, to Virbac.

NOTICE. I didn't take any notices nor did I keep a diary during my years in Ciba-Geigy and Novartis. The lines in this article about those years are just memories that have survived forgetfulness but may not be accurate. They are my very personal current view of those days. Other people involved may have perceived them differently. I apologize for incompleteness or inaccuracy.

If you are interested in other "insider" stories like this one on lufenuron, you may wish to visit the articles in this site on the discovery & development of dicyclanil (CLiK) and fluazuron (ACATAK), two additional IGRs in which I was heavily involved during my years in Novartis AH (1985-1998).