The Ups and Downs of Drug Development
Pfizer scientists reveal the story behind the world’s first JAK inhibitor for rheumatoid arthritis.
William Aryitey, Stephanie Sutton |
Back in the 1990s, Pfizer began investigating how Janus kinases (JAKs) were linked to inflammatory responses – and discovered a promising compound during high-throughput screening. It was rough and not optimized, but scientists saw the potential for a JAK inhibitor. Fast-forward to the present, and a synthetic analog of the compound is now on the market for rheumatoid arthritis (RA). Tofacitinib, marketed as Xeljanz, was approved by the FDA in November 2012 and by the European Medicines Agency in January 2017.
In the human body, diseases often arise when signaling pathways go awry. The JAK signaling pathway helps regulate a variety of functions, including immune responses and hematopoiesis. Since their discovery, JAKs have attracted much attention as a therapeutic target for chronic inflammatory disease. To date, only a few JAK inhibitors, including tofacitinib, have reached the market: ruxolitnib (Jakavi, marketed by Incyte and Novartis), which was approved by the FDA in 2011 for myelofibrosis and polycythemia vera; and baricitinib (Olumiant; marketed by Eli Lilly and Incyte), which was approved by the EMA in February 2017 for RA, but rejected by the FDA in April 2017 (the agency has requested more trial data around dosing). Pfizer’s animal health business, Zoetis, also received approval for a JAK inhibitor for treating allergic dermatitis in dogs in 2013. It’s still early days for this class of drug, but there are a number of JAK inhibitors in clinical trials for a variety of diseases, including Crohn’s disease, psoriasis and ulcerative colitis.
“When we started working on our JAK program in the 1990s, research in the field was in its early days – as was research with other kinases – but was really starting to blossom,” says Mark Flanagan, an Associate Research Fellow at Pfizer, who was involved with the early development of tofacitinib. “We started to look at JAKs as potential modulators of inflammatory response partly because of the work performed at the National Institutes of Health by John O’Shea. In the early 1990s, O’Shea was studying specific mutations in JAK signaling. During an immunology conference, he struck up a conversation with Paul Changelian, an Immunology Biologist at Pfizer, studying suppression of the immune system. Their discussion and scientific curiosity eventually led to a collaborative effort between Pfizer and the NIH.”
O’Shea’s research gave the team at Pfizer greater confidence and quelled fear surrounding a burning question: would modulating the activity of JAK be sufficient to elicit a therapeutic effect?
A challenging target
In the high-throughput screen that followed, more than 400,000 compounds were assayed against the catalytic domain of JAK. One hit seemed particularly promising, inhibiting both enzyme activity and cellular immune responses. But despite promising early research, there were still questions – both inside and outside of Pfizer – about whether a JAK inhibitor could ever reach the market.
Eileen Elliott (today Pfizer Kendall Square Site Director) recalls the excitement and trepidation of those early days, noting how novel the work was back in the 1990s. “At the time, few kinases had been taken forward as therapeutic modalities – except in oncology. We were interested to see how we could modulate the immune system to dampen it enough to have a therapeutic benefit, but without overly suppressing the immune system, which could cause further issues for a patient,” she says. “We were learning constantly from new research in genetics and we applied a number of new technologies, such as structural modeling, which we used to understand how our compounds docked with proteins.”
How Does it Feel?
How does it feel to help discover a drug that eventually makes it way to the market? With drug discovery and development often taking over a decade, it’s hard for researchers in the early stages to know which drugs will or won’t make it to market. Even the most promising drugs sometimes fall by the wayside because of unforeseen challenges in development. So when a drug does it make it, it is hugely rewarding for those involved.
“Those of us in drug discovery like to think we wake up every morning and say ‘We’re going to make a drug today’, but really we are driven by the science. We love what we do and I think we all joined this industry because we’d like to one day be associated with something that does make it all the way to patients,” says Flanagan.
“It’s been a long journey for tofacitinib,” Elliott adds. “The work is very fulfilling, but incredibly challenging. I’ve spent countless late nights and weekends in the lab. I’ve stood watching machines, waiting for results to emerge. (We have spreadsheets and algorithms to help make sense of the data that comes from our equipment, but we ran the experiments so many times that I could look at the data rolling off the machine and know if it did or didn’t work...) So I was really excited when it launched in the US in 2012, and I am filled with pride whenever I see an advert for the product on television – I recorded the first advertisement because I wasn’t at home! And it’s great to see tofacitinib launching in other countries too. Personally, I really look forward to hearing patient stories about how a drug has improved their lives. The industry has been researching RA for many years and although treatments are available, not all of them work for everyone. When I hear patient stories, it reminds me of why I joined the industry.”
RA has been a challenging target for the pharma industry for decades and so early therapeutics simply focused on pain relief. Says Flanagan, “Finding new drugs for any disease is hard. But when it comes to RA, the root cause is very complex. The industry has been accumulating knowledge around RA for many years to figure out which signaling pathways are the best ones to inhibit.”
Today – thanks to improved research around the disease – drugs aim to modify the disease process or inhibit the out-of-control immune response to help prevent joint damage and disability. Most new launches for RA tend to be biologics, which need to be administered intravenously or subcutaneously. But Pfizer was always interested in a small-molecule approach. “We knew there was a lot of industry activity around biologics, but we felt that an oral therapy would be best – and we had a lot of expertise in this area,” says Elliott.
A challenging development process
Back in the early 1990s, many kinases were still being discovered so it was very much unknown territory. “We didn’t know how many kinases there were, but we knew there were a lot of them and that selectivity would be a significant hurdle,” recalls Flanagan. “In fact, there was quite a bit of skepticism, not only within Pfizer, but externally, concerning whether it would be possible to make a selective enough kinase inhibitor to work, especially in a chronic disease like RA. But we were given the green light to try.” Sometimes ignorance is bliss – would the size of the human kinome – over 500 kinases – have been enough to turn the green light to red?
Flanagan and fellow Pfizer researchers began the unenviable task of working through the many design cycles needed – monitoring potency and selectivity, and tweaking the drug structure as they went. Eventually – over 1000 synthetic analogs of the original lead later – they identified tofacitinib, which ticked all the right boxes – including selectivity. Flanagan admits that the long and winding struggle to balance all the necessary properties cast doubt over tofacitinib’s future more than once. But perseverance pays. “One ‘eureka’ moment came at a time when we felt we might not be able to progress any further. While making new sets of analogs and testing them in our assays, we found that if we put one methyl group on the molecule at a specific location, it resulted in a ten-fold improvement in potency, as well as a large improvement in terms of the kinase selectivity of the compounds.”
More challenges came during scale up. The specialized synthetic chemistry used to build the molecule was easy to perform in the lab, but significantly more difficult at commercial scale. “One example was putting a side chain on a molecule called a cyanoacetamide,” says Flanagan. “It was really tricky to pull off, but the process development team came up with some brilliant chemistry to overcome the problem. The whole development of tofacitinib was about collaboration.”
Pfizer’s story illustrates just how lengthy (and expensive) drug development can be. It took almost 20 years of discovery, development and clinical testing for tofacitinib to be approved by the FDA – and even longer to gain EMA approval. But Flanagan notes, “You need to remember that JAK inhibitors were really new at the time. We were the first company to work with this set of enzymes; it takes a little bit longer when you have to perform the more basic exploratory research. When we started work on our JAK programs, there were no crystal structures of any of the JAK enzymes. All of the work we did was empirical.”
Elliott adds that, given the challenging journey, it was important to set milestones and to celebrate achievements. “When we found the molecule that had an effect in our in vitro assays, we celebrated. Achieving potency was another huge milestone – and celebration. And then we had to build in other functions, such as oral bioavailability and a good safety profile, and every time we checked a box, we saw it as an achievement.”
Over the intervening years, Elliott’s role at Pfizer has changed considerable. But even though she moved away from early discovery and tofacitinib, Elliott stayed up to date with progress. “Pfizer’s team is large but very inclusive and I always received updates from studies and exciting results. The drug discovery process is long and arduous, and the number of failures far outweigh the number of successes. Some people in this industry go their entire careers without ever having a successful molecule make it to market, so I always followed the story with a great deal of pride.”
Since the 1990s, drug discovery and development processes and technologies have advanced significantly. Today, Flanagan notes that there is greater use of computational chemistry early on in programs, which enables molecules to be designed and assessed in silico – “It tends to speed up drug development programs and we get to decision points more quickly and make better compounds,” he says. “But sometimes there’s no substitute for getting in the lab, making the molecule, and seeing how it works!”
Says Elliott, “It’s a very exciting time to be working in the pharma industry. There have been tremendous advances in drug discovery technologies, which result in better medicines for patients. A number of previously life-threatening or debilitating diseases have been wrestled into reasonably managed chronic diseases. And we’re also moving into the curative space with some incredible activity around cell therapies. I actually believe that the industry is on the cusp of new types of therapies for many different diseases. Such breakthroughs are thrilling to see no matter where they originate from in the industry.”
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