to prove that blocking PI3k can have a big impact on cancer patients, but a number of companies have been working on various small-molecule drugs in earlier stages of development. Gilead Sciences paid $375 million up front last year to acquire Seattle-based Calistoga Pharmaceuticals, which developed a specific PI3k inhibitor aimed at its so-called “delta” variations of the enzyme that are implicated in blood cancers. Millennium paid $190 million up front last year to take over San Diego-based Intellikine and its portfolio of PI3k-inhibitors against lots of different variations of the target.
Mike Gallatin, the co-founder and former president of Calistoga, says the movement over the past several years has been away from broader “pan” PI3 kinase inhibitors of the various alpha, beta, delta, and gamma varieties, and more toward “selective” PI3k inhibitors that hit just one subtype. As data mounts to support various selective inhibitors, he says companies will likely look to come up with potent combinations of selective PI3k inhibtors.
“When you look at PI3 kinases in general, they are important enough that if you hit them in the right way, you’ll have an effect. But they’re not so broad in their expression that you’ll have issues with profound toxicity. It’s a goldilocks profile,” Gallatin says.
The contenders in the race to develop various PI3 kinase inhibitors includes Roche/Genentech, Novartis, Bayer, Sanofi, Pfizer, GlaxoSmithKline, Gilead Sciences, Millennium/Takeda, Oncothyreon, and Infinity Pharmaceuticals.
IL-17: This is one of the hot targets for research into autoimmune/inflammatory diseases, in which the immune system goes haywire and attacks healthy tissue like an invading virus. Major strides were made for a lot of patients when drugmakers found out how to inhibit excessive amounts of TNF, and now another inflammatory protein called IL-6. Part of what’s so enticing to drugmakers here is that these targets are implicated in a wide variety of diseases, so it’s possible to make one drug that works against several diseases, as TNF inhibitors like Amgen’s etanercept (Enbrel) and Abbott Laboratories’ adalimumab (Humira) have been shown to work against rheumatoid arthritis, psoriasis, and other conditions.
But inflammation is a complex process, with lots of different proteins involved, and signals being sent between various cells. Hitting one protein target like TNF or IL-6 isn’t going to be the silver bullet for everybody. IL-17, in a couple of different variations, is also thought to be a key player. Eli Lilly recently published some impressive data from a mid-stage psoriasis trial for an anti-IL17A antibody in the New England Journal of Medicine, which will probably encourage more activity in the field after some setbacks. Besides Lilly’s ixekizumab, other players in this field are Novartis, Merck, and Amgen.
JAK: The family of enzymes known as Janus kinases 1, 2 & 3 has been gaining momentum for some time now in drug development circles, and it gets the prize for the easiest-to-pronounce acronym. Pfizer is moving hard with a JAK3-inhibiting compound called tofacitinib, which aspires to set a new standard with an oral pill for inflammatory diseases. Since drugs for many of these autoimmune/inflammatory diseases need to be taken throughout a person’s life, there’s long been a strong desire to move away from injectable biologics and toward more convenient oral pills. Incyte recently won FDA approval for its JAK1 and JAK2 inhibitor ruxolitinib (aptly marketed as Jakafi for myelofibrosis), while Rigel Pharmaceuticals, Vertex Pharmaceuticals, Sanofi, YM Biosciences and others have programs in development.
“The JAK kinase data from Pfizer as well as some small companies (e.g. Incyte) look impressive,” Perlmutter says. It’s possible, he adds, that a JAK inhibitor given as an oral pill could be as effective as an injectable TNF inhibitor. That means the new class of drugs could be used more widely among patients.
The list of really interesting biological targets could easily go into the dozens, maybe even the hundreds, given how much interesting work is happening in various niches of biology. And like I said before, it doesn’t matter much in the grand scheme of things until hard proof rolls in from clinical trials. The nature of drug development says that a lot of drugs against these targets will fail. But some will probably work, and there will be big opportunities for those that do.
