Hardly anybody wants new drugs that act like a sledgehammer, bashing diseased and healthy cells like old-school cancer chemotherapy. Many drugs today are supposed to be smart enough to work like laser-guided missiles that hit the diseased cells and mostly spare the healthy ones.
But if your goal is to create one of these amazing “targeted” therapies, you’ve got to start by having a great biological target to aim at in the first place. These are the protein receptors on the cell surface, the enzymes that perform dirty work inside cells, the signaling pathways that cells use to send messages, or the RNA sequences that give rise to bad proteins. Much as the biologists can study these targets, nobody really knows for sure what will happen—good and bad—until a drug to inhibit the target’s activity gets tested in human beings.
Writing about biological targets is not an easy thing. Scientists have some funny naming habits and love acronyms as much as your average federal agency. But it’s worth cutting through some of that fog, because there are cool things happening now in biology to help us better understand the genetic and environmental factors that combine to make us diseased or healthy. As the genomics researcher Daniel MacArthur wrote on Twitter this week: “The present period is the most exciting time ever in the history of biology. True or false? If not now, when?”
I agree, so I thought it would be worthwhile to ask a few industry leaders to offer advice on what science says are the hottest biological targets for drug development today. For the purposes of this exercise, “hot” doesn’t necessarily mean “best”—only that there’s intense interest in the target by at least a handful of companies making drugs against it. This is also not about listing the most proven biological targets—HER2, VEGF, TNF, EGFR and more. This is just a short list of targets that are currently generating a lot of interest in development today, and which I think you’re going to see discussed a lot in the news. If you’ve got other targets you’d like to add to the list, please post a comment at the end of this article, or send me a note at firstname.lastname@example.org.
Without further ado, here goes:
PCSK9: This enzyme target has gained a lot of momentum in the past year as the next big thing for fighting cardiovascular disease, by lowering cholesterol. The idea here is that when people have an overactive form of PCSK9, it reduces the number of LDL cholesterol receptors that appear on the surface of their liver cells. When you have fewer of those receptors, it becomes more difficult to break down the LDL that comes from your average cheeseburger, causing the cholesterol to build up in the bloodstream. On the flip side, researchers have shown that people with certain mutations that limit PCSK9 activity are naturally able to keep their cholesterol quite low.
Once that was established in 2005 and 2006—as Bloomberg summed up in a feature last November—it was off to the races. The bar is high for drug developers since statin drugs are now cheap, generic, and quite effective, but many companies believe PCSK9 drugs will work in patients who don’t get enough benefit from statins alone. Contenders in this competition include various targeted drugs from Amgen, a collaboration between Sanofi and Regeneron Pharmaceuticals, Pfizer, Merck, and Alnylam Pharmaceuticals.
“At this point, it’s the most exciting target in the cardiovascular field,” says Roger Perlmutter, the former executive vice president of R&D at Amgen. “The human genetic data are powerful, and data from both Regeneron/Sanofi and Amgen demonstrate impressive LDL cholesterol lowering in phase 1/2 clinical trials.”
PI3 kinase: This has been one of the hot targets in cancer biology for years. The PI3 kinase pathway has been shown to be involved in critical processes like cell proliferation, differentiation, migration, and survival. When these normal functions get flipped into an overactive mode, it’s a key step on the journey for cancer cells that grow out of control. Once the PI3 kinase machinery is out of whack, other enzyme targets can go off-kilter downstream, too, like AKT and mTOR.
There hasn’t been a big Phase III clinical trial yet 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.
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