In Pursuit of Hot Autoimmune Target, GSK and Academics Team Up

Xconomy San Francisco — 

Drug targets are like fashion items. When a trendsetter proves one is worth spending money on, a lot of followers pile in. That’s no knock on drug developers, necessarily: When a new target shows some promise, it’s good to have lots of researchers with different ideas and approaches trying to find a drug to hit it. In the last few years, many of those researchers from the academic and industry camps who traditionally wouldn’t work together are joining forces.

Enter drug giant GlaxoSmithKline (NYSE: GSK), which has tried various schemes to make its research groups more biotech-like, including the spin-out of an immunology team into a separate biotech company. That company, Tempero Pharmaceuticals of Cambridge, MA, has teamed up with two academic labs to go after one of the most intriguing targets in immune disease, the IL-17 pathway, and a paper they published recently has caught the eyes of their peers.

First some background about IL-17, short for interleukin 17. Companies such as Novartis, Amgen, and Eli Lilly are developing monoclonal antibodies against IL-17 or related targets to treat psoriasis, rheumatoid arthritis, and other diseases in which the patient’s immune system turns against his or her own body. IL-17 is a small protein that plays key roles in bringing the body’s immune ammunition to bear against invaders. But at times the immune system misfires and produces too much IL-17, driving many autoimmune diseases. IL-17’s main source is a cell, discovered less than a decade ago, called T helper 17 or Th17.

The discovery of Th17, and the attention devoted to it, has opened up potentially a new way to attack IL-17-mediated autoimmune disease: go after the master switches that control Th17’s development. Toggling those switches off would block IL-17 production and possibly a host of other mischievous effects the cell produces, which in turn could lead to therapies effective against multiple autoimmune disorders.

Tempero, which is majority-owned by GSK, and two academic labs teamed up in a series of studies published recently in the journal Immunity to describe how a protein known in shorthand as RORγT (“ROR gamma T”) is critical to Th17’s development. Combining T cell biology, genomic analysis, and massive drug libraries from GSK, the group also found three compounds that could provide a rough model for future treatments for autoimmune diseases.

By targeting RORγT instead of targeting IL-17 directly, these small molecules “blocked the ability of Th17 to create IL-17,” said Alex Marson of the University of California, San Francisco, a coauthor of the Immunity paper. “We also found they improved outcomes in a mouse model of multiple sclerosis. They are blocking the pathogenic function of Th17 cells.”

Marson’s lab collaborated with Vijay Kuchroo of Harvard Medical School and scientists at Tempero, which Kuchroo helped found in 2009. The study caught the eye of Daniel Cua of Merck Research Laboratories in Palo Alto, CA, whose work helped bring Th17 cells to light. In an accompanying review in Immunity, Cua and his Merck colleague Jacob Lee lauded the study’s reach and “potential clinical value.”

“What distinguishes this study from others is the combined use of a large-scale pharmaceutical discovery platform with innovative genome-side analysis of RORγt target genes in Th17 cells,” wrote Cua and Lee.

That’s a recipe an academic-only group would be hard-pressed to follow, and it’s a measure of how far the industry and academic sides, once philosophically isolated, have come together in recent years. Academia needs new sources of funding, with National Institutes of Health funding subject to sequestration-era budget cuts. And pharma, making research cuts of its own, needs to find new sources of innovation.

The next step, meanwhile, is to take the compounds that showed promise in mice and refine them via the long process of medicinal chemistry. Being first into the clinic isn’t necessarily the goal, said Tempero principal scientist Jianfei Yang. “Lots of Big Pharma are in this field, but being first in human doesn’t mean your compound will be approved by FDA,” Yang told Xconomy. “You need a high quality compound.”

Whitehouse Station, NJ-based Merck’s (NYSE: MRK) agreement last year with Plymouth, MI-based Lycera is one example of recent dealmaking around RORγT. Amgen’s (NASDAQ: AMGN) tie-up with Japanese firm Teijin is another.

There are other industry collaborations, but Tempero’s work to date remains solely in GSK’s hands. As Xconomy first reported in 2009, the firm was spun out of GSK’s Immuno-Inflammation Centre of Excellence in Drug Discovery, or CEDD, to house the group’s regulatory T cell team and recruited Kuchroo and two other academic founders to contribute their T cell expertise. “In order to attract the academic experts, and build a group quickly, the decision was made that this was a ripe opportunity to set this up as an independent company with a biotech model,” former CEO Spiros Jamas explained to Xconomy in 2010. (Jamas left in 2012.)

Tempero also recruited independent directors John Maraganore, CEO of Cambridge, MA-based Alnylam Pharmaceuticals (NASDAQ: ALNY), and Rich Aldrich, both mainstays of the Boston biotech scene. Although both have venture ties—Maraganore is now a venture partner at Third Rock, and Aldrich runs the Longwood Fund—Tempero has no outside backers.

The academic research that fed into Tempero has, of course, received funding from a number of sources, including the National Multiple Sclerosis Society, which funded some of the work in Kuchroo’s lab that has elucidated Th17 biology. “I’m excited there’s a possibility here for multiple sclerosis, but it’s broader than just MS,” said National Multiple Sclerosis Society chief research officer Tim Coetzee. “There are implications for a range of autoimmune diseases.”

That’s because the three compounds that the Marson-Kuchoo-Tempero team identified are not only blocking Th17 cells from producing IL-17, but they are also preventing “naïve” T cells that haven’t yet differentiated from turning into Th17 cells. It’s both a short-term and long-term fix, said Yang. “If the drug only blocks the differentiation of Th17, that takes a long time to get efficacy. But if you could block Th17 cytokine production, you could see [faster] efficacy, then [also have] long term blocking of differentiation.”

Much work remains to be done to prove that targeting RORγT is a viable—and safe—approach in humans. RORγT is a transcription factor; that is, it binds to a cell’s DNA and controls its gene expression. One curiosity Marson noted and Cua highlighted in his review was that two of the three IL-17-blocking compounds seemed to cause RORγT to bind to new sites in the Th17’s DNA. That could be a hint that such compounds could unintentionally trigger the production of proteins that make a patient worse, not better. Is it merely a curiosity, or is a potential safety problem? That’s a question to be answered in further studies, along with many, many others.