INCB7839 for cancer
INCB7839, currently in a breast cancer phase II, is the least validated but probably the most undervalued asset in Incyte’s pipeline. It employs a mode of action long abandoned by the pharmaceutical industry, but Incyte might succeed where other industry leaders such as Pfizer (
PFE) and Bayer have failed.
839 inhibits the enzymes
ADAM-10 and
ADAM-17 that are found on the cell surface of cancer cells.ADAM-10 and ADAM-17belong to a class of proteins called matrix metallo-proteases (
MMPs) that were heralded as promising targets for cancer therapy in the 90’s. Unfortunately, all the MMP inhibitors failed in the clinic due to safety and efficacy issues. Incyte’s approach is a little bit different, as it decided to target only two members of the MMP family, which might be a good enough difference. More importantly, while past trials of MMP inhibitors included chemotherapy drugs,
Incyte wisely chose a different setting where the addition of 839 makes a lot of sense.
MMPs clip other proteins on the cell surface and release them to the bloodstream (a phenomenon known as shedding). Some of their clients are important therapeutic targets, such as Her2, the target of
Herceptin. The clipping of Her2 results in two unwanted outcomes. First, it creates an active form of Her2 that constantly sends growth signals to the cancer cell. In addition, because the clipped part of Her2 contains the binding area of Herceptin, MMPs decrease the number of available targets on the cancer cell and create decoy targets that can bind and neutralize Herceptin in the bloodstream. Therefore, there is a strong rationale in using 839 in combination with Herceptin.
Another factor which makes 839 so interesting is the ability to focus on the right patient population. Since shedding of Her2 can be measured, it is relatively easy to identify patients who have a high level of Her2 shedding and are therefore more likely to derive benefit from 839. Such a strategy decreases the addressable market but it can also dramatically increase chances for approval and market acceptance, similar to
the case in Lilly’s Alimta.
Not surprisingly, patients with increased Her2 shedding are less responsive to treatment with Herceptin, creating an ideal opportunity for Incyte. If Incyte can show that 839 sensitizes patients who do not do well on Herceptin, it would serve as a fast route to market as well as a preliminary proof of concept for the drug’s activity. The ideal way to prove that 839 works is a trial that compares Herceptin with or without 839 in patients who are have high levels of Her2 shedding.
But before that, Incyte decided to do a single arm trial hoping to get some preliminary signs of efficacy. The trial, which is enrolling patients who are Her2 positive with high shedding levels but have never been treated with Herceptin, is a difficult one to enroll. First and foremost, most patients receive Herceptin in combination with chemotherapy, while Incyte’s trial does not include chemotherapy. Moreover, the Her2 segment is packed with new investigational agents (see
table), which might explain the relatively low rate of accrual and Incyte’s decision to conduct the trial in India.
Preliminary results from the trial were encouraging and the company expects to present an update in December at The San Antonio Breast Cancer Symposium. Because the trial is not a comparative study, the results should be approached conservatively, but good results in comparison to historical data of Herceptin monotherapy in this patient population might be enough for a modest licensing deal.
Regards
Joe
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