Incyte used the basic research-focused American Association of Cancer Research meeting to articulate its drug development strategy going forward. In essence, the lessons learned from the development of ruxolitinib appear to have transitioned the company firmly into an oncology drug developer. To wit, compare a pipeline presentation from June 2008 (left) to now:
One can’t be blamed for drawing a blank at the various candidates that existed 7 years ago. Attrition of clinical candidates is inevitable, leaving the more salient observation that the therapeutic areas of focus have narrowed. The large depth of field view that once kept diseases such as multiple sclerosis and HIV in focus has changed to a shallow depth of field firmly focused on the in-house oncology programs.
Going forward, the company plans to treat its IDO1 inhibitor INCB24360 as a clinical area of focus and expansion, much the same as it has done for ruxolitinib. Unlike the monotherapy approach for ruxolitinib, Incyte has initiated multiple clinical trials examining INCB24360 in combination with PD-1 and PD-L1 targeting approaches offered by the likes of Merck and Bristol Myers. Arguably this is an attempt to use INCB24360 as the spearhead of their advance into immuno-oncology. Within this space, Reid Huber introduced a two-pronged approach:
- IDO1, JAK and PI3Kδ as intracellular (read: small molecule) targets that can modify the mix of suppressor and effector lymphoid and myeloid cells within the tumour environment.
- Antibody-based approaches to activating (GITR / OX40) or antagonizing (TIM-3 / LAG-3) cell surface targets to manipulate T cell function.
This framing was followed by a brief presentation from Gregory Beatty to introduce some principles behind immune escape mechanisms, the role of various T cell populations, and how IDO1, JAK and PI3Kδ signaling can be written into the immuno-oncology narrative. This blended nicely into Peggy Scherle’s presentation of in-house efforts to demonstrate the parts that JAK, IDO1 and PI3Kδ inhibition can play, alone or in combination, in modulating the balance of suppressor versus effector lymphocyte populations that infiltrate the tumour. The talk focused solely on their preclinical work, comprised of a standard biotech menu of flow cytometry data accompanied by tumour growth inhibition in mouse models. Nonetheless, the preclinical PAN02 model outlining the divergence of JAK inhibition efficacy in immunocompetent versus immunocompromised mice was interesting. In addition, the continued emphasis on the populations of tumor infiltrating lymphocytes suggests that the company is very interested in context-specific changes in these cells populations following JAK1, PI3Kδ and IDO1 inhibition. At the least, these data provided a strong preclinical rationale for their view that exploiting JAK and its near-neighbour pathways may help build on top of the immuno-oncology edifice.
As for those related pathways, two subsequent speakers introduced and expanded on the rationale behind the PIM kinase and BET bromodomain inhibitor programs. Candidate INCB53914 is an inhibitor of all three PIM kinase isoforms and based on preclinical data appears poised for use in acute myeloid leukemia (AML) and multiple myeloma (MM), two settings proposed to have PIM1/3 and PIM2 dependency, respectively. The mechanism of action of this inhibitor appears to involve reducing BAD phosphorylation, thereby supporting a pro-apoptotic context, as well as reducing the activation state of AKT and mTORC. The PIM kinase inhibitor may additionally help to reduce the stability of Myc, a canonic proto-oncogene that is also targeted by their new BRD inhibitor INCB54329. This new candidate is Incyte’s first entry into the epigenetics area, and was demonstrated to reduce c-Myc expression in tumours and to combine agreeably with JAK1 inhibition in MM models.
During the discussion of these preclinical data, this signaling figure got plenty of screen time. With JAK1/2 and PI3Kδ inhibitors already in the clinic, they will soon be joined by PIM kinase and BRD inhibitors. In effect, Incyte appears focused on exploiting its internal strength in targeting the JAK / STAT pathway. One perspective on this strategy is to accept that the company is branching out targets in a thorough and organic manner. However, is there a risk of expending resources in a redundant fashion? Is there a significant advantage to be had by reducing c-Myc expression via a BRD inhibitor and a PIM kinase inhibitor versus just the one? Is the concomitant reduction in downstream mTORC1 signaling mediated by a PI3Kδ inhibitor usefully augmented by PIM kinase inhibition?
The implicit message in the Incyte approach is that there can be significant gains by made by employing both, not simply because of their shared targets, but also because of their differentiated, contextual effects. For example, in the PAN02 model, JAK1 inhibition and PI3Kδ inhibition had distinct effects on the population and balance of effector versus suppressor lymphoid and myeloid cells. Although either drug alone may reduce tumor burden through slightly overlapping pathways, their unique effects on the balance of effectors and suppressors may be the nuance that rationalizes their use in combination.
My impression behind this iterative and overlapping pursuit of pathways is that there is an internal belief they will benefit from some gains in overall response rate, but that the larger gains will be from patients who go into deeper remission. In other words, significant gains in response duration are being valued rather than a rote focus on response rates. This may be prudent, as more and more presentations from prominent immuno-oncology approaches (CTLA4, PD-1, PD-L1) are showing the value of deep remissions and a flattening of the Kaplan-Meier curve. Perhaps the value of this type of combination therapy was revealed by their enthusiasm for the upcoming data testing JAK1 + PI3Kδ inhibition in advanced and refractory Hodgkins Lymphoma. They specifically noted having observed an “interesting signal” and that discussions with the FDA on a registration strategy were to be initiated. Since the combo is just now emerging from a dose finding trial, a meaningful signal in the clinic may have galvanized their internal thinking about the feasibility of their overall strategy.
Odds and Ends
- One point of discussion was the clinical trial examining the combination of the JAK1 inhibitor INCB39110 with gemcitabine and nab-paclitaxel. Focusing on first line pancreatic cancer patients, it was noted that discontinuations within the first 2-4 months were greater than they had expected. In that regard, they will explore a lower dose of INCB39110 that will maintain JAK1 inhibition at the level observed with ruxolitinib treatment in the RECAP trial. The hope is to reduce discontinuations while maintaining adequate target inhibition. I suspect that this continued dosing will continue and push back the phase 3 initiation until some JANUS data are revealed. The JANUS data will provide a strong readout on the ability of JAK1/2 inhibition to make an impact, if at all, on the target subsets of pancreatic cancer patients. If JANUS-1/2 do not show efficacy, it would be difficult to get excited about another phase 3 with a selective JAK1 inhibitor. I’m skeptical about the prospects for this indication.
- For long time Incyte followers, they’ll remember that the announcement of the Jakafi (INCB18424) collaboration with Novartis included a seemingly out of place piece: worldwide development and commercialization rights to INCB28060, a c-Met inhibitor. At the time it was hard to see how the two assets were related, and beyond that, it was surprising that they licensed a compound even before it had dosed a patient in a phase I study. With the strategy articulated at AACR, it may be that this molecule was an early victim of their future focus, and the licensing agreement was a practical divestiture of a tangential asset. c-MET dependent signaling relies on multiple adaptor proteins (SHC / Grb / Gab) and can activate a downstream MAP kinase pathway. Incyte may have decided at the time that this was divergent to their focus on JAK / STAT related signaling, prompting them to license the asset to Novartis.
- The counterpoint to the above is that the company is also exploring an FGFR inhibitor, INCB54828, that can impact MAP kinase signaling. However, this receptor can also activate PI3K signaling, suggesting they may have arrived at this program organically through their JAK/PI3Kδ work.
- INCB54828 is billed as a selective FGFR inhibitor. The IC50 values for FGFR1, 2 and 3 are ~1 nM, but for FGFR4 and VEGFR2 they are 30 an 70 nM, respectively. Although clearly potent against FGFR1-3, the single dose PK data presented with the poster suggests that FGFR4 and VEGFR2 inhibition can also be expected.