Category Archives: B cell lymphoma

CAR T updates – tangled tales unwound

Last month we saw a biomedical media campaign go a bit off the rails. A press release from the American Association for the Advancement of Science (AAAS: see for example https://www.sciencenews.org/article/memory-cells-enhance-strategy-fighting-blood-cancers) and the Fred Hutchinson Cancer Center, was picked up by multiple media outlets who quickly spun the story of CAR-T-cell mediated rapid and complete clearance of B cell leukemias and some lymphomas from very ill patients and turned it into the “cancer cured” sort of headlines that serve as great click-bait but don’t do much to really educate the reader.

But what first caught my eye was an odd distortion of the data as presented in the session entitled “Fighting Cancer and Chronic Infections with T Cell Therapy: Promise and Progress” (see https://aaas.confex.com/aaas/2016/webprogram/Session12231.html). Several credible sources were telling very different stories about the progress presented. To take one example, BioWorld Today told the story of the clear benefit of using naive T cells as the recipient for cellular therapy, while FierceBiotech (and many other outlets) focused on the benefit of using memory T cells instead (see http://bit.ly/1UdLqDs). Indeed the claim was made that even a single memory T cell could affect a cure – which was not really the point, or an important conclusion of the presented works.

It follows that the pressers were used to talk up CAR T cell company stocks, which have been languishing along with the rest of biotech.

All of this came across as garbled and confusing. I found it all very frustrating.

So now I’ve gone through the abstracts presented at AAAS and some of the primary literature, and I’ve a Cliff Notes version of what data were actually presented and what the data mean and don’t mean. I seems clear that the confusion regarding the results arose from the oversimplified weaving of two talks (by Dirk Busch and by Steven Riddell) into one tangled “story”. Lets untangle the knot and follow the threads.

Riddell’s work is closely followed in the CAR T field – not surprising as Dr. Riddell, from the Fred Hutchinson Cancer Center in Seattle, is a technology leader and a cofounder of Juno Inc. The story presented at the AAAS symposium is interesting but perhaps more controversial than one might have gathered from the press reports. Some of the work was recently published (http://www.nature.com/leu/journal/v30/n2/full/leu2015247a.html). They start with the observation that in all reported CAR-19 clinical trials, patients have received back a random assortment of their (now CAR-transduced) T cells, meaning that the cell population is a collection of naive T cells, effector T cells and memory T cells representing both the CD4 and CD8 T cell lineages. This introduces a variable into therapy, as different patients are likely to have different percentages of these various T cell subsets. Indeed there is quite a list of variables that may impact the efficacy of CAR T cell treatment including baseline immune competence, prior treatments and antigen load. With this in mind Riddell and colleagues are trying to control the one variable that they can, which is the composition of the transduced T cells going into the patient. By analyzing CAR cell subsets for tumor cell killing function they arrive at the “most potent” combination of CD4+ T cells and CD8+ T cells and conclude that the findings will be important for the formulation of CAR T cells therapeutics for use in patients.

The data in the paper are derived from normal donor and cancer patient PBMC samples that are tested in vitro using cell culture assays and in vivo using humanized mice (NOD/SCID/yc-deficient mice; NSG) reconstituted with T cells and tumor target cells (Raji) that express CD19. The CAR T construct is a “generation 3″ CAR having CD28, 41BB and CD3 signaling domains downstream of the well-studied FMC63-derived anti-CD19 scFv.

Some results:

- substantial differences were seen in the T cell populations between normal donors and cancer patients, with most patients having a higher percentage of CD8+ than CD4+ T cells.

- patient samples also contained more memory T cells than did normal donor samples. A further refinement to the memory T cell definition allows one to identify effector memory and central memory T cells. The latter are a long-sustained population of antigen-educated T cells that contribute to immunological memory, such as one retains after a vaccination against a virus for example.

- both CD4+ and CD8+ T cells were readily transduced with the CAR-19 construct, and when presented with target cells in vitro both cell types responded. CD8 T cells mediated target cell lysis more effectively than CD4+ T cells, but the latter proliferated more vigorously and produced more pro-inflammatory cytokines such as IFNy and IL-2.

- among the CD4+ subset, naive T cells (those not previously antigen-activated) produced more cytokines than the memory cell subsets. In vivo, naive T cells were more potent in controlling tumor growth than central memory T cells which were in turn more potent than effector memory cells.

- similar analyses of CD8+ cells revealed that, of the three subsets, central memory CD8+ T cells were the most potent in vivo, a result that was most closely associated with the enhanced proliferation and expansion of this subset.

- the activity of CD8+ central memory T cells was further enhanced by the addition of CD4+ T cells, notably those of the naive subset. This effect was seen using cells from normal donors and cells from B cell lymphoma patients (specifically, Non-Hodgkin Lymphoma (NHL) patients). The improved in vivo activity was due to enhanced proliferation and expansion of T cells in the NSG mouse model, specifically an increase in the peak of CD8+ cell expansion, in line with clinical results (see below). I’ll note as a reminder that all of the available clinical results are from CAR T cell populations that had not been sorted into naive and memory subsets. Also, many researchers in the field believe that naive T cells (CD4 and CD8) have the best proliferative capacity and potency.

Regardless, the Riddell work suggests a straightforward improvement in the ability to create more potent CAR T cell preparations for use in the clinical setting. There are some caveats however. In the in vitro and in vivo models used, antigen (CD19) is abundant, even in the NSG mouse, due to robust expression of rapidly dividing CD19+ Raji cells. As noted earlier, antigen availability may be an important limiting feature for some patients, and may be more important than the composition of the T cell subset tested. Fortunately the relative importance of these variables could easily be examined in vivo by using sub-optimal Raji cell numbers, or using transfected cells with different levels of CD19 expression, to vary the antigen load.

The Busch study at the same symposium was notable for dispensing with CD4+ T cells altogether and using just CD8+ central memory T cells to control CMV infection (that can occur following allogeneic hematopoietic stem cell transplantation). Nearly all of this work has been performed in mouse models, with a small number of patients treated under compassionate use protocols (see e.g. http://www.bloodjournal.org/content/124/4/628). In the mouse models very small numbers of antigen-specific memory T cells can expand to control viral infection, and this has been taken as evidence (in the popular press mainly) that similar technology could be applied in the CAR T setting. However, numerous studies have shown conclusively that very large-scale expansion is required to achieve optimal potency, to a degree that would seem beyond the capacity of a small number of cells or a single cell. Further, studies in acute lymphocytic leukemia patients presented by Carl June last fall at the Inaugural International Immunotherapy meeting in NY showed that clonal selection and perhaps competition was a component of successful therapy for some patients, a process that would be eliminated or reduced by using a limited cell number in preparing the CAR T cells. The Busch study makes the further argument that central memory CD8+ T cells themselves possess “stem-ness”, that is, they can give rise to functionally diverse CD8+ T cell lineages and as such should have no limit to their proliferative capabilities. While this was demonstrated convincingly in mouse models it would seem a difficult finding to translate to the CAR T setting, although the work may find utility in the adoptive cell transfer setting (e.g. of selected but not transduced T cells, such as tumor infiltrating T cells).

The “stem-ness” concept reminded me of older literature that aimed to dissect the basis for long-lived CD8+ T cell memory in the context of viral immunity (see here for a recent review: http://journal.frontiersin.org/article/10.3389/fimmu.2012.00357/abstract). There were at one time two broad classes of thought – first, that such memory required a consistent supply of antigen, for example, a depot that periodically re-stimulated the antigen-specific T cell population. The second school of thought, more reminiscent of the Busch finding, was that memory CD8+ T cells were self-renewing, and therefore did not require life-long antigen stimulus. The “big bang” hypothesis of T cell memory development, a hypothesis that the work of Dr. Busch and colleagues has definitively supported (see: http://www.bloodjournal.org/content/124/4/476?sso-checked=true) holds that once stem-like T cell memory is created, these cells can be used just like stem cells, i.e. to reconstitute cellular function, in this case, the ability to control viral infection.

Let’s get back to CAR T cells. Recent work has demonstrated clearly that the establishment of persistence in cellular therapy requires a robust response to abundant antigen. Only then can CD8+ T cell memory develop and from that point on be maintained. This observation informs the next set of studies, presented at the Clinical Application of CAR T Cells conference (#CART16 – https://www.mskcc.org/event/car-t-cell) held at the Memorial Sloan Kettering Cancer Center, the Adoptive T-Cell Therapy Congress held in London (http://tcellcongress.com/resource-center/) and the Advanced Cell Therapy Symposium (https://www.immunology.org/document.doc?id=1807) held at Guy’s and St Thomas’ NHS Foundation Trust and King’s College, also in London. Much of the work presented highlighted at these meetings addressed attempts to move CAR T cells into solid tumors.

Here I am a little hamstrung, as I’m relying on information presented on slides (as shared on Twitter by @JacobPlieth @VikramKhanna and others). Let’s try to define some themes here regardless.

Jacob has reviewed some #CART16 data: http://epvantage.com/Universal/View.aspx?type=Story&id=627150&isEPVantage=yes. Please see that link for his viewpoints.

First, to stick with CAR19 therapeutics, we have some posted Novartis data on responses in Non-Hodgkin Lymphoma (NHL). NHL is comprised of diverse B cell lymphomas, some of which are highly refractory to treatment. Examples of the refractory class include diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) among others. Here we see some rather impressive results treating these lymphomas:

Screen Shot 2016-03-20 at 9.55.18 AM

The data are hard to read, but let’s pull out some numbers from the table. Note that essentially all patients got the optimal dose of 5 x 10e8 cells (1 exception) and that the peak cellularity is defined as %CD3+/CAR19+ cells in peripheral blood. We can therefore look at expansion, time to peak cellularity and outcome:

Screen Shot 2016-03-20 at 10.00.38 AM

There seems no correlation between day to peak and outcome, unless it is very short – day 1 or 2 – and even then that is likely due to abortive expansion. If we arbitrarily set 10% as an exploratory setting with which to parse the %CD3+/CAR19+ data we quickly see that above 10% (black line), half of the patients responded, which below 10% only a third of patients responded.  So expansion is important, as we already knew. With respect to the earlier discussion, we do not know the critical variable at work here, be it CAR T cell persistence (likely), CAR T cellular composition (per Riddell), patient variability, antigen density, or something else.

The FL data are a little bit more confusing:

Screen Shot 2016-03-20 at 10.05.07 AM

Again we can pull out some of the data:

Screen Shot 2016-03-20 at 10.07.43 AM

And now we are really hard-pressed to see any correlation between outcome and peak cellularity, no matter where we might draw the arbitrary line for analysis. What data is missing? I suspect it is a measure CAR T cell persistence over time, as this is most often associated with positive response. We should note that CD19 is an unusual target antigen in that it is expressed on the cancer cells (B cell leukemia or lymphoma) and on normal B cells that we can deplete without undue harm to the patient.

Other B cell antigen targets are under development as CARs, including CD22 and BCMA. BCMA is expressed on plasma cells (relatively uncommon B cells that secrete antibodies) and on essentially all multiple myeloma cells. Early promising results generated using a BCMA CAR to treat multiple myeloma were presented at ASH (http://www.ascopost.com/issues/march-10-2016/car-t-cell-therapy-may-have-role-in-treating-multiple-myeloma/).

Screen Shot 2016-03-20 at 9.39.58 AM

Updated results are a little less encouraging as the complete response patient (#10) has since relapsed as was reported at #CART16. It is unclear if advanced multiple myeloma is simply more refractory to CAR treatment, if the lower cell number infused led to poor persistence, if the CAR were different, or if antigen load was too low. Thus we are again faced with multiple variables to assess.

So now we can ask what happens when there is little or no persistence, which is the case with most CARs directed to solid tumors. This is data from Nabil Ahmed and Stephen Gottschalk from Baylor College of Medicine. This group is collaborating with Celgene on cellular therapeutics. Here we see the results of treatment of HER2+ advanced solid tumors with CAR-HER2 T cells. The response is minimal.

Screen Shot 2016-03-20 at 10.12.07 AM

This is very likely due to the very short persistence of the CAR-HER2 T cells, in most cases gone in a week or so.

Screen Shot 2016-03-20 at 10.12.27 AM

Interestingly, analysis of resected or biopsied tumor after treatment revealed that the CAR T cells had migrated preferentially into the tumor, but had not proliferated extensively. Novartis presented nearly identical data on an EGFRvIII targeting CAR T cell study at the Boston PBSS Immuno-Oncology Workshop (http://www.pbss.org/aspx/homeBoston.aspx), and similar data has been presented on a host of solid tumor targets.

To return briefly to CD19+ tumors, it was reported recently that the response to CAR19 therapy in chronic lymphocytic leukemia was about 25%, but that all of those responders were durable complete responders (i.e. potential cures). Why the seemingly digital nature of response here? Again this is most likely due to CAR T cell persistence which itself is most likely a reflection of antigen load (among other variables). With this in mind I was struck by a slide from Seattles Childrens Hospital (I’m not sure from which meeting):

Screen Shot 2016-03-20 at 10.17.40 AM

In point #3 the presenter is basically suggesting injecting an artificial antigen presenting cell expressing CD19, i.e. increasing the antigen load.

We can conclude by saying that there is a fundamental issue with CAR T cell antigens – those that are tumor specific are either not abundantly expressed and/or have been removed during the course of therapy. This is an issue that may not be solved by adding 4-1BB or IL-12 or anti-PD-1 antibody or whatever other immunological “help” one might envision. This issue impacts the entire field, which is why we now see analysts who once talked of the emergence of dominant CAR T platform companies now wondering who will win the CAR19 race to the finish line. That is still a noble race to run, but the patient numbers cannot justify the number of companies competing for the prize. Yet change will come and progress will be made…

What to do?

stay tuned.

ps. thanks again @JacobPlieth @VikramKhanna and others for kindly sharing slides (and getting great seats at conferences!)

Three high-altitude take aways from AACR14

The American Association for Cancer Research (AACR) 2014 meeting last week was high energy and high impact. We will dive into particular talks and specific pathways and indications in later posts, in the meantime I wanted to mention a few key themes.

1) Immunotherapy Versus The World.  That’s a deliberate overstatement of a subtle shift in emphasis from last year’s big meetings, where combinations of immunotherapy with just about anything else were the hot topic. This year there were several talks which emphasized the futility of chasing oncogenic pathways and all of their resistance mutations, one after the other, as opposed to letting the immune system do the work. However, it seems to me overly optimistic to believe that immune modulation can defeat a high percentage of patient  tumors on its own, as some speakers acknowledged. Combinations remain necessary although we will have to work past some notable failures in combo trials, such as the liver toxicity seen in the ipilimumab + vemurafenib combination phase 1, discussed briefly by Antonio Ribas               (see http://www.nejm.org/doi/full/10.1056/NEJMc1302338).

2) Immunotherapy Versus Itself.  In the ultimate battle of the titans, we see different immunotherapeutic modalities squaring off. This is a theme we’ve touched on before in this space, but the  competition is getting heated. In some indications, the leukemias, lymphomas, perhaps melanoma and some other solid tumors, there is an abundance of therapeutic choices, and the hard question of which therapy best suits which patient will ultimately need to be addressed outside of the context of clinical trial enrollment. Several talks really brought this message home. Roger Perlmutter of Merck (and before that, Amgen) envisions an important role for multiple immune therapies including bi-specific antibodies, chimeric antigen receptors (CARs), and immune checkpoint modulators like Merck’s anti-PD-1 antibody MK-3475.  For B cell lymphoma for example, there is blintumumab (Amgen), a potent bi-specific that redirects T cells to CD19+ tumor cells (and normal B cells), and there is CTL019, a CAR therapeutic which does much the same thing. The therapeutic profiles and toxicity differ, but the general idea is the same. One big difference is that while CTL019 drives T cell expansion and the development of long term anti-tumor memory, the bi-specific does not. Which is better? We don’t know yet. He did not mention that one might do well trying a course of BTK inhibition plus anti-CD20 antibody therapy, perhaps with restricted chemotherapy first e.g ibrutinib plus rituximab and chemo (R-BR or R-F). That choice comes down to efficacy, then toxicity, and eventually cost. Efficacy seems to be a home run with the CAR therapeutics, although these may run into trouble in the area of toxicity and cost calculation. Renier Brentjens discussed the CAR therapies being developed under the Juno Therapeutics umbrella. Acute lymphoid leukemia (ALL) can be treated with CAR 19-28z modified T cells to achieve a >80% complete response rate with >70% of patients showing no minimal residual disease, an outstanding result. However, 30% of treated patients end up in the ICU due to cytokine release syndrome and other toxicity, and recently patients in the ALL trials have died from unanticipated tox causes. Juno stopped 5 trials of their CAR technology last week due to toxicity. Apparently one patient died of cardiovascular complications and another of CNS complications (severe uncontrolled seizures) – it was hard to nail down as Dr Brentjens had gone off his prepared talk for these remarks which were off the cuff, so comment please if you have better info on this. Carl June discussed Dr Brentjens’ presentation, noting that the clinical results were really quite striking, and contrasting the CD28 motif-based CARs with the 4-1BB-based CARs (as designed by Dr June with U Penn and licensed to Novartis). He also stressed that in chronic lymphocytic leukemia (CLL) they have had patients who have failed up to 10 prior therapies, including rituximab and/or ibrutinib, and these patients have responded to CAR treatment. That’s very impressive data. The roadblocks to widespread use of CAR therapy however are large and include the toxicity, the “boutique” nature of the current protocols, the cost. Perhaps, Dr June suggested, CAR will end up as third line therapy, reserved for salvage therapy. I for one hope not.

Also in the immunotherapy space were hot new targets (e.g. CD47, OX40, GITR), advances on the vaccine front, and a few surprises. We’ll update soon.

3) The Medicinal Chemists Have Been Busy.  Not to be drowned out by the Immunotherapy tidal wave, small molecule therapies targeting specific oncogenic pathways continue to be developed and show promise. Most readers will be aware of the high stakes showdown (so billed) between Novartis, Pfizer and Lilly in the field of specific CDK4/6 inhibitors – in addition to bringing forward some really nice phase 2 data (we’ll discuss these another time) this “showdown” also illustrates that current portfolio strategy drives a lot of overlapping effort by different companies. As expected, much of the action is moving downstream in the signaling pathways, so we saw some data on MEK1 inhibitors and ERK1/2 inhibition. There were some new BTK inhibitors, nice advances in the epigenetics space, and some novel PI3K inhibitors. All grist for the mill.

stay tuned.

Kites Fly: Effective CAR-T Therapy in Non-Hodgkin Lymphoma? Hematological Malignancies Part 4

Sorry for the slight delay getting this out. I was trying to account for each patient as even 1 or 2 misplaced will impact the response numbers in these small trials. Took a while.

Our last post focused on the CAR technology coming out of the MSKCC and affiliated institutions, being brought together under the Juno company umbrella. Juno was funded by ARCH Venture Partners and the Alaska Permanent Fund, through a partnership managed by Crestline Investors, along with Bezos Expeditions, and Venrock. We noted in closing that CAR T cell technologies were performing very well in acute lymphocytic leukemia (ALL), but not as well in the Non-Hodgkin Lymphomas (NHL). In early data sets response rates were not trending very high.

Recently I came across Kite Pharma’s JPM update on their version of CAR therapy. Kite is financed by Pontifax Ltd., Alta Partners, Commercial Street Capital, and individual investors, in partnership with the National Cancer Institute (NCI) Surgery Branch under a Cooperative Research and Development Agreement (CRADA). This reflects that the technology is coming out of NCI labs.

I was struck again by the duration and response rates reported and the indications they were pursuing. It seems that there is one extra patient in the JPM slide deck, so I went back to the ASH talk to get the right numbers. So lets review. Kite calls its lead CAR construct a very straightforward name: anti-CD19 CAR. Like 19-28z CAR from Juno/MSKCC, this CAR is built with a anti-CD19 scFv, followed by CD28 and CD3 signaling components. Quite unlike the 19-28z effort however, the lead here is NHL indications, specifically as seen here:

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Click to read the full blog post

Hematological Malignancies – who will win the battle for patients? Part 2: BiTEs & CARTs targeting CD19

 We talked last time about the potential of Macrogenic’s DART bi-specific technology and we focused primarily on the T cell engaging bi-specifics, such as DART006, a CD3 x CD123 therapeutic. Lets just quickly state the hypothesis:

Bi-specific modalities will allow the targeting of the patients T-cell driven immune       system to a precise (tumor-expressed) antigen.

Other outcomes are possible. For example, the drugs might not work at all, or they might not be as specific as designed, or they act in ways we have not anticipated. In the context of the Macrogenics platform, we actually don’t know yet, as DART006 is very early in clinical development. BiTEs (Bi-specific T cell Engagers), Micromet’s version of a bi-specific technology, have been around a while and are further advanced. Acute Lymphocytic Leukemia (ALL) patients are now being recruited into Phase 3 clinical trials for blinatumomab, the anti-CD3 x anti-CD19 BiTE, with study completion due in July 2017. Micromet was acquired for 1.2BB dollars in January 2012 by Amgen. At the time Amgen R&D head Roger Perlmutter pointed to the Phase 2 clinical trial results in ALL as driving Amgen’s interest in the technology. Indeed, blinatumomab has produced some remarkable data in ALL. Historically, chemotherapy treated ALL patients had a complete response rate (CR) of about 38% and a median overall survival (OS) of 5 months. Rituximab (anti-CD20) didn’t perform much better than chemo. In the blinatumomab Phase 2 trial of adult relapsed/refractory (r/r) ALL, patients received a continuous IV infusion of blinatumomab for 28 days followed by 14-days off drug. Patients who responded could re-up for 3 more cycles of treatment or proceed to allogeneic stem cell transplantation (HCST). There was a very high rate CR of ~70% and the apparent absence of minimal residual disease (MRD) in many patients. Blinatumomab also impacted overall survival (OS) in ALL, as reported at the American Society of Hematology conference (ASH) in 2012 (Abstract #670). The CR was still 69% with most patients being MRD negative. The OS for responders was 14.1 months while the OS for non-responders was 6.6 months (so median OS = 9.8 months). Thirteen of the 36 patients enrolled were able to receive allogeneic HSCT.

The most common adverse events (AEs) were fever, headaches, tremors, and fatigue. Some patients experienced severe AEs (SAEs) such as cytokine release syndrome (CRS) and central nervous system events, including seizures and encephalopathy. One patient stopped treatment due to fungal infection leading to death. So, there is tox to consider.

A smaller study directed to salvaging patients with MRD despite prior treatments showed even more dramatic results: 16/21 patients became MRD negative and the probability for relapse-free survival was 78% at a median follow-up of 405 days. This is a remarkable result. An SAE led to one drug discontinuation.

Last year at ASH (Abstract #1811) we saw early results from an open label phase 2 study in r/r Non-Hodgkin’s Lymphoma (NHL), specifically, Diffuse Large B cell Lymphoma (DLBCL). Blinatumomab was administered by continuous IV for 8 weeks. Patients received either stepwise blinatumomab dosing of 9, 28, and 112 μg/d during weeks 1, 2, and thereafter, or received 112 μg/d throughout. All patients received prophylactic dexamethasone. So you can see some dose modifications here designed to reduce SAEs. After a 4-weeks off drug, patients who had responded could receive a 4-week consolidation cycle. 11 patients had been enrolled, 7 patients were evaluable for response. These patients had failed >2 prior therapies, including some patients who had relapsed after HSCT. The overall response rate (ORR) was 57% (14% CR plus 43% partial response (PR); 30% had progressive disease (all from the stepwise dose regimen). Note this is a very small sample size so every patient has a large impact on the response numbers. Ten of 11 patients had at least one grade ≥3 AE with 2 patients having grade 4 AEs (one patient with neutropenia and leucopenia; one with respiratory insufficiency). There were no drug related fatalities. Ten of 11 patients had central nervous system (CNS) AEs, mostly tremor, speech disorder and disorientation: in 5 patients these CNS toxicities were grade 3. The overall benefit/risk assessment suggested stepwise dosing (9, 28, 112 μg/d) to be the recommended dose.

Well first of all let’s point out here that blinatumomab has orphan drug status for ALL and NHL. That’s just to remind ourselves that these are pretty rare diseases with high unmet need. For ALL in particular this seems a good risk/benefit scenario. Within the diseases that make up NHL, DLBCL is not the most treatable (nor the least), and we note also that there is no attempt in the open-label phase 2 to characterize DLBCL into its subclasses – these have different oncogenic drivers and different outcomes for patients. Blinatumomab has also been in Phase in in other NHL classes, including Mantle Cell Lymphoma and Follicular lymphoma. Response rates were generally below current standard of care. Similarly, we can go back to look at rituximab, ofatumumab, and even ibrutinib, idelalisib and ABT-199 in NHL and likely find better treatment paradigms for r/rDLBCL than this, although maybe not as a monotherapy (see those earlier posts here: http://www.sugarconebiotech.com/?p=16).

Given the modality (CD3 x CD19 bi-specific) maybe the most interesting comparison is with Novartis’ CAR-T CD19 technology CTL019. CTL019 is the product of genetic engineering technology developed by Carl June’s group at U Penn, and is currently advancing in close to 20 clinical trials. The most advanced is a Phase 2 trial in r/r ALL, with a primary outcome completion due in July of 2015. As a quick reminder, CARs combine a single chain variable fragment (scFv) of an antibody (e.g. anti-CD19) with intracellular signaling domains from CD3 and 4-1BB into a single genetically engineered chimeric protein. The CD19-specific version of this technology is termed CTL019. Patient’s T cells are lentivirally transduced with a CAR, expanded ex vivo then infused back into the patient. Infusion of these cells results in 100 to 100,000x in vivo T cell proliferation, anti-tumor activity, and prolonged persistence in patients carrying CD19+ B cell tumors. Results from a pilot study in pediatric and adult r/r ALL were presented at ASH in 2013 (Abstract #67). Most patients received lymphocyte-depleting chemotherapy just a few days prior to infusion. This helps de-bulk the malignancy. In this small trial, 82% achieved a CR, 18% did not respond. Of the patients achieving CR, 20% subsequently relapsed. The rest of the patients are being followed and there has been no update. Responding patients all developed CRS, and about 30% of patients were treated with the IL6-receptor antagonist tocilizumab plus corticosteroids to control CRS symptoms.

We have a little more data on CTL019 from NHL studies, specifically r/r CLL. In December 2013, Phase 2 data were presented at ASH (Abstract #873).  Patients with r/r CLL received lymphocyte depleting chemotherapy and then one of several doses of transduced T cells (this is a dose study in that regard, although, cutting to the chase, no dose response was seen, so lets skip over that). Median follow-up for analysis was 3 months at which time the ORR = 40% (20% CR plus 20% PR, with clearance of CLL from the blood and bone marrow and at least a 50% reduction in lymphadenopathy. The toxicity profile was similar to that described above, dominated by treatable CRS. In a small Phase 1 study (Abstract #168), adult patients with r/r NHL including patients with chemotherapy-refractory primary mediastinal B cell lymphoma and DLBCL were enrolled. They received chemo to reduce disease burden and then an infusion of CTL019. 12 of 13 evaluable patients responded (ORR = 93%), the CR = 54% and PR = 38%. These are outstanding responses.

So let’s take a step back. It is a bit hard to compare these regimens head-to-head as they are in different stages of clinical development, the trails are generally small, and in the case of NHL, we have limited data on different types of lymphomas. At the same time we have to consider the larger landscape of therapies available, and ask ourselves how patients will best be served. In the case of the T cell engaging bispecific antibody landscape, it is very clear that robust anti-tumor responses are generated with very low concentrations of antibody. It seems to me very likely that there will be malignancies or subsets of malignancies where this technology will be very useful, including ALL, as we just saw. It will be important to either improve the antibody construction or alter the dose regimen sufficiently to reduce the toxicities associated with the BiTE therapeutic and competing modalities, including the DARTs. Now, people will claim that the tox is not so bad, and that it is only efficacy that matters, and that’s fine, but in the face of competition from CTL019 and other therapeutics, maybe this becomes a differentiating issue. This might also be different for the pediatric population (a critically important population in ALL) versus the adult population. When we look at the CAR T cell transduction technologies we need longer follow-up on the phase 2 studies but certainly anecdotal evidence from smaller trials suggests that some patients will experience long-lasting remissions. If this observational information holds up in the larger clinical trials than the technology will cement itself a place in ALL therapy, and perhaps in other diseases as well. We don’t know yet whether the BiTE therapeutic blinatumomab or the CAR therapeutic CTL019 will have a top-tier profile in NHL. This may change as more data become available, as some of the small studies are very encouraging. One of the interesting twists to the CAR technology is the question of how to make it widely available. In host-institutions (The U Penn system, MD Anderson, NCI) this is a centralized procedure, and in medical institutions world-wide, core patient cell facilities are commonplace. However it is rumored that Novartis at least wants to maintain the core facility model, as they picked up the Dendreon facility in Morris Plains New Jersey (at a bargain price) specifically to support CAR technology, and plan to duplicate those capabilities in Basel and in Singapore. Perhaps yesterday’s pickup of Israel’s Gamida Cell also plays into this centralized cell handling model. None of these complexities will bother the bi-specific therapeutics as these are injectable – that said, I’m not sure anyone will choose walking around with an IV pump for two months if they can avoid it.

So while these therapies and those like them are very potent, we will have to see how patients and providers ultimately use them.

Now, we’ve unfairly used blinatumomab and CTL019 to illustrate what are both pretty large areas of therapeutic development. We’ll come back to talk about the other players in the bispecific antibody and CAR spaces very soon.

stay tuned.

Oncology drug development questions for 2014: Combination therapies for B cell lymphoma

Part 1 – Ibrutinib and the development of combination therapies for B cell lymphoma

For physicians, patients, investors etc, major medical conferences are a way to check in on the progress of a company’s drugs in the context of the medical communities response to the data, i.e. the buzz. Negative buzz is generally pretty straightforward, reflecting poor results or unexpected toxicity in a clinical trial. Positive buzz should be (and often isn’t) more nuanced, as positive data, while great to see, need to be placed into the context of evolving clinical practice and the ever-present competition for patients. Results, positive or negative, need to be vetted for robustness: clinical trial stage, sample size, design; endpoint design; therapeutic window (the dose range between efficacy and toxicity); and duration of response.

Last year saw extraordinary advances in the treatment of B cell lymphoma, particularly the Non-Hodgkin Lymphomas (NHL) that include well known cancers like Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), indolent NHL (iNHL) and many others. This advances included small molecule therapeutics that target critical drivers of lymphoma cell proliferation and survival, novel antibodies (“naked”, enhanced, payload carrying), ex vivo modified patient T cells that attack lymphomas upon reinjection, and a variety of other modalities. It was interesting to see that the companies getting the most buzz varied during the year, with different companies “winning” different conferences. Be assured that in this context, winning reflects wins for the stock price! Winning in the medical marketplace is a whole different story.

With the medical marketplace in mind, a reasonable question for 2014 pops up when you step back and look at the breadth of the B cell lymphoma therapeutic landscape.

How will biopharmaceutical companies, physicians, and payers develop and use combinations of these therapies?

Lets think about the possible combinations. The most obvious are those that we are already seeing widely used, such as the combination of a small molecule inhibitor with a tumor-targeting antibody. One example is the combination of ibrutinib, a BTK inhibitor, and rituximab, an anti-CD20 monoclonal antibody. Ibrutinib was approved for treatment of relapsed/treatment refractory (rr) MCL in November 2013 under the brand name Imbruvica, and approval for rrCLL is expected soon (these indications were filed for approval together, in August 2013). Patients with relapsed/refractory small lymphocytic lymphoma (SLL) were included in the CLL arm of the clinical trial.

CLL is a good example of the power of combination therapy. Rituximab monotherapy in rrCLL/SLL produced overall response rates (ORR) in the range of 55% and a complete response rate (CR) of somewhere under 10%, depending on the trial. Note here that ORR and CR refer to assessments of tumor burden at a specific and predetermined time after treatment is initiated. A CR does not indicate a cure but rather is a measure of the degree of efficacy. The ORR and CR measurements are most meaningful when presented in the context of duration of response (DOR) or in the context of progression-free survival (PFS) or overall survival (OS).

Monotherapy of rrCLL/SLL with ibrutinib produced ORRs ranging from 70-80%, with CRs ranging from 0 – 10%. Duration of response was good, and there was a measurable impact on PFS. There are different classes of rrCLL patients, based on cytogenetic status. High risk CLL patients commonly carry a deletion on chromosome 17 (del17p) and/or other abnormalities. Such mutations predict poor prognosis for these patients. Last April, the FDA granted Ibrutinib Breakthrough Therapy Designation for high-risk rrCLL/SLL del17p patients based on achievement of a 50% ORR in these patients when given ibrutinib monotherapy.

Now to the combination of ibrutinib and rituximab (and a chemo agent, bendamustine). As discussed in earlier coverage of the American Society of Hematology Annual Meeting (ASH), linked here, treatment of high-risk CLL patients with the combination therapy produced an ORR of 95%, with 78% maintaining response through 18 months. While only 10% of the responses were designated CR, the long duration of the partial responses (PR) was a dramatic result.

The cost of Rituxan treatment for B cell lymphoma is generally quoted at ~10K/month but billed to insurance at about 5K monthly, so we are somewhere between 60-120K per year per patient in the US. Imbruvica will cost 130K per year per patient in the US. Note here that neither therapy, given alone, is considered curative. We don’t know yet what the durable remission rate will be for the combination therapy, where we define durable remission as no detectable disease (in the blood, lymph nodes, bone marrow) without maintenance therapy. Curative treatment means no disease in a patient who no longer requires drugs.

So it’s fair to say that these combination therapies will be very expensive and may need to be used for a long time. Given the current climate of cost control, especially outside of the US, what are companies doing to anticipate eventual pushback on premium pricing?

Just a quick reminder that Imbruvica (ibrutinib) is a Pharmacyclics/Johnson&Johnson (J&J) product and the Rituxan is a Roche product and further, that Roche has a next generation anti-CD20 antibody, obinutuzumab, recently approved for the treatment of CLL (including as first line treatment), under the brand name Gazyva. This antibody given in combination with a cheap chemotherapy agent, chlorambucil, produced an ORR = 78% and a CR of 28% in the phase 3 trial. This antibody was significantly better than Rituxan (rituximab) plus chlorambucil in the same clinical trial (ORR = 65%, CR = 7%). The trial was done in rrCLL patients including high-risk patients defined as del17p.

Another anti-CD20 antibody, ofatumumab from GSK, has been approved for second-line use in rrCLL. This drug, priced at 120K yearly, ran into reimbursement pressure in Europe and the UK as not showing sufficient benefit to justify the price. This is a hint of price pressures to come.

This is where I think things get really interesting. I spent some quality time on clinicaltrials.gov, trying to understand how companies competing in the B cell lymphoma space are looking ahead, the assumption being that one can do this by looking at the trials planned or underway for the top tier drugs. Many of the oral drugs in advanced development for B cell lymphomas are reviewed here.

Nearly all advanced oral drugs for B cell lymphoma have trials underway or planned with an anti-CD20 antibody. Most of these trials are done with rituximab, probably just reflecting the wide availability of this antibody. Perhaps some companies are sticking with rituximab in the belief that generic biosimilar forms of this antibody will become available in Europe (where it is now off-patent) and in the US (where patent protection expires in 2018), which may make combination therapy more widely available. The rituximab trials are not done in collaboration with Roche, with one notable exception which we will get to later.

There are 11 clinical trials listed as active that include ibrutinib with rituximab either alone or with various other agents. Some of these trials have already read out results:

TRIAL NUMBER
PHASE
DATE FILED
IBRUTINIB WITH
INDICATION
NCT01980654210/24/2013rituximabuntreated FL
NCT0188056726/4/2013rituximabrrMCL
NCT0152051921/25/2012rituximabhigh risk CLL, SCL
NCT0161109035/15/2012rituximab/bendamustinerrCLL, rrSCL
NCT0177684031/24/2013rituximab/bendamustineuntreated MCL
NCT01479842111/1/2011rituximab/bendamustinerr DLBCL,MCL,iNHL
NCT0185575035/14/2013R-CHOPDLBCL-ABC
NCT0188687236/24/2013noneuntreated CLL
rituximab
v rituximab/bendamustine
NCT01974440310/28/2013R-CHOPrr iNHL
v rituximab/bendamustine
NCT0188685916/24/2013lenalidomiderrCLL, rrSCL
NCT0182956814/9/2013lenalidomide & rituximabrrFL
NCT0195549919/27/2013lenalidomide & rituximabrr iNHL

Note that FL is follicular lymphoma and DLBCL is diffuse large B cell lymphoma. DLBCL-ABC is a subtype. These are all types of B cell lymphomas. R-CHOP is rituximab plus a standard mixture of chemotherapeutic agents, and I may or may not have defined this correctly, suffice to say if it says CHOP then there is a potent mix of chemo being given; “v” means versus, that is, it is a comparator arm.

There are another seven or eight single agent ibrutinib trials also, but I did not include those here, so what we see all together is a full court press of clinical trials designed to show benefit of ibrutinib in multiple different B cell lymphomas, as first line or second line therapy. These trials will produce a tidal wave of data that, if positive, will by their sheer volume place ibrutinib at the top of the heap of B cell lymphoma oral agents. So, yes, I’m betting on Pharmacyclics (stock symbol PCYC) and J&J to win the marketplace, at least for the near term.

Ibrutinib development does not stop there. There are three trials with lenalidomide, also known as Revlimid, approved as second line therapy for multiple myeloma (MM). A monotherapy trial of lenalidomide in CLL was halted last year due to an increase in deaths seen in the active arm. Even at a reduced dose (I’m guessing here) the use of this agent plus ibrutinib plus rituximab seems risky. Also, the drug is owned by Celgene. So why conduct trials with lenalidomide at all? The answer to that question will be found in the list of clinical trials for CC-292, Celgene’s BTK inhibitor under development for B cell lymphoma.

But just to finish with ibrutinib. Here are the rest of the active clinical trials I could find:

TRIAL NUMBER
PHASE
DATE FILED
IBRUTINIB WITH
INDICATION
NCT020131281,212/11/2013ublituximabCLL, MCL
NCT0157870734/11/2012v ofatumumabrrCLL
NCT012177491,210/7/2010ofatumumabCLL
NCT01478581211/18/2011nonerrMM
NCT0184172321/24/2013noner Hairy Cell leukemia
NCT019627921,29/27/2013carfilzomibMM

Ublituximab is a new anti-CD20 antibidy from TG Therapeutics and the clinical trial is being run by that company, not by J&J/PCYC. In contrast the ofatumumab trials, which are “active but not recruiting” are sponsored by Pharmacyclics.

Finally, just some tidbits. Ibrutinib presentations recently have included studies in some interesting new indications, particularly MM. There are two MM trials shown here, the second one being run in collaboration with Onyx Pharmaceuticals, whose proteosome inhibitor carfilzomib, has been approved for treatment of rrMM under the name Kyprolis.

I suspect we will see many more such collaborative efforts as the field matures.

Next up we will look at the efforts of two of the compounds seeking to compete with ibrutinib, Gilead’s idelalisib and Celgene’s CC-292.

Stay tuned.

SnapShots, American Society of Hematology Abstracts – Part 3

Part 3. Additional studies featuring small molecule inhibitors for Chronic Lymphocytic Leukemia and other B cell lymphomas.

November 18, 2013

The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx

Lets start with other compounds targeting Btk, PI3K and related kinases in the BCR signaling cascade. In part 1 of this series we looked at Idelalisib, a PI3Kdelta (d) inhibitor, and in part 2 we reviewed Ibrutinib, a Btk inhibitor. In both of those reviews we focused on data from CLL trials, as CLL is the most common B cell malignancy.

Other Btk inhibitors are moving through the clinical development process. Abstract #1630 presents Phase 1 data for relapsing/refractory Non-Hodgkin’s Lymphoma (NHL) patients, including CLL and SLL patients. CC-292 is a covalent inhibitor of Btk developed by Avila and acquired, along with that company, by Celgene. The Phase 1 is a dose escalation/dose schedule trial, with various doses between 125 and 1000 mg given once (qd) or twice (bid) a day. The maximum tolerated dose (MTD) was not reached and AEs were as usual in these trials, with cytopenias being the most common toxicity. The patients enrolled were rrCLL/SLL with high-risk characteristics, as were outlined in Part 1. Of 83 patients enrolled, response data are shown for the 55 efficacy-evaluable patients who had at least a PR (so, 66%). These patients were treated at the highest 4 dose levels: 750 mg qd, 1000 mg qd, 375 mg bid and 500 mg bid (qd = once daily and bid = twice a day). Across these 4 dose groups the ORR = 60% and all responses were PR. Some patients showed evidence of reduction of nodal (lymph node) disease as seen by a reduction in size of the nodes. Abstract #4169 lays out the pharmacodynamic (PD) assays that will likely be used in support of further optimization of this drug’s PK/PD profile. The assays include the familiar Btk autophosphorylation and PLC-g2 phosphorylation assays. Applied to the Phase 1 trial, the PK/PD analysis shows that BID dosing is preferable for CC-292, with 94% target coverage achieved at trough over 24 hours vs 83% target coverage (+/- 17%) at trough with qd dosing. This is important data that has already been applied to further clinical trials underway.

I’m hopeful that optimized dosing will allow CC-292 to achieve higher response rates. Looking beyond lymphomas, Celgene investigators will present preclinical data showing that CC-292 given in combination with a proteosome inhibitor carfilzomib had activity in Multiple Myeloma models (Abstract #682) suggesting other therapeutic areas for the development of Btk inhibitors.

Ono Pharmaceuticals will be presenting Phase 1 clinical data for ONO-4059, a covalent BTK inhibitor (Abstract #676). The trial enrolled 16 high risk rrCLL patients for a dose escalation study (20 – 320 mg). ONO-4059 is shown to have a half-life in circulation (T1/2) of 6 hours. Remarkably, PD analyses shows Btk target coverage of 100% at 24 hours at all doses tested. AEs were typical and not dose limiting. All patients initially responded. ORR is given as 70%, and 1 of 16 patients progressed. Notably, 15/16 patients are reportedly still on treatment. A second Phase 1 study (Abstract #4397), enrolled 14 patients (mantle cell lymphoma n=7, follicular lymphoma n=3, plasmablastic DLBCL n=1, ABC-DLBCL n=1, small lymphocytic lymphoma n=1 and Waldenstrom’s macroglobulinaemia n=1) using the same dose escalation design. This is a complex and difficult group of patients. ONO-4059 induced an initial response in all patients. The ORR (all patients) = 42% and for MCL patient ORR = 50%. AEs are similar to other Btk and P13K inhibitors.

The limited available data suggest that ONO-4059 is highly potent and will be an interesting drug candidate to watch. Preclinical data show synergistic efficacy with anti-CD20 antibody Obinutuzumab/GA-101 treatment, anticipating next steps (Abstract #3069).

Gilead is bringing forward a new Syk inhibitor, now in phase 2 clinical trials. Syk is the kinase just upstream of Btk and is required for Btk activation (see the model shown in Part 1). Early Syk inhibitors from Rigel and Portola were not selective and did poorly in the clinic, as discussed previously: http://sugarconebiotech.blogspot.com/2013/04/syk-inhibitors-continue-to-struggle-in.html. Gilead’s new inhibitor GS-9973 (Abstract #1634) is presented as having 7.6 nM activity against Syk with no other kinase being inhibited below 100nM. The abstract presents early activity data, with most patients responding to therapy within 4 weeks. AEs are mild except for grade 3/4 liver transaminase elevations in a small number of patients. Gilead will give a fuller picture of this phase 2 trial at the meeting. Gilead is developing GS-9973 as a single agent and also in combination with Idelalisib – the latter trial is recruiting patients with diverse types of B cell lymphomas (NCT01796470). Here again we are seeing the development of a rational combination – targeting two key elements of the signaling cascades that support lymphoma proliferation and survival.

Certainly there appears to be room for the development of additional BTK inhibitors, as this space is hardly crowded, and it will be important for companies to control their own compounds, for use in combination studies.

New PI3K inhibitors will report data at ASH, with IPI-145 from Infinity Pharmaceuticals updating a Phase 1 trial in B cell lymphomas, including rrCLL. IPI-145 is a potent PI3Kgamma/delta inhibitor, and impacts signaling through both of these isoforms at a sub-nM KD. The Abstract #677 reveals a maximum tolerated dose of 75 mg bid and also suggests that 25 mg bid is sufficient for target coverage by PK/PD analyses. The PK/PD analysis is shown in abstract #1633. These are the data that support the dosing regimen used in the ongoing Phase 3 clinical trials. The preliminary ORR for the rrCLL patients in the Phase 1 trial (19 patients) = 53%, and it appears there were a high number of discontinuations. Importantly, AEs appear to be in line with other drugs in this class. At the meeting, Infinity will present updates data from treatment-naïve CLL patients who received IPI-145 at 25 mg bid and R/R CLL patients who received IPI-145 at 25 or 75 mg bid.

Amgen is developing AMG 319, a selective PI3Kdelta inhibitor. Results from the Phase 1 dose escalation trial are shown in Abstract #678. Doses were 25 – 400 mg qd. AEs were diverse and included colitis in some patients at the 400mg dose. Ex vivo analysis of the phosphorylation of AKT (downstream of PI3K) showed nearly 100% inhibition 24 hours after dosing at 400 mg. Clinical activity was seen in all patients at all doses, with dose dependent activity observed.

Gilead has a 2nd generation PI3Kd inhibitor in clinical development, GS-9820. In Abstract #2881 dose escalation results from the Phase 1b trial are shown for doses ranging from 50 – 400 mg bid. No MTD was observed, there was no liver toxicity and 9/12 patients showed some response to therapy.

Bayer has a very interesting presentation of phase 2 data with BAY 80-6946, a selective PI3Kalpha/delta inhibitor. This drug is given IV at 0.8 mg/kg. There are notable toxicities (neutropenia, hyperglycemia, hypertension) but the efficacy is impressive at least at this early stage of development. I calculated %ORR and %CR by B cell lymphoma type, as follows (note that the sample sizes are small):



The hypertension AE is being studied in a sub-study of the ongoing Phase 2 trial (NCT01660451).

TG Therapeutics will show early data for TGR-1202 a novel orally available PI3Kdelta inhibitor. Patients have been dosed from 50 – 400 mg qd. DLT was not observed and at the 200 mg dose about half the patients had stable disease and half had progressed. The company plans to present updated results at the meeting.

Sanofi will present phase 2 results of its pan-PI3K inhibitor SAR245409, using the MTD as defined in solid tumor studies. This drug also targets the downstream signaling proteins mTORC1 and mTORC2. Data are presented in Abstract #4170. Focusing just on the CLL patients (n=10) 5 patients have SD, PFS ~ 6 months and 5 patients have a PR, PFS ~ 16.5 months.  That’s not a bad result, except that AEs are notable – all patients have cytopenias, GI complications, and hypotension. An update will be presented at the meeting. Follicular lymphoma (FL) patient data from the same trial is shown in Abstract #86. rrFL patients were given SAR245409 at 50 mg bid until disease progression (PD) or withdrawal. 36% of patients were lost to PD and 7% to AEs. 24 patients were available for evaluation, as they had responses as follows: ORR = 50%, PR = 36%, CR = 7%. For those 28 patients PFS had not been reached at 8 months.

As we can see from this Sanofi drug, moving to a pan-inhibitor and also moving further down the signaling pathways (mTORC1/2) doesn’t necessarily translate to better mono-therapeutic efficacy.

A different approach is seen with the Merck drug MK2206, an allosteric AKT inhibitor. Abstract #2882 presents a very interesting Phase 1 study. There is a 1 week “run-in” with MK2206 alone, sufficient to demonstrate a PD effect. After the first week, MK2206 is given along with bendamustine (B) and Rituxan (R). The MTD is shown to be 90 mg/week. Early results show an ORR = 89% and CR = 22% in the small Phase 1 study (n=9). These results compare favorably to BR alone (9% CR and 59% ORR) in rrCLL patients.

Other PI3K, AKT, mTOR and related drugs are in the pipeline for hematologic malignancies, and this is an area that should evolve quickly.

Next we will look at few promising pathways and drugs, coming up in Part 4.

Targeted kinase inhibition in inflammation & oncology: lots of gambling, and some winners

We’ve had a lot of news in the last 6 weeks from ACR, ASH and the release of clinical trial results. Here’s what we’ve learned in, and some thoughts on what might come next:
1) Rigel and partner AstraZeneca threw craps in the RA game. Syk inhibition is less effective than Jak inhibition in Rheumatoid arthritis (RA), per ACR presentations on Jak inhibitor tofacintinib and clinical trial data released on Syk inhibitor fostamatinib. Whether the difference in efficacy is due to suboptimal dosing of the Syk inhibitor fosta’nib, or reflects distinct biological readouts is a critical question, particularly as fosta’nib has off-target activity on Jak1 and other relevant kinases. It is interesting that Pfizer’s tofacitinib, widely viewed as a pan-Jak inhibitor with potential toxicity issues, has scored approval in DMARD-IR patients, and can therefore be prescribed before biologic therapy.  I’ll admit I did not see this coming and felt tofa’nib would get approval, to start, in TNF-IR patients only. AZN is clearly running the clinical trials needed to show a clean safety profile for fosta’nib, but may now lose out in the marketplace on the basis of efficacy. It remains to be seen how this will play out as Rheumatologists weigh the safety/efficacy profiles of these drugs, but clearly in a “treat to target” regimen, where the target is no clinical sign of disease and no advance in joint degradation, fosta’nib has a tough road ahead. They may yet persevere but it will take a combination of squeaky-clean safety data and a clear demonstration of protection from joint damage. The compound is also moving forward in B cell malignancies (see below).

            We will not learn anytime soon if better Syk inhibitors would be better RA drugs, as Biogen Idec may have lost its bet on Portola’s Syk inhibitor. Biogen has quietly withdrawn its phase 2 clinical trial for PRT062607, aka BIIB057 (clintrials.gov). The withdrawal occurred prior to the recent data coming out on fosta’nib and seems more likely to be related to the specific compound than to the pathway. Looking more widely at drug development in this space, the only other clinical stage compound is the inhaled Syk inhibitor R343, for asthma and other lung diseases, currently in phase 2 and unlikely to provide any insight into the systemic inhibition of the pathway in RA. We may have to wait for clinical readouts in RA following inhibition of Btk – this is the next kinase downstream of Syk – before we understand the utility of targeting this pathway. More on Btk to follow.
2) Jak inhibitors: does three of a kind equal two pair? There are actually four Jak kinases: Jaks 1,2,3 and Tyk2. People used to spend a lot of time discussing the specificity of different Jak inhibitors and the toxicity/efficacy expectations of targeting Jak3 vs Jak2 vs Jak1. The reality is that all Jaks are obligate hybridizers: distinct Jaks hybridize to transduce signals from cell surface receptors. It is very likely that different Jak specificities matter less than we think and that the current crop of Jak inhibitors are more alike than they are different, off target specificity aside. That being said, the Jak inhibitors appear to be poised to reap hefty winnings, in wildly distinct diseases. Novartis’ and Incyte’s ruxolitinib (Jakafitm),first-in-class “Jak2-selective” inhibitor, was approved for use in myelofibrosis in early 2011 and in 2012 is already poised to take in $100MM in sales as patients move onto this drug earlier in the treatment paradigm. The therapeutic rationale of Jak inhibitor use was well understood from genetic analysis of myelofibrosis, and the commercial and clinical validation is now clear, prompting Gilead to recently pay ~$400MM to buy the phase 1 Jak1/2 inhibitor CYT387 along with the rest of YM Biosciences. Other Jak2-selective inhibitors in development include the Sanofi Aventis compound SAR302503, currently in phase 2, and the Cell Therapeutics compound pacritinib. While myelofibrosis is the clear POC arena for these compounds, look for companies to begin moving these into new therapeutic areas as the compounds advance.

 3) Jaks are wild in RA. I’ve already mentioned the success of Pfizer’s pan-Jak inhibitor tofacitinib (brand name Xeljanztm), recently approved for use in RA patients who have an inadequate response to DMARDs such as methotrexate. Other Jak inhibitors being developed to compete in the inflammation area include the Jak1-specific inhibitor GLPG0634 from Galapagos, licensed in early 2012 by Abbott (now AbbVie), who paid $150MM upfront for rights to the Phase 1 compound. It should be noted that GLPG0634 does appear to have a different side effect profile than the other Jak inhibitors, in that no impact on lipid levels were seen, nor signs of anemia and neutropenia. These side effects have been seen in clinical trials of ruxolitinib and with tofa’nib and are generally ascribed to Jak2 inhibition. Given the promiscuous nature of Jak heterodimerization this differentiation remains somewhat surprising. Indeed, Cell Therapeutics, who is developing S*BIO’s Jak2-inhibitor pacritinib in myelofibrosis, claims not to see anemia or thrombocytopenia (another class side effect) in the clinic. Finally, Vertex has moved its Jak3-selective inhibitor VX-509 into phase 2b following decent results in a phase 2a RA trial. No matter how you look at it, the data suggest that hitting any combination of Jaks, or just one if we believe the Galapagos selectivity data, is sufficient for efficacy in RA. This is almost certainly due to the prevalence of heterodimerization, as mentioned, but also due to the sheer number of pathogenic pathways impacted by Jak inhibition, including numerous cytokine and growth factor pathways. Despite the risk of side effects from such broad blunting of the immune system, this approach so far appears to be more efficacious, and at least as safe, as inhibition of Syk. On the basis of efficacy in RA, one might be tempted to move Jak inhibitors into stubborn and complex diseases like systemic lupus erythematosis. That’s another bet altogether but I’ll be looking for those investigator trials!

4) PCI’s Btk inhibitor shows its hand. The recent American Society of Hematology (ASH) meeting was a showcase for Pharmacyclics’ (PCI) and JNJ’s Btk inhibitor ibrutinib, aka ib’nib. This Btk inhibitor produced remarkable efficacy in several B cell lymphomas, including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) and Mantle Cell Lymphoma, the latter being generally viewed as a very intractable disease. The data have been reviewed in detail elsewhere (e.g. fiercebiotech story), but clearly ib’nib has validated Btk inhibition as a therapy with broad application in B lymphoma oncology. The field is still young, with the next closest drug in development Avila’s AVL-292, who reported phase 1b data at ASH. AVL-292 demonstrated efficacy in Non-Hodgkin’s Lymphoma (NHL), CLL, multiple myeloma (MM) and other indications. Avila was acquired by Celgene earlier this year, further highlighting the interest in Btk inhibition in oncology. Ib’nib and AVL-292 covalently bind to the kinase domain of Btk, forming an irreversible bond that prevents substrate from accessing the active site of the enzyme. Historically, covalent inhibition has been associated with off-target toxicity, as it is possible for the drug to link irreversibly to unwanted targets. Happily, this does not appear to be an issue with this new class of covalent inhibitors, and toxicity is generally considered mild. Regardless, non-covalent inhibitors are being developed by several companies, perhaps with the goal of differentiating from the leading compounds. The CGI compound GDC-0834, now held by Genentech, in a non-covalent active site inhibitor under development for inflammatory disease, as is the Roche compound RN486.  Given the current status of the Syk inhibitor fosta’nib in RA, it will be interesting to see if these companies stay the course, or move their inhibitors onto new disease targets. It was the success of Syk inhibition in early RA and B cell lymphoma trials that stirred interest in Btk, and the field will respond accordingly to any new Syk inhibitor data.

This is a lot of information to absorb, but it stimulates the obvious question: What’s next? Here are just a couple of thoughts:

- What is considered safe and efficacious today will change tomorrow. As combination therapy takes hold in B cell oncology, additive toxicity may become problematic. If we consider the obvious combination of a Btk inhibitor with other kinase inhibition, or with biologic therapy, the safety/efficacy profile of these compounds will evolve. This is even more true in RA, where toxicity will drive physicians away from drugs.

- Escape is possible (or inevitable). As has already been described in myelofibrosis, patients needing chronic therapy may select for drug resistance. In myelofibrosis, such resistance is associated with the recruitment of other Jaks to take over for Jak2. Having a well-stocked armory may allow continued control over the disease, even as signaling pathways shift – in the context of B cell lymphomas this may mean Syk inhibitors, Btk inhibitors, PI3K inhibitors, mTOR inhibitors, in succession or in tolerable combination therapies.

- In RA the success of tofa’nib heralds a new wave of oral medications that can challenge biologic therapies, in particular the anti-TNF biologics. This is no surprise, and it will be of considerable interest to watch how clinical practice evolves. I’m hoping that diligence is being applied to the collection of samples for analysis of response and non-response in patients receiving the new, targeted orals as it will be fascinating to understand why some patients fail while some succeed – something not yet adequately understood in RA.

- Finally its important to remember that “success” in RA still means that most patients fail to reach ACR 50 and ACR 70 scores, suggesting that they are continuing to experience disease despite treatment. Until these numbers come up, perhaps in the context of personalized medicine, we cannot declare that the work in RA is done. We note in passing that there are a plethora of diseases that could benefit from these new kinase inhibitors, and expect to see their use tested more widely.

A bit more news from ASH 2012

Following up on our Immunotherapy post, here is a link to The In Vivo blog’s writeup of the deal struck between UPenn and Novartis to commercialize the CAR (and specifically CART19) technology that we discussed in our last post:

http://invivoblog.blogspot.com/2012/12/alliance-deal-of-year-nominee_418.html

In Vivo highlights this deal as one of its “Alliance” nominees of the year, and it illustrates the race going on among big pharma and biotech to tie up academic assets at an early stage. Indeed other big players tried very hard to secure this technology.

The Btk inhibitor Ibrutinib made its own splash over the last few days at ASH, including startling clinical data in CLL and MCL:

here’s the CLL press release (via FierceBiotech):

http://www.fiercebiotech.com/press-releases/new-investigational-agent-targets-gene-signaling-pathways-improve-therapeut

and the MCL story off the JNJ website:

http://www.jnj.com/connect/news/all/follow-up-results-of-phase-2-study-of-investigational-agent-ibrutinib-in-relapsed-refractory-mantle-cell-lymphoma-presented-at-american-society-of-hematology-annual-meeting

Taken together you have to wonder how these competing technologies – orally dosed small molecule kinase inhibitors v ex vivo T cell manipulation – will play out. Add a big dose of new biologics to the mix, and its clear that the field of B cell lymphoma treatment will become a very interesting scientific, clinical practice and commercial landscape.