Category Archives: Ibrutinib

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

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.

Combination therapies for B cell lymphoma, part 2

Combination therapies for B cell lymphoma: CC-292 and idelalisib.

Lets begin by recapping where we were yesterday. We reviewed ibrutinib, the clear frontrunner in the race to bring new targeted oral therapies to B cell lymphoma physicians and patients. Ibrutinib is being developed by Pharmacyclics and Johnson & Johnson’s (JNJ) Janssen division, and was recently approved for the treatment of MCL. The drug is moving forward in many clinical trials spanning the B cell lymphoma space, and most of these trials are done in combination with other therapeutics, notably the antibody therapy rituximab (Rituxan). None of the trials are being run as collaborative efforts with other companies with one exception, a collaboration put in place with Onyx (now part of Amgen). None of the combinations are wholly owned by Pharmacyclics (PCYC) and JNJ. The interesting question of how best to tackle the cost of very expensive combo therapies in the oncology marketplace was raised.

Gilead (GILD) has developed the very exciting PI3Kdelta inhibitor, idelalisib (access to a recent review is here). Idelalisib data generated at lot of buzz at the American Society of Clinical Oncologists meeting (ASCO) and at ASH. While generally considered somewhat inferior to ibrutinib as a monotherapy, the phase 3 data in combination with rituximab was striking. The trial was run in rrCLL patients who had failed prior therapies (rituximab or chemo), so these are patients quickly running out of options. The ORR was 81%, but what was really impressive was the impact on PFS and OS. At 24 weeks twice as many patients were progression free in the idelalisib plus rituxumab arm (95%) versus the rituximab alone arm (46%). We’ll have to see how this therapy holds up, and we can expect interesting data at the 2014 conferences.

But back to our question for 2014 and beyond: how will combination therapies continue to develop for the treatment of lymphoma? Lets look at Gilead’s active clinical trials for idelalisib – note that some of these trials have already read out results.

Trial Number
date filed
NCT01732913311/14/2012rituximabrr iNHL
NCT0120393029/15/2010rituximabuntreated CLL, SCL
NCT01980875311/5/2013rituximabuntreated CLL
or chlorambucilÿ
NCT01732926311/14/2012bendamustine/rituximabrr iNHL
NCT01980888311/5/2013bendamustine/rituximabuntreated CLL
NCT0108804811/12/2010RituximabrrCLL or rrMCL or rr iNHL
Rituximab + Chlorambucil
Lenalidomide + Rituximab

At first glance this looks a lot like the list of trials listed for ibrutinib, and it is very similar. We see multiple combo trials with anti-CD20 mAbs (rituximab, ofatumumab), and several trials with Celgene’s lenalidomide (Revlimid), approved for MM. Again the choice of lenalidomide is interesting. The combination makes good sense biologically – lenalidomide should impact cells lodged in the bone marrow, where they would otherwise be resistant to anti-CD20 or idelalisib therapy. The question is how well is this combination therapy tolerated. The other interesting observation is that there are a fair number of trials in which the partner therapy is a chemotherapy (fludarabine, chlorambucil, bendamustine). Now these are all careful targeted to specific lymphomas in the last trial listed, NCT01088048, and you can look at the details here. I think this suggests that in addition to the high impact rituximab combinations, GILD is banking on seeing good efficacy in combination with standard chemotherapies. If so this will give the company an effective marketing and pricing edge.

Finally, and sensibly, we see a clinical trial in combination with Gilead’s own Syk inhibitor GS-9973. Gilead has advanced this inhibitor while also conducting a well publicized hunt for a BTK inhibitor to license, apparently without luck (and really, there just aren’t many good ones). The idea here is to knock out the Syk signaling to BTK, thus mimicking the effect of ibrutinib, in combination with eliminating PI3Kdelta signaling. If the combo is synergistic, and (importantly) well tolerated, GILD may be sitting on a unique therapeutic option. Again thinking of the marketplace, this could provide leverage with physicians and payers, although no one is suggesting that Gilead won’t price a combo as high as possible, as shown by the recent pricing of its HCV cocktail – and that drug at least can induce outright cures.

This brings us to Celgene, who is attempting to build combination therapies for lymphoma that it can control. Celgene is well behind ibrutinib in their development of CC-292, acquired with the Avila deal. Recently however they have adjusted the dosing schedule (to twice a day: bid) and are seeing reasonable ORRs between 55 – 67% depending on dose, as reported at ASH. The bid dosing regimens produced sustained responses through 7 months.

What is so interesting about the Celgene program is shown in the following table.

Trial Number
date filed
CC-292NCT017665831b10/29/2012lenalinomiderr NHL
CC-292NCT01732861111/14/2012lenalinomiderr CLL, SCL
CC-292NCT01744626112/5/2012rituximabrr CLL, SCL
AVL-292NCT0135193515/10/2011nonerr NHL, CLL, WG
lenalinomideNCT014006851,2April/May 2011bendamustine/rituximabCLL
lenalinomideNCT0193800139/5/2013rituximabrrNHL, rrFL
lenalinomideNCT0119957528/31/2010rituximabrr CLL
lenalinomideNCT0155677633/14/2012nonehigh risk CLL

What we see here is a nice focused effort on bringing forward CC-292 with perhaps lenalinomide. I don’t know the regulatory hurdles imposed since the withdrawal of lenalidomide from a CLL trial earlier this year (but please comment if you do), and so the issue may be moot, but the idea is a good one – to rationally develop combinations that are wholly owned.

We can make some predictions.

JNJ will buy a clinical stage compound suitable for further development with ibrutinib. This could be an antibody targeting B cell lymphoma antigens (CD20, CD22, CD19, etc) or another small molecule asset.

Celgene will make similar moves but may take assets at a slightly earlier stage, maybe IND ready or Phase 1.

Gilead will continue development of its Syk inhibitor, but I suspect will also license clinical stage assets in order to diversify around idelalisib.

Assuming success in the early stage studies in relapsed/refractory patient populations, Gilead will aggressively position idelalisib for use with chemo in treatment naive patients.

If you have different ideas feel free to send those along. Next there will be just a short take on Abbvie, as they are on a slightly different course.

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, 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:

NCT01980654210/24/2013rituximabuntreated FL
NCT0152051921/25/2012rituximabhigh risk CLL, SCL
NCT0161109035/15/2012rituximab/bendamustinerrCLL, rrSCL
NCT0177684031/24/2013rituximab/bendamustineuntreated MCL
NCT01479842111/1/2011rituximab/bendamustinerr DLBCL,MCL,iNHL
NCT0188687236/24/2013noneuntreated CLL
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:

NCT020131281,212/11/2013ublituximabCLL, MCL
NCT0157870734/11/2012v ofatumumabrrCLL
NCT0184172321/24/2013noner Hairy Cell leukemia

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.


ASH13 previews

Part 8.   ABT-199
Part 7.   CAR-T tech                        

Part 6b. new targets for Myelofibrosis           

Part 6a. Jak inhibitors in Myelofibrosis                       

Part 5.   Biologics for Non-Hodgkin Lymphomas              

Part 4.   New & noteworthy: CLL etc             

Part 3.   Btk and PI3K inhibitors for CLL      

Part 2.   Ibrutinib                              

Part 1.   Idelalisib

pre-ASH post on ADC technology:  here                         

SnapShots from the 2013 American Society of Hematology Abstracts – PART 2

Part 2. Small molecule BTK inhibitor Ibrutinib in the treatment of Chronic Lymphocytic Leukemia (CLL).
November 15, 2013
The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at
Note that I’ve defined most of the terms we are using in Part 1, so please refer to that section for help with any abbreviations. In Part 1 is also some background on CLL and the signaling pathways downstream of the B Cell Receptor, which are targeted by these drugs. Finally, I introduced the patient populations typically encountered in CLL clinical trials.
So now we come to the Btk inhibitors and specifically to Ibrutinib, the Pharmacylics compound partnered with the Janssen arm of Johnson & Johnson. This soon-to-be blockbuster drug has been approved for the treatment of Mantle Cell Lymphoma (MCL) at an anticipated cost of 150,000 USD/year.
As mentioned in Part 1, CLL is the most common of the B cell lymphomas, so it is of keen interest to see how Ibrutinib performs in that patient population, especially given the efficacy seen with Idelalisib from Gilead.
Abstract #675 presents data from a 40 patient phase 2 trial in which Ibrutinib (IBRU, 420mg/day) was given with Rituxan anti-CD20 antibody (Rtx). The trial is notable for the inclusion criteria that enrolled patients only if they had high-risk disease: del(17p) or TP53 mutation (treated or untreated), PFS < 36 months after frontline chemotherapy + anti-CD20 treatment, or relapsed CLL with del(11q). Most patients responded well (see the table), very few patients were lost to followup and AEs were well tolerated.
Abstract #525 presents data from a small phase 1b trial in high-risk rrCLL/SLL patients (SLL is a form of CLL called small lymphocytic lymphoma, in which most of the cancer cells are located in lymph nodes). In this trial patients received IBRU + Rtx + B (bendamustine, see part 1). The response rate was very high (see the table) although the authors do note that 30% of patients eventually discontinued treatment, 10% due to progressive disease. Responses appeared to be independent of specific high-risk cytogenetic factors. Grade 3 or higher AEs were GI related, cytopenias (including 6.7% febrile neutropenia), and infections. The data from these 2 abstracts are shown below, and compared to published data (Byrd et al. 2013 NEJM 369:32-42). Note the caveats described above when reading these response percentages.
It is a little hard to directly compare these results with the Idelalisib data, partially reproduced here from Part 1, with one correction to the table (column 3: DOT = median duration of treatment):
It is tempting to conclude that the response rates with Ibrutinib are a little higher, but such comparisons will required much larger data sets. At the moment it is fair to say that these therapeutics both provide superb novel options for rrCLL patients.
Returning to Ibrutinib, there will be additional data from monotherapy studies shown at ASH. Abstract #4163 reports on an extension study of Ibrutinib monotherapy in treatment-naive CLL and in rrCLL patients. An important parameter of this study is that it included treatment-naive (likely newly diagnosed) patients; the data for discontinuation due to disease progression (PD) shows that nearly all of these early-treated patients maintain a response for at least the DOT.
After 2.5 years, 76% of this patient population was still alive, an impressive number.
Abstract #673 also examined the impact of Ibrutinib monotherapy, in this case in elderly patients with or without the del(17p) cytogenetic factor indicating high risk for progression. In this study there was a significant difference in the PR percentage, with 81% of patients with wild-type 17p responding while only 53% of patients with a deletion of 17p responded (p = 0.04). This suggests more (or larger) studies will be required to sort out the best patients for Ibrutinib therapy.
A very nice study will be presented by investigators at The Ohio State University (Abstract # 2872). Using multivariate analyses of patient response, progression and survival, these investigators compare Ibrutinib monotherapy to checkpoint-inhibitor therapy (alvocidib, dinaciclib, or TG02) to “other” therapy, in del(17p) rrCLL patients. “Other” is unfortunately not identified, but must include standard-of-care, which would normally be chemotherapy plus Rituxan. Here is a snapshot of the data at 24 months (the analysis is beautiful and I won’t reproduce their graphs here):
These data really drive home the importance of the new therapeutics and new therapeutic combinations, where we are seeing improvement in PFS.
There are a swarm of newer small molecule drugs coming up, and these will be covered in Part 3.

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 ( 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:

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):

and the MCL story off the JNJ website:

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.