Monthly Archives: December 2012

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 Biogen has quietly withdrawn its phase 2 clinical trial for PRT062607, aka BIIB057 ( The withdrawal occurred prior to the recent data coming out on fosta’nib and seems more likely to be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.

Immunotherapy update


We start with breaking news from ASH 2012 ( where my old friend and colleague Carl June from University of Pennsylvania has presented remarkable data on the use of gene-modified T cells to attack and clear CD19+ acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL). In addition to the transduction with a chimeric antigen receptor to CD19, the T cells also contain the CD3zeta signaling domain and the 4-1BB costimulatory protein. The work has been well described in the literature (eg. Porter et al. 2011. NEJM. 365: 725-733). Basically a viral vector is used to string together the requisite pieces for transduction of the isolated patient T cells, which are then returned to the patient where they undergo expansion in the presence of antigen (in this case the abundant CD19 present on both lymphoblastic and normal B cells), under the potent influence of CD3 signaling and 4-1BB costimulation.

What has caught the attention of the public is the story of a pediatric patient, nearly lost, having failed all current therapies, and too ill from chemo to receive any more rounds. The story of her remarkable recovery after treatment is compelling and moving – this work represents a dramatic step forward in immunotherapeutic treatment of an advanced cancer.

So lets back up a bit. Cancer immunotherapy can be defined as medical mobilization of the immune system to attack tumor cells in the hope of clearing the tumor in a way that establishes long term protection, ie. tumor immunity. The field is advancing rapidly, with headline grabbing news from ASCO last summer on the use of anti-CTLA4 and anti-PD1 or PD1-receptor antibodies to unleash the immune system – CTLA4 and the PD1 pathway down-regulate immune responses, so by blocking these molecules the immune system goes into overdrive. You can achieve a similar effect by signaling through pathways that upregulate the immune response, like 4-1BB or OX40. An alternative way of stimulating anti-tumor responses is to vaccinate the patient with tumor antigens. This is the strategy behind Provenge, which uses tumor antigen loaded dendritic cells to activate the immune response to treat prostate cancer.

To date, none of the classical immunotherapy approaches has been broadly effective, that is, they help subsets of patients, maybe 25% or less obtain real relief from disease.

Carl June’s approach has reported about a 50% success rate in the small number of patients treated, and this makes sense, since they have combined a tumor antigen specific approach (the CD19-specific chimeric antigen receptor) with immune stimulation through 4-1BB. Its worth noting that the immunotherapy community has been calling for such combo therapies, and many companies are working hard to figure out what combinations make the most sense, and for which cancer types. One mainstream idea is to combine two different immunomodulators, like anti-CTLA4 antibody plus anti-PD1 antibody.

Back to the pediatric patient – a few notes to get us grounded: First, the patient very nearly died from a massive acute immune response when she received the engineered T cells. This “cytokine release syndrome” was triggered by a massive release of IL-6, a potent pro-inflammatory cytokine. She was rescued by a dose of Actemra (aka tocilizumab, an antibody to IL-6). Second, the patient is likely to remain highly immunosuppressed, and its unclear for how long – perhaps for a long time. This is because all of her CD19+ cells, not only the tumor cells but also normal B cells, were depleted, and its possible that enough modified T cells will remain to deplete any normal B cells that develop.

On balance the results are highly encouraging, and have attracted investment from Novartis, which hopes to commercialize the technology

If we take all this together – remarkable success using a combination therapy technique with potent costimulation, but significant challenges in terms of toxicity and potential for immunosuppression, we can ask ourselves what the next steps might look like.

First and foremost the concept of combining a stimulatory boost to the immune system in the context of tumor vaccination should be pushed hard – this may be the simplest way to achieve similar results without having to remove and genetically alter patient cells.

Second the concept of combining immune modulators should be approached with care, as the potential for runaway and dangerous hyper-immune responsiveness is very real (readers will remember the infamous TeGenero anti-CD28 antibody clinical trial). Clinical trial evolution in this are in encouraging, as we are seeing the development of multi-arm adaptive trial designs that allow single and combo agent arms that can advance or be dropped on timely efficacy/toxicity readouts.

Third, in the context of ALL and CLL, the lymphoblastic leukemias treated by Carl June’s team, additional progress will come from the development of highly selective kinase inhibitors – and these too may eventually see use in combination with the therapies discussed above.

Finally its important to remember the tumor specific nature of these advances: each medical advance tackling very specific diseases. It is in this regard that this newest approach may be most important since theoretically one might target other cancers simply by redesigning the chimeric antigen receptor to recognize different tumor antigens. Indeed, this technology is already being developed.

We will update as new results come in.

Sugar cones: perfect content and analysis

Introducing the Sugar Cone Biotech Blog

When we consider sources of biotech and pharma intel and insight, we see striking differences in style. Lets look at two very common types of content, then offer an alternative.

Style 1: Wafer Cone Analysis. Short on insight, full of reposts and recycled story lines. This is the most common form of biopharma “news” and clogs the web with redundant traffic. Apt to show up uninvited in your inbox, the Wafer Cone wraps just enough fluff around a bit of information to give the appearance of substance while adding nothing of its own. Cheap or free, of little value regardless.

Style 2: Waffle Cone Analysis. Always too much of a good thing, layering heavy “added value” to otherwise straightforward analysis. Bloated and expensive, the Waffle Cone is the speciality of large consulting houses that churn out commercial analyses of technology development, of clinical stage therapeutics, of medical practice and of the competitive landscape. Characteristics include broad consensus with client’s existing assumptions, a ‘tell ’em what they want to hear’ approach to analysis, and the selective use of supportive quotes from KOL’s. Add a sprinkle of the latest business buzz words and you’ve got it. And its going to cost you plenty.

These are obviously extremes on the spectrum that spans biopharma news, blogs and consulting.

I’d like to define a better approach:

Sugar Cone Analysis. A problem-driven approach designed to capture essential data and provide critical insight to enable action. No more, no less. We track critical trends in drug development, medical research and practice, translational efforts, clinical trial design, and breakthrough technologies. All posted here for open commentary. There are already many excellent science and business blogs that capture content (see who we follow), but we push analysis to generate hypotheses: what will or should happen next. And we’ll check back in to see how our hypotheses fare in the real world.

Through Clarion Bio Consultancy we offer our clients transparent, critical data analysis and its’ impact on the questions at hand. We specialize in helping biotech and academic groups build out research programs and investment clients build out companies. We focus on creating research plans the drive asset momentum, staging programs for investment, and critical assessment of existing programs. We ensure upfront that the questions, underlying assumptions and timelines are clear. Iterative communication ensures alignment on goals and progress. Outcomes and recommendations are presented without prejudice, allowing confident and crisp action.

Contact us for more information:

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