Category Archives: Rheumatoid arthritis

Brodalumab for Psoriasis – what a mess

Amgen, Astra Zenenca, biologics, IBD, IL-17, IL-23, immunology, inflammation, autoimmunity, fibrosis, inflammatory bowel disease, Johnson & Johnson, lupus, monoclonal antibodies, Novartis, psoriasis, Rheumatoid arthritis, SLE

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Let’s agree that the headline “Suicide Stunner” – penned by John Carroll for FierceBiotech – can never auger anything but very bad news, and never more so then when it is used to describe clinical trial results. Released on the Friday before the long US holiday weekend, bookended to the announcement of positive news on it’s PSCK9 program, Amgen stated that it was walking away from an expensive co-development program with AstraZeneca, basically washing it’s hands of the anti-IL-17 receptor (IL-17R) antibody brodalumab because of suicidal tendencies and actual suicides that occurred in the Phase 3 psoriasis trials. Brodalumab is under development for the treatment of plaque psoriasis, psoriatic arthritis and axial spondyloarthritis. Amgen stated that they believed that the approval label for brodalumab would contain warning language regarding suicide risk, and this would limit the success of the drug. By using such language while pulling the plug Amgen has essentially put AstraZeneca in the position of having to prove to the FDA that there is no suicide risk.

Holy crap.

Note here that we are not talking about a psychiatric drug, where the risk of suicide might be the consequence of trying to re-align an aberrant central nervous system. Instead we are talking about a drug that targets autoimmune disorders by blocking the action of T cells. This is not a biology linked to psychiatric health, at least not as we understand it today (more on this later).

Backing up: in April 2012, AstraZeneca and Amgen announced a collaboration to jointly develop and commercialize five clinical-stage monoclonal antibodies from Amgen’s inflammation portfolio: AMG 139, AMG 157, AMG 181, AMG 557 and brodalumab (aka AMG 827). The drivers for the collaboration were Amgen’s biologics expertise, the strong respiratory, inflammation and asthma development expertise of MedImmune (AstraZeneca’s biologics division), AstraZeneca’s global commercial reach in respiratory and gastrointestinal diseases, and the shared resources of two experienced R&D organizations

Under the terms of the agreement, AstraZeneca paid Amgen a $50MM upfront payment and the companies shared development costs. The breakout was as follows: AstraZeneca was responsible for approximately 65 percent of costs for the 2012-2014 period, and the companies now split costs equally. Amgen was to book sales globally and retain a low single-digit royalty for brodalumab. Amgen retained a mid single-digit royalty for the rest of the portfolio with remaining profits to be shared equally between the partners.

It gets even more complicated. Amgen was to lead the development and commercialization of brodalumab (and AMG 557, see below). Amgen was to assume promotion responsibility for brodalumab in dermatology indications in North America, and in rheumatology in North America and Europe. AstraZeneca was to assume promotion responsibility in respiratory and dermatology indications ex-North America. AstraZeneca remains responsible for leading the development and commercialization of AMG 139, AMG 157 and AMG 181. We’ll touch on these other antibodies at the very end.

Back to brodalumab. On balance, Amgen was on the hook for the development and commercialization costs, direct, indirect and ongoing, for dermatology indications in the US and also rheumatology, which in this case refers to psoriatic arthritis and axial spondyloarthritis. On the other hand, AstraZeneca was on the hook for commercialization in respiratory indications worldwide, and dermatology ex-US. This is interesting because brodalumab failed in its’ respiratory indication, moderate to severe asthma, and failed late, in a Phase 2b patient subset trial. So, on balance, much of the overall development cost seems to have shifted back onto Amgen over time (this is not to say that the companies would not have changed terms mid-term, they may have).

Two weeks ago I chaired a session on “Biologics for Autoimmune Disease” at the PEGS conference on Boston. In my opening remarks I used psoriasis as an example of an indication in which we were making clear and important progress, including with IL-17-directed therapeutics. Indeed, psoriasis is now a “crowded” indication commercially, with antibodies and receptor fusion proteins targeting the TNFs, IL-6, IL-12, IL-17, and IL-23 pathways all showing at least some activity. Notably, IL-17 and IL-23 targeting drugs appear to offer the greatest benefit in clearing psoriatic plaques. These pathways intersect in myriad ways, not all of which are well understood. This cartoon shows the effector cytokines and the receptors are expressed by diverse cell types, including dendritic cells, macrophages, T cells, and keratinocytes in the dermis.

IL-17 and friends

In simplistic terms, IL-6 triggers IL-12 and IL-23, and IL-23 triggers IL-17. As mentioned, the IL-17 and IL-23 targeting agents have great efficacy in psoriasis. Amgen and AstraZeneca were preparing an NDA (new drug application) for FDA submission based on results from three large Phase 3 studies. Here are the listed Phase 3 programs for brodalumab:

broda 1

I suppose those Phase 3 studies in psoriatic arthritis will now be tabled or transferred to AstraZeneca. For the sake of completeness here are the earlier studies:

broda 2

Certainly the clinical program was a robust one. So, what went wrong? Amgen R&D head Sean Harper summed up Amgen’s thinking about the suicide issue in the press release: “During our preparation process for regulatory submissions, we came to believe that labeling requirements likely would limit the appropriate patient population for brodalumab.”

The news aggregator and commentary website UpdatesPlus had this to add, questioning whether this result was “bad luck, bad target or victim of brodalumab’s efficacy: Despite high efficacy in Phase 3 studies, whispers of suicidality associated with brodalumab started to emerge at AAD.  At the time Amgen suggested this was related to disease however the company refused to comment on total rates and whether events were seen across arms … The question is whether Amgen is being hyper-cautious or whether the risk of suicidality is especially concerning.  Questions also emerge around the cause of risk – is this a spurious cluster of events unrelated to brodalumab; is suicidality perhaps related to relapse from the excellent efficacy associated with brodalumab after withdrawal (remember most patients exhibited at least PASI 90 on treatment but durability was very poor upon withdrawal); or perhaps suicidality is related to blocking the IL-17RA (note that suicidality has not to our knowledge been reported for the IL-17A ligand mAb Cosentyx) … One final point is whether regulators will now reevaluate suicide risk of IL-17 related molecules as a class – much greater clarity of brodalumab data is required to make a judgement.” That’s quite a nice summary from UpdatesPlus.

FierceBiotech’s report added “AstraZeneca would face some stiff competition if it decides to move forward solo on the drug. Novartis is already well in front with its IL-17 program for secukinumab, approved in January as Cosentyx. Eli Lilly has also been racking up positive late-stage studies for its IL-17-blocking ixekizumab, trailed by Merck’s MK-3222 and Johnson & Johnson’s IL-23 inhibitor guselkumab.”

Still, brodalumab demonstrated remarkable efficacy in psoriasis – Amgen and AstraZeneca went so for as to include a PASI100 score in one of their trials, meaning 100% clearance of psoriatic plaques, and the drug would have shown well against the best of breed, which today is likely Novartis’ anti-IL-17 antibody secukinumab. It is crowded space however, with antagonists targeting multiple nodes in the IL-17/IL-23 axis, alongside the biologics mentioned earlier.

Here is the current landscape from CiteLine (including brodalumab):

CiteLine

All in all, a tough crowd, and one that Amgen likely felt it could not face with a compromised label.

Let’s go back to the question posed above: bad luck, bad target or victim of superior efficacy? “Bad luck” suggests a statistical fluke in the data, potentially caused by the generally higher rates of suicidal tendencies observed in the moderate to severe psoriasis patient population. “Victim of superior efficacy” is in a sense a related issue, since the suggestion is that the loss of responsiveness to the drug, or a relapse, triggers a suicidal response as plaques return. Neither of these statements is really formulated as a hypothesis, and it doesn’t matter, as we don’t have the actual trial data yet with which to perform hypothesis testing.

“Bad target” is the most worrisome suggestion, and this can be formulated as a hypothesis, formally, the null hypothesis is that targeting the IL-17 receptor does not cause suicidal tendencies. Unfortunately, we still can’t test the hypothesis, and it seems likely that having the actual data won’t really help, that is, the study is probably not powered to reject that particular null hypothesis. So, what do we know? A few things, as it turns out.

First is that a link between the immune system and the nervous system is well established, although much of the focus has been on the role of neuronal enervation on immune responses. But clinically at least, the picture is muddier than that. High dose IL-2 can cause neurotoxicity, even hallucinations, according to Dr. Kathleen Mahoney, an oncologist at Beth Israel Deaconess and the Dana Farber. But what is really interesting is what else happens: “Some IL-2 treated patients can have odd dreams, really crazy dreams, and they last for weeks after treatment, long past the time when IL-2 would still be present in the body”, Dr. Mahoney said. Interferon alpha therapy is associated with pathological (severe) fatigue and also depressive symptoms that develop after 4–8 weeks of treatment. Of note, preventive treatment with anti-depressants, in particular serotonin reuptake inhibition attenuates IFN-alpha-associated symptoms of depression, anxiety, and neurotoxicity. Some researchers have suggested (controversially) that anti-TNF antibodies can control depression. Such anecdotal clinical observations suggest that we really do not yet understand the immune system connection to CNS activity.

On the other hand, antagonism of cytokine activity, and particularly of the cytokines IL-6, IL-17 and IL-23, has not been associated with neurological symptoms. For example the anti-IL-6 receptor antibody tocilizumab has shown a positive impact in rheumatoid arthritis patients quality of life scoring, which includes fatigue, anxiety, depression and a number of other factors. More to the point, the anti-IL-17 antibody secukinumab, that targets the IL-17 ligand (rather than the receptor), has not shown a link to suicide.

Clearly more data are needed, and it would not be surprising if the FDA began a drug class review if the data in the brodalumab trials warrant. They could cast quite a wide net given the complexity of this pathway, which overlaps with IL-6, IL-12 and IL-23. This casts a pall over the dermatology and particularly the rheumatology landscape, which is really waiting for novel therapeutics to move them successfully into new and important indications such as lupus and Type-1 Diabetes. The IL-17/IL-23 axis was to be that next great hope, and with luck we will still see these drugs moving out of their core indications of psoriasis and inflammatory bowel disease into new indications.

One last thing.

Those other antibodies – where are they now? A quick scorecard:

snapshot

It is readily seen that none of these are beyond early Phase 2, so it’s fair to say that the rest of the Amgen/AstraZeneca partnership has a long way to go. I, for one, wish the ongoing collaboration the very best of luck, particularly in the lupus indications, where we can really use some good news.

stay tuned.

Cautionary Tales from Human Microbiome Frontier

gut microbiome, H pylori, inflammatory bowel disease, Rheumatoid arthritis

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The concept of symbiotic microbiomes (yes, plural) influencing our health seems now, in hindsight, to be obvious, and the fact that the science has caught up to the folk medicine has all sorts of people buzzing. Some of the buzz is well informed (see below), some not, but all in all we are making progress understanding a few of the ways in which our vast mucosal environment interacts with the outside world. At the same time its fair to say that we know very little yet, and have a long way to go. Some recent findings drive this point home.

We can think of the frontier mentioned in the title in two ways. One, maybe obvious, is to think about the frontier of science, as this is where we find ourselves as the technology to do the some of this work was not widely available until recently (e.g. affordable deep sequencing). More subtly, we can think of the mucosal environments – oral, pulmonary, digestive, excretory, reproductive – as frontier environments where self interacts with non-self in an exploratory manner, that is, not confrontational a priori. There is a lot at stake: pathogen recognition and defense, nutrient uptake, metabolic regulation, waste disposal, on and on.

It makes sense that there are tightly controlled and very complex rules of engagement. The new findings I want to review touch on some of these rules and suggest layers of control and organization that we really don’t understand yet. Secondarily, we can study these systems with an eye on drug discovery.

Back to back papers in the December 16/26 double issue of Nature identify a critical pathway for the development of regulatory T cells (Tregs) in the gut. Data from the Ohno lab in Japan and the Rudensky lab in NYC paint broadly similar stories of the role of the specific commensal bacteria in fostering Tregs (see references 1 and 2, below). Both papers show that the fatty acid butyrate stimulates the development of Tregs. This in itself is not a new finding. Butyrate is a major energy source in mammalian metabolism and not surprisingly it’s production is driven by commensal bacteria, notably the abundant Clostridia class of bacteria (some species within Clostridia are pathogenic, but that’s a different story). Again, it’s not particularly surprising that one of the most abundant mammalian commensals gives off good vibes in the form of fatty acids that support a quiet immune system. The papers differ in some curious ways, in particular, the Ohno paper states that the induction of Tregs was limited to the gut, while the Rudensky papers highlight Treg production in the lymph nodes and spleen, but not the colon. Regardless, the reason these papers made it into Nature is that they identify the mechanism by which butyrate induces Treg differentiation, and this is by inhibiting a histone deacetylase (HDAC IIa) thereby allowing for the specific acetylation (and therefore activation) of DNA elements that support Treg differentiation, notably at the FoxP3 promoter and enhancer.

Cool.

But before we all run out and start swallowing a bunch of butyrate capsules and subject ourselves to butyrate enemas (yes, both are available), lets be clear about what these papers are saying and what they are not saying. First, we are dealing here with inbred mouse strains on carefully defined diets. Translation of the results to outbred humans on diverse diets is not so straightforward. That said, the results support eating a high fiber diet, which will yield plenty of butyrate and related fatty acids. Second, the papers agree on one thing very specifically, which is that the generation of Tregs in the gut is a local phenomena, specific to the colon (large intestine, south of the caecum). This makes sense of course, as that is where the Clostridia are cranking out the fatty acids. The application of these findings to colonic disease, notably Ulcerative Colitis, is worth exploring. But broadening the scope to include general health, well-being and immune serenity is not warranted – despite the pile on by the Supplements and Wellness Industries.

A very different story just came out in PNAS (reference 3), and this one concerns the response of different populations to a gut pathogen found in the gastric mucosa (lining of the stomach). The bacterium Helicobacter pylori is found in about half of the human population worldwide. H. pylori is a causative agent of gastric adenocarcinoma in a small percentage of the people who are infected, less than 1%, although hotspots are known. One such hotspot was studied by a team from Vanderbilt who found that the higher incidence of H. pylori induced precancerous inflammation correlated with the presence of a European strain of the bacterium infecting an Amerindian population in Columbia. In contrast, an African strain of H. pylori infecting the descendants of African slaves nearby did not cause inflammation and cancerous lesions. The investigators conclude that H. pylori is mainly pathogenic when it occurs in a population distinct from that with which it co-evolved. So, a fine line between commensal and pathogen is drawn.

Ok, one more.

The gut microbiome has been implicated in the development of Th17 effector T cells, at least in mice. This is interesting in light of where we started, with the generation of Treg cells, since in some ways Tregs and Th17s are the result of different developmental pathways that T cells take. Note that the first two studies reviewed were focused on extrathymic (in that case, colon-specific) Treg generation. Mice that are raised with no pathogens in their environment, including their food, which is irradiated, don’t develop very many Th17s as a percentage of the total T cell population. Since Th17 cells are associated with diseases (including rheumatoid arthritis (RA), psoriatic arthritis (PA), psoriasis, inflammatory bowel disease) it seems reasonable to ask whether a Th17 inducing microbiota is linked to any particular disease. Littman’s lab at the Rockefeller in NY has done exactly that (reference 4). Newly diagnosed RA patients were found to carry the intestinal bacterium Prevotella copri at much higher levels (75%) than PA patients (37%) or healthy control patients (21%). This association of a specific pathogen with an autoimmune/chronic inflammatory disease is very striking. When mice were infected with a rodent-compatible strain of P. copri they developed pronounced intestinal inflammation, but not arthritis. Still, the intestinal inflammation was associated with the induction of Th17 cells, and so the hypothesis that this may underlie more systemic inflammation (e.g. RA) is still reasonable.

There are some problems with the story. The clinical development of IL-17 targeting drugs has shown that these do very well in PA and psoriasis, perhaps in inflammatory bowel disease, but they have failed to show sufficient benefit so far in RA. So at the level of drug discovery the link of an intestinal pathogen to Th17 T cells producing IL-17 and then to the disease, RA, seems to falter.

Thinking more broadly, the application of microbiome studies to drug development is in its infancy, and I think there is some reason for optimism as these studies become more sophisticated. The H. pylori and P. copri studies mentioned make it clear that many factors influence the response of a given population or individual to their microbioma. One interesting approach, the use of fecal transplantation to treat severe diarrhea and also Crohn’s disease, has made it into early clinical trials. Isolation of the critical components that reset the immune system in the local (inflammatory bowels diseases) and systemic (RA and other non-gut inflammatory diseases) settings is going to take significant time and effort, so we’ll have to stay tuned.

References
1) Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells, Nature, http://www.nature.com/nature/journal/v504/n7480/full/nature12721.html
2) Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation, Nature, http://www.nature.com/nature/journal/v504/n7480/full/nature12726.html
3) Human and Helicobacter pylori coevolution shapes the risk of gastric disease, PNAS, http://www.pnas.org/content/early/2014/01/08/1318093111
4) Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis, elife, http://elife.elifesciences.org/content/2/e01202

Inflammation, autoimmunity & oncology drug development questions for 2014: RA

JAK inhibitors, monoclonal antibodies, Rheumatoid arthritis

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I think we’d all agree that 2013 was an exciting year for biotech and pharma drug development. New drug approvals, great late stage clinical trial results and exciting scientific data gave us all a wealth of topics to think about and discuss. There will be much more of this in 2014 and we can expect the excitement to continue. In the middle of all this however sits a big pile of unresolved questions and a plethora of diseases for which new therapies remain few of lacking. I want to pull a few things off that pile and have a look. What follows is a short list of drug development questions in the fields of inflammation, autoimmunity and oncology.

1) Will the use of biologics for Rheumatoid Arthritis (RA) begin to taper?

The blockbuster TNF antagonists Remicade, Enbrel and Humira continue to dominate the market for disease-modifying RA therapies (DMARDs). These drugs, other anti-TNF drugs, Stelara (anti IL-6 antibody), Orencia (CTLA4 fusion protein) and Rituxan (CD20 antibody) have transformed RA patient care to the point that the Rheumatologist’s goal has become disease remission.

Two challenges to the dominance of biologics were brought forward in 2013. One was the hypothesis that “triple therapy” – the use of a combination of the old and cheap chemical drugs methotrexate, sulfasalazine and hydroxchloroquine was just as effective as a TNF antagonist with or without methotrexate. This debate played out at the American College of Rheumatology conference in November. The consensus view that emerged was that triple therapy was effective for patients with mild RA who could tolerate the regimen. The problem is that triple therapy is very unpleasant and compliance can be very poor, especially in younger patients. The debate, while energetic, does not seem to have had an impact on the biologics market in RA.

The second challenge was brought on by the approval of Pfizer’s Jak2 inhibitor, a once-daily oral drug. Orals are considered the holy grail of RA drug development, allowing patients to move off of therapies that require either IV injections (in a health care setting) or subcutaneous injections (in a health care setting or self-administered). All approved biologics for RA are injectable drugs.

I reviewed Pfizer’s Jak2 inhibitor Xeljanz (tofacitinib) a while ago.

As discussed in that earlier post, Xeljanz showed impressive efficacy in RA clinical trials, and as approved by the FDA for use in methotrexate-refractory patients. This second-line label meant that patients did not have to try a biologic first, they could go directly to this nice, convenient once-a-day oral. So what happened?

Not much. Physicians balked at some of the side effects, and payers balked at the cost. The result was that this presumed blockbuster oral drug has posted very poor sales to date. It may be that Xejanz gains traction over time, we’ll have to see, but already we can take away several interesting lessons. One is that physicians have gotten comfortable with biologics, and being an oral drug does not automatically confer advantage. The second, which is really an old lesson, is that drug efficacy is paramount, and new drugs need to offer better efficacy. This is especially true if they are bringing some side-effect baggage along with them.

Is anything else in development that can challenge the established biologics in the near term? I think the short answer is no. Apremilast, Celgene’s PDE4 inhibitor, has trialed well in psoriatic arthritis and psoriasis, but did poorly in RA trials, so poorly that scheduled trials were terminated or withdrawn. Other Jak inhibitors and Syk, BTK and other inhibitors are currently in RA trials, but these are years away from approval. Some, like the Syk inhibitors fostamatinib from Rigel/Astra Zeneca and PRT062607 from Portola/Biogen Idec, have already failed.

Perhaps the next hurdle for the RA biologics will be the launch of biosimilar products, essentially generic versions of the antibody or protein. Thats a topic for another time.

In section 2 we will turn to an autoimmune disease that remains very poorly treated.

Syk inhibitors continue to struggle in the clinic

$AZN, $BIIB, Btk, fostamatinib, JAK, Rheumatoid arthritis, Rigel, Syk, tofacitinib

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Syk inhibitors have had a rough ride, with both Rigel and Portola running into significant issues in clinical development.

Rigel and partner Astra Zeneca released data from a Phase 2 Rheumatoid Arthritis study, summarized here:

“In the study known as OSKIRA-1, two doses of fostamatinib significantly improved the signs and symptoms of rheumatoid arthritis compared to a placebo following 24 weeks of treatment. However, fostamatinib failed to show improvements over placebo in bone erosion and joint-space narrowing as measured by X-ray.” from http://www.thestreet.com/story/11888193/1/astra-rigel-arthritis-pill-posts-mixed-trial-results.html).

Sadly thats about all you need to know about fostamatinib, especially given that earlier data have been unimpressive as we discussed in December. There is no clear role for this drug in RA given the label granted to Pfizer for their JAK inhibitor tofacitinib, approved for use as second line therapy for RA. Tofacitinib also has shown clear evidence of protection from joint damage, something fostamatinib has failed to do.

Fostamatinib is apparently moving forward in multiple oncology indications, and therein may lie its future, if it has one.

Portola’s Syk inhibitor, licensed by Biogen Idec, is in development limbo, and the clinical trial in RA was withdrawn. Whether this is due to toxicity issues, efficacy concerns, or commercial strategy is not known, as Biogen has not provided an update on this drug.

In the meantime companies continue to focus on kinases that signal downstream of Syk, notably Btk and PI3K. While PI3K inhibition may carry too much toxicity for use outside of oncology, Btk inhibitors appear to be safe enough to develop in autoimmunity and inflammation. We will continue to watch the development of small molecule inhibitors in this space, and anticipate success for novel Btk inhibitors.



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

B cell lymphoma, fostamatinib, Ibrutinib, myelofibrosis, RA, Rheumatoid arthritis, ruxolitinib, SLE, tofacitinib

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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.