Monthly Archives: January 2014

Alemtuzumab and MS – Just The Facts

Lemtrada For Multiple Sclerosis – Just The Facts

The debate over the FDA’s reluctance to approve alemtuzumab (brand name Lemtrada, an anti-CD52 antibody, aka Campath) continues, with heated opinions being expressed, mainly by those that want Lemtrada approved. We note without comment that a fair number of the FDA’s fiercest critics have exposure to stock warrants tied to this drug’s commercial success. The FDA stance seems to some to be overly tough, particularly as the drug has been approved for MS in other markets, notably the often risk-adverse EU.

I’ve been puzzled by this debate, and more puzzled since it is taken place more of less without discussion of the Phase 3 clinical trial data. Granted this is hard for some of us to get. I do not have the FDA documents for example. The clinical trial data is behind a paywall at the Lancet, and I’m just annoyed enough at the price to resist paying it. So let’s see what we can do using just publicly available information.

The Lancet summaries are available. Here is the first one (via http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61769-3/abstract):

Background

The anti-CD52 monoclonal antibody alemtuzumab reduced disease activity in a phase 2 trial of previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of first-line alemtuzumab compared with interferon beta 1a in a phase 3 trial.

Methods

In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18—50 years with previously untreated relapsing-remitting multiple sclerosis. Eligible participants were randomly allocated in a 2:1 ratio by an interactive voice response system, stratified by site, to receive intravenous alemtuzumab 12 mg per day or subcutaneous interferon beta 1a 44 μg. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and once per day for 3 days at 12 months. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00530348.

Findings

187 (96%) of 195 patients randomly allocated interferon beta 1a and 376 (97%) of 386 patients randomly allocated alemtuzumab were included in the primary analyses. 75 (40%) patients in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0·45 [95% CI 0·32—0·63]; p<0.0001), corresponding to a 54·9% improvement with alemtuzumab. Based on Kaplan-Meier estimates, 59% of patients in the interferon beta 1a group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab group (p<0·0001). 20 (11%) of patients in the interferon beta 1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group (hazard ratio 0·70 [95% CI 0·40—1·23]; p=0·22). 338 (90%) of patients in the alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious. Infections, predominantly of mild or moderate severity, occurred in 253 (67%) patients treated with alemtuzumab versus 85 (45%) patients treated with interferon beta 1a. 62 (16%) patients treated with alemtuzumab had herpes infections (predominantly cutaneous) compared with three (2%) patients treated with interferon beta 1a. By 24 months, 68 (18%) patients in the alemtuzumab group had thyroid-associated adverse events compared with 12 (6%) in the interferon beta 1a group, and three (1%) had immune thrombocytopenia compared with none in the interferon beta 1a group. Two patients in the alemtuzumab group developed thyroid papillary carcinoma.

Interpretation

Alemtuzumab’s consistent safety profile and benefit in terms of reductions of relapse support its use for patients with previously untreated relapsing-remitting multiple sclerosis; however, benefit in terms of disability endpoints noted in previous trials was not observed here.

What is this telling us?

1) this is a 2-year trial in previously untreated MS patients; the dose regimen is 12 mg daily for 5 days and then at 12 months a second regimen of 12 mg daily for 3 days
2) the active comparator is Rebif, a beta-interferon
3) there was a benefit seen in relapse rate: about 20% fewer patients had a relapse in the alemtuzumab arm as compared to the Rebif arm
4) there was no improvement in time to 6-month sustained accumulation of disability
5) 90% of alemtuzumab patients had infusion reactions but only 3% on these were serious
6) Over 60% of patients experienced infections, over 60% developed cutaneous herpes, over 60% developed thyroid associated adverse events, and 1% developed immune thrombocytopenia.

Summary: alemtuzumab hit one of its primary endpoints, missed the second, and had a challenging toxicity profile.

How about that second paper in Lancet? Well, here is the abstract (via http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61768-1/abstract)

Background

The anti-CD52 monoclonal antibody alemtuzumab reduces disease activity in previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of alemtuzumab compared with interferon beta 1a in patients who have relapsed despite first-line treatment.

Methods

In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18—55 years with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer. Eligible participants were randomly allocated in a 1:2:2 ratio by an interactive voice response system, stratified by site, to receive subcutaneous interferon beta 1a 44 μg, intravenous alemtuzumab 12 mg per day, or intravenous alemtuzumab 24 mg per day. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessments. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00548405.

Findings

202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses. 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI 0·39—0·65]; p<0·0001), corresponding to a 49·4% improvement with alemtuzumab. 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p<0·0001). 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 [95% CI 0·38—0·87]; p=0·008), corresponding to a 42% improvement in the alemtuzumab group. For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 [66%] of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia.

Interpretation

For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumab’s main adverse effect of secondary autoimmunity.

Again, what is this telling us?

1) this is a 2-year trial in patients with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer; the dose regimen is 12 mg or 24 mg daily for 5 days and then at 12 months a second regimen of 12 mg or 24 mg daily for 3 days. The 24 mg dose was discontinued.
2) the active comparator was Rebif, a beta-interferon
3) there was a benefit seen in relapse rate: 16% fewer patients experienced a relapse on alemtuzumab as compared to Rebif
4) importantly, 65% of patients were relapse free at 2 years
5) there was an improvement in time to 6-month sustained accumulation of disability
6) 90% of alemtuzumab patients had infusion reactions
7) 77% of alemtuzumab patients experienced infections, 16% developed thyroid associated adverse events, and 1% developed immune thrombocytopenia.
Summary: alemtuzumab hit both of its primary endpoints and had a challenging toxicity profile.

How does this efficacy compare to other treatments? The reduction in annualized relapse rate (ARR) lies between the beta-interferons or copaxone and highly efficacious drugs like natalizumab (Tysabri), daclizumab or fingolimod (Gilenya). The following data are taken from the UPTODATE website, last updated January 15, 2014.
(http://www.uptodate.com/contents/treatment-of-relapsing-remitting-multiple-sclerosis-in-adults)

agent
trial(s)
ARR (across doses)
ARR/comparator
SAD met?
dimethyl fumarate (Tecfidera)CONFIRM24%40% (placebo)trend/ns
dimethyl fumarate (Tecfidera)DEFINE18%36% (placebo)yes
fingolimod (Gilenya)FREEDOMS17%40% (placebo)yes
fingolimod (Gilenya)TRANSFORMS18%36% (interferon beta 1-a)not assessed
alemtuzumab (Lemtrada)CARE-MS I22%40% (interferon beta 1-a)no
alemtuzumab (Lemtrada)CARE-MS II (relapsed patients)35%53% (interferon beta 1-a)yes
natalizumab (Tysabri)AFFIRM (relapsed patients)26%81% (placebo)yes
natalizumab (Tysabri)SENTINEL (relapsed patients)38%82% (placebo)yes

So it seems to me that we have an efficacy/toxicity profile on a par with fingolimod and natalizumab. Of note, the UPTODATE profile concludes the section of alemtuzumab as follows:

“Although its precise role in the management of RRMS is not yet settled, alemtuzumab will probably be used as a second-line agent for patients with RRMS who have an inadequate response to treatment with interferons and glatiramer. The role that alemtuzumab will play in the context of other newer MS disease-modifying agents (eg, fingolimod, teriflunomide, and BG-12) is still undefined. Alemtuzumab therapy requires monitoring for infusion reactions and prophylaxis for herpes virus infections and Pneumocystis jirovecii (PCP) pneumonia during treatment and for several weeks after treatment. Prolonged surveillance for bone marrow suppression, infections, and autoimmune disorders such as immune thrombocytopenia is also necessary.”

So that seems to be the heart of the problem, that the comparison to the most relevant medications is not well defined and you have a lot of toxicity that requires monitoring.

As the title said, “just the facts” – I don’t aim to draw conclusions here but just lay out the data so when we see arguments pro or con for this drug, we have a place to turn to look at the data.

High Fiber, Butyrate, Tregs & Immune Responses – Evaluating Recent Papers in Nature, Nature Medicine and Immunity

Last week I reviewed four recent papers on the impact of gut microbial commensals and pathogens on immune function, focusing on regulatory T cell (Treg) generation and on the role of effector Th17 T cells (Th17s) on disease. See the post here: http://www.sugarconebiotech.com/?p=6.

The other day another paper on the role of dietary fatty acids in the regulation of immune responses appeared (see http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3444.html). Honestly, the results presented in this new paper are sufficiently distinct from the prior two papers in Nature that a reappraisal makes sense, as there are clearly a whole host of unresolved questions in this body of work. Also, we will touch briefly on an Immunity paper, also just out.

The driver for all of these studies is the extensive observations on the ability of particular fatty acids to modulate the immune response. There are similar observations on the role of fatty acids in regulating metabolism – that work will not be discussed here.

In particular, the investigators are trying to understand if, and how, short-chain fatty acids (SCFAs) produced by gut bacteria, such as butyrate, propionate and acetate, can modulate the immune system. The stakes are high, as there is early clinical work aimed at manipulating the microbiome in order to treat diseases, notably gut diseases such as inflammatory bowel disease (IBD) and severe diarrhea. Also there are the massive supplement and wellness industries already selling such SCFAs, without much understanding of the science.

Suffice to say we are entering the high fiber diet metaverse, cautiously.

Here is a quick recap of the earlier papers, taken one at a time and in a little more detail. I’ll highlight some similarities and differences. The first two studies were published in Nature on 19 December 2013. The key findings are summarized below. Note that this and the other studies discussed here are done in pure strain inbred mice.

  • commensal microbes support Treg development
  • specifically, large bowel (colonic) production of the SCFA butyrate induces Tregs
  • butyrate functions by inhibiting HDAC IIa
  • HDAC inhibition allows more extensive acetylation of FoxP3 and other genes
  • expression of FoxP3 and other genes drives Treg differentiation
  • butyrate blocks the development of IDB in a T-cell dependent mouse colitis model

The first study was led by Hiroshi Ohno from the RIKEN Center in Kanagawa, Japan. The colitis experiment was shown in that paper. Now onto some of the other details – there are 4 figures in the text and 22 supplemental figures so we can’t cover everything.

The Tregs under discussion in this paper are peripherally generated (i.e. not thymic in origin) and are identified in flow cytometry (FACS) experiments as FoxP3+/neuropilin-/Helios-. About half the high-fiber diet (HFD) induced Tregs were activated and therefore CD103+. Critically, Ohno and colleagues show that this Treg population in restricted to the local (colonic lamina propria) environment. There are plenty of Tregs in the lymphoid organs – mesenteric lymph nodes and spleen – but the percentage of FoxP3+/neuropilin-/Helios- cellsdoes not change in these organs in response to the HFD. The investigators then demonstrate that the microbes responsible for fermenting the HFD into beneficial SCFAs are bacteria of the class Clostridiales and that the potentially beneficial SCFAs include the very potent butyrate and the less potent propionate. Acetate had no effect.

Now this is where is starts to get a little complicated. Having demonstrated that the gut SCFAs induce Treg differentiation only in the colonic lamina propria, the authors next show that T cells isolated from the mouse spleen can be differentiated into Tregs using stimulation conditions that include TGFbeta and butyrate plus stimulatory antibodies to CD3 and CD28. This might indicate that there is some barrier that prevents butyrate reaching sites other than the gut wall, and that this accounts for the local aspect of the Treg response to butyrate. However, while most of these SCFAs are passively and actively taken up by intestinal cells, SCFAs can also be detected in circulation. The absorption of SCFAs can be saturating, i.e. above some concentration SCFA uptake into the circulation is maxed out. These observations suggest that there is a requirement for locally high concentrations of SCFAs in order to induce Treg differentiation – this would explain why these induced Tregs were only found in colonic tissue and not in spleen or LN. I can’t find the relevant concentration data nor is there any dose response data – this is disconcerting. They also report that butyrate can drive naive T cells to a Treg phenotype irrespective of pro-inflammatory Th1, Th2 or Th17 inducing conditions. This is a very dramatic result but suffers from the same lack of critical experimental detail.

The observations made using butyrate stimulation of T cell are followed up in vivo using SCFA supplemented diets. As noted earlier the MOA here is the antagonism of the deacetylase HDAC IIa, thereby allowing increased acetylation and activation of the FoxP3 gene. Finally, using an activated CD4+ T cell transfer colitis model (a model in which Tregs are specifically excluded from the transferred cells) the investigators show protection from disease when the mice are fed diets containing butyrate.

OK, we still have no idea how this is mediated, but the observation is in line with other papers that have examined to ability of butyrate to control colitis (its a large body of work). So, we are not criticizing this whole story, but just suggesting that more experimental detail would be useful, especially in a world where one can buy butyrate capsules or arrange for butyrate enema treatment. A more general critique is offered at the end of this post.

The second Nature paper is by Alexander Rudensky and colleagues from Memorial Sloan-Kettering in NY and reaches broadly similar conclusions as the Ohno paper. Their naive T cell culture conditions are a little different, substituting dendritic cells and Il-2 for the anti-CD28 antibody signal, and they do show dose response data. The latter results indicate a sharp rise in Treg induction above 30uM butyrate. To manipulate the system in vivo these investigators used antibiotics to clear the SCFA producing bacteria. Thus the model is rigged to show an increase above an artificially low background. That’s OK, but let us just be clear about it.

Using sodium butyrate in the drinking water, the investigators induced Treg differentiation in the peripheral LN and spleen. The serum concentration achieved with the drinking water regimen was 500pg/ul which is ~ 4.5uM, a physiological concentration in wildtype, untreated mice. In other words, they brought the SCFA level back to normal, and that induced T regs. In order to induce Tregs in the colonic lamina propria they used either butyrate-enriched food, or a butyrate enema.

The conclusion of all that work is that systemic exposure (drinking water) can induce Tregs in the periphery (spleen, LN) but that local exposure (food, enema) is required to induce Tregs in the gut. Note that this latter conclusion echoes the Ohno paper. Turning to propionate and acetate, they next show that propionate in the drinking water can induce peripheral Tregs in the spleen and LN, and that both propionate and acetate can induce local Tregs in the colon. However, these latter cells are possibly thymic-derived, not extrathymic Tregs, as shown by independence from the CNSI gene (required for extrathymic Treg differentiation). The other option is that these cells are preferentially recruited from the circulation. Note that the acetate result is at odds with this prior paper.

So this has now gotten very complicated, with three abundant starch-derived fatty acids being endowed with both unique and overlapping abilities to induce different types of Tregs in different geographies. Just to make this even more complicated, the Rudensky team next shows that this biology is not just T cell specific, but that butyrate can also endow dendritic cells (DCs) with the ability to preferentially induce Tregs. Lets not go into detail except to say that this effect on DCs did not depend on GPR109a, the niacin and butyrate specific G-protein-coupled receptor (GPCR). More on GPCRs later. The rest of the story – HDAC inhibition and FoxP3 induction – is familiar from the Ohno paper (and many others, the HDAC mechanism is pretty well known).

Finally, I mentioned at the top the Nature Medicine paper that triggered this reappraisal (http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3444.html). Using a mouse model of house dust mite (HDM) antigen allergic asthma, Benjamin Marsland and colleagues from the University of Lausanne, Switzerland, demonstrate that the susceptibility to and severity of HDM-induced asthma was worsened on a low fiber diet and improved on a high fiber diet. They traced the change in asthmatic response to a change in the gut microbiota supported by the different diets, bringing us again to the SCFAs produced. Higher concentrations of the usual suspects (butyrate, propionate, acetate) were produced when the microbiome was dominated by the Phylum Bacteroidetes, to which the class Clostridiales belongs. Note that the differences in the composition of the microbiome on the low and high fat diets were not significant. This is an issue we will revisit.

The asthma paper is strikingly different from the two Treg papers. In this paper the focus in on propionate, not butyrate, and on systemic effects, not local effects. The premise is that the dietary changes impact the bone marrow, not the local lung tissue. Indeed SCFAs could not be detected in the lung. Propionate treatment reduced Th2 immune responses to HDM in a manner that was dependent on GPR41, a SCFA receptor. This receptor is expressed at high levels in the colon where it mediates a variety of responses to SCFAs, however, in this paper the impact of propionate was traced to the CD11bhisubset of DC in the lung-training LN. How this impacts the allergic-asthmatic response is hypothesized to be (and I’m quoting the paper here) “after inflammation, the lung DC compartment is replenished with inflammatory monocyte-derived DCs that have been exposed to SCFAs in the bone marrow and circu­lation, leading to a maturation profile that is ineffective at driving Th2 cell responses.”

Therefore the authors conclude that they have elucidated a “gut-lung axis for the formation of the airway microbiota” and therefore I suppose, lung immune responses.

Really?

What we have here are three reductionist tales, necessary to help us understand the rules of the system but perhaps not sufficient in themselves to draw sweeping biological and pathological conclusions. It’s very clear from the disparate results obtained that we are still working out the rules. Also, one cautionary note, a recent study in human subjects showed that plasma butyrate concentration remained very close to 2uM under a variety of high fiber meal and fasting conditions, suggesting that this SCFA may not be as variable in concentration as is seen in mice (http://jn.nutrition.org/content/140/11/1932.full).

A somewhat more straightforward study just published last week in Immunity (http://download.cell.com/immunity/pdf/PIIS1074761313005645.pdf?intermediate=true). Vadivel Ganapathy and colleagues from the Georgia Regents University in Augusta show that GPR109 signaling is required to maintain IL-10 dependent Treg activity in the colon, and they trace this function to DC and macrophage responses. Butyrate (or niacin, the nominate ligand for Niacr1 aka GPR109a) treatment of DCs and macrophages induced a phenotype that supported Treg differentiation. Note that this result contradicts the Rudensky paper, in which GPR109a was ruled out as the causative receptor, at least on DCs.

GPR109a gene-deficient mice were then shown to be more susceptible to colitis and inflammation induced colon carcinogenesis, and this effect was shown to be dependent on both the hematopoietic compartment and colonic tissue cells. This final study is satisfying, as now we are seeing pharmacological manipulation of a defined receptor, albeit with a molecule (niacin) that has a pretty checkered history as a therapeutic.

Where does this leave us? I think the take home message is that these systems are very complex, and by trying to simplify them we have the benefit of gaining some insight but the risk of over-interpretation. The human microbiome is incredibly variable, over time and between individuals. The fact that we are seeing different results from manipulation of highly inbred strains of mice on very carefully defined diets should give us pause, especially when some studies can’t statistically distinguish between components of the microbiota they are describing. However, at the very least these studies support the belief that high fiber diets that producing lots of butyrate and propionate should be beneficial, and we have identified some targetable GPCRs, which should drive further research. Finally, we are perhaps a step or two closer to understanding how to manipulate Treg cell populations in human disease. This last goal, the ability to regulate immune responses via regulatory T cell modulation, has proved to be an elusive one so far.

Cautionary Tales from Human Microbiome Frontier

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, PNAShttp://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

The development of combination therapies for B cell lymphoma: ABT-199

The role of ABT-199 in the development of combination therapies in lymphoma.

Following yesterday’s blockbuster win for PCYC and JNJ – the Phase 3 trial versus Arezza was stopped early on clear PFS and OS benefit – it seems a little deflating to return to AbbVie, whose Bcl2 inhibitor ABT-199 has been dogged by Tumor Lysis Syndrome (TLS) problems, some fatal, and recent rumors of oversight problems at one clinical site. I stated the other day that ibrutinib would win the medical marketplace for B cell lymphoma treatment, based on its impressive suite of clinical trials, and the results announced yesterday support that opinion. I still believe that combo therapy is the critical path forward in this field, and ibrutinib and idelalisib are the clear leading candidates for combo treatment protocols.

However, ABT-199 remains a wildcard and could be transformative if developed carefully. The drug demonstrates ORR and CR responses in B cell lymphoma that are very dramatic, as detailed earlier. In the spirit of our earlier January posts, lets look at the clinical trial spectrum for ABT-199. There are five trials listed for ABT-199 monotherapy in oncology, including the phase 1 extension. These include trials in relapsed/resistant NHL, CLL, high-risk CLL (del17p), MM, and AML. The inclusion of acute myeloid leukemia (AML) distinguishes ABT-199 from the other lymphoma drugs, and is based on the mechanism of action and profiling of different tumor types for sensitivity to Bcl2 inhibition.

The combination trials are very narrow in scope and reflect the fact that the ABT-199 is partnered with Roche/Genentech, and therefore the anti-CD20 mAbs used are those developed by Roche, that is, rituximab and obinutuzumab (Gazyva). Obinutuzumab is already approved for the treatment of previously untreated CLL, i.e., as first line therapy. The obinutuzumab trial with ABT-199 is sponsored by Roche/Genentech, illustrating the depth of this collaborative effort. Roche has an ongoing preclinical BTK program, and it will be interesting to see if a combination trial with ABT-199 is eventually filed.

Here are the combination trials listed:

Trial Number
Phase
date filed
Combination
Indication
NCT0159422914/20/2012bendamustine/rituximabrrNHL and DLBCL
NCT0167190418/10/2012bendamustine/rituximabCLL (rr & untreated)
NCT016826161b6/26/2012rituximabrrCLL and SLL
NCT0168589219/12/2012ObinutuzumabCLL (rr & untreated)

The ultimate success of the program will depend in large measure on controlling the TLS issue. Its worth reminding ourselves that TLS did not suddenly become a toxicity concern in the treatment of B cell lymphoma. It occurs with anti-CD20 treatment and with chemotherapy treatment, as a result of triggering the death of a large number of tumor cells. The problem for ABBV and ABT-199 is that TLS does not seem to be related to dose given, remaining somewhat unpredictable (aside from worrying when patients present with bulky disease, which indicates huge number of tumor cells in the lymph nodes, bone marrow, etc). The recent outcry over moving one patient from one dose to another (150mg to 1200mg if I remember right) seems a little silly when a dose of 50mg can trigger TLS in a lymphoma patient. That said, the burden is on AbbVie to demonstrate that they can provide better efficacy than the competing drugs (ibrutinib and idelalisib), safely. If they can do this, I predict that ABT-199 will have a big role to play in the treatment of B cell lymphoma. If they continue to struggle then this drug will will still have a role, but may be relegated to second line or even salvage therapy status. Given the resources behind it, from both AbbVie and Roche, I imagine that a huge effort will be brought to bear on understanding and controlling the TLS toxicity.

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
Phase
date filed
Combination
Indication
NCT01732913311/14/2012rituximabrr iNHL
NCT0153951232/12/2012rituximabrrCLL
NCT0120393029/15/2010rituximabuntreated CLL, SCL
NCT01980875311/5/2013rituximabuntreated CLL
or chlorambucilÿ
NCT01732926311/14/2012bendamustine/rituximabrr iNHL
NCT01980888311/5/2013bendamustine/rituximabuntreated CLL
NCT0156929533/27/2012bendamustine/rituximabrrCLL
NCT0164479917/17/2012lenalidomide/rituximabrrFL
NCT018384341,24/19/2013nonerrMCL
lenalidomide/rituximab
NCT0165902138/3/2012ofatumumabrrCLL
NCT0179647022/19/2013GS-9973rrCLL,MCL,iNHL,DLBLC
NCT0108804811/12/2010RituximabrrCLL or rrMCL or rr iNHL
Bendamustine
Ofatumumab
Fludarabine
Everolimus
Bortezomib
Chlorambucil
ÿLenalidomide
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.

Drug
Trial Number
Phase
date filed
Combination
Indication
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
and
NCT01558167
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 clinicaltrials.gov, trying to understand how companies competing in the B cell lymphoma space are looking ahead, the assumption being that one can do this by looking at the trials planned or underway for the top tier drugs. Many of the oral drugs in advanced development for B cell lymphomas are reviewed here.

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

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

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

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

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

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

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

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

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

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

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

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

Stay tuned.

Inflammation, autoimmunity & oncology drug development questions for 2014: Multiple Sclerosis

In thinking where Multiple Sclerosis (MS) treatment is heading, and what critical question to ask, it bears quickly reviewing advances made in the past year. I’ll be brief however, as this subject has been extensively covered. 2013 saw the approval of multiple new therapies for relapsing and remitting MS (rrMS), the common form of this disease. BG-12 was approved under the name Tecfidera in March in the US, and more recently in the EU. This is an oral drug from Biogen Idec with a decent efficacy profile and tolerable side effects. This drug is widely seen as having blockbuster potential (greater than 1BB in annual sales) and has been taking market share from Novartis’ Gilenya, an oral drug approved in 2010 and having similar efficacy as Tecfidera but a more difficult toxicity profile. Tecfidera may also be taking patients who would otherwise go onto Tysabri, Biogen’s flagship MS therapy and considered to be the most efficacious MS drug. Tysabri also has toxicity issues that complicate its use, especially for longer than 2 years. Since both Tecfidera and Tysabri are part of Biogen’s portfolio this is seen as a net positive (thinking of investors here who, like myself, are BIIB long).

Sanofi won approval in the EU and (eventually) the UK for its reformulated version of terifluonimide, the active metabolite of leflunomide, an old immunosuppressive drug developed for RA among other indications. The drug was approved under the name Aubagio in the US in 2012. It is hard to guess where this drug will end up in the MS medicine chest. Early estimates had Aubagio hitting 500MM-700MM USD a year in worldwide sales by 2015-2016. Currently Aubagio is running at about 120MM Euros for 2013 (165MM USD) and its prescription trajectory was impacted by the Tecfidera launch (much like Gilenya). On the other hand this is a once a day oral with a pretty clean toxicity profile and a positive impact on relapse rate, so it may be a good choice for relatively mild MS patients who are coming off of a beta-interferon therapy or off Copaxone and need something more potent. At the moment Aubagio trails the other oral MS drugs.

Sanofi’s more potent rrMS therapy hit a wall in the US just a few days ago. Lemtrada was rejected by the FDA, shutting this drug out of the US market for now. Lemtrada was approved in the EU earlier in 2013. This is yet another old drug, the anti-CD52 mAb once known as Campath or alemtuzumab. Sanofi/Genzyme pulled this drug from the lymphoma market, anticipating more value in MS. This appears to have been a poor bet but Sanofi had smartly hedged this bet when it acquired Genzyme, by creating warrants whose value was tied to Lemtrada approval and sales milestones. Those warrants have dropped in value form $24 to under $1 at last check.

I admit to some ignorance as to why this drug hit such a snag with the FDA. I’ve been told that the doses used for MS therapy are much lower than those that had been used to treat lymphoma, and the side effect profile was tolerable. On the other hand the FDA briefing documents used language regarding safety that was very negative, similar to what we heard a few years ago regarding cladrabine, an oral drug from EMD Serono with truly nasty toxicity. There were also questions regarding the design of Aubagio’s Phase 3 trials, which clouded the efficacy claims.

For much more on these drugs please see my earlier post on MS orals (here).

So where are we now? The array of drugs available to neurologists to treat MS is remarkable and the arrival of Tecfidera may provide long-term protection for many patients. The trio of Tecfidera, Gilenya and Aubagio means that there are real choices for patients who can benefit from oral therapy. Finally, more severe patients can turn to Tysabri for even greater efficacy, assuming that the toxicity is managed, particularly in regards to PML, a demyelinating disease caused by JC virus infection in the CNS. Biogen has done a good job of risk mitigation for PML. I predicted some time ago that we would see PML associated with the use of Gilenya as well (here) and to date have happily been proven wrong.

Ok, questions for 2014:

  1. Will novel pathogenic pathways underlying rrMS be discovered and will these yield useful therapeutic targets? Large scale GWAS and epigenetic analyses of MS have been published recently and it will be interesting to see if new therapeutic approaches will emerge from these data.
  2. What will the next generation of S1P antagonists yield? Gilenya is in this class but acts promiscuously on S1P receptors. Will more specific S1P antagonists bring equivalent efficacy with less toxicity? This is a very active area and we will begin to see advanced clinical development soon. BAF312 (siponimod, Novartis) and ONO-4641 (ONO Pharma) are in late Phase 2. These are S1P selective modulators and showed benefit in Phase 2. These drugs still cause cardiovascular abnormalities however.
  3. What will the next generation of NRF2 modulators yield? Tecfidera acts in part as an NRF2 agonist, eliciting potent anti-oxidative and anti-inflammatory effects. Can a specific NRF2 agonist provide next generation drugs for rrMS? I’ll note in passing that antagonism of the NRF2 regulatory protein Keap1 is also an attractive drug development option.
  4. Drugs available to date provide benefit primarily by preventing lesion growth, new lesion formation (aka relapse) or both. Will we see drugs developed that promote the repair of damaged tissue, more specifically, promote remyelination of nerve axons before they are completely destroyed? We are beginning to see a real focus on repair mechanisms, and a therapeutic that could stop disease and promote repair would be transformative.
  5. Finally, what about progressive MS? As far as I know, no tested drug has improved outcomes in progressive MS (please correct me if I’m wrong here). In progressive MS there are no remissions and relapses, its just chronic progressive destruction of the CNS. Lemtrada had been touted as one drug that might help here (however, without clinical evidence), will there be others? Notably, siponimod is listed on clintrials.gov as recruiting for Phase 3 in secondary progressive MS (SPMS), and ONO-4641 is listed as recruiting for Phase 3 in both rrMS and SPMS.

MS is a disease whose treatment has drastically changed patient’s lives in the past 20 years. I was at Biogen in 1996 when Avonex was approved, and treatment options at that time were ineffective and did not prevent disease relapse. Avonex and other beta-interferons marked the beginning of a radical transformation in the treatment of MS. We’ve come a very long way in 20 years. I think we still have a long way to go.

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

Lupus and lupus nephritis update

The title includes the word “update” but that may be a bit generous. A dive into the American College of Rheumatology (ACR) abstracts shows that there is not much to update (http://acrannualmeeting.org/). Progress with new therapeutics remains slow.

Most patients are treated with various combinations of cytotoxic agents and immunosuppressants. These include prednisolone, mycophenolate mofetil, tacrolimus, cyclophosphamide, and azathioprine among others. Unlike the situation in RA, we do not have a new suite of drugs for systemic lupus erythrmatosis (SLE) and lupus nephritis (LN) patients.

Newer therapies can be grouped into 2 classes. The most effective class includes the B-cell depleting antibodies rituximab (anti-CD20, aka Rituxan) and epratuzumab (anti-CD22). Clinical trials report consistent and durable improvement in patient symptoms and perhaps even rate of flares. In 2012 the ACR included Rituxan use in its treatment guidelines for patients with advanced diseases (grades III-IV). Rituxan in combination with cyclophosphamide or other standard of care is currently in clinical trials for use in SLE and LN. Epratuzumab is being developed by UCB and Immunomedics and is currently in phase 3 for SLE, with data due in 2015. Certainly the available clinical data indicate that this drug will find use in the treatment of lupus.

The second class consists of the BAFF/Blys and April antagonists. Belimumab (brand name Benlysta), developed by HGS and then acquired by GSK, is an antibody to Blys, a B cell growth and survival factor. Belimumab continues to report long term benefit for patients with generally mild to moderate SLE. There is consistently improvement in patient symptoms by the SLEDAI and BILAG outcome scores, reduction in proteinuria, and in some cases a reduction in the dose of steroids required to control diseases flares. Blisibimod, a peptibody inhibitor of Blys, had updated results from SLE trials, showing reduced proteinuria and Ig levels from the PEARL-SC trial. However, outcome data from that trial was lacking. This drug from Anthera has had a mixed track record in terms of efficacy and so the jury will remain out until the phase 3 data are reported. Other drugs in the space have failed outright, including atacicept, a TACI receptor fusion protein that antagonizes both Blys and April. Toxicity associated with this drug, and lack of efficacy, halted development.

Following the outright failure of the Interferon alpha antagonists a year or more ago, new drugs are few and far between. One of these reported at ACR is AMG811, an anti-interferon gamma antibody from Amgen. This drug appears to have significant adverse event issues, and no sign of efficacy in an early clinical trial. However Amgen is still recruiting for phase 2 trials in cutaneous lupus and SLE with renal involvement. Another Amgen drug, AMG557, is an anti-B7RP-1 (aka ICOSL) antibody which will be interesting to track.

Again, this is an underserved area in terms of new and effective drug development, and it may be we have to rely of the B cell inhibitors and Bly inhibitors for the foreseeable future. Following the failure of many therapeutics over the past few years, we appear to be in a slow period for clinical development. The question we can ask for 2014 and beyond is pretty simple: what will be the new therapeutic hypotheses for lupus and lupus nephritis?

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

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.