Category Archives: MS

Holiday Reading

some of the stuff we’re reviewing over the holiday break. N.b. paywalls ahead!  And at the very end, some current non-science favorites.

Tumor Mutational Landscape

Age related variants of variants occurred in three genes (DNMT3A, TET2, and ASXL1) are associated with hematological malignancy risk and

News and Views on the NEJM papers

using siRNA to identify driver genes in breast cancer


a primer on the role of PD-1 pathway inhibitors in Hodgkin’s Lymphoma, from Nat Rev Clin Oncol

the role of TILs and TIL-associated TNF in the survival of CRC patients

nivolumab in metastatic RCC, published data

resistance to T cells in melanoma (hint: they lose MHC expression)

interesting look at PD-L1 expression of the response of RCC to targeted therapies

it’s hard to control ipilimumab-induced tox 2353.abstract

IO combination review

tumor/microenvironment cross-talk mediated by microRNAs

functional blockade of miR-23a releases TILs in an ex vivo NSCLC assay

neutrophils, T cells and lung cancer

Given the new immunotherapy data in bladder cancer, a review of the molecular drivers of this tumor type is most welcome

MDSC requirements for survival

Gene Therapy and CAR T

Novel gene therapy methods puts a safety brake on a retrovirus-based vector

a new review of the CRISPR, Talen, and ZFN technologies for gene editing

NY-ESO-1 CAR T P1 results in solid tumors: long term follow-up and correlates of response

Targeted Therapies

A very timely primer of the role of different PI3K isoforms in diverse cancers

a Notch in the cancer treatment belt? Nope, a bit of a toxic mess made with anti-DLL4 antibody Demcizumab from OncoMed

IL-17 and colon cancer?

Hematological Malignancies

von Adrian and Sharpe tease apart Follicular Lymphoma

the role of one of gp130 in multiple myeloma

Fibrosis, Inflammation, Metabolism, MS

a brand new fibrosis review

the TRPV4 pathway, TGFbeta and IPF

The role of novel branched fatty acid esters of hydroxy fatty acids in Type 2 diabetes

will STING finally yield a useful target in lupus?

an animal model of JCV infection and PML

Investment and Deals

Pharma funding to pull programs out of the academic space

some color from NRDD on the Genentech + NewLink IDO-1 inhibitor deal

Also notable

300,000,000. A violent graphic lurid hypnotic novel of the dissolution of consciousness and the consequence of multiple realities converging within our unprepared empty minds and upon our decadent culture. Horrific and wonderful, but not for the squeamish.

Thug Kitchen – eat like you give a #$%@^. Fun, but you get the idea.

Death & Co: Modern Classic Cocktails. Drink like an adult.

A worthy campaign by patients for the National MS society

Healthline has launched a video campaign for MS called “You’ve Got This”. Patients living with MS can record a short video to give hope and inspiration to those recently diagnosed with MS.

You can visit the homepage and check out videos from the campaign here:

They will be donating $10 for every submitted campaign video to the National MS Society, so the more exposure the campaign gets the more the videos they receive and the more Healthline can donate to MS research, support groups, treatment programs, and more.

contact Maggie Danhakl • Assistant Marketing Manager p: 415-281-3124 f: 415-281-3199

Healthline • The Power of Intelligent Health
660 Third Street, San Francisco, CA 94107 | @Healthline | @HealthlineCorp
About Healthline:

Biogen Idec, multiple sclerosis, and the anti-Lingo story

It’s AAN conference week, and we were looking around, trying to get caught up on multiple sclerosis after a few months dedicated to oncology. We stumbled across this analyst report, and just had to comment.

Credit Suisse (CS) recently released a deep-dive report on Biogen Idec’s (Nasdaq: BIIB) anti-Lingo antibody program, assigning between $5-10BB (billion) USD of the total relapsing/remitting Multiple Sclerosis (rrMS) market share to the program by 2020. The program is currently in Phase 2. This analysis, in part, supports CS’s current price target for BIIB stock at $400, leveraging presumed growth due to the view on continued success of the anti-Lingo program. In other words, positive news on this program will help support inflated multiples through 2018, when pivotal trials may actually read out. The analysis seems ill considered, misses key aspects of BIIB corporate strategy, and places undo pressure on an early Phase 2 program. Further, intense focus on the anti-Lingo antibody program in turn places pressure on two early phase clinical trials, one due to read out in 2H14. The implication is that the base case for the price target could be undermined if the very early clinical development of the anti-Lingo program falters. That’s an unfair burden for a single high-risk program to bear.

Let’s dive in. Our focus will be on the science, but we’ll first set the stage. Our driving goal when looking at any biotech company or program is to bet the science, not the hype.

Two years ago the company set an internal goal of “400 in 5″, essentially promising to drive EPS in support of a sustained stock price of $400 USD by 2017. They came close during the biotech bubble that burst earlier this year. The stock is holding its’ own at around $320 USD. The “400 in 5″ goal is in place irrespective of the success or failure of the anti-Lingo program, which cannot read out pivotal clinical trials until at least mid-2018. With that in mind we can deconstruct the CS analysis, and create our own. Importantly, our analysis drastically de-risks the impact of the anti-Lingo program on the trajectory of BIIB growth, while leaving room for very attractive upside if this program hits.

The CS analysis correctly estimates that oral MS drugs will take over an increasing % of market share running from 2014 through 2020. No argument there, and BIIB will take the bulk of this market with Tecfidera, per multiple analysts. But CS believes that the “pipeline focus” is on the anti-Lingo antibody program to will help drive the stock price as the program matures. A few comments:

1) Analyst and/or investor focus on the anti-Lingo program is a sign of pipeline weakness, not strength. Where, one might ask, is the rest of the pipeline?

2) The program is very high-risk (and thus high return) for multiple reasons beyond the inherent weakness of being in Phase 2.

3) Management recognizes the oversized risk of the program, and will not tether stock performance to this program, instead they will act to de-risk the pipeline and performance.

Let’s look at these points one by one. First, the portfolio and pipeline. We agree that top-line growth will continue to be robust, driven by Tecfidera in the expanding orals segment of the market. We believe that the Daclizumab program is likely to succeed (the data being shown at AAN this week is very good) but it seems likely that this drug will compete for the declining injectable biologics market share with Tysabri. Maybe not, if it is successfully positioned for JC virus antibody positive patients, and can hold off the orals. Ocrelizumab may successfully evolve into the successor for Rituxan, an anti-CD20 antibody pulled from the MS market by Genentech/Roche because of exposure to generics competition. STX-100, an excellent program for fibrosis, is emerging into a rapidly evolving IPF treatment landscape (pirfenidone, nintedanib), and we’ll see if the company can eventually steer this drug into other indications, such as systemic sclerosis. The hemophilia biologics Eloctate and Alprolix are approved and launch-ready, with a consensus view that these will pull in 500MM over the first full year of sales, rising to 1BB by 2018. That’s already baked into the current forecasts.  The rest of the programs are as high risk as the anti-Lingo program, so let’s be conservative and assume half or more of these programs eventually fail. Point #2 is that the anti-Lingo program is high risk and can fail for a variety of reasons. At least three can be articulated. First, the therapeutic hypothesis, that axonal regeneration can be induced by a therapeutic in the setting of MS, has never been demonstrated. So there is an inherent biology risk. Second, the preclinical data package supports the hypothesis that blocking Lingo will improve myelin sheath regeneration and axonal function after insult or injury. However the preclinical package using MS animal models is very weak. Finally, the technical hypothesis, that sufficient quantity of antibody can be delivered across the blood-brain barrier in a robust and reproducible manner, patient to patient, has not been demonstrated. So there is an inherent technical risk. It’s also critical to note that the optic neuritis trial, the first Phase 2 to read out, perhaps addresses the therapeutic hypothesis (we could debate this, but won’t) but simply fails to address the technical hypothesis. Focusing investor attention on a Phase 2 readout in optic neuritis as a surrogate for efficacy in MS is a shell game that will go bad quickly if that Phase 2 trials comes in with negative results.

So we agree with CS that anti-Lingo antibody might work in rrMS, and it might not. We disagree that this program should be the focus of interest in the pipeline. We disagree outright with a few of their more outlandish predictions, including the statement that anti-Lingo “has potential in SPMS” the progressive and untreated form of the disease. There is no support for this statement. And while we agree that anti-Lingo is likely to be used in combination with other BIIB MS drugs, trials supporting such use are a very long way away. There is no basis to evaluate such a statement at this time. Finally, instead of concluding that pipeline focus on the anti-Lingo program is a positive, as CS does, we see this as a sign of a fundamentally weak BIIB pipeline.

Should we be surprised? Let’s consider that BIIB has not successfully developed a novel internal program since Avonex and Amevive, well over 15 years ago (yes there is Peligry, but that’s just pegylated-interferon, still, they did develop it). What else? Rituxan came from Idec. Tysabri came from Elan. Tecfidera came from Fumapharm. Daclizumab came from PDL Biopharma/Abbvie. Ocrelizumab came from Genentech/Roche. Long acting Factors XIII and XI came from Syntonix Pharmaceuticals. STX-100 is a BIIB moelcule but had to leave for 5 years in order to be successfully developed by Stromedix. In the meantime the Immunology Department has produced no drugs since it’s inception in the mid-80s, well over 20 years ago. The oncology experiment (BIIB San Diego) produced no drugs. The BIIB hemophilia group will produce no new drugs (more on this below). The medicinal chemistry effort has produced no drugs (although we think they will). The BIIB neurology research group has produced no drugs outside of the interferon space, although they are getting closer (anti-Lingo, BIIB037). So why is this company even competitive, indeed dominant, in MS?

The answer is simple and compelling. BIIB excels in the development of in-licensed, clinical stage MS programs. Look at what they’ve brought in and then brought to registration: Tysabri is the single best MS drug available (nothing else is even close); Tecfidera is the single best oral MS drug, and again it’s not even close; Daclizumab will present an extraordinary efficacy/safety profile, and so on. Let’s also consider that while BIIB was accumulating and developing these assets, their competition was developing cladribine, alemtuzumab (campath), lemtrada, aubagio and other hideous potions. Even Novartis came razor close to missing with Gilenya, a nicely efficacious drug that has a challenging toxicity history

Perhaps anti-Lingo antibody will join the BIIB parade of success in MS, but company management is not counting on it. When management set a goal of “400 in 5″ in 2012, they meant it, which means they cannot wait for anti-Lingo or any other early Phase 2 program to mature. This is our final point from above, that management will de-risk the pipeline. This means they have 2 choices, and they have been excellent at executing on either or both of these choices:

1) Buy a late clinical stage MS asset/company.

2) Cut costs in order to manage EPS aggressively.

A third possible outcome of course is that they will do both. A very interesting question is: what attractive MS asset/company could BIIB buy? There are some very compelling answers, and maybe we’ll share these, but not today. A less interesting question, because the answer is so obvious, is where to cut. Let’s go back to those hemophilia drugs, brought in on a wave of enthusiasm for the much broader hematology space. What happened? When costs needed to be trimmed a “strategic review” quickly revealed that hematology was not so attractive after all. So the hemophilia R&D group was slashed, and only the clinical programs retained. Note further that those Factor XIII and Factor XI drugs are utlilizing very valuable and expensive bio-manufacturing capacity for the company. What might happen here? BIIB could sell the programs for 10-20x annual sales to Bayer or Novo Nordisk and keep the manufacturing rights for 5 years or more. We’re just guessing, but we also think it’s a very good bet.

The other obvious target is the Immunology group. A possible hint here is that a new department has been formed, carrying the name Remodeling and Repair or something similar. The department is built around the very interesting Phase 2 fibrosis program STX-100, mentioned above. A simple decision would be to move the few Immunology clinical assets (the anti-TWEAK and anti-CD40L antibodies) under this new department, and jettison the Immunology Research efforts. Such a move would mimic what was done in the hematology space, and would further move the company further away from basic Research, which historically has failed to move therapeutics forward, and further toward Development: in-licensing, clinical execution, regulatory execution and bio-manufacturing, the company’s true core competencies.

Will BIIB do any of these things? We have no idea. But we have watched this company for a long time, and if top-line results fail to drive EPS to the goals promised, the company will act decisively to control the bottom line. Personally, we expect to see an acquisition in short order, rather than further cuts. Just to reinforce what we said at the beginning: the proposed corporate strategy fundamentally de-risks the impact on the anti-Lingo program on the company fortunes, leaving intact the potential for a large upside if that program performs well in the clinic.

disclosures: PDR was a senior member of BIIB’s Immunology department for a long time, and retains both positive and negative biases. PDR is also long BIIB stock.

stay tuned

Interesting Dilemma for Genzyme and Other MS Players in Europe.

Guest Blog Post courtesy of Stephen Ames – Life Sciences Analyst

As Paul mentioned in the first paragraph of his post, Aubagio recently received positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the EMA. The committee is recommending the granting of marketing authorization for the treatment of adult patients with relapsing multiple sclerosis, which is by far the most common form of MS. Additional marketing applications for the drug are currently under review globally.

But there is a limitation in the recommendation that may have important consequences in the MS market, and was a very disappointing piece of news for Genzyme (a division of Sanofi). Although CHMP did recommend marketing authorization, they did NOT recommend that Aubagio receive a “new active substance” (NAS) designation. This was based on their opinion that the drug is simply a revamped version of a much older drug. The outcome means that Genzyme gets fewer years of market exclusivity than they would otherwise, which clearly erodes potential profits. Why? Because generics companies won’t have to wait as long as usual to enter the market with a less expensive, bioequivalent version of Aubagio which would result in “generic erosion”, a reduction in potential profits for Genzyme’s sales of the drug.
The relatively quick introduction of generic Aubagio in the European market would not only dig into Genzyme’s sales, it would also likely result in revenue erosion in European sales for MS therapies produced by Genzyme’s competitors. MS therapies are some of the most expensive in medicine, and over the years many of their price tags have actually increased. A lowering of prices in response to an oral generic would be a market first. Ironically, generic Aubagio would likely also erode potential sales of Genyzme’s own MS drug Lemtrada which is currently under review and if approved, would hit the market in 2014.
To keep things simple here, it is fair to say that Genzyme has two choices when considering the European market. They can launch Aubagio and try to earn as much revenue as they can during the relatively short period of market protection, or they can decide not to launch, which would then preclude the entrance of generics in the EU market (generic drug companies cannot market drugs in a country where there isn’t a “reference” drug – in this case Aubagio) which means the company doesn’t have to spend for a rollout, and means that they won’t have to compete with generic Aubagio. The latter is a safe play and is probably what the competition in Europe is hoping for. Biogen-Idec, for example, is expecting EU approval of their first oral MS drug Tecfidera, and would clearly prefer to play in a market space without a competing branded oral and certainly without a generic oral. 
In my opinion, the former approach (marketing) is more likely. Even if Genzyme is granted only one year of market protection, the actual length of this protection is likely to be extended given the usual delays that historically accompany the process of getting generics onto the market. In addition, this window of time will allow the company to develop relationships with MS prescribers across Europe. This latter point is crucial because establishing this network will grease the rails for Lemtrada if approved.

Genzyme is planning to request a re-examination of the NAS decision, and so we’ll have to wait and see what comes of that step. This is an interesting story to be sure, and one that the field will be following very closely as it evolves.

By the way, Biogen-Idec received FDA approval to market Tecfidera in the US today.

A Science-Side Guide to the New Oral Multiple Sclerosis Drugs

Back to the blog now that I’ve settled into a new career (more on this another day).

Last week brought a wave of commentary on the evolving Multiple Sclerosis (MS) marketplace, as the European Medicines Agency (EMA) rendered positive opinions for two new oral drugs for the treatment of relapsing and remitting MS: Tecfidera (dimethyl fumarate or BG-12) and Aubagio (teriflunomide). FDA approval of Tecfidera is expected this week; Aubagio won FDA approval in September 2012. The focus of much of the discussion was the impact these new drugs would have on the companies that dominate the MS market: Biogen Idec, Novartis, Sanofi/Genzyme, Teva, EMD-Serono, and Takeda/Millenium. A summary of last week’s approvals can be found at FierceBiotech:

The consensus is that these new drugs will very quickly impact MS treatment paradigms and alter the fortunes of companies operating in this market. This is therefore a particularly good time to have a look behind the hype, and review the scientific rationale behind some of these new therapies. I’ll address the landscape with one eye on drug efficacy and one on known and potential side-effects of this new class of MS therapeutics.

The current stage was set in September 2010 with the approval of Gilenya (fingolimod), an S1P receptor modulator developed by Novartis. S1P receptors regulate a bewildering array of biological and pathological responses. Gilenya acts on at least 4 different S1P receptors, so formally speaking its’ mechanism of action in MS is undefined. It does appear however that the basis for the efficacy of this drugs lies in its ability to down-regulate the activity of the S1P receptor 1 (S1P1). S1P1 has many functions, including regulating the exit of lymphocytes, particularly T cells, from lymph nodes. Since all T cells that are in circulation will move through both the bloodstream and the lymphatic system, they all move through lymph nodes, which are organs that lie within lymphatic circulation. As T cells become trapped in lymph nodes, the number of circulating T cells in the bloodstream drops precipitously. In MS, autoreactive T cells use the blood circulatory system to gain access to the central nervous system (CNS) and attack myelin and other CNS antigens, thereby causing the disease. Gilenya is effective in MS because it prevents T cells from reaching the CNS, instead trapping them inside lymph nodes. This mechanism of action (MOA) is superficially similar to that of Biogen Idec’s Tysabri (natalizumab), a biologic drug that acts on T cells by preventing their exit from the bloodstream into the CNS (and other tissues). Both drugs therefore impact MS via effects on T cell movement. Tysabri is the single most efficacious drug developed for MS capable of reducing the annualized relapse rate by 68%. However, use of this biologic drug requires intravenous infusion (IV) and extended therapy is associated with a variety of side-effects, including the very dangerous disease PML. Its fair to say that Biogen-Idec has worked very hard at defining and managing PML risk associated with Tysabri use, and Tysabri continues to be a dominant drug in this market. I’ll come back to the efficacy and side-effect profiles of Gilenya in a bit, but first lets introduce the newer drugs.

Tecfidera was developed by Biogen Idec and is their first oral drug for MS. On March 20th the EMA’s Committee for Medicinal Products for Human Use (CHMP) issued a positive review of Tecfidera as a first-line therapeutic for the treatment of relapsing remitting MS. A positive CHMP opinion means that the drug is likely to be approved by the EMA for sale in the EU within a few months. FDA approval for use in the US is expected on March 28th. Tecfidera, like Gilenya, does not have a formally defined MOA, although there is good evidence to support the hypothesis that this drug primarily acts as an NRF2 activator. This is a compelling MOA, as NRF2 is a master regulator of the oxidative stress response. The drug may very well act on both the inflammatory response to myelin and other CNS proteins, blunting its intensity and impact, and directly on cells within the CNS, via cytoprotective effects. The efficacy of this drug was demonstrated in 2 large phase III studies (DEFINE and CONFIRM) and is impressive. Pooled phase III data showed reduced disease burden as measured by annual relapse rate (reduced by 49%) and identification of new or enlarged MS lesions (reduced by 78%) among other favorable outcomes. Equally compelling is the safety profile of this drug, with side-effects generally limited by unpleasant gastrointestinal (GI) symptoms including nausea, diarrhea and abdominal pain. For many patients these side effects wane after the first month.

Aubagio was developed by Sanofi and its’ subsidiary Genzyme. Aubagio is the teriflunomide metabolite of leflunomide, an approved drug for rheumatoid arthritis. These drugs are pyrimidine synthesis inhibitors that function by targeting the mitochondrial enzyme dihydro-orotate dehydrogenase. Inhibition of pyrimidine synthesis blocks DNA replication and causes cell death of dividing cells like activated T cells and B cells, thereby reducing lymphocyte proliferation. Not surprisingly, this class of cytotoxic drugs was first developed in the context of cancer therapy.

So with Aubagio we are back to effects on lymphocytes, presumably impacting activated T cell survival and function, reminiscent of Tysabri and Gilenya that also target T cell activity. Aubagio has a rather different efficacy/toxicity profile than the other drugs we have discussed so far. With a risk reduction of approximately 30% in annualized relapse rate, Aubagio has an efficacy profile similar to the beta interferons (Avonex, Betaseron, Rebif) and Copaxone, drugs that are delivered by cutaneous injection. On this basis, Aubagio would benefit from the fact that it is an oral medication, not requiring injection. The safety profile for Aubagio is perhaps more problematic, as this drug carries a black box warning for liver toxicity and is contraindicated in women who are pregnant or are likely to become pregnant due to concerns about teratogenicity. Also Aubagio is associated with increased susceptibility to infections, alopecia (hair loss) and GI effects.

Despite the safety concerns, Aubagio has attracted use among US neurologists whose patients want an oral medication, and this is despite the modest efficacy profile. This brings us back to Gilenya, the first oral MS drug approved in the US and EU. Gilenya is certainly efficacious, with a reduction in the annualized relapse rate of 54%, which is very similar to Tecfidera. Gilenya has a challenging risk profile, with a still poorly understood cardiovascular risk and a high rate of opportunistic infections. Recently, 15 unexplained patient deaths have triggered a review by the EMA that could lead to new safety warnings. Bradycardia continues to be an issue with Gilenya use, requiring patient monitoring after the first dose for at least 6 hours. Despite this safety profile, the efficacy of Gilenya has driven substantial use, and Novartis reported at the American Association of Neurologists meeting last week that no new toxicities have been seen in long-term extension studies.

It’s worth briefly mentioning two other potential oral medications for MS. Laquinimod is an immunomodulator from Teva and Active Biotech. Laquinimod’s MOA is not well understood. The drug has given mixed results in 2 phase III MS clinical trials, with pooled data showing only a 21% reduction in annualized relapse rate. A third trial is underway. The drug appears to be relatively safe, and may be appropriate for some patients although the limited efficacy will make wide use of this drug difficult to justify. Cladribine, from Merck Serono, is another drug that interferes with DNA metabolism and is broadly cytotoxic. It was withdrawn from consideration for use in MS after FDA rejection and negative EMA guidance. Cladribine was associated with an array of severe toxicities consistent with its cytotoxic MOA, including high risk of infection, neutropenia, liver toxicity, effects on the CNS and other side effects.

What we see then among the class of oral MS drugs is a spectrum of efficacy and toxicity profiles that will determine the evolution of their use in the context of existing injectable drugs. We see distinct mechanisms of action that will allow for class differentiation and, perhaps, for combination therapy. This latter goal, likely to be a critical development to stopping MS progression completely, will be achieved if, and only if, the toxicity profiles of potential combination therapies allow. In this regard the use of injectable beta interferons may be most compatible with the use novel orals like Tecfidera. A few combination therapy trials are underway.

Watch this space for further updates on developments in autoimmunity and oncology, my favorite subjects in drug development.

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