Category Archives: Gilenya

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

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


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.


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, number NCT00530348.


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.


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


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.


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, number NCT00548405.


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.


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.

ARR (across doses)
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.

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 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.

Gilenya and PML: cause, effect and risk

Today the FDA followed up on a case of progressive multifocal leukoencephalopathy (PML) in a multiple sclerosis (MS) patient, first reported in July, by announcing an investigation. FiercePharma spelled it out as follows: 

Novartis’ MS drug Gilenya tied to rare brain infection FDA sends out alert
That’s a pretty scary headline, and the news drifted across twitter streams like a dry fly on a light tippet. Novartis quickly declared that there was no indication that Gilenya caused the rare brain infection, the patient was on co-medications, had been given intravenous steroid treatment, etc. etc. 

Lets back up. 

PML is caused by an infection of the JC virus within the central nervous system (CNS). PML is common and almost always benign, unless it occurs in a patient who in severely immunosuppressed. Of note, PML first came to public attention in the early days of the AIDs epidemic, appearing in HIV patients whose disease had progressed to the point that they had no more T cells in circulation. T cells are a critical arm of the immune system, that, along with B cells and other cells, control pathogen infections, including viral infections.   

MS, as readers know, is a chronic inflammatory autoimmune disease in which T cells, B cells and other components of the immune system engage in a deranged attack on the CNS, particularly targeting the myelin and other proteins that encase neurons in a sheath (thus, the myelin sheath). Neurons stripped of myelin do not signal properly and die off pretty quickly. The disease occurs in flares, geographically localized. The product of a flare is a “lesion” within the CNS, where the effect of demyelination and neuronal die back can be visualized by an MRI image. 

So, immune system cells, particularly T cells, are necessary for protection from JC-virus induced PML on the one hand, and cause MS flares and lesions on the other hand. It should be noted that more flares = more lesions = MS relapse or progression = more disability. 

The interplay of immune defense or immune surveillance and the pathology of MS first came to light with the development of two powerful immune modulating agents: Tysabritmand Rituxantm. Tysabri is a monoclonal antibody to the alpha4beta1 integrin (thus, a4b1) developed by Elan and licensed to Biogen. Tysabri is the single most potent agent developed to date for the treatment of MS, and its mechanism of action suggests why this is so. T cells use the a4b1 integrin to migrate out of circulation and across cell layers like endothelium. To gain access to the CNS, T cells must cross an endothelial cell membrane, a layer of basement membrane and then an epithelial cell membrane. This collection of barriers between the circulation and the CNS is called the blood-brain barrier. Importantly, a4b1 is necessary for efficient trafficking of T cells out of circulation and into the CNS (also into the lung, the gut mucosa and other tissues). When a4b1 is blocked by treatment with Tysabri, which binds and neutralizes a4b1, T cell movement out of circulation is effectively stopped. Indeed one of the first effects of Tysabri treatment is a rapid increase on the white blood cell count, as T cells excluded from tissues begin to accumulate in the bloodstream (and lymph). 

Tysabri treatment reduces signs and symptoms of MS, reduces relapses, number of flares, time to flare, number of lesions, and disease progression. Tysabri treatment also puts patients at a low, but still troubling, risk of developing PML, since the population of T cells excluded from the CNS also include those T cells that normally would control JC virus. In this case the mechanism of action (MOA) of Tysabri contributes to the risk of PML, and this can be seen in patients treated only with Tysabri (as monotherapy) as well as in patients taking multiple medications. The risk is handled in several ways: patients are monitored for the presence of antibodies to PML, that indicate exposure and likely the presence of quiescent virus in the patient, and by temporarily suspending Tysabri use for several months, usually after 2 years and intermittently thereafter. Its not a well defined art at this point, but because of the efficacy achieved with use of Tysabri, most patients and their physicians tolerate the risk, now estimated at about 1% across all patient groups. 

PML in Rituxan treated patients presents very differently. Rituxan is an antibody that binds to CD20 expressed on the surface of B cells, and this binding causes the B cells to be depleted. The antibody was developed by Idec and acquired by Biogen when those two companies merged to become Biogen Idec. Before Rituxan was essentially removed from the clinical MS landscape – a truly scandalous story for another time – it had undergone clinical trials in MS, showing excellent efficacy and limited toxicity, which did not include PML. Rituxan causes PML very rarely, and almost exclusively in lymphoma patients, who have been treated previously or concurrently with chemotherapy. In other words, PML was seen in heavily immunosuppressed cancer patients. Rituxan is also used in rheumatoid arthritis (RA) and a host of other inflammatory and autoimmune indications, and the risk of PML in these patients taking Rituxan is at least 10-fold lower than in lymphoma patients taking Rituxan. This is because RA patients are much less immunosuppressed than cancer patients. What we see then with the risk of PML from Rituxan is that the risk is really dependent on the prior immune status of the patient. In this sense you would not make the claim that Rituxan causes PML, but rather that it contributes to the risk of developing PML. IN the same way, Tysabri treatment doesn’t cause PML, but also contributes the risk of developing the disease. It is the case that the risk is higher with Tysabri than with Rituxan. 

Why Rituxan treatment allows JC viral escape and the occurrence of PML is a result of the depletion of the B cells that Rituxan targets. B cells make antibodies to pathogens, including anti-JCV antibodies, and this contributes to the control of virus by clearing both free viral particles and infected cells. Further, B cells supply “help” to T cells by secretion of cytokines and other factors that induce T cell survival, proliferation and function. So, T and B cells together are required for efficient JC virus control, although the available data suggest T cells are more directly critical. 

OK, back to Gilenya. I guess it was 4 or so years when the phase 3 data was coming out that I had a conversation with Jeff Browning, then at Biogen Idec and now at BU, about the results. He said something along the lines of, “sure, impressive results, but wait until they start to get PMLs.” 

Prescient, and certainly a well informed view. Jeff, myself, Paula Hochman (all from Biogen) and Reina Mebius (a key collaborator) along with a host of colleagues both inside and outside the company, had reinvigorated the study of lymph node biology in the mid-90s by unraveling the mechanisms by which these organs develop (search PubMed if interested), and as the field literally burst with new findings, attention turned to the control of lymphocyte (T cell and B cell) movement through the lymphatic system, within which lymph nodes are the critical organs. Lymph nodes (LN) provide the essential microenvironment for surveillance of tissues, including the CNS. Many labs unraveled the biology of cell traffic through LN, but it was Jason Cyster at UCSF who discovered that an agent in clinical trials called FTY720 functioned by shutting down the molecular pathway that allows T cells to exit LNs. The molecular pathway was driven by a bioactive lipid called sphingosine 1 phosphate (S1P). S1P bound and signaled through a class of receptors (the S1P receptors) and S1P receptor 1 was shown to be critical for T cell egress from LN. 

FTY720 became Gilenya. Thus, the mechanism of action of Gilenya is eerily similar to that of Tysabri – it controls the trafficking of T cells, in this case by trapping them inside of lymph nodes (B cells as well, although not so completely). The fact that Gilenya treated patients do not develop lymphadenopathy(LN enlargement) suggests that these trapped T cells die off. Gilenya treated patients experience a rapid drop in circulating white blood cell number – the opposite of what is seen in Tysabri treated patients – but the net effect is the same: T cells do not access the CNS, and therefore the signs and symptoms of MS are reduced, the relapse rate drops, the number of new lesions drops, etc, more or less similar to Tysabri treatment, albeit somewhat less effective. Gilenya has a host of non-immune system toxicities, which we won’t discuss here, but until July, Novartis, who developed the drug, had reported no patients with PML. 

Now, back to the headline. What Jeff Browning had recognized was that by its’ mechanism of action of Gilenya should increase the risk of PML, just as Tysabri increased that risk. Both stopped T cells from entering the CNS, by different mechanisms, and therefore both should prevent immune defense against JC virus in the CNS. Furthermore, the degree of risk should be proportional to the extent to which the exclusion of T cells was achieved. Since the efficacy of the drug should also be proportional to the extent to which t cells were excluded from the CNS . . . it follows that efficacy and risk of PML should be correlated. 

When Novartis states that Gilenya does not cause PML, they are being accurate, as accurate as when we state that Tysabri and Rituxan do not cause PML. More importantly and usefully, Gilenya is now hypothesized to be associated with the risk of developingPML, although it’s certainly a low risk. More specifically, the null hypothesis should be that Gilenya is associated with PML risk, based on its’ mechanism of action, and regulatory agencies and physicians should take note accordingly. 

We’ll watch out for other cases and comment as the clinical landscape develops. 

As always, stay tuned. 


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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