Monthly Archives: March 2013

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: http://tinyurl.com/cekba9r.

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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