Category Archives: BG-12

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.