After many years of near-stasis in multiple sclerosis, the international MS meeting ECTRIMS revealed the extent of change in the space. Where injectables like Copaxone and the interferons have dominated treatment of the neurodegenerative condition since the mid-1990s, it is now looking like as many as four oral agents could be on the market in the next two to three years, whilst antibodies could be taking a bigger role in the near future.
With Novartis’ pill Gilenya already on the market and Biogen Idec’s BG-12 likely to be filed next year, ECTRIMS demonstrated that oral agents will be moving up in treatment algorithms as doctors and patients become increasingly comfortable that these novel treatments are safe as well as effective. With mixed trial results for others, however, the future of those candidates may lie in combination therapies or as lower tier treatments as specialists seek to stave off disability or prevent relapses.
At the top
If Biogen Idec’s performance in executing its clinical plan for BG-12 and reviving the fortunes of Tysabri were the spotlight moments of ECTRIMS, the scientific confab also included cautionary statements from presenters and observers that the full potential of the Massaschusetts company’s offering will not be known until tests against existing therapy have been completed.
As EvaluatePharma forecasts stand now, Copaxone will retain its title as the top-selling MS therapy in 2016, 19 years after it was introduced, with $2.59bn in sales (Copaxone just holds MS top spot in 2016 as oral therapies grow, October 19, 2011). But as a sign of the change in market expectations, the number two spot will be held by Gilenya, in spite of physicians’ concerns about adherence for a once daily drug and the requirement that patients undergo six hours of monitoring following the first dose because of slow heart rates.
With BG-12 performing as well as it has in trials – and with the potential for the Confirm trial results to be disclosed by year’s end to demonstrate superiority over Copaxone – there seems to be little doubt that there will be a significant share of MS patients taking it. The question is whether the Confirm trial will show superiority or merely non-inferiority to Copaxone; if the former is the case BG-12 could threaten Gilenya's number two slot, while if the latter is the case switching to the pill may be more gradual.
Tysabri, meanwhile continues to remain a backbone in treatment, as a body of evidence supporting its safety in patients without the progressive multifocal leukoencephalopathy-causing JC virus, and in those with shorter treatment durations, has meant dramatic upward revisions to its 2016 forecast, which has nearly doubled to $2.56bn in the past year - helped, no doubt, by its best-in-class relapse rate reductions of 63%.
Laquinimod continues to lag
What Ectrims did for laquinimod was help to confirm the drug’s position as an also ran in the MS field. While doctors remained impressed by its ability to reduce disability progression, 33.5% versus 28.7% for patients on Avonex, the drug again fell short on its ability to prevent relapses. Laquinimod’s 23% reduction in relapses is the lowest rate for all of the current crop of new MS drugs.
This left some doctors questioning whether the drug would have shown better relapse reduction scores at a higher dose, and if Teva’s decision to use a lower dose in order to avoid some of the cardiac issues thrown up in earlier trials had been the right one.
Relapse rates aside, laquinimod’s clear neuro-protective properties naturally suggest that it could be used in patients with very mild MS symptoms or in combination with other drugs demonstrating higher relapse rate prevention. However, Dr Eva Havrdova of Charles University, Prague, argued one of the problems with this approach would be reimbursement in class that is already predicted to command high prices.
“You can do combinations in oncology because in three years the patients are dead, they [combination drugs] are never used for 20 years, which is how long treatment can be in MS. So here you will have to have cheaper drugs because you are using them for such a long time,” she said.
Pregnant pause for teriflunomide
Although it displayed no safety signals, teriflunomide failed to make much of an impact at Ectrims due to its perceived lack of efficacy compared with BG-12, a 31% relapse rate prevention versus BG-12’s 53%, and also the concerns over its effects on pregnancy.
Over 70% of MS patients are women, with many of them of childbearing age, given that symptoms of the disease often start in the late 20s or early 30s. While no MS drug is safe to take in pregnancy, with the exception of Copaxone, there has been much focus on the side effects of teriflunomide, meaning that many see its use being limited to the smaller populations of men and women past the menopause. Analysts at Bernstein also believe its lower efficacy rate would mean that doctors would be unlikely to switch patients from injections, despite its more convenient oral administration.
Big maybe for the mabs
The other disappointing section of the conference were the handful of antibody treatments for MS, all of which continue to throw up worrying safety signals that had many doctors reserving judgement on their use. “People will be come more comfortable with antibody treatments over time if there are no safety issues, but it is good we are finally looking at the genetics of this disease,” said Dr Daniel Kantor, a clinician from Ponte Vedra Beach, Florida.
Lemtrada, which had hoped to make waves in the space due to its infrequent dosing schedule, was not only derailed by failing to show clinical significance against older interferon Rebif in disability progression, quashing some of the hopes that the drug could actually reverse disability, but again displayed a range of adverse events including 30% of patients developing a autoimmune thyroid-related disorder and several cases of blood disease, immune thrombocytopenic purpura (ITP).
The disappointing data and the drug’s safety profile, that would require a strict REMs programme, have almost certainly moved it into the third line behind the likes of Tysabri and Gilenya; the only hope of pushing it up the ranks rest in results from the phase III trial Care MS-2 due by the end of the year. But it is not expected that the drug will show the disability reversal shown in phase II trials that intially got observers excited.
Lead investigator, Professor Alistair Compston, head of the Department of Clinical Neurosciences at Cambridge University was, however, still positive that the drug could play a part in MS treatment. “This is unique in that it is targeting the very early stages of the disease before people start to show any disability. I don’t think that the thyroid changes are an issue, roughly 2% of the UK population have thyroid disease. ITP is, however, more of an issue, but if it is detected it is treatable and curable.”
Like Tysabri before it, the immunosuppressant daclizumab has shown promising efficacy, but has set off alarm bells on safety – elevated liver enzymes in the phase IIb Select trial but, more seriously, a death related to a psoas abscess (Daclizumab dazzles on efficacy but sours on safety, August 10, 2011). However, it is surprising, and perhaps a demonstration of the differences in views between the investor and physician communities, that the specialists attending ECTRIMS did not raise questions about the death when the Select trial data was presented.
Professor Gavin Giovannoni, professor of neurology at Barts and the London School of Medicine and Dentistry who presented data on the monthly injectable antibody, said the abscess was discovered on a post-mortem examination, and the treating physicians had not been providing therapy for such a condition. Elevated liver enzymes, meanwhile, are manageable using protocols similar to interferons, Dr Giovannoni argued.
There were clear winners and losers from ECTRIMS this year. What the conference made most clear, however, was that the growing number of agents currently in development will importantly not only give specialists the opportunity to combine drugs and attack different aspects of the disease, but also offer patients much needed choice in this difficult progressive disorder. "
MS is really a group of diseases and what is great is that we now potentially have a range of drugs to choose from," said Dr Havrdova.