A new treatment called Ocrelizumab has been found to have a positive effect on RRMS, but the nature of the market could mean it stays an expensive drug.

Hope in the MS world

In the MS world there is much reason for hope. On an almost weekly basis there is news of a scientific breakthrough in our understanding of the disease, a potential cure, or a new and exciting treatment, and Ocrelizumab (Ocrevus) is certainly one such treatment.

In November 2017, the European Medicines Agency (EMA) granted marketing authorization to Ocrelizumab as the first licensed treatment for primary progressive MS (PPMS) and also for its use in relapsing remitting MS (RRMS).

The EMA recommendation followed approval in the United States, Australia and Switzerland. In two studies of 1,656 patients with RRMS, the average number of relapses in patients treated with Ocrelizumab was about half that in patients treated with Interferon beta-1a (0.16 vs. 0.29 relapses per year).

Whilst this is impressive, the bigger news came in a third study of 732 patients with PPMS. It showed the group taking Ocrelizumab reduced their chance of worsening disability after 12 weeks by a quarter (24%), compared with those taking a placebo.

This is truly newsworthy, as there has never been a treatment for PPMS, an especially relentless and aggressive form of MS. Many of those affected by PPMS could quite rightly have felt abandoned by the medical community in the past, as they watched drug after drug being released to treat RRMS; the most common form of the disease, but with little hope of a breakthrough that could help them in their fight.

The reason for this lack of progress was in no doubt partly due to difficulty in understanding PPMS. Some argue it is a clinically distinct form of the disease, with little similarity to RRMS, whilst others say they are just different ends of the same spectrum.

Research and funding

But perhaps another reason for this is simpler than needing to unravel the complicated biology of disease. We all know that companies largely exist to make profit, and pharmaceutical companies are no different.

Could it then be argued that as only 15% of MS cases are primary progressive (approximately 375,000 patients worldwide), there just wasn’t the market to invest the funds needed into research and development compared with the more lucrative RRMS, which makes up eight in every ten cases of MS first diagnosed?

There is another interesting aspect to consider. You see, Ocrelizumab isn’t really that new at all. It is the pharmaceutical offspring of another drug, Rituximab (Rituxan), which has been around since 1998. Initially it was a treatment for the blood cancers of lymphoma and leukemia, but it has also been used off-label with great success in the treatment of MS.

Studies showed that in RRMS, those given a single dose of Rituximab had significantly fewer relapses and lesions on MRI, an effect that remained after 48 weeks. In Sweden, where doctors have greater freedom to prescribe drugs for their patients,

Rituximab is estimated to be used in 3,500 people with MS (pwMS). Doctors and patients alike realize its benefits. It is given as a single infusion once or twice a year, doesn’t carry many of the side effects of the other MS drugs that can so negatively impact on daily quality of life, it’s relatively cheap and most importantly it works in treating the disease.

In another recently published study of 494 MS patients, it was shown that in newly diagnosed RRMS, those taking Rituximab were significantly less likely to stop taking their therapy than any other disease modifying drug (DMD).

It also performed better in terms of relapses and new MRI lesions than the injectable DMDs and Dimethyl Fumarate (Tecfidera) with borderline benefits compared with Natalizumab (Tysabri) and Fingolimod (Gilenya). Overall, they suggest that Rituximab outperforms the most commonly used MS medications. But unfortunately, few other pwMS around the world have access to Rituximab.

The main reason for this is that it never completed a phase III clinical trial, the gold standard required of a drug before it can be licensed to treat a disease. The makers, Roche Holding AG, never put it forward for this and have never tried to market its use in MS, instead they chose to develop Ocrelizumab.

Patents

It should be noted that this is a common practice within the pharmaceutical industry. When a drug is being developed, it has a patent usually lasting twenty years. During this time, no other company can manufacture the drug, allowing the owners time to recover the costs incurred in development and testing.

At the end of the patent period however, any drug company can make the drug, introducing competition and driving down costs to patients.

That is the reason, for example, you can buy generic paracetamol (acetaminophen), as well as branded Panadol in the U.K. The patent for Rituximab expired in 2016. This minor tweaking of an old drug to create a newly patented product is both commonplace and in no way illegal but does drive up costs. Prof. Stephen Hauser, of the University of California in San Francisco, led MS trials for both Rituximab and Ocrelizumab. He says that while the two drugs have minor differences, doctors and patients must decide whether it’s worth buying Ocrelizumab, which is:

“10% more effective, 10% easier to administer, but 10 times more expensive”.

Ocrelizumab costs $65,000 per year, while Rituximab costs around $2,400 annually in Sweden, or $8,000 - $10,000 in the U.S. for those who can get it. The two medications work in the same way. They are both antibodies artificially manufactured to attack a part of the immune system called the B-cell (CD-20).

Until recently, many scientists didn’t think B-cells played a part in MS, and many still don’t, but the trial results certainly indicate they are involved somewhere in the disease.

The structural differences referred to are essentially in the types of protein building blocks that make up the antibody. Ocrelizumab has more protein from humans and less from mice than Rituximab.

Roche state that this will cause fewer side effects and patients will not become resistant to the drug over time, so it is specifically engineered for long-term use in chronic diseases. The hard work seems to have paid off, the launch of Ocrelizumab has so far generated nearly $200 million in sales, making it Roche’s most successful launch ever.

With approval now given in Europe, it is predicted that profits will top $3.5 billion annually by 2021. So this then is a story of a growing drug family that can give us reason for great hope, perhaps tinged with a little frustration at the manner in which the system operates.

Ocrelizumab is without doubt another potent weapon in the MS arsenal and the first to be shown to be of benefit in PPMS, which is news for great celebration. Just exactly how it is deployed by your local health service remains to be seen, but it will almost always come down to cost as much as the potential benefit to the patient.

Perhaps let us wish then that each of our own little corners of the world can become just a bit more Swedish, and not just in terms of flat-pack furniture and gripping detective dramas!

Dr Jonathan White MBChB MRCOG

 

Update May 2019: Ocrelizumab (Ocrevus) Gets NICE Approval for PPMS!


References:

  • Bloomberg: How Roche Tweaked an Aging Drug to Keep Profits Rolling In
  • JAMA Neurology: Comparative Effectiveness of Rituximab and Other Initial Treatment Choices for Multiple Sclerosis
  • European Medicines Agency: New medicine for multiple sclerosis
  • European Medicines Agency: Ocrevus
  • New England Journal of Medicine: B-Cell Depletion with Rituximab in Relapse-Remitting Multiple Sclerosis
  • Forbes: Solving The Drug Patent Problem
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