Silva GD, Castrillo BB, Apóstolos-Pereira SL, Callegaro D. Is there a role for off-label high-efficacy disease-modifying drugs in progressive multiple sclerosis? A network meta-analysis. Acta Neurol Scand. 2022. doi: 10.1111/ane.13697.
Ocrelizumab and siponimod are the two on-label drugs used for progressive forms of multiple sclerosis (PMS). However, many patients with PMS do not have access to these high-efficacy disease-modifying drugs (DMDs). Off-label prescription of other high-efficacy DMDs (fingolimod, rituximab and natalizumab) may be a strategy to improve access to immunotherapy for these patients. We aim to compare on-label and off-label high-efficacy drugs for their effect on disability progression in PMS. In December 2021, we searched MEDLINE (PubMed), Embase, Cochrane Central and Scopus databases for randomized clinical trials involving patients with PMS. High-efficacy drugs were considered as intervention and placebos as comparison. The outcome contemplated was risk of Expanded Disability Severity Scale (EDSS) progression at 2 years. A network meta-analysis was performed to compare the relative risk of EDSS progression at 2 years compared with placebo in on-label and off-label drugs. We included five studies with 4526 patients. The median EDSS progression at 2 years in patients that received any immunotherapy was 30%, compared with 35% in placebo groups. Overall, the risk of bias of individual studies was low. Network analysis revealed overlapping confidence intervals in off-label drugs (CI95% 0.51-2.16) versus ocrelizumab (reference) and off-label drugs (CI 95% 0.53-1.96) versus siponimod (reference), suggesting similar efficacy. The same result was found even after excluding studies with the risk of publication bias. Off-label high efficacy immunotherapy in PMS has biological plausibility and presented similar effectiveness to on-label DMDs in this network meta-analysis. The use of fingolimod, rituximab or natalizumab may be a strategy that reduces costs and improves access to immunotherapy for patients with PMS.
The cynic in me asks about whether we are being deluded when we think it is about having “cheap drugs” to treat MS. If you ask a basic scientist about choices for drugs they will select agents based on cost if the off-label agent has the same efficicay/side effect profile as the same as the licenced product. Some neurologists have the same view. However we have to remember that pharma has paid many millions to show their drugs work in secondary progressive /primary progressive MS. Should they not be able to recoupe costs?
Fingolimod verses siponimod are they the same? In the US they suggest yes as they have the same use indication based on the Label issued by the FDA. However, in Europe siponimod is currently licenced for active secondary progressive MS but fingolimod is licenced for highly active relapsing MS. Now I must say I dont think these differences are really based on biology. But are they the same? Fingolimod binds to S1P1, S1P3, S1P4, S1P5 receptors, has to be activated to become active and takes time to be broken down. Siponimod binds S1P1, and S1P5 well , does not need to be activated and is broken down more rapidly. Importantly when it was developed siponimod didn’t bind to S1P3, so it was thought that it would not induce the heart arthymias associated with fingolimod, because in mice this is controlled by S1PR3. However in humans this appears to be a load of tosh and the heart athrymias are probably a product of S1PR1 so they both, as well as ponesimod and ozanimod, have the issue. However fingolimod failed in the trial of primary progressive MS, siponimod was active in secondary progressive MS. Is there a difference or is it just because the manufactureres learned how to do progressive MS trials to see a positive. Indeed they learned from the percieved failures with rituximab, fingolimod and natalizumab. I say percieved ” because the current study argues that fingolimod is the same as siponimod as the confidence interval passes through one. However, the confidence interval is large (CI95% 0.51-2.16) suggesting it could be twice as good (e.g. 0.5) or twice as bad (e.g. 2.00). However, because siponimod does not have to be activated by sphingosine-1-phosphate kineses does that mean it could work better in the brain than fingolimod. Is it because ocrelizumab is a better killer of B cells than rituximab or is it by doing the right trial.
However, we see lots of papers harping on about costs and the evil pharma who are fleecing you/us with high- drug costs. However it depends how you finance treatment. In the US, health is a big business and you are paying top dollar and CEOs need fat salaries, so you get the haves and have-nots in Society without access to the same treatment. It is a monster that has been allowed to grow and something that the “haves” have fostered as they and their politicians have gone along with it. Companies make more but you get innovation and something new and better….Is this the American Dream?
The companies get big bucks whilst they have a patent. They try to extend this life by filing follow-on patents. The typical patent lasts 20 years but for neurological conditions, it often takes about 15 years to develop so you have a short time to claw-back the investment made) and this can be for a long long time as seen with glatiramer acetates, invested in 1970s patents expire about 2014. Whilst there extending patents are often based on a new dosing schedule….which typically seem obvious (a reason to stop a patent being successfully defended) to me….and so are rapidly challenged. This is done to stop the originator filling their pockets too much. However, I think once the patent life is about to expire, the generic companies often go after the original patent, becuase if they can show this is no good then there is going to be no hurdle for the generic companies to come into the market. The drug costs tumble but they still make enough from the pharma trough to be profitable, but once the patent life goes price competition can start. A good example of a patent with holes in it is one from ProfG and ProfKappor about phenytonin and progressive MS, in the patent it talks about a meetings report published years early showing the inventive step….However because the meetings report is “public disclosure” before the patent was filed, the patent would have been undefendable. Yes an extreme example but it it occurs.
Now in rituxiland they use alot of rituximab which is off-label to ocrelizumab. They both deplete CD20-B cells. However I think the neurologists are in control of their budgets so it makes sense to get a bigger bang for your buck. In the UK the cost is born by the government and so the decisions on prescriptions are based on government guide lines (NICE) and the government stance is to be pro-pharma and promote on-label use of drugs and innervation. So NHS england I understand do not re-imburse the use of rituximab. My experience trying to develop a generic for MS (i.e. cladribine) was that you would have to jump through the same hurdles as pharma and they want to encourage innovation. How many MS drugs have come from rituxiland? Hoewever, I applaud the neuros who are giving their patients options
Disclaimer: This views are made by the author nd no body elsebut are not necessarily the position of the author a
It’s now difficult to get neuros to prescribe and administer Rituximab. They push Ocrevus out as it’s apparently better. Really? (What a coincidence that the Rituximab patent was running out… )
it is surely safer if doctors stick to on-label drugs e.g. something happen when they give you rituximab and they are sued?
Changing things as patent lifes disappear is not unususual e.g. once a day glatirame acetate 20mg was replaced with 40mg twice weekly, pegylated interferon appeared as beta interferon patents expire….what comes next after natalizumab?
why would authorities approve these changes? how could pharmas argue theres a benefit? is the world insane?
It’s the way the world is I’m afraid and the thinking goes if companies can see they can make profits in a clinical arena such as MS then more companies will enter the field. This has undoubtedly been the case, with many more companies in the MS field than there used to be. Unfortunately, the downside is that much less effective drugs have their prescribing life extended and are continued to be prescribed by lazy risk-averse neuros (there were other inducements way back when). So, all in all, it’s a bit of a double edged sword but if patent extension was not possible, then a highly effective drug such as Cladribine would have been lost.
” …innovation and something new and better….Is this the American Dream?” I think so, but how much better is better and I’m so damn tired of new stuff! I used to know everything. Now I know nothing.