#ECTRIMS2019 – Are Injectables Inappropriate for Active Relapsing MS Treatment?

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by Ana Pena PhD |

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use of injectables

With more high-efficacy therapies becoming available, is it now inappropriate to prescribe older injectables — interferon beta and glatiramer acetate — to people with active relapsing multiple sclerosis (MS)?

This question was at the core of what was called a “burning debate” at this year’s European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Conference, recently held in Stockholm, in which two speakers discussed the benefits and risks of low- versus high-efficacy disease-modifying treatments (DMTs).

Gisela Kobelt, PhD, a health economist and president of the European Health Economics Association in France, supported the use of high-efficacy therapies as a first-line treatment, whereas Magd Zakaria, MD, a neurologist, professor, and head of the MS unit at Ain-Shams University in Egypt, argued in favor of older DMTs for first use.

The debate was broadcast, and the audience was encouraged to participate by tweeting comments and questions using #burningdebate. At the end, the audience voted to name the winning debater through Twitter.

Older injectable use is inapproppriate

Kobelt argued that ample data from both clinical trials and real-world practice favor newer disease-modifying treatments (DMTs). DMTs used as second-line treatments, compared with first-line injectables, offer benefits in several clinical outcomes, namely annual relapse rates, disability progression, treatment resistance, and health-related quality of life. 

Use from the start

Early intervention is key.

“We really have a window of opportunity,” Kobelt said. “The disease starts even before we can see anything,” and quality of life deteriorates as the disease progresses, so the opportunity to make a change is at the beginning of the disease process.

Kobelt led a large study looking at the cost-effectiveness of MS treatments in Europe, which included 16,808 patients, approximately half of whom had relapsing-remitting MS (RRMS). Results showed that costs and utility (meaning the patient’s quality of life) were highly correlated with disease severity and progression.

In fact, some researchers suggest there are two stages of disability progression, one stage at Expanded Disability Status Scale (EDSS) 1–3, and another thereafter. These two stages are not linked, and the predictive value of relapses only work for the first stage,” she said. “As we reach EDSS 4, the train has left the station.”

The same is true for costs, which increase with disease severity. Shifting the cost curve when disability is already high “doesn’t really make a dent in the budget,” but intervening early does, she said.

“I’m arguing that we should use the cannons early in the life of the patients, and we should not use the water pistols,” she said.

Data shows there is a lower risk of conversion to secondary progressive disease (SPMS) when newer therapies are used in patients who have not received prior treatment (treatment-naïve).

Several studies have shown that therapies such as rituximab and Tysabri (natalizumab) are effective for RRMS when given earlier, i.e. in untreated patients and those with less disability.

“Here is my premise — we should continue using [the older treatments] but as placebos,” she said.

Market for MS treatment “not efficient”

Although the effectiveness of many MS treatments has been questioned, “the prices in the U.S. since approval have gone up six times, and they’re all at the same level of prices — that makes no sense to me, honestly,” Kobelt said.

“MS drugs are definitely not cost-effective in the way they are used,” Kobelt said.

And older first-line therapies became not cost-effective very quickly after entering the market, she said. “The minute that you come into the real world, you are no longer looking at a defined population; you’re looking at Mr. and Mrs. Everybody, and therefore, the effect is less, compliance is less,” she explained. “So the effect is no longer what we’ve seen in trials, and it’s definitely not related to the cost.”

Kobelt said she is “shocked” that many patients at EDSS 7–9 are being treated with DMTs. “Who has ever shown that interferons or the first-line, or even the second-line drugs for that matter, are effective at EDSS 7-9?

“I think here we’re wasting our resources, and making the whole thing not cost-effective because we are spending, but we don’t get any effect, because they don’t work at that stage,” she said. “If you compare a new drug to something that has no effect and only cost, it’s very easy to be cost-effective. But you’re completely outside the realm of where things are efficient.”

In addition to decreasing prices, she proposed a delisting or a dramatic reduction in prices of BRACE (Betaseron, Rebif, Avonex (all interferon beta-1a), Copaxone (glatiramer acetate), and Extavia [interferon beta-1b]), and the use of biosimilars at a large discount so they can be used as a “placebo.”

“We still don’t know if the effect that we see is actually due to the drug … rather than to patients being take care of very well,” Kobelt said.

To improve the cost-effectiveness of MS treatments, “we actually have to work together with authorities. That should allow much wider access to these drugs, also in jurisdictions that have not yet the economic power to use them for all patients. At minimum, we should reduce the prices outside OECD [Organisation for Economic Co-operation and Development] countries.”

Patient follow-up and a continual reassessment of results is necessary, she said: “We cannot wait another 20 years to even ask the question whether what we are doing is right.”

Older injectable use still appropriate

In his presentation, Zakaria started by saying his mission “is not to show you that these injectables are the best medication, nor to show you they should be given to any case of active MS. My mission is to raise reasonable doubts among you that although their role is declining, they do not deserve to be excluded from the management spectrum.”

First-line therapies are prescribed to active MS patients who are “early in the window of opportunity and have good prognostic signs.” For this group of patients, neurologists’ “first concern would be safety” so they use the maintenance-escalation approach.

Zakaria points out that he is not talking about highly active or aggressive MS here, but active MS, which is generally milder and defined as the occurrence of relapses or MRI activity, or both, with minimal disability.

So first-line injectables are not “inappropriate in general,” he said. And they should be compared with newer first-line treatments used in active MS, such as Tecfidera (dimethyl fumarate), Aubagio (teriflunomide), and Gilenya (fingolimod).

Misleading comparisons

Regarding efficacy, most of what we know comes from randomized controlled trials. “These represent the highest level of evidence-based medicine,” Zakaria said.

But a common error is to compare the relative risk reduction (RRR) — a statistical measure of efficiency — of a given treatment in one trial with that of another treatment in a different trial.

We “automatically assume that drugs with a higher relative risk reduction are more effective than drugs with a low relative risk reduction. In fact, most of the perceived low efficacy reputation of the injectables come from this.”

But RRR is “not an absolute number; it’s a relative number.” Taking relapse rates as an example, the RRR does not tell us if the treatment prevented just a few or many relapses.

In contrast, the absolute risk reduction (how many events a therapy prevented) and the number needed to treat (the number of people needed to treat to prevent one relapse) “give the clinical meaning,” Zakaria said.

In an article discussing the limited value of RRR, Zakaria shows that older medications — interferons, glatiramer acetate, and Tysabri (natalizumab) — have a lower RRR than oral medications — Gilenya, Aubagio, Tecfidera, and Mavenclad (cladribine). But the absolute risk reduction and the number needed to treat is “much better” with the older medications.

“Of course, this does not mean that the old medications are more effective; it simply means … that in the old trials, this 33% relative risk reduction was more clinically meaningful than the 55% in the recent trials, as reflected by a lower number needed to treat,” Zakaria said.

“Cross-comparison between the different trials for relative risk reduction is wrong,” he added. “Direct head-to-head comparative trials is the best way to assess the relative efficacy of different drugs.”

First-line injectables equally effective

Zakaria gave several examples of head-to-head trials and real-world studies where injectables demonstrated equivalent effectiveness to oral treatments for relapsing MS.

But, he says, “the highest evidence in favor of injectables” comes from a 2019 study based on a 10-year prospective analysis involving almost 5,000 patients in the U.K., which investigated the long-term effectiveness of interferons and glatiramer acetate, particularly in terms of disability progression.

After 10 years, there were clinically significant benefits both in terms of disability and quality of life measures. Importantly, these treatments enabled a four-year delay in reaching EDSS 6. “These are very strong conclusions,” Zakaria said.

According to Zakaria, another factor to keep in mind is that there appears to be a decrease in these medications’ effectiveness over time. In addition, those who seem to benefit the most from injectables are “women with early relapsing multiple sclerosis and early treatment,” he said.

“So, there’s no solid evidence that the oral first-line therapies are more effective than injectables.” Yet, they are still present “in all the current guidelines as first-line therapies,” he said.

Injectables are safe

First-line injectables have a “very well-classified” and the best safety profile of all the available treatments for MS, and their monitoring burden is minimal, Zakaria said. 

With 25 years of experience in the market, they have not been associated with opportunistic infections or malignancies.

According to Zakaria, issues with injectables include adherence (compliance with treatment) and persistence (continuing treatment). However, non-adherence is not only a problem of injectables, but also of oral therapies.

Among others, a U.S. study shows that over the first one to five years of treatment, 25–40% of injectable users and nearly 30% of oral therapy initiators had stopped treatment or were considered non-adherent.

The good news is that it is possible to change patients’ adherence and persistence, Zakaria said: “You can change it by sharing decision-making; you can change it by motivation; you can change it by frequent counseling; you can change it by electronic devices, by auto-injectors.”

Another important topic when referring to safety is pregnancy, which “is definitely one of the strongest points of the injectables,” Zakaria said.

No wash-out period is required, and the label of many of these injectables is currently being re-evaluated to be used during pregnancy. Both ECTRIMS 2018 guidelines and the U.K. consensus agree that injectables, interferons included, can be used until pregnancy is confirmed, or until conception.

Findings from the German MS registry, accompanying 251 pregnant women exposed to interferons during the first trimester, and 194 women non-exposed, showed no differences in birth weight, birth length, spontaneous abortions, or congenital anomalies.

In contrast, in clinical practice, experts recommend stopping Tecfidera before conception, although preliminary data suggest it may be safe for pregnant women.

Cost-effectiveness not comparable across countries

Cross-country comparisons regarding cost-effectiveness are not valid, Zakaria said.

Cost-effectiveness thresholds (which define whether a given treatment is cost-effective) greatly vary between low- and middle-income countries. They depend on each country’s gross domestic product per capita (GDP). According to the World Health Organization (WHO), to be cost-effective, a treatment should cost less than three times the GDP for each disability-adjusted life-year (DALY) prevented.

Zakaria also noted that in the EU’s Big 5 economies (France, Germany, Italy, Spain, and the U.K.) “you have at least 37.6% using injectables.”

If you see that a patient profile “can still benefit from the first-line injectables, then I urge you not to exclude them from the management spectrum of MS,” he concluded.

Final remarks and poll results

In his final remarks, Zakaria said: “As clinicians, the important thing is to have close communication with your patient. Even if you use a medication that is under question … the important thing is to follow the patient closely. As long as the patient is benefiting — whether he is benefiting really or is a placebo effect — then you can continue on.”

“We should question what we do. If a drug costs very little, if it’s a cheap placebo as I said, and it doesn’t harm the patient, I’m OK because it means the patient gets taken care of. But if we have a price level in Europe of 10,000 euros a year … then I think we are not spending the resources of society wisely,” Kobelt said in her concluding statement.

Before the debate, the poll results on Twitter showed that 54% of those who voted agreed that injectables were inappropriate, while 46% disagreed. At the end of the presentation, however, the result shifted, with final results showing 40% agreeing that injectables were inappropriate and 60% disagreeing, making Zakaria the winner of the burning debate. 

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