Interferon Tumbles, Oral Agents Gain for MS Treatment

Prescribing patterns of initial disease-modifying therapies for multiple sclerosis have shifted dramatically since 2001, with oral agents driving down the use of platform injectables 73.8% by 2020.

The inflection point occurred during 2010-2013, when oral disease-modifying therapies (DMTs) began to come online and the use of injectables such as interferon beta products (Betaseron, Rebif) and glatiramer acetate (Copaxone) plummeted, Mackenzie Henderson, PharmD, of Rutgers University in New Brunswick, New Jersey, and colleagues wrote in JAMA Neurology.

Every year thereafter, the use of platform injectables continued to drop, while oral DMTs continue to gain popularity, said Henderson and co-authors.

There was little change in the use of infusion therapies, newer injectables, or off-label agents, each of which accounted for fewer than 10% of treatment initiations.

Several factors are likely driving the shift, the team explained. “First, [oral agents] are more convenient to take and do not require a visit to clinicians or infusion centers,” they wrote. “Such considerations may have played a more outsized role early in the COVID-19 pandemic. Second, their increasing popularity may also be driven by direct-to-consumer advertising, as well as potential coverage limitations imposed by insurance companies, including formulary restrictions, prior authorization requirements, and cost-sharing.”

To build the analysis, the researchers plumbed prescribing data contained in the IBM MarketScan Commercial Claims and Encounters system. They identified 153,846 new DMT initiations for adults 18-64 years old and 583 for children younger than 18. Initiations were defined as a first-time prescription for a given agent, that is, not having been prescribed in the previous year.

The researchers examined 19 DMTs, classifying them into five categories:

• Platform injectables: interferon beta and glatiramer acetate
• Oral products: dimethyl fumarate (Tecfidera), diroximel fumarate (Vumerity), fingolimod (Gilenya), siponimod (Mayzent), ozanimod (Zeposia), teriflunomide (Aubagio), and cladribine (Mavenclad)
• Infusion drugs: natalizumab (Tysabri), ocrelizumab (Ocrevus), and alemtuzumab (Lemtrada)
• Newer injectables: daclizumab (Zinbryta) and ofatumumab (Kesimpta)
• Other DMTs including off-label therapies: rituximab (Rituxan), azathioprine, cyclophosphamide, mitoxantrone, and mycophenolate mofetil

Among adults, platform injectable therapies accounted for 99.3% of DMT initiations in 2001 — no surprise since it was the only truly effective DMT approved at the time — but dropped to just 25.5% by 2020 (P<0.001). This was largely driven by a precipitous decline in the use of interferon beta. Glatiramer acetate showed a more varied course, increasing from 27% in 2001 to a high of 39.3% in 2009. Thereafter, glatiramer use as an initiation therapy declined, landing at 14.4% by 2020 (P<0.001).

Infused antibodies remained the least commonly prescribed DMT initiations throughout the study period. By 2004, they accounted for just 3.2%. This increased slightly – but not significantly – with the 2017 introduction of ocrelizumab. Prescribing of natalizumab remained at 3% or fewer of initiations from its 2017 introduction to study’s end.

Ocrelizumab, also approved in 2017, accounted for 4.3% of DMT initiations that year; by 2020, 5.8% were for ocrelizumab (P=0.10) The newer oral therapies, which began to show up with the 2010 approval of fingolimod, had little impact on infusion initiation rates, the researchers said. But once they were introduced, they rapidly became the initiation DMT of choice, surging from 1.1% in 2010 to 62.3% in 2020 (P=0.002).

Over the study period, dimethyl fumarate, approved in 2013, was the most frequently prescribed oral initiation. Clinicians and patients immediately embraced it, reaching 36.4% of initiations that year. It did decline somewhat over the study period, accounting for 23.3% in 2020 (P=0.001).

Fingolimod use peaked at 18.4% in 2015 and remained relatively steady. “Similarly,” the authors wrote, “initiations of teriflunomide [approved in 2012] increased steadily after its approval, peaking at 15.5% in 2018 [P=0.002]. Additionally, the increase in use of oral DMTs between 2019 and 2020 was driven largely by uptake of newer agents within the class, including cladribine [3.2% of initiations in 2020], diroximel fumarate [6.7%], ozanimod [1.1%], and siponimod [3.3%].”

Off-label medications (azathioprine, cyclophosphamide, mycophenolate, rituximab) and mitoxantrone comprised less than 2% of initiations in adults over the study period.

These trends were similar among pediatric patients, with the exception of fingolimod. While fingolimod use declined in adults after 2015, it rose significantly among children and adolescents (P=0.002). By 2019-2020, fingolimod was the most commonly prescribed DMT initiation for this group (68.8%). “This distinction coincides with the 2018 publication of the PARADIGMS trial results and subsequent 2018 [FDA] approval of fingolimod in children 10-17 years old,” Henderson and colleagues wrote, noting that it remains the only FDA-approved DMT for the pediatric MS population.

The results might not be capturing the full picture, cautioned John Corboy, MD, of the Rocky Mountain MS Center at the University of Colorado in Aurora. “These findings are a marker of change in use of MS DMTs over time,” he told MedPage Today. “They likely reflect turnover in use of drugs, noting the persistence of medication use is higher with the infusible, more highly effective drugs, and insurance step-edits requirements, demanding that patients fail multiple drugs before paying for newer, better, infusible drugs.”

He suggested sales data to provide insight. “The alternative way to look at this question is to look at market share per year, which would take ongoing use into account, and likely give very different results.”

The researchers also noted limitations of the study. The results can be broken down only by adult and pediatric use, because the MarketScan database doesn’t include any information on race, ethnicity, or socioeconomic status, which can affect prescribing patterns and disease severity. And, they pointed out, the data only cover patients with commercial insurance, so the findings offer no insight on how people not included in the IBM database — about 45% of the U.S. population — are treated.

Nor does the database differentiate MS subtypes, which may affect a prescriber’s choice of initial DMT. Finally, the group had little to no data on the newest agents, including ponesimod (Ponvory) and others approved from 2019 onward.