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Ocrevus FDA approval marks watershed moment for MS market

Roche’s exciting new multiple sclerosis (MS) drug Ocrevus (ocrelizumab) was approved by the US Food and Drug Administration (FDA) on 29 March 2017 (Roche, 2017). The drug is indicated for relapsing-remitting MS (RRMS) on the strength of the two OPERA studies, which showed clear superiority over the current standard of care, Rebif (interferon beta-1a; Merck KGaA/Pfizer). Furthermore, the FDA has endorsed its use in primary progressive MS (PPMS), making Ocrevus the first approved drug for this underserved population with high unmet need. Ocrevus is very well placed to penetrate treatment practices across the whole spectrum of MS, and is forecast to achieve annual sales of $4bn by 2025 in the US and five major EU markets (France, Germany, Italy, Spain, and the UK), facilitated by Roche’s bold pricing strategy.

 

Phase III studies show superiority over Rebif in RRMS and efficacy in difficult-to-treat PPMS subset

Roche’s identically designed OPERA studies in RRMS patients showed that Ocrevus treatment produced a statistically significant 46–47% reduction in annualized relapse rate (ARR) compared with Rebif. This effect on relapses was also accompanied by a 40% reduction in the risk for confirmed disability progression (Roche, 2015). Both OPERA I and OPERA II yielded extremely similar outcomes, strengthening the evidence that Ocrevus is clearly superior. These data are very impressive considering that Rebif is a well-established and effective drug for RRMS.

 

OPERA I and OPERA II also showed the tolerability of Ocrevus; the proportion of patients experiencing adverse events (AEs) was identical across both treatment groups (83.3%), while the proportion of patients with serious AEs was similar between the two groups, with Ocrevus coming out marginally superior (6.9% vs 8.7%). Ocrevus’s most common AEs were infusion-related reactions, which occurred in 34.3% of patients, compared with 9.7% for Rebif (Roche, 2015).

 

The ORATORIO trial – the first ever for a drug in PPMS to meet its primary endpoint – suggests that Ocrevus is an effective treatment for this difficult-to-treat patient subset. Ocrevus treatment was associated with a 24% risk reduction in confirmed disability progression sustained for 12 weeks compared with placebo (Roche, 2015). While the magnitude of effect is not as large as that seen in RRMS patients, it is profound because there are no other effective treatment options for PPMS.

 

Ocrevus treatment also had other benefits on secondary endpoints, including disability progression sustained for 24 weeks, timed 25-foot walk, and magnetic resonance imaging (MRI) measures of disease activity. Ocrevus had a slightly higher incidence of AEs than placebo (95.1% vs 90.0%), and was again associated with infusion-related reactions (39.9% vs 25.5%), but the proportion of patients with serious AEs, including serious infections, was similar to placebo (20.4% vs 22.2%) (Roche, 2015).
Ocrevus Phase III data in multiple sclerosis

    
    

Trial  Sample size  Target patients Study design Dosing tested and duration Results Reference 
OPERA I (NCT01247324) (Phase III) 821 RRMS Randomized, double-blind, parallel-group study with placebo and active comparator

Ocrevus 600mg every 24 weeks, Rebif 44mcg three times weekly, or placebo

Duration: Two years 

46% reduction in ARR compared with Rebif
43% risk reduction in CDP 
Trialtrove; Roche, 2015 
OPERA II (NCT01412333) (Phase III)  835
RRMS
Randomized, double-blind, parallel-group study with placebo and active comparator 

Ocrevus 600mg every 24 weeks, Rebif 44mcg three times weekly, or placebo

Duration: Two years 

47% reduction in ARR compared with Rebif
37% risk reduction in CDP sustained for 12 and 24 weeks 
Trialtrove; Roche, 2015 
ORATORIO (NCT01194570) (Phase III)  732  PPMS  Randomized, double-blind, placebo-controlled, parallel-group study 

Ocrevus 600mg every 24 weeks, or placebo, in addition to methylprednisolone

Duration: 120 weeks

24% risk reduction in CDP sustained for 12 weeks  Trialtrove; Roche, 2015 
ARR = annualized relapse rate; CDP = confirmed disability progression; PPMS = primary progressive multiple sclerosis;  RRMS = relapsing-remitting multiple sclerosis
Source: various (see above)

 

 

Considerable unmet need remains for disease-modifying treatments in progressive MS subtypes

Neurologists surveyed by Datamonitor Healthcare in the US and five major EU markets rated the lack of disease-modifying treatments (DMTs) for patients with progressive forms of MS as one of the key unmet needs.

 

A high proportion of MS patients display a progressive disease course at some point in their lives, but they presently have very few therapeutic options available to them. It is estimated that together, PPMS and secondary progressive MS (SPMS) patients amount to more than 50% of the 2.3 million worldwide cases of MS. This means that over 1 million MS patients worldwide have no effective therapy to slow down disease progression and the accumulation of disability. As a result, many patients will eventually require hospitalizations, will display increased functional disability, and will experience a gradual decline in quality of life. Altogether, disease progression is a major source of MS’s economic burden (Thompson, 2015).

 

“I think the biggest single need [in the treatment of MS] is some form of effective therapy for the progressive forms of the disease.”
US key opinion leader

 

Ocrevus’s PPMS data suggest that for the first time, such patients will have an appropriate DMT that will help to slow their disease course. Although PPMS is a minor segment of the total MS population, accounting for around 16% of surveyed neurologists’ diagnosed cases, the impact of a novel treatment option here will be profound. Furthermore, as many RRMS patients will go on to develop a progressive disease course and be diagnosed as having SPMS, Ocrevus has good potential for off-label use and straddling both disease subtypes. Its efficacy, both in reducing relapses as well as benefits in reducing disability progression for progressive patients, will make it an appropriate treatment option for SPMS patients.

 

 

Roche will claim a dominant position in the MS market

Ocrevus is very well placed to penetrate MS treatment practices, both for relapsing and progressive MS subtypes, owing to its impressive clinical data. The two OPERA trials showed Ocrevus to have efficacy that is among the best in the market for RRMS, while also having a relatively benign safety profile. Drug treatment reduced ARR by 46–47% compared with Rebif, which is an established standard of care for MS. This result potentially places Ocrevus at a slight advantage to Tysabri (natalizumab; Biogen), which has demonstrated ~60% ARR reduction against placebo, and is almost identical to the 45% ARR reduction over Avonex (interferon beta-1a; Biogen) shown by the recently launched Zinbryta (daclizumab; Biogen/AbbVie). These efficacy data, when combined with the drug’s favorable risk-benefit profile, will help Roche position Ocrevus as the second-line drug of choice among patients who have not responded to oral therapies or interferon beta.

 

Furthermore, Ocrevus’s data in PPMS will become one of its key differentiators. Owing to the announcement of the first positive clinical data in 2015, there will be significant patient and physician demand for the drug, and awareness of the product will be high. While the PPMS patient segment may not necessarily be Roche’s most lucrative, it will help to create a very strong impression around the brand that will benefit its wider prescribing, and also open up the SPMS market.

 

Despite being a newcomer to the MS market, Roche has employed a brave strategy, undercutting the cost of current DMTs by 25%, and pricing Ocrevus at $65,000/year (Endpoints, 2017). This will be highly disruptive to the MS market, which has long enjoyed double-digit annual price increases, and so it is only possible for a newcomer to the market to take such a bold pricing decision and not harm other products in the company’s portfolio. Such a discount will allow Ocrevus to secure favorable formulary placements and reimbursement decisions, ensuring full market penetration to the detriment of its competitors. Accordingly, Datamonitor Healthcare projects Ocrevus to achieve annual sales of $4bn by 2025 in the US and five major EU markets, placing it behind only Biogen’s Tecfidera (dimethyl fumarate) as the leading MS drug on the market.

 

 

Bibliography
Endpoints (2017) Megablockbuster day for Roche too as MS game-changer Ocrevus gets a green light at the FDA. Available from: https://endpts.com/megablockbuster-day-for-roche-too-as-ms-game-changer-ocrevus-gets-a-green-light-at-the-fda/ [Accessed 29 March 2017].

 

Roche (2015) Roche’s ocrelizumab first investigational medicine to show positive pivotal study results in both relapsing and primary progressive forms of multiple sclerosis. Available from: http://www.roche.com/media/store/releases/med-cor-2015-10-08.htm [Accessed 29 March 2017].

 

Roche (2017) FDA approves Roche’s OCREVUS™ (ocrelizumab) for relapsing and primary progressive forms of multiple sclerosis. Available from: http://www.roche.com/media/store/releases/med-cor-2017-03-29.htm [Accessed 29 March 2017].

 

Thompson AJ (2015) A much-needed focus on progression in multiple sclerosis. The Lancet Neurology, 14(2), 133–135.

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