ECTRIMS Preview: Ocrevus Success Brings Rivals Crowding In

The congress will highlight competition in anti-CD20 and other novel multiple sclerosis drug classes

Of all the new products helping Roche transition away from its old blockbuster portfolio, multiple sclerosis drug Ocrevus (ocrelizumab) is one of the biggest contributors.

Now other companies with similar products in development are trying to get in on the act, and data for these are due to be presented at the upcoming European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting in Stockholm, Sweden, later this week.

The first drug approved to treat primary-progressive multiple sclerosis (PPMS, around 15% of patients) as well as the more common relapsing multiple sclerosis (RMS), Ocrevus was an instant hit when it was launched in the US in mid-2017 and early 2018 in Europe.

The anti-CD20 monoclonal antibody has taken the market by storm thanks to its stellar results in cutting the number of annual relapses in RMS patients, around 50% fewer than those taking standard interferon beta treatment Rebif.

In addition to its efficacy, Ocrevus’s six-month dosing regime is far more convenient for patients than a daily pill (Novartis AG’s Gilenya) or a three-times-a-week subcutaneous injection (Teva’s Copaxone), while its US price has also significantly undercut these established rivals.

Ocrevus revenues rose 63% to CHF1.7bn ($1.72bn) in the first half of 2019, helping it overtake Novartis’s SP1 modulator Gilenya for the first time, which fell back 6% to $1.59bn in the same period as its rival grabbed market share.

Analysts forecast Ocrevus could hit annual revenues in excess of $4bn by the mid-2020s.

Rivals On The Horizon

The success of Ocrevus has encouraged other companies with anti-CD20 candidates, most notably Novartis with ofatumumab and TG Therapeutics with ublituximab, both in Phase III development, and both challengers will be showcasing their latest data at ECTRIMS.

TG Therapeutics will be presenting a first look at demographic data from its ULTIMATE Phase III study of ublituximab (UTX) as well as continued long-term follow-up data from its Phase II MS trial.

The company says its molecule is differentiated by targeting a specific and unique epitope on the CD20 antigen, and is glyco-engineered for enhanced B-cell targeting through antibody-dependent cellular cytotoxicity (ADCC).

TG Therapeutics hopes that its candidate will offer greater ADCC potency, which could in turn allow for lower doses and shorter infusion times than Ocrevus.

The company expects to have topline data from its Phase III ULTIMATE program in the middle to second half of 2020.

Two Phase III trials, ULTIMATE I and II pit UTX against Sanofi’s Aubagio (teriflunomide) in patients with RMS.

However Aubagio is far from being one of the strongest contenders in the field, producing only a 36% reduction in the relapses rate in RMS compared with placebo. This contrasts with the much more impressive performance of Ocrevus, which showed a 46% and 47% reduction in relapses compared to interferon beta-1 in its OPERA-1 and OPERA-2 trials respectively.

Aubagio is also the comparator in Novartis and Genmab’s pivotal ASCLEPIOS I and II studies for ofatumumab.

Novartis released headline results from the trials recently, announcing that they had met the primary endpoints in producing significant and clinically meaningful reduction in the annualized relapse rate (ARR). The drug also met key secondary endpoints of delaying the time to confirmed disability progression, and full results will be presented as a late-breaker study at ECTRIMS on 13 September. 

Novartis is differentiating ofatumumab as the first subcutaneous B-cell therapy, which will allow patients to self-administer the drug at home once a month, though whether this will be more appealing than a twice-yearly infusion of Ocrevus is a moot point.

While ofatumumab and ublituximab might not represent much of a direct challenge Ocrevus, they could ride on its coattails and take market share from other existing therapies.

Meanwhile Roche is moving full steam ahead with a broad range of further clinical trials of Ocrevus to maximise its penetration across disease types and into earlier use in MS.

New Ocrevus data at ECTRIMS

The company has a number of significant results to showcase at ECTRIMS for Ocrevus. The first investigates neurofilament light chain (NfL) as a potential new biomarker for predicting future MS disability outcomes.

NfL is a protein that provides structural support to nerve fibers in the brain, and an increase in the amount of NfL in blood serum or cerebrospinal fluid may serve as a marker for axonal (nerve) damage.

Also being presented are longer-term data of more than six years from the Phase III open-label extension studies of the pivotal OPERA I, OPERA II and ORATORIO trials. These show patients treated earlier with Ocrevus had lower rates of disability progression compared with RMS patients who switched from interferon beta-1α or PPMS patients who switched from placebo after the double-blind phase.

Finally, Roche is also presenting Phase III data from what is set to be a new addition to its presence in neurology.

A novel interleukin-6 receptor-targeting compound, satralizumab, is being studied as a treatment for neuromyelitis optica spectrum disorder (NMOSD).

A debilitating autoimmune disease of the central nervous system, NMOSD is commonly misdiagnosed as MS. It is associated with pathogenic AQP4-IgG auto-antibodies that target and damage a specific cell type, called astrocytes, resulting in inflammatory lesions of the optic nerve(s), spinal cord and brain.

The Phase III results from the SAkuraStar study investigating satralizumab as a subcutaneous monotherapy for NMOSD will be presented at the congress on 12 September.

The results look likely to set the compound up for filing in the near future. However, it will need to compete with the Alexion Pharmaceuticals Inc.’s newly approved Soliris (eculizumab, which became the first product approved for this indication in the US and EU this year, plus there are other similar products in development including Viela Bio Inc.’s inebilizumab which was recently filed for approval in the US. (Also see "Alexion's Soliris To Treat EU Patients With NMOSD" - Scrip, 28 Aug, 2019.)

(S1P) receptor modulators

There remains room for other novel entrants and modalities in the MS field, however. These include plus Celgene Corp./Bristol-Myers Squibb Co.’s ozanimod, recently filed with the FDA and Novartis’ Mayzent (siponimod), newly launched in the US.

These are both from the oral, sphingosine 1-phosphate (S1P) receptor modulator class, and are both forecast for future blockbuster status.

A number of studies from the EXPAND trial program of Mayzent will be presented at ECTRIMS, all focused on its effects on disability, cognition and the condition of the brain in patients with secondary progressive MS.