Ocrevus (ocrelizumab), a recently approved therapy for relapsing and primary progressive multiple sclerosis (MS), is now on the U.S. market, but research into its use is far from over.
Multiple Sclerosis News Today took a closer look at the goals of these trials, and spoke to Dr. Hideki Garren — Genentech’s Group Medical Director of Ocrelizumab — about new insights they might offer.
The trials have similar age limitations as earlier Phase 3 studies. Only people older than 18 or younger than 55 will be able to participate.
All currently running trials stick to the infusion procedure listed on Ocrevus’ label. The first course of treatment involves two infusions — two weeks apart — in which the 600 mg dose is split in two. All remaining infusions will be administered as a single 600 mg infusion at six-month intervals.
Ocrevus in previous treatment failures
Among the largest of the ongoing trials are two nearly identical Phase 3 studies. They are looking at the safety and effectiveness of Ocrevus among patients who failed to respond to an earlier disease-modifying treatment.
Those conducting the studies — one taking place in North America (NCT02637856) and a second recruiting patients across Europe and Australia (NCT02861014) — plan to enroll 600 relapsing MS patients each. Since earlier disease-modifying treatments are approved only for relapsing-remitting MS, no progressive MS patients are eligible for these studies.
In the two trials exploring Ocrevus’ effectiveness in patients who failed to respond to a disease-modifying treatment, participants will receive a maximum of four treatment rounds.
The trials will measure the percentage of participants who do not experience a relapse, new or enlarging brain lesions detected by magnetic resonance imaging (MRI), or disability progression at 24 weeks.
Researchers will keep track of both active inflammatory brain lesions and older lesions, and measure total brain lesion burden. In addition, they will analyze the time it takes before patients experience new disease activity or worsened disability, and record adverse events.
The trial registration pages do not offer much information about the disease-modifying treatments that patients needed to have experienced before being eligible to participate. Garren said the studies are accepting patients who failed to respond to at least six months of treatment with any currently approved disease-modifying therapy, with a few exceptions.
Researchers are using a strict definition of treatment failure. They define it as at least one relapse, at least one new inflammatory brain lesion, or at least two new or enlarging T2 lesions.
No washout with T-cell to B-cell treatment switch
Many patients who experienced treatment failures worry about being without treatment, because suboptimal treatment can also lead to an inability to harness the disease.
So far, there has been no information about the need for a washout period when switching between drugs in the trial, especially between T-cell-based therapies and Ocrevus, which targets B-cells. A washout period is a time when trial participants receive no treatment between a previous regimen and the therapy the trial is testing. The goal is to eliminate the previous treatment from the trial participants’ bodies.
For those worrying about being left without treatment, however, Garren offers good news.
“No washout period is required, but patients who have been on [Gilenya] fingolimod or [Tecfidera] dimethyl fumarate prior to entry must have a normal lymphocyte count at entry into the study,” he said. Lymphocytes are a type of white blood cell that are a component of the immune system.
Trial not for everyone
Although the two trials focus on people who discontinued another disease-modifying treatment because it did not improve their disease, there are several restrictions on the types of patients who are eligible.
Patients need to have a disability score of no more than 4.0 on the Expanded Disability Status Scale (EDSS) when they enter the study. Also, the trial protocol does not allow patients who were treated with more than three previous disease-modifying treatments for at least six months.
Garren said the restrictions were put in place because the study will focus on patients who are not in advanced stages of the disease. Patients previously treated with Lemtrada (alemtuzumab) or Tysabri (natalizumab) are generally excluded from the study because the two drugs are usually used to treat patients with more advanced stages of MS, Garren explained.
There are exceptions with Tysabri users, however. Those treated with Tysabri within a year of the start of the Ocrevus trial can participate if their treatment failure was due to anti-drug antibodies, and if they were treated for less than a year.
Use of listed immunosuppressive drugs, along with other types of B-cell-depleting treatments, also excludes patients from participation.
Garren said enrollment in all currently running trials is “progressing extremely well,” and that all the studies are sticking to their timelines.
The European/Australian trial data is expected by December 2020. The North American trial will be completed a year earlier.
Early relapsing disease
A Roche-sponsored Phase 3 (NCT03085810) clinical trial of Ocrevus is focused on patients in early stages of relapsing-remitting MS.
“The aim of this study is to evaluate the effectiveness of ocrelizumab by measuring the evolution of disease activity, and progression of disability, over four years,” Garren said.
Results of the Phase 3 OPERA trials showed that early-stage relapsing patients also benefitted from Ocrevus. To obtain more data on this group, the global trial will study 600 patients with an MS diagnosis of three years or less.
Participants need to have a maximum EDSS score of 3.5 and to have had no earlier MS treatments or other B-cell-targeting drugs.
Patients in this study, who will be followed for nearly four years, will receive a maximum of eight Ocrevus treatments over 192 weeks.
The trial has 22 primary outcome measures. One is the proportion of patients who experience disease progression and those who improve. Other measures will include changes in disability, the time it takes for patients to relapse, and annualized relapse rates at different time points during the trial.
Two secondary measures will be no evidence of disease activity (NEDA) and no evidence of disease progression (NEP). In addition, the study will use a measure called NEPAD, or no evidence of progression that lasts at least 24 weeks and no active disease.
These measures will provide a comprehensive picture of all facets of disease activity, including relapses, the presence of brain lesions, and disability.
Patients will be followed for up to 48 weeks after the last treatment, so the final study data is not expected until 2022.
Ocrevus and vaccination
Ocrevus is a medication that depletes CD20-type B-cells, which are known to be involved in the immune response to a vaccination.
Because of this, Ocrevus’ prescription label says that vaccinations that use so-called live-attenuated or live vaccines are not recommended during treatment, and until these B-cells have been replenished.
So far, researchers have yet to test if certain vaccines lose their ability to trigger an immune response after Ocrevus treatment. A Phase 3 trial (NCT02545868) in the United States and Canada will examine that.
“The aim of this study is to evaluate whether ocrelizumab-treated patients can mount protective immune responses against clinically relevant vaccines to further help guide immunization recommendations,” Garren said.
The study will recruit 102 relapsing MS patients who will be randomized to receive different vaccines after the first round of Ocrevus. Patients who receive the vaccines without pretreatment with Ocrevus will serve as controls.
Researchers will focus on four vaccines. One is against tetanus toxoid, commonly known as lockjaw. Another is a vaccine against 23 strains of the pneumonia-causing bacteria Streptococcus pneumoniae. The third is an influenza vaccine, and the fourth a keyhole limpet hemocyanin, or compound used as a vaccine carrier protein because of its immunogenic properties.
Response to the tetanus vaccine will be the main focus of the trial. A positive response eight weeks after immunization will be the trial’s main outcome measure.
Although the study started in 2015, and is no longer recruiting participants, Roche does not expect the trial to be completed until 2022.
Disease mechanisms and other treatment facets
The focus of an Ocrevus study that differs from the other trials — both in its design and aims — is how the drug impacts MS. The trial (NCT02688985) is detailed in a separate article.
Other features of Ocrevus are also under scrutiny in clinical trials, Garren assured.
“We are continuing to investigate long-term efficacy and safety of Ocrevus in clinical studies, including in patients switching from a variety of MS therapies,” he said.
“Our goal is to both clarify the role of Ocrevus across the MS treatment landscape, as well as evolve how MS clinical trials are conducted to ensure day-to-day patient needs are being considered in the development of innovative treatments for MS.”