Up to 15 percent of people with MS are diagnosed with primary progressive multiple sclerosis (PPMS).

The disease is named “primary progressive” because it progresses from the onset of the first (primary) symptoms. PPMS symptoms steadily worsen over time without relapses or remissions, unlike relapsing-remitting multiple sclerosis (RRMS), which is characterized by exacerbations followed by periods of symptom-free remission.

The progression of symptoms in PPMS varies between patients. The disease is called “active” when a patient experiences occasional relapses or there is evidence of new lesions on an MRI. “Not active” or “with progression” means there is evidence that a symptom is worsening over time with or without relapse, or new lesions are shown on an MRI.

People with PPMS have fewer brain lesions and inflammation than people with RRMS. Conversely, people with PPMS usually have more spinal cord lesions than people with RRMS.

PPMS diagnosis

Accurate diagnose of PPMS requires at least three characteristics. The patient must have one year of disease progression (worsening of neurological function without remission), and two additional characteristics that could include a brain lesion that is recognized as typical of MS, two or more lesions of a similar pattern in the spinal cord, or evidence of immune system activity in the central nervous system (shown in an elevated IgG index or an oligoclonal band in the spinal fluid).

PPMS diagnosis can take a long time, especially in cases when neurologic symptoms have just begun. In fact, PPMS diagnosis can take two to three years longer than RRMS diagnosis.

Typically, PPMS is diagnosed between 40 and 60 years old, but earlier diagnosis can happen. The disease affects women and men equally.  People with PPMS usually experience more problems with walking and working, and may require assistance for everyday activities.

Treating PPMS

On March 28 2017, Ocrevus (ocrelizumab) became the first treatment approved by the U.S. Food and Drug Administration (FDA) specifically to treat PPMS. In clinical trials, Ocrevus slowed disease progression in PPMS patients.

Other treatments are still in development. There are ongoing clinical trials (such as NCT02284568NCT01776060 and NCT02913157) assessing various experimental PPMS medications.

People who experience relapses or show evidence of disease activity on an MRI are sometimes prescribed approved RRMS disease-modifying therapies that are made to reduce inflammation in the central nervous system.

There are also ways for PPMS patients to manage the disease, beyond medication. Appropriate exercise and healthy eating habits are important for people with MS. When relapse or worsening of symptoms occur, physical and occupational therapy can help minimize muscle weakness and help restore movement.

Be sure to follow the latest developments on PPMS treatments by following Multiple Sclerosis News Today’s Progressive Multiple Sclerosis Experimental Therapy Tracker.

SMA News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.


Dr. Patricia Coyle at CMSC 2016 Discussing Progressive MS Treatment

Ocrevus Increases Proportion of PPMS Patients with No Disease Progression or Activity, Phase 3 Trial Shows

Treating primary progressive multiple sclerosis patients with Ocrevus (ocrelizumab) led to a three-fold increase in the proportion of those showing no evidence of disease progression and no signs of inflammatory disease activity over more than two years of treatment, results of a Phase 3 trial show, and support new measures that might better capture disability in PPMS patients.

The research, “Evaluation of No Evidence of Progression or Active Disease (NEPAD) in Patients With Primary Progressive Multiple Sclerosis in the ORATORIO Trial,” was published in the journal Annals of Neurology.

Measuring disease progression in clinical trials and clinical practice requires reliable and comprehensible measures. Although widely used, the Expanded Disability Status Scale (EDSS, range 0-10) cannot fully capture changes in walking speed and hand or arm function, which are key determinants of overall disability in progressive forms of MS.

No evidence of progression (NEP) is a newer measure that reflects the absence of disability progression, including upper limb function and walking speed.

Maintaining NEP status means stable disease with no worsening in EDSS, in walking ability (assessed by the Timed 25-Foot Walk (T25FW) test, or the time it takes to walk 25 feet as quickly and safely as possible), and in upper limb function (assessed by the 9-Hole Peg Test (9HPT), a test of arm and hand dexterity).

Patients with PPMS have less frequent signs of disease activity, which include relapses and brain lesions (assessed though magnetic resonance imaging or MRI).

So scientists proposed a new measure — called “no evidence of progression or active disease” (NEPAD) — to evaluate both NEP and clinical and MRI measures of active disease. The researchers believe that NEPAD may represent a more sensitive and comprehensive measure of disease control in PPMS patients.

The randomized, double-blind ORATORIO Phase 3 trial (NCT01194570) analyzed the efficacy and safety of Ocrevus — developed by Genentech, part of the Roche group — in 732 PPMS patients (age range 18–55).

Results showed that Ocrevus treatment delayed the relative risk of disability progression by 25% compared to placebo, while also reducing the volume of chronic brain lesions and total brain volume loss. As a result, Ocrevus became the first therapy approved by the U.S. Food and Drug Administration and the European Commission for both PPMS and relapsing MS.

Now, researchers assessed Ocrevus’ effect in PPMS patients included in the Roche-funded ORATORIO study using as trial goals changes in NEP and NEPAD.

These people received either 600 mg of Ocrevus or placebo by intravenous (IV) infusion every six months for a minimum of 120 weeks (about 2.3 years). The trial’s main goal was time to onset of clinical disability progression (CDP) sustained for at least 12 weeks. CDP was defined as a 1.0 point or greater increase in EDSS score from a baseline (study start) score of 5.5 or less, or a 0.5-point increase from a baseline score greater than 5.5.

NEP status, analyzed in 230 placebo- and 461 Ocrevus-treated patients, was defined as no evidence of CDP for 12 weeks, no 20% or more change in hand/arm function as measured by the 9HPT for 12 weeks, and no 20% or more change in walking ability as measured by the T25FW test for 12 weeks. “The 20% cut-off for progression on the T25FW test and the 9HPT has previously been shown to be a clinically meaningful magnitude of disease progression,” the study noted.

In turn, NEPAD — assessed in 234 placebo- and 465 Ocrevus-treated patients — included NEP, no brain MRI-measured disease activity, and no relapses. Relapses were defined as new or worsening neurological symptoms attributable to MS lasting longer than 24 hours and preceded by neurological stability for a minimum of 30 days.

Brain MRI scans were conducted at baseline, and weeks 24, 48, and 120; new or enlarging T2 lesions and/or T1 enhancing lesions were considered evidence of MRI disease activity (T1 MRI imaging offers information about current disease activity by highlighting areas of active inflammation, while a T2 MRI image provides information about disease burden or lesion load).

Overall, the majority of the PPMS patients analyzed experienced clinical disease progression or evidence of disease activity.

From baseline to week 120, Ocrevus-treated patients who achieved NEP (42.7% of 461 people) or NEPAD (29.9% of 465)  — no disease activity or progression — were found to have lower T2 brain lesion volume and a lower EDSS score (lesser disability) compared to those with evidence of MS progression. They also had a slightly superior performance on the 9HPT and the T25FW test.

Patients who reached NEPAD also showed fewer T1 lesions than patients with progressing or active disease.

Compared to placebo treatment, the proportion of Ocrevus-treated PPMS patients maintaining NEP or NEPAD from baseline to week 120 was higher — for NEP, 42.7% versus 29.1% in the placebo group; for NEPAD, 29.9% versus 9.4% in the placebo group.

These results showed that Ocrevus treatment increased the proportion of PPMS patients with NEPAD throughout the 120 weeks of the study by three-fold.

“In conclusion, ocrelizumab (Ocrevus) increased the proportion of patients with PPMS with no evidence of progression and no clinical and subclinical disease activity compared with placebo,” the team wrote. “As such, NEPAD may represent a meaningful and comprehensive disease outcome in patients with PPMS.”

However, data from ORATORIO’s open-label extension and real-world data are needed to “determine whether NEPAD maintained throughout 120 weeks will translate into sustained NEPAD and enhanced protection against accrual of disability in patients with PPMS over the long term,” the researchers concluded.

Of note, five of the study’s 11 authors are employees and/or shareholders of Roche or Genentech.

NICE Rules Against Bringing Ocrevus into NHS for Primary Progressive Patients in UK

The National Institute for Health and Care Excellence, better known as NICE, issued a final decision against including Ocrevus (ocrelizumab) as a treatment for primary progressive multiple sclerosis (PPMS) in the subsidized public health system for England and Wales. The agency’s “final appraisal,” which mirrors its draft June ruling, is based on the cost-effectiveness of the Genentech therapy […]

Progressive MS Patients with Considerable Disability Ably Treated with Cladribine, UK Case Study Reports

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MS News that Caught My Eye Last Week: Medical Cannabis in Australia, Solvents and Common Pollution, Ocrevus and PPMS

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NICE Opposes Ocrevus as PPMS Treatment in UK’s Public-funded Health System

The National Institute for Health and Care Excellence, known as NICE, has decided against recommending that Ocrevus be part of public-funded treatments for adults with primary progressive multiple sclerosis (PPMS). The National Health Service (NHS) is the subsidized, publicly funded healthcare system for England, with similar structures in other parts of the U.K. A positive NICE opinion […]

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First Clinical Trial to Focus on Improving Hand Function in PPMS Patients Announced

A new clinical trial will be the first in the world to recognize the importance of retaining hand function for wheelchair-bound patients with primary progressive MS (PPMS), according to a press release from Queen Mary University of London. The international trial, which will be conducted by a research team from Queen Mary University of London, Barts […]