ClinicSpeak: spreading hope

The ocrelizumab ORATORIO results give hope to PPMSers #MSBlog #MSResearch #ClinicSpeak

"Earlier this week I made the diagnosis of primary progressive MS (PPMS) in one of my patients. This is the first time I have done so since the ECTRIMS meeting in Barcelona where the ocrelizumab PPMS trial (ORATORIO Trial) results were made public. What a difference this made! For the first time I was able to offer someone with PPMS hope. I countered the bad news of having just been given a diagnosis of PPMS with the news that for the first time a treatment had been shown to slow down the acquisition of disability in PPMS. This was an uplifting experience for all of us involved; for the first time PPMS has become a tractable disease. We shouldn't underestimate the effect of good news and being able to do something positive; it affects on our body language, our mood, the way we present ourselves, in short it gives hope." 

"The downside of this news is that in reality ocrelizumab will only be available, realistically, under the NHS in approximately 2 years time. The latter is assuming it clears EMA and NICE hurdles. The NICE hurdle is important for PPMSers in the UK; we are only allowed to prescribe DMTs that are shown to be cost-effective. NICE is pretty effective at driving a hard bargain with Pharma and explains why the cost of DMTs in the UK are probably the lowest in the developed world. Costs and access to ocrelizumab aside, could you imagine being diagnosed with PPMS, you are still mobile (able to walk ~100 m) and your neurologists tells you that you will have to wait 2 years to see if you may be eligible for the drug? Two years is a long time in the life of someone with PPMS; in 2 years their disability could progress to a stage when they need to use a wheelchair. The latter may make them ineligible for ocrelizumab. What should I do? Should I prescribe rituximab off-label? At least we have a reasonably robust evidence-base now to use rituximab in PPMS. Unfortunately, as rituximab is a high-cost drug we would need to get NHS England permission. NHS England have stopped us using rituximab in this setting."

"What I ended up doing is putting this patient forward for the laquinimod PPMS, or ARPEGGIO, study (see below). Ocrelizumab is not going to be enough on its own to treat PPMS, we will almost certainly need to combine it with a neuroprotective treatment in the future. Based on preclinical, and clinical, data laquinimod is the one neuroprotective drug we have in development that is likely to get through the pipeline first."

A Phase 2 Clinical Study in Subjects With Primary Progressive Multiple Sclerosis to Assess the Efficacy, Safety and Tolerability of Two Oral Doses of Laquinimod Either of 0.6 mg/Day or 1.5mg/Day (Experimental Drug) as Compared to Placebo Identifier: NCT02284568
Ages Eligible for Study: 25 Years to 55 Years
Genders Eligible for Study: Both

Inclusion Criteria:
  1. Patients must have a confirmed and documented PPMS diagnosis as defined by the 2010 Revised McDonald criteria
  2. Baseline magnetic resonance imaging (MRI) showing lesions consistent with PPMS in either or both brain and spinal cord
  3. Patients must have an Expanded Disability Status Scale (EDSS) score of 3 to 6.5, inclusive, at both screening and baseline visits
  4. Documented evidence of clinical disability progression in the 2 years prior to screening.
  5. Functional System Score (FSS) of > or equal 2 for the pyramidal system or gait impairment due to lower extremity dysfunction
  6. Patients must be between 25 to 55 years of age, inclusive
  7. Women of child-bearing potential must practice an acceptable method of birth control for 30 days before taking the study drug, and 2 acceptable methods of birth control during all study duration and until 30 days after the last dose of treatment is administered.
  8. Patients must sign and date a written informed consent prior to entering the study.
  9. Patients must be willing and able to comply with the protocol requirements for the duration of the study.
Exclusion Criteria:
  1. Patients with history of any multiple sclerosis (MS) exacerbations or relapses, including any episodes of optic neuritis.
  2. Progressive neurological disorder other than PPMS.
  3. Any MRI record showing presence of cervical cord compression.
  4. Baseline MRI showing other findings (including lesions that are atypical for PPMS) that may explain the clinical signs and symptoms.
  5. Relevant history of vitamin B12 deficiency.
  6. Positive human T-lymphotropic virus Type I and II (HTLV-I/II) serology.
  7. Use of experimental or investigational drugs in a clinical study within 24 weeks prior to baseline. Use of a currently marketed drug in a clinical study within 24 weeks prior to baseline would not be exclusionary, provided no other exclusion criteria are met.
  8. Use of immunosuppressive agents, or cytotoxic agents, including cyclophosphamide and azathioprine within 48 weeks prior to baseline.
  9. Previous treatment with fingolimod (GILENYA®, Novartis), dimethyl fumarate (TECFIDERA®, Biogen Idec Inc), glatiramer acetate (COPAXONE®, Teva), interferon-β (either 1a or 1b), intravenous immunoglobulin, or plasmapheresis within 8 weeks prior to baseline.
  10. Use of teriflunomide (AUBAGIO®, Sanofi) within 2 years prior to baseline, except if active washout (with either cholestyramine or activated charcoal) was done 2 months or more prior to baseline.
  11. Prior use of monoclonal antibodies ever, except for: natalizumab (TYSABRI®, Biogen Idec Inc), if given more than 24 weeks prior to baseline AND the patient is John Cunningham (JC) virus antibody test negative (as per medical history)rituximab, ocrelizumab, or ofatumumab, if B cell count (CD19, as per medical history) is higher than 80 cells/μL
  12. Use of mitoxantrone (NOVANTRONE®, Immunex) within 5 years prior to screening. Use of mitoxantrone >5 years before screening is allowed in patients with normal ejection fraction and who did not exceed the total lifetime maximal dose.
  13. Previous use of laquinimod.
  14. Chronic (eg, more than 30 consecutive days or monthly dosing, with the intent of MS disease modification) systemic (intravenous, intramuscular or oral) corticosteroid treatment within 8 weeks prior to baseline.
  15. Previous use of cladribine or alemtuzumab (LEMTRADA®, Sanofi).
  16. Previous total body irradiation or total lymphoid irradiation.
  17. Previous stem cell treatment, cell-based treatment, or bone marrow transplantation of any kind.
  18. Patients who underwent endovascular treatment for chronic cerebrospinal venous insufficiency (CCSVI) within 12 weeks prior to baseline.
  19. Use of moderate/strong inhibitors of cytochrome P450 (CYP) 3A4 within 2 weeks prior to baseline.
  20. Use of inducers of CYP3A4 within 2 weeks prior to baseline.
  21. Pregnancy or breastfeeding.
  22. Serum levels ≥3× upper limit of the normal range (ULN) of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at screening.
  23. Serum direct bilirubin which is ≥2×ULN at screening.
  24. Patients with a clinically significant or unstable medical or surgical condition that (in the opinion of the Investigator) would preclude safe and complete study participation, as determined by medical history, physical examinations, electrocardiogram (ECG), laboratory tests or chest X-ray.
  25. A known history of hypersensitivity to gadolinium (Gd).
  26. Glomerular filtration rate (GFR) < or equal 60 mL/min at screening visit.
  27. Inability to successfully undergo MRI scanning, including claustrophobia.
  28. Known drug hypersensitivity that would preclude administration of laquinimod, such as hypersensitivity to mannitol, meglumine or sodium stearyl fumarate.
CoI: multiple

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