Friday, 16 September 2016

Anti-CD20 in Primary Progressive MS

Which drug had a good effect on slowing loss of hand function?
P746 - An exploratory analysis of 12- and 24-week composite confirmed disability progression in patients with primary progressive multiple sclerosis in the ORATORIO trial

G. Giovannoni1, D.L. Arnold2,3, A. Bar-Or2, J. De Sèze4, B. Hemmer5,6, X. Montalban7, K.W. Rammohan8, S. Belachew9, C. Bernasconi9, P. Chin10, H. Garren9, D. Masterman10, A. Sauter9, W. Wei9, J. Wolinsky11, on behalf of the ORATORIO Clinical Investigators1Queen Mary University of London, London, United Kingdom, 2McGill University, 3NeuroRx Research, Montreal, QC, Canada, 4University Hospital of Strasbourg, Strasbourg, France,5Technische Universität München, 6Munich Cluster for Systems Neurology (SyNergy), Munich, Germany, 7Hospital Vall d’Hebron University, Barcelona, Spain, 8University of Miami, Miami, FL, United States, 9F. Hoffmann-La Roche Ltd., Basel, Switzerland, 10Genentech, Inc., South San Francisco, CA,11University of Texas Health Science Center at Houston, Houston, TX, United StatesBackground: Data from Phase III trials suggest that selective B-cell targeting may be a potential therapeutic approach in relapsing and primary progressive multiple sclerosis (PPMS). Ocrelizumab (OCR), a humanised monoclonal antibody that selectively targets CD20+ B cells, has shown superior efficacy compared with placebo (PBO) in the Phase III ORATORIO study in patients with PPMS, in which the primary endpoint was 12-week confirmed disability progression (CDP). To address limitations in using the Expanded Disability Status Scale to define clinical disability progression, a composite measure of CDP (cCDP), which also includes measures of upper extremity function and ambulation speed, was used to assess the effect of OCR in patients with PPMS. 
ObjectiveTo assess the effect of OCR on 12- and 24-week cCDP in patients with PPMS. 
MethodsPatients were randomised (2:1) to receive OCR 600mg as two 300mg intravenous infusions 14 days apart or matching PBO every 24 weeks for ≥120 weeks until an overall prespecified number of CDP events occurred. cCDP was defined as time to first onset of either CDP, ≥20% worsening on the timed 25-foot walk (T25FW) test or ≥20% worsening on the 9-hole peg test (9HPT) sustained for ≥12 or ≥24 weeks. In this exploratory analysis of 12- and 24-week cCDP among the ORATORIO intention-to-treat population, 244 PBO- and 488 OCR-treated patients were evaluable. 
ResultsCompared with PBO, OCR significantly reduced the risk of 12- and 24-week CDP by 24% (hazard ratio [HR] [95% confidence interval (CI)]: 0.76 [0.59-0.98]; p=0.0321) and 25% (HR [95% CI]: 0.75 [0.58-0.98]; p=0.0365), respectively. OCR vs PBO reduced the risk of 12- and 24-week cCDP by 26% (HR [95% CI]: 0.74 [0.61-0.89]; p=0.0014) and 29% (HR [95% CI]: 0.71 [0.58-0.87]; p=0.0008), respectively. Compared with PBO, OCR also consistently and significantly reduced the risk of 12- and 24-week confirmed ≥20% worsening on T25FW by 25% (HR [95% CI]: 0.75 [0.61-0.92]; p=0.0053) and 27% (HR [95% CI]: 0.73 [0.59-0.91]; p=0.0055), respectively, and the risk of 12- and 24-week confirmed ≥20% worsening on 9HPT by 44% (HR [95% CI]: 0.56 [0.41-0.78]; p=0.0004) and 45% (HR [95% CI]: 0.55 [0.38-0.77]; p=0.0006), respectively. 
ConclusionsIn ORATORIO, OCR treatment showed consistent benefit on disability progression, ambulation and upper limb function, as demonstrated by significant reduction in the risk of cCDP in patients with PPMS. 
Sponsored by F. Hoffmann-La Roche Ltd.

COI ProfG multiple

9 comments:

  1. Did it work for everyone with PPMS, or a subset? And at what cost in terms of side effects - also future side effects?

    ReplyDelete
    Replies
    1. We have to wait until the results are published

      Delete
  2. I find it interesting that when a DMT works for progression the time frame is considered acceptable (above) and when it does not the time frame is considered unacceptable (lamotrigine) or the trial was not wide enough (Charcot). If the smouldering effects of MS in progression mean that - as you have so often said - positive results can take years to emerge, isn't that argument slightly undercut when you suggest a DMT works on progression so quickly? Isn't this strongly suggestive, also, that this is potent anti-inflammatory activity taking place and not, as is the holy grail in progression, neuroprotection or myelin repair?

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    Replies
    1. The trial above is phase III and so perhaps ready for prime time, lamotrigine actually worked.

      Positive trials take years to emerge because it takes years to recruit enough people to the studies

      Delete
    2. Lamotrigine actually worked?

      "The effect of lamotrigine on cerebral volume of patients with secondary progressive multiple sclerosis did not differ from that of placebo over 24 months, but lamotrigine seemed to cause early volume loss that reversed partially on discontinuation of treatment."

      http://www.ncbi.nlm.nih.gov/pubmed/20621711

      I am not sure that a drug that gives you more, not less, cerebral volume loss works MouseDoctor?

      Delete
    3. You brain is composed of alot of water and it swells when you have inflammation. Now take a drug that blocks the swelling and the brain appears to shrink compared to doing nothing.

      So in the ocrelizumab trial they did not compare the brain scan to before drug but compared it to 6months after drug. The brain would have shrunk due to inhibition of inflammation and then they can see that the rate of loss of brain volume is halted compared to placebo and hey you have a positive drug.

      So know back to lamotrigine. It caused some side effects so 50percent of people were not taking their drugs properly. Can a trial work when people are not taking their drug. When the paper was published this fact was not known. Now when you looking the blood for evidence of nerve damage it was significantly less in people taking drug compared to those not taking drug.

      No yes lamotrigine worked in my opinion and the finding with phenytoin supports this idea further.

      Delete
    4. Time of trial.
      It depends on how big it is an academic trial may have about one hundred people on drug and take a long time to see an effect. In the siponimod trial there were eleven hundred people on drug so the time to see an effect can be shorter.

      Delete
    5. You brain is composed of alot of water and it swells when you have inflammation. Now take a drug that blocks the swelling and the brain appears to shrink compared to doing nothing.

      So in the ocrelizumab trial they did not compare the brain scan to before drug but compared it to 6months after drug. The brain would have shrunk due to inhibition of inflammation and then they can see that the rate of loss of brain volume is halted compared to placebo and hey you have a positive drug.

      So know back to lamotrigine. It caused some side effects so 50percent of people were not taking their drugs properly. Can a trial work when people are not taking their drug. When the paper was published this fact was not known. Now when you looking the blood for evidence of nerve damage it was significantly less in people taking drug compared to those not taking drug.

      No yes lamotrigine worked in my opinion and the finding with phenytoin supports this idea further.

      Delete

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