Wednesday, 29 January 2014

Another big beast joins the fray: ofatumumab phase 2 trial results

Another big beast arrives on the MS scene. #MSBlog #MSResearch

"MS used to be a orphan disease. Interferon-beta-1a (Avonex) was licensed by the FDA under the orphan drug legislation. What is an orphan disease? Orphan diseases are rare diseases that only affect a small percentage of the population. Orphan drug acts were put in place  to incentivise drug companies to take the risk and develop drugs for these diseases. MS is no longer an orphan disease; sales of DMTs for MS are close to $15billion a year. In the beginning the Pharma companies in the MS space were relatively small, but as the market expanded the big beasts started to arrive; Novartis, Sanofi, Roche and now GSK. GSK is developing ofatumumab for MS; the stunning phase 2 results are presented below."


The Big Beast: GSK joins the fray
"Ofatumumab is a completely humanised monoclonal antibody that depletes B-cells by binding to CD20 on their surface. You will have noted that this is not a unique strategy and ofatumumab follows on the results of rituximab and ocrelizumab. In other words ofatumumab is a me-to drug. Big Pharma like to play it safe; there is little chance of ofatumumab not being effective in MS. In this study ofatumumab suppressed MRI activity by >99%. These results is one of the best results to date in the MS space. The bad news is that at sometime during this study the small Danish biotech, Genmab, who was developing this product decided to partner with GSK. GSK for strategic reasons took the decision that a subcutaneous route would be a better option for this drug and had to repeat the phase 2 development programme. The simple switch from intravenous to a subcutaneous formulation will delay the development of ofatumumab by about 4-5 years. This is a great pity for MSers. Why so long? GSK were simply too slow out of the blocks in getting the repeat phase 2 study designed and done. one of the more nimble smaller competitors would have done this in 18-24 months. Despite the delay ofatumumab offers MSers in the future another very highly-active drug with a side effect profile that looks very promising."

"I predict that the class of monoclonal antibodies that deplete B-cells (anti-CD20 and anti-CD19) will be the real game-changers in the field; they come with very high-efficacy and have a relatively good safety profile. There are, however, several unanswered questions around their use in MS. (1) How should they be used; as maintenance therapies or as induction therapies. A maintenance therapy requires the drug to be given continuously and indefinitely. In comparision, an induction therapy require a treatment period of say 2 years and then a watch and see approach with re-treatment given if MS disease activity reemerges. No prizes for guessing what class of drug Pharma want. The distinction between maintenance and induction is not trivial and affects pricing and reimbursement. In short it gives Pharma executives a big headache. (2) How safe is long-term B cell depletion? Can you survive without any circulating B cells for 30 or 40 years? I suspect you can as there are a large number of hereditary disorders, which affect B cells. We simply treat these patients with immunoglobulin or antibody replacement therapy. (3) Do anti-CD20s work in non-relapsing progressive MS? The Roche ocrelizumab PPMS trial will address this question. (4) How do B cell depleters work? Are they working via an anti-EBV mechanism? As you know EBV resides in B-cells and B-cell depleting agents are very good at suppressing EBV viral loads. In fact Rituximab, which is very effective in MS, is the only licensed anti-EBV drug on the market; it has a license for EBV-associated post-transplant lymphoproliferative disease. (5) Do other drugs and strategies that transiently deplete B cells working in the same way, for example mitoxantrone, cyclophosphamide, alemtuzumab, cladribine, bone marrow transplant, etc.? I love it when science results in more questions be asked than it answers; innovation feeds innovation."

"Let's celebrate these results. Well done to the investigators and MSers for participating in this trial. And thank you Genmab and GSK; it is good to have another kid on the block."


Epub: Sorensen et al. Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: A phase 2 study. Neurology. 2014 Jan 22.


OBJECTIVES: We present the first study to explore safety and efficacy of the human CD20 monoclonal antibody ofatumumab in relapsing-remittingmultiple sclerosis (RRMS).

METHODS: In this randomized, double-blind, placebo-controlled study, patients received 2 ofatumumab infusions (100 mg, 300 mg, or 700 mg) or placebo 2 weeks apart. At week 24, patients received alternate treatment. Safety and efficacy were assessed.

RESULTS: Thirty-eight patients were randomized (ofatumumab/placebo, n = 26; placebo/ofatumumab, n = 12) and analyzed; 36 completed the study. Two patients in the 300-mg group withdrew from the study because of adverse events. No unexpected safety signals emerged. Infusion-related reactions were common on the first infusion day but not observed on the second infusion day. None of the patients developed human anti-human antibodies. Ofatumumab was associated with profound selective reduction of B cells as measured by CD19+ expression. New brain MRI lesion activity was suppressed (>99%) in the first 24 weeks after ofatumumab administration (all doses), with statistically significant reductions (p < 0.001) favoring ofatumumab found in new T1 gadolinium-enhancing lesions, total enhancing T1 lesions, and new and/or enlarging T2 lesions.

CONCLUSIONS: Ofatumumab (up to 700 mg) given 2 weeks apart was not associated with any unexpected safety concerns and was well tolerated in patients with RRMS. MRI data suggest a clinically meaningful effect of ofatumumab for all doses studied. Results warrant further exploration of ofatumumab in RRMS.

CoI: mutiple

Some older posts of interest regarding CD19 and CD20:

14 Nov 2012
In response to a query re anti-CD19 treatment. Unfortunately, you can't access anti-CD19 treatment at present it is not a licensed therapy. However, we are doing a clinical trial of this agent so if you are interested you can ...

04 Dec 2012
"In response to a comment regarding the safety of rituximab and ocrelizumab in MS. This poster was presented at ECTRIMS. This is very reassuring in that the anti-CD20 look as if they will be in the upper zone of efficacy and if ...
12 Aug 2013
Instead they decided to develop the follow-on compound ocrelizumab. This latter decision will delay the access of an anti-CD20 therapy for MSers by about 4 years. At the time Genentech-Roche made the decision not to ...

04 Jun 2011
Please note that Ocrelizumab is the follow-on compound of Rituximab; both these drugs are monoclonal antibodies that target a protein CD20 that is expressed on B cells. Exactly how these drugs work is not known. However ...
30 Jul 2013
BACKGROUND:Rituximab is an anti-CD20 monoclonal antibody approved for non Hodgkin lymphoma and rheumatoid arthritis. It is being considered for the treatment of MS. OBJECTIVES:To evaluate the efficacy and safety ...

19 comments:

  1. Is it expected that subcutaneous route will achieve same effect?

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    1. Yes the two routes of delivery can both cause blood levels of the antibody, there difference is the speed and duration of this event and the amount that reaches the blood.

      The subcutaneous route often means longer exposure to the drug..it is a sensitizing route so will you get more neutralizing antibodies. Hopefully not.

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    2. Is body producing neutralizing antibodies for humanized anitobidies?

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    3. I think you can get neutralising antibodies against Alemtuzumab, amazingly enough. Not sure about Tysabri.

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    4. I think you can get them with natalizumab/Tysabri, At least I´ve been tested. It normally happens in the first months and more often if you get an allergic reaction.All the best
      //Swedish Sara

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  2. Prof G,

    Is there a chance this is the most effective drug so far for suppressing standard MR disease activity? Is this the only study far with any significant amount of information on this? Is there any atrophy data for ofatumumab (or studies looking at MTR or spectroscopy)?

    Thanks as always

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  3. What is slower:
    1. movement of glaciers
    2. evolution of species
    3. half-time show of the super bowl (people still watch but need lots of alcohol)
    4. big pharma bringing drug to market

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    Replies
    1. I have my guess but even as Brit I KNOW SUPER BOWL IS COMING

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  4. This should be celebrated - Prof G is right. I've read the paper and the MRI data at the highest doseage level is remarkable - it essentially shuts off all MRI activity. If that was sustained over an indefinite period than arguably it is close to a cure (defining a cure as something which stops worsening as opposed to recovers previous damage). This, of course, presupposes the link between inflammatory MRI activity and progression which I think is becoming increasingly accepted.

    My question, which might seem odd, is as follows. I have already received Alemtuzumab which, itself, is a highly effective treatment, I realise. However, it's data is not as impressive - even at phase 2 stage - as this; MRI activity only stops in about 50% of people as opposed to almost 100% here if I understand the data correctly. If I was to not be lucky enough to achieve a state of NEDA on Alemtuzumab would I be able to consider, in the future, something like Ofatumumab? Or once I've been treated with one monoclonal antibody am I stuck forever with that one? One of my concerns with Alemtuzumab - as lucky as I am to have received it - was that I might have nailed my colours to the mast too soon, only for Rituxumab or Ofatumumab to turn out to be more effective. Have I?

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    1. With alemtuzumab it is out of yoir system relatively soon but creates benefit. No reason to worry about nailing choices to a kast. But if you have an induction therapy that wotks do you need to take other drugs.

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  5. I would rather have an induction therapy than a maintenance one. As a recipient of alemtuzumab some seven years after fist infusion, not having to take anything is a real bonus. Glad to see that other highly effective treatments are on the horizon. Good news for patients and neuros (as long as NICE play ball).

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    1. Could I ask you if the alemtuzumab helped your fatigue (if you had it)? Sorry to hijack the thread, but I can't seem to find an answer to this. Thanks!

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    2. No longer an issue. I think Prof G has noted that wome fatigue must be a consequence of underlying inflammation in the brain. Stop the inflammation and fatigue should improve.

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    3. Thanks, that's good to hear.

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  6. This is is very hopeful news! My question is, would ofatumab be available to those with spms? I guess it would help to slow disease in the same way as for rrms...Jill

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  7. Thanks for this news! My question is, whether ofatumumab will be available to those with spms as well as those with rrms? My guess is that the drug would stop disease progression in the same way...
    Jill

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  8. Once trial data is available and only after that

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  9. Prof. G a better analogy for big pharma joining the fray are hyaenas coming to feast on the carcass. Once they have finished there will nothing left for the vultures.

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  10. Interestingly, ofatumumab is put down as having a risk of subsequent herpes outbreaks... this is interesting insofar as it might challenge some thoughts about MS and the herpes virus, possibly??

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