Wednesday, 8 June 2016

NewsSpeak & ResearchSpeak: What a difference a day makes?

Will Biogen double-down their bet on anti-LINGO-1 and remyelination? #ResearchSpeak #MSBlog #NewsSpeak

"You will have heard already that the Synergy phase 2 anti-LINGO-1 remyelination study was negative. This was a study we were pinning our hopes on to prove that a remyelination therapy is needed and works in MS. The initial proof-of-concept RENEW study showed that anti-LINGO-1 (opicinumab) engaged its target and was able to improve conduction velocity in the optic nerve in people presenting with acute optic neuritis. What peopled seem to ignore in the optic neuritis study was the fact that there was no difference in the retinal nerve fibre layer thickness between those who received anti-LINGO-1 and those who received placebo. In other words anti-LINGO-1 was not neuroprotective. The latter is not a subtle point, but critical to interpreting the results of the latest phase 2 study. It has always been our position that you need acute neuroprotection first, followed by enhanced remyelination, and that both these strategies (neuroprotection and remyelination) would work in a relatively narrow window that we have called  the inflammatory or immunological penumbra. The case that chronic, persistent, demyelination is a problem in MS is not really supported by good data. The bottom line is that if you suppress inflammation in pwMS with a high-efficacy therapy you get spontaneous remyelination and recovery in acutely damaged pathways. I would be interested to see what the recovery rates were like in study subjects in the natalizumab SPMS, or ASCEND, study and the ocrelizumab in PPMS, or ORATORIO, studies. I would not be surprised if we saw spontaneous recovery in pathways with reserve capacity. If we do see significant recovery in these progressive populations without an add-on 'remyelination' therapy then I would argue the null hypothesis has been proven, i.e. we don't need remyelination therapies in MS, but simply highly-effective anti-inflammatories and neuroprotective therapies to deal with post-inflammatory neurodegeneration."

"Biogen's mistake with the SYNERGY trial is that they added anti-LINGO-1 onto interferon-beta. If you want a 'purer experiment' you need to go to the top of the efficacy tree. A much better trial would have been to have added anti-LINGO-1 on top of natalizumab or alemtuzumab. What I am saying is that the SYNERGY experiment is not the ultimate experiment I would have liked to see. I can't wait to have a look at the full data-set to see if hidden in the data there is a hint of efficacy."

"It is interesting to see the impact that Biogen's press release (below), had on their share price. Despite the market's reaction I must congratulate Biogen for being prepared to take risks. Without risk taking we don't get innovation and we would not advance the treatment of MS. I would estimate that the cost of the anti-LINGO-1 development programme is close to $1-billion already, which makes you realise how expensive drug development really is and why we can't do this in academia. The question is will Biogen double-down their bet on remyelination in MS? I am not sure they will, simply because the biological rationale that a remyelination therapy is necessary to treat MS has yet to be established, at least in my mind."

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-- Opicinumab Missed the Primary Endpoint --

-- Biogen Continues to Analyze Data to Inform Next Step in Clinical Development Program --

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Today Biogen (NASDAQ: BIIB) reported top-line results from the Phase 2 SYNERGY study evaluating opicinumab (anti-LINGO-1), an investigational, fully human monoclonal antibody being developed as a potential neuroreparative therapy in people with relapsing forms of multiple sclerosis (RMS). In the study, opicinumab missed the primary endpoint, a multicomponent measure evaluating improvement of physical function, cognitive function, and disability. However, evidence of a clinical effect with a complex, unexpected dose-response was observed.

“It is only through taking thoughtful, calculated risks that we can bring major advances to patients,” said Alfred Sandrock, M.D., Ph.D., executive vice president and chief medical officer at Biogen. “Achieving repair of the human central nervous system through remyelination would be a substantial achievement, and while we missed the primary endpoint, the SYNERGY study results suggest evidence of a clinical effect of opicinumab. Due to the complex nature of the data set, we continue to analyze the results to inform the design of our next study.”

Opicinumab also did not meet the secondary efficacy endpoint in SYNERGY, which evaluated the slowing of disability progression. Safety and pharmacokinetics (PK) were also assessed as secondary endpoints. Opicinumab was generally well-tolerated and the safety profile was consistent with what has been observed in prior studies. Opicinumab showed a linear, well-behaved PK profile over the studied dose range. SYNERGY results will be presented at future medical meetings.

About the Opicinumab (anti-LINGO-1) Phase 2 Development Program

The two Phase 2 trials (RENEW and SYNERGY) were designed to assess the biological activity and clinical potential of opicinumab (anti-LINGO-1) in central nervous system (CNS) demyelinating diseases.

RENEW was a randomized, double-blind, placebo-controlled Phase 2 study designed to evaluate the effect of opicinumab treatment following a first episode of acute optic neuritis. Opicinumab 100 mg/kg was administered intravenously once every four weeks for 20 weeks (total of six doses). Results from RENEW showed improved latency recovery, as measured by the primary endpoint full-field visual evoked potential (FF-VEP), among opicinumab participants, compared with placebo. The study showed no effect on the secondary endpoints of change in thickness of the retinal layers (optic nerve neurons and axons) or visual function, as measured by spectral domain optical coherence tomography (SD-OCT) and low contrast letter acuity, respectively.

SYNERGY was a randomized, double-blind, placebo-controlled, dose-ranging Phase 2 study that evaluated the impact of opicinumab among 418 participants with relapsing forms of multiple sclerosis (both relapsing-remitting and secondary progressive) over 72 weeks. The primary endpoint of the SYNERGY study was a multicomponent measure evaluating the number of study participants who experienced three month confirmed improvement of ambulation (Timed 25-Foot Walk; T25FW), upper extremity function (9-Hole Peg Test; 9HPT), cognition (3-Second Paced Auditory Serial Addition Test; PASAT) and standard measures of physical disability (Expanded Disability Status Scale; EDSS). Secondary endpoints measured slowing of progression on the same components, as well as the safety and pharmacokinetics of opicinumab. Statistical testing assessed the dose-response trend based on the primary or secondary endpoint. Opicinumab was administered intravenously every four weeks at doses of 3 mg/kg, 10 mg/kg, 30 mg/kg or 100 mg/kg. All study participants received concurrent treatment with 30 mcg interferon beta-1a intramuscular injection once weekly.

About Biogen

Through cutting-edge science and medicine, Biogen discovers, develops and delivers worldwide innovative therapies for people living with serious neurological, autoimmune and rare diseases. Founded in 1978, Biogen is one of the world’s oldest independent biotechnology companies and patients worldwide benefit from its leading multiple sclerosis and innovative hemophilia therapies. For more information, please visit www.biogen.com. Follow us on Twitter.

Safe Harbor

This press release contains forward-looking statements, including statements relating to further analysis of the results of the Phase 2 SYNERGY trial of opicinumab (anti-LINGO-1) for the treatment of MS and any future study designs. These statements may be identified by words such as "believe," "expect," "may," "plan," "potential," "will" and similar expressions, and are based on our current beliefs and expectations. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. Factors which could cause actual results to differ materially from our current expectations include the risk that unexpected concerns may arise from additional analysis of the results obtained during the Phase 2 SYNERGY trial. For more detailed information on the risks and uncertainties associated with our drug development and commercialization activities, please review the Risk Factors section of our most recent annual or quarterly report filed with the Securities and Exchange Commission. Any forward-looking statements speak only as of the date of this press release and we assume no obligation to update any forward-looking statements.

CoI: multiple

24 comments:

  1. A large number of senior Biogen executives are a lot poorer today. Should we feel sorry for them?

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    1. Yes and No. Yes, because a high-risk treatment strategy has failed. It is not nice to have an experiment fail. No regarding the share price and their share options. Biogen is one of the Biotech companies that has made many of their staff very wealthy already.

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    2. You call yourself an ex-Biogen investor. I assume you sold your shares ahead of this announcement?

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  2. Not sure myself if I believe serious remyelination can occur via meds.

    Stem Cell therapy coming from stroke may well be the golden earing.

    Have you tried stem cells in mousies?

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  3. "neuroprotective therapies to deal with post-inflammatory neurodegeneration"

    So are you absolutely sure that neurodegeneration requires inflammation to begin? That the neurodegenerative component is not actually the underlying one?

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    1. Yes, this is *exactly* what I've been wondering too.

      I've been trying to ask this very question for a while now but I couldn't find a simple way of explaining it.

      The idea that inflammation is primary and degeneration is secondary is a comforting one, because it implies that highly-effective DMDs probably will prevent a lot of early RRMSers from converting to SPMS.

      But is there evidence for this hypothesis? Could it be that inflammation is just a secondary side-effect?

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    2. inflammation is protection and repair so it will do both and so can and is likely both primary and secondary

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    3. The HSCT/Alemtuzumab data re long-term remission is pretty convincing. I have previously proposed that if you get to 15 years with NEDA there is a good chance you may be cured. It is looking increasingly likely that inflammation is primary and driving all the disease processes.

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    4. But are some people not still becoming progressive on some therapies which suppress inflammation?

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    5. "It is looking increasingly likely that inflammation is primary and driving all the disease processes."

      If we accept the above to be true - perhaps it is - this is still not the "core" of MS though? Something has to trigger and drive the aberrant inflammation... A true "cure" would target this trigger, surely, and thereby allow preservation of our immune systems - which are kind of essential?

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    6. we should not use the term inflammation to mean it is one thing the inflammation driven by T & B cells are very different from inflammation driven by microglia, the later type of inflammation is not really targeted by current MS drugs.

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  4. It is perhaps the Big Farma understand that we need Neuroprotective.

    If Gabapentin can be neuroprotective by acting towards calcium receptors, I don't know but I remember well that I just caught my left leg movement on the 5th day we took the Gaba.

    Perhaps Biogen has put a lot of expectations on Anti-LINGO1 alone would make the myelin back almost "magically", so may have decided by participants who were treated with Interferons, which is a weak DMT but with side effects as of "big people"...

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  5. RE: "The bottom line is that if you suppress inflammation in pwMS with a high-efficacy therapy you get spontaneous remyelination and recovery in acutely damaged pathways"

    I completely agree with above. I used to have pretty bad balance issues. Switched to Tysabri and noticed a remarkable improvement in symptoms after the first infusion. I was still newly diagnosed at the time. Unfortunately, I could only get 2.5 infusions though as I developed an anaphylactic reaction to it.

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  6. RE : "I completely agree with above. I used to have pretty bad balance issues. Switched to Tysabri and noticed a remarkable improvement in symptoms after the first infusion"

    Same here. Except it took for me 5 infusions and the improvement is not that drastic, but clearly noticeable.

    ProfG, as I understand, Anti-Lingo-1 can increase the efficiency of the oligodendrocytes to promote remyelination. Can we imagine that it will increase the reserve capacity or do we have to except that with a poor reserve capacity, Anti-Lingo-1 will have a less good effect. ... or neither and I did not understand anything at all :)

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  7. I got treated with Alemtuzumab 4 moths into my diagnosis... I still have some sensory "burning" sensations on my feet, but its tending to disapear, some days i can't hardly notice it anymore, 0 numbness, 0 balance issues... so yes, remylination happens. When I got my diagnosis I decided I wanted the relapse to be treated like a stroke, save as much of my brain as you can.. now, not after "failing" on less effective treatment... to me it just made sense, and maybe its early to say, but I feel it paid off.

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    1. Where were you getting these burning sensations, Anon? I get these too, in the 'pits' of my feet. Right in the center, under the arches. You're the first person I've met thus far who also has described this. I'm just wondering if you're getting them in the same part of the foot.

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    2. At the relapse the sensation was all the way to the knees,(there was numbness aswell) it fade away in weeks and stayed in the feet, i could hardly wear socks or shoes, it was very unconfortable for me, after treatment it got worse for some weeks, then got much better and stayed on my toes, nowadays i cant hardly notice it, and that just when im wearing tight shoes. We probably have a similar lesion on the spine.

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  8. I wonder will this be seen as a failure of EAE where the anit-LINGO-1 was claimed to work and then move to MS and failure appears to occur.

    I think it is very disappointing but this was an incredibly hard ask to get a positive result

    (a) Try to show recovery where disease activity is only controlled by a weakly active DMT rather than using a highly effective DMT. Any worsening because of disease activity would mask any benefit.

    (b) Delivery a drug which does not really get to its target well such that 99.9% delivered is wasted. Yes some will get in but surely a small molecule that enters the CNS is going to make the likelihood of success higher

    (c) Unvalidated outcomes that where there is no proof that they are measuring remyelination.

    (d) Doing a trial when it was never reported to an active approach in animals such as chronically demyelinated/gliotic lesions

    Pathologists around the world must have the tissues that can show that if you have effective DMT (e.g. natalizumba, alemtuzumab) with MS and non-MS related death whilst on treatment, are the lesions remyelinated or chronically demyelinated. If they are remyelinated profG is correct if not you need to kickstart remyelination. If you do is a short course of treatment enough or do you need long term treatment.

    This is just the beginning. At the beginning of DMT research there were many failures, now we know how to do trials and measure efficacy we can find active drugs within a few months

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  9. ProfG or MD: thinking of the encouraging results on Clemastine as a remyelinating agent presented at AAN, what do you make of this paper just published in the Journal of Neuroimmunology
    https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-016-0600-0

    Do you think this can give us some insight into clemastine's putative MoA?

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  10. Well it looks like another possible solution to SPMS bites the dust. Does this just leave MS-SMART to potentially slow down progress of SPMS?

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  11. How does Clemastine compare to this? If I read that right, both of these trials were phase IIs. The one trial of Clemastine was also a phase II, and it had a positive outcome. If so, wouldn't that provide some evidence that medical remyelination is a reality? Even if big pharma may have a hard time cashing in on it?

    The way I'm reading the data on the two treatments is Anti-Lingo = maybe a remyelinator, but in need of better trials, and Clemastine Fumarate = probably a remyelinator, but not likely to get definitive phase III trials to verify.

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    1. The two trials are too different the clemastine trial is more like the optic neuritis trial

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  12. I believe that Natalizumab has worked wonders for me. I felt a stomach cramp telling me that I needed to go to the bathroom 6 months ago. Haven't felt that in years. Just a few weeks ago I felt a cramp even lower in my gut. Was almost knocked over by the feeling, it was such a shock, so 'new' feeling and then it felt like I remembered the sensation just a second later.

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