Monday, 27 February 2017

What's Happening with the Clinical Trial Data

As soon as rituximab and then Ocrelizumab was found to inhibit relapsing MS, companies began the hunt for "me-toos" to do the same thing.


Ocreliziumab depletes CD20 B cells and blocks relapses, so it gets rid of memory B cells, but not the earliest of B cells or the antibody forming plasma cells.

Unless you know what CD20-B cell depletion is doing, getting rid of the all B cells may not seem unresponable.

Companies thought that they could get rid of B cells by depleting B cell growth factors

A few companies had the same type of idea to make a buck

Merck made a fusion protein to block BAFF and APRIL B cell growth factors called Atacicept.


Eli Lilly made an antibody that blocked BAFF called LY2127399 or tabalumab


There was another one called Belimumab, which never made it into MS.....Luckily.

Rather than selecting a cashcow, looks they got a different beast
In fact Atacicept made things worse in trials!

1. Atacicept in Subjects With Optic Neuritis (NCT00624468)
2.A Phase 2 Study of Atacicept in Subjects With Relapsing Multiple Sclerosis (ATAMS) (NCT00642902)

It said

Sponsor voluntarily decided to prematurely terminate this trial due to an increase in multiple sclerosis (MS) disease activity observed in atacicept arms of both trials as compared to placebo.

Both trials were eventually published 




Sergott RC, Bennett JL, Rieckmann P, Montalban X, Mikol D, Freudensprung U, Plitz T, van Beek J; ATON Trial Group. ATON: results from a Phase II randomized trial of the B-cell-targeting agent atacicept in patients with optic neuritis. J Neurol Sci. 2015; 351:174-8.

So is the problem APRIL, BAFF or both?

The answer comes with the result of what happened with tabalumab that blocks only BAFF.

A Study of Patients With Relapsing Remitting Multiple Sclerosis NCT00642902

The company has reported on Clinical tiral. gov that the trial was completed.  

What happened.?

We don't know because the results have not been reported.

Blocking BAFF gets rid of  mature B cells and can even get rid of plasma cells and reduce antibodies, but they appear to have the potential to increase the memory B cell pool, which recently we suggested could be the problem in MS.

Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K. Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017. pii: S2352-3964(17)30045-2.

Therefore both tabalumab and atacicept could make MS worse.

Response to therapy may help elucidate whether the idea has any legs, it may help us understand treatement and may help us personalise this treatment. 

For Merck it may help us to understand how Cladribine actually works

For Lilly it may help with responsible reporting and help determine if BAFF inhibition is what makes MS worse

You prompted us to ask more about access to the data, notably Lilly


The company website (Click) says "..companies must act to earn the trust of the public they serve"

However, as we have no access to data or the result, which one could predict worsened MS,  many years after the trial was completed, how is that going to lead us towards trust?

They say "We have an online portal to facilitate requests from legitimate researchers for clinical trial data there



So when requested it is "out of scope"

"Whether favourable or unfavourable, Lilly posts the results of all Lilly-sponsored Phase II, Phase III and Phase IV clinical trials of Lilly marketed products conducted anywhere in the world that were initiated on or after October 15, 2002"

When asked specifically, it was said that "this standard only applies to marketed compounds".

So as Talabummab was not a marketed we are not getting access to the data, 

"Lilly discloses results of Lilly-sponsored clinical trials for compounds whose development terminates on or after October 1, 2009". 

In response to this question about disclosure the response was "We expect to submit the results of this study to Clinicaltrials.gov in the third quarter of this year following the official termination of the molecule’s development marked by the inactivation of the IND this year". 

This will no doubt say the trial failed, but will it say it worsened disease? 

However, on clinical trials.gov it is unlikely to talk about the immunostaining and disease activity, which is the data that will help us understand what occurs in MS.

If there was an increase in B memory cells? How long did this occur, does it relate to disease activity?


I guess, we will never know.

Companies do preclinical testing to ensure their drugs are relatively safe, so that they can make an IND filing.


IND means an Investigational New Drug (IND) program is the means by which a pharmaceutical company obtains permission to ship an experimental drug to clinical investigators before a marketing application for the drug has been approved. The IND application is reviewed for safety to assure that research subjects will not be subjected to unreasonable risk. If the application is cleared, the candidate drug usually enters a Phase 1 clinical trial and beyond until they apply for a New Drug Application (NDA) which allows companies to market a product.

  • Is the drug safe and effective (efficacy) in its proposed use(s) when used as directed, and do the benefits of the drug outweigh the risks?
  • Is the drug’s proposed labeling (package insert) appropriate, and what should it contain?
  • Are the methods used in manufacturing the drug (good manufacturing practice [GMP]) and the controls used to maintain the drug’s quality adequate to preserve the drug’s identity, strength, quality, and purity?

It seems development of Talabumab is not going to occur, so why hide results from people?

We will have to wait so see if EL actually does anything


Even with providing access data, the publication process would mean that nothing would get published before Q3 (third quarter) 2017.

Is this just another case of Bad Pharma?

13 comments:

  1. The result must have been a miserable fail ( and since they try to conceal it) possibly worsening of MS.
    Pharma markets ANYTHING with a trace of clinical effect, belimumab is microscopically effective in real patients with lupus. After some marketing it sells here for ca £1000 for a monthly dose. Miracles of pharma.
    MD, have you tried to ask clinicaltrials.gov to get the result you want. If there is a site they bother maintaining to add transparency, then maybe they have some influence on what is reported?

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  2. It would be helpful if you keep to the colour coding font for your commentary text so we can see what Pharma says compared to you.

    ReplyDelete
    Replies
    1. Pharma in orange,

      I have had to amend this post so many times as there "blogger" has been automatically changing fonts and colours and over the weekend.

      I have been trying to keep my comments purple (to match with the blog) but this is difficult to see difference from black

      What colour should I do my text in future?

      Delete
  3. Full credit to Merck. ATON and ATAMS may have failed on the surface but what a vital point they have elucidated. No such thing as bad results ;-) might not be what you hoped for but results are results (so long as method ok of course).
    Very bad show Eli Lilly :-(
    Makes it sound like MS probably got worse. Will 'results' in third quarter not be full results? Guess you have to wait and see. If no help send Lilly CEO your paper with para on tabalumab highlighted and letter saying how the corporation is frustrating MS research. If you don't I might do it for you ;-)

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    Replies
    1. Before we start patting Merck on the Back, hate to say it they have not been total angels.

      There maybe still useful data from that trial, that they did not publish. We have asked.

      Delete
    2. If you want we could sign a petition to Lilly CEO. (I believe patients participating in trials have the right to be informed about the trial results - anybody reading this blog or anybody who knows anybody who has tried this widget from Lilly?)

      Delete
    3. And what did they say?
      Should have known it sounded too good to be true (in which case it probably is)

      Delete
    4. I believe patients participating in trials have the right to be informed about the trial results.

      I agree with you...are any of the readers people who participated in the trials. Where you informed of the results

      Delete
  4. MD, try and post this question as a title in big letters tomorrow - somebody who knows somebody who was in the Lilly trial should raise their hand.

    ReplyDelete
    Replies
    1. 245 people from US and Europe. Here's MD earlier Missing Data post

      http://multiple-sclerosis-research.blogspot.com/2017/02/the-missing-data.html?m=0

      Delete
  5. I am having my first infusion of Ocrelizumab next week!

    ReplyDelete

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