When does Bad Pharma Become Good Pharma Publishing phase I studies

Savic RM, Novakovic AM, Ekblom M, Munafo A, Karlsson MO.
Population Pharmacokinetics of Cladribine in Patients with Multiple Sclerosis. Clin Pharmacokinet. 2017. doi: 10.1007/s40262-017-0516-6. [Epub ahead of print]

PURPOSE:The aims of this study were to characterize the concentration-time course of cladribine (CdA) and its main metabolite 2-chloroadenine (CAde), estimate interindividual variability in pharmacokinetics (PK), and identify covariates explaining variability in the PK of CdA.
METHODS:This population PK analysis was based on the combined dataset from four clinical studies in patients with multiple sclerosis (MS): three phase I studies, including one food and one drug-drug interaction study, and one phase III clinical study. Plasma and urine concentration data of CdA and CAde were modeled simultaneously.
RESULTS:The analysis comprised a total of 2619 CdA and CAde plasma and urine concentration observations from 173 patients with MS who received an intravenous infusion or oral tablet doses of CdA as a single agent or in combination with interferon (IFN) β-1a. CdA PK data were best described by a three-compartment model, while a one-compartment model best described the PK of CAde. CdA renal clearance (CLR) was correlated with creatinine clearance (CLCR), predicting a decrease in the total clearance of 19%, 30% and 40% for patients with mild (CLCR = 65 ml/min), moderate (CLCR = 40 ml/min) and severe (CLCR = 20 ml/min) renal impairment, respectively. Food decreased the extent of CdA absorption by 11.2% and caused an absorption delay. Coadministration with IFNβ-1a was found to increase non-CLR (CLNR) by 21%, resulting in an increase of 11% in total clearance.
CONCLUSIONS:Both CdA and CAde displayed linear PK after intravenous and oral administration of CdA, with CdA renal function depending on CLCR. Trial registration number for study 25643: NCT00213135.

We have been complaining about Eli Lilly not releasing their data from a trial (please sign our petition).

But in reality Merck does not smell of roses. 

Furthermore, I have to say to ProfG…..”Kettle and Black” Spring to mind too.

The CLARITY trial of oral cladribine was published in 2010 meaning the trial finished in about 2009 and only now data is beginning to surface.

The extension study of CLARITY was completed many years ago and abstrasts presented but where is the data? 

You may say that is not as bad as not reporting a trial at all…where’s the Charcot Project? 🙂
Anyway back to the bad boys and in his study we are not talking about hiding data for 6-7 years, we are more likely talking ten or more years.

The trials reported in this study are unlikely to be only NCT00213135, as that is a phase CLARITY phase III. This study also reports on the Phase I study and therefore likely have to been completed well before 2005 before CLARITY started.
However, because the marketing machinery is beginning to turn as Merck hope that the regulators see favourably on their new application to get oral cladribine licenced we are seeing old data surface. 

Only about 40% of oral cladribine reaches the blood, if you use generic subcutaneous caldribine 100% reaches the blood. This study reports what happens to cladribine, after it is injected

In the three-compartmental modeling, three compartments describe the fate of a drug once administered: the central compartment, which represents the plasma; the highly perfused compartment, which represents the organs and tissues highly perfused by the blood; and the scarcely perfused compartment, which represents the organs and tissues scarcely perfused by blood (e.g.bone or fat).

However, this does make a point about how you all publish trials? 
Phase I trials are safety studies and they are dull as dishwater if all goes well and are boring as boring can be. 

Yes, this is important safety data that people should be aware of but generally there is an investigators brochure, given to clinical people within the trial so they can see that would carry this information. 

But should this be published within a year of completion as suggested by Ben Goldarce.

Companies wait until it is to their advantage (e.g. for marketing purposes) or until they are no longer interested beforwe they publish…However, if the data show worsening perhaps that should be criminal bnot to report it instantly, as it is negligent. 

Do we publish all trials within one year… No in fact 

Hands up M’Lud…guilty as charged, we have yet to publish our phase I trial and it has been over a year…It is on its way, but it is so boring I have put it all in supplementary data.

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  • Is no research team posting any new research this year? Cambridge? Edinburgh? Bristol? Overseas research teams? This must be the fourth or fifth post on unpublished trials data this month? I for one consider this an academic issue (I'm pretty bored of it). What's happening to EBV research or myelin repair trials? The MS research world seems to be in limboland at the moment. We have Alemtuzumab which is very effective at shutting off relapses . Ocrelizumab may become available in the next c.18 months. What else is in the therapy or research pipeline. No doubt we'll soom be into the conference season – AAN, ECTRIMS etc. i can't see any thing new or breakthrough being presented. It's all go too comfortable for the research establishment.

    • You are correct the publications have been pretty dull, we can only post on falls and MRI and meta analysis so many times. We are also very busy at the moment because of teaching commitments and we are dealing with publications.

      Yes we are publishing on unpublished trials results because it is an very important issue.

      It is also topical to the work we have in the pipeline and it is important that we set the scene. It is also important to help work out how treatments works.

      You have being put to risk and the information is not being published!
      Is this acceptable? If the Tabalumab shows disease worsening it is negligant.

      Importantly this information helps us understand how treatments work and it speaks to the B cell study that we published a couple of weeks ago. We will be building on this over the next few months

      Furthermore, this unpublished information means that you are be put at risks for which you may not been properly informed. Should we keep our mouths shut of should we expose it.

      ProfG can report on EBV research and as to myelin repair trials…we can report on these when the data is published? The first trials have been completed but where are the trial reports? So we are back to the clinical trial reporting issue.

      Another trial started a few weeks ago but until we know the results there is nothing to report on. If the trials are not performed on top of effective control of inflammation the chances or success are limited..

      What trials are in the pipeline, a whole set of fingolimod me-too trials, will they work of course. So we do a feature on how they work. The companies have given us theis neat idea that they keep cells in lymph glands, but do people on fingo get John Wang nuts as those in the groin swell? How does fingolimod work in mice or fish that have no lymph nodes.
      Is this more pharma spin?

      I do not think it is comfortable for the research establishment, if is a state of flux, because if MS pharma dis-engage then will the space be filled with new blood or has the golden age of MS treatments passed.

    • what is the mechanism of action you propose for fingo, then? :-).
      Obseravation on a number of patients N=1 (myself), the lymphocytes came back to normal within 2 weeks of stopping fingo (I was on half dose, though). So it seems something was keeping them out of the circulation, or?

    • MD, I think you are right, the golden age of MS treatments passed. The highly effective dmds and induction therapies have lead to a complacency in research. Maybe we are just catching our breath. Progression and neurodegeneration are now at the forefront of research.

    • The S1P1 modulator is part of the action but I suspect there is a killing mechanism too as the absolute numbers drop. There are some people that do not repopulate for a very long time after stopping.

  • I really should read the Ben Goldacre book but I fear it would throw me into anger and depression at the sleaze of Big Pharma.

  • Or it could inspire people to take action and change things for the better(it's Sunday, I am feeling optimistic :-).

    As for publishing: there is the publishing in mediacal journals ( takes eons and a lot of effort) or the quick way for pharma to register the result on the clinicaltrials.gov site(no trouble) and provide additional data (for the especially interested) on request. Is that too much to ask?
    If the result of the tabalumab trial was serious side effects Lilly would have to show it immediately or face big trouble. So the trial probably yielded an uninteresting result that was shoved in an "uninteresting result drawer number 101". But it could be something that is important from another point of view, don't we all learn from our failures?

  • And as for more granular data… could you ask dr Klaus S. and Co to show more detail on their epidemiological study on MS in East London. "South Asian" kind of covers a large area :-D.

    • I'm sorry CD20 that's the granularity the NHS coding provides atm. Incidentally, the team met last week to discuss progress on a more detailed study, which will include the year of moving from low to high prevalence (i.e. UK) territory; we could try and include more detail in terms of exact territory too. Problem is that local epidemiology data are quite sparse, and prevalence – as far as we know – low so any attempt to look at subgroups leads to small absolute figures and large confidence intervals.

    • Well, coding is as it is , so I hope you can squeeze out more detail out of what you have :-). At least country of origin, would be good. And how long it takes to develop MS after moving.
      Epidemiology of MS is getting more interesting as people move like crazy these days 🙂

  • Ok was initially just pleased to hear that Merck came clean on atacicept.Good pharma. But they left it far too late (ATAMS 2014, ATON 2015) had they alerted immediately tabalumab might have been abandoned sooner. Very bad pharma. Then refusal to provide the data when asked. The data is years old. Bad pharma.
    Meanwhile, turning back to cladribine, why all the fuss about it being an oral dosage form? A handful of doses once a year! Big deal. Offer me the choice of sc inj 100% bioavail v oral 40% (and probably depends what I've had for breakfast) I'll go sc thanks very much (managed 4 years injecting their Rebif sc and that stuff was like lemon juice). And more ancient data coming to light only now. Agreed, Merck are very bad pharma.
    But Eli Lilly are big time BAD PHARMA and yes, it really really matters. It's not about side effects it's whether it made MS worse. We need to know. It's important for understanding how other things work and for an effective early targeted safer treatment being available in future. Yes, too late for many of us I know. But not too late for some or the people yet to experience first symptoms, perhaps our children/grandchildren should they have inherited our MS prone genes.

    • The paper was 2014 butt the change on clinicaltrials.gov
      was much earlier. Lily would know of the Merck failure as the company spies would have spread the word pretty quickly I suspect.

      You are making the assumption that tabalumab was abandoned. This is on the unsubstantiated report on the Swiss hospital website. On clinical trials it says completed. If it was abandoned then it would be bad pharma
      We have to wait to see what gets published

      We don't know what the Lily data is, maybe a simply negative result. We have six months to wait if they are being truthful

    • What would be e bigger loss for any big pharma CEO : losing his face(not being sexist here, are there any women on top of big Pharma?) or losings some share value after bad news? Bad news is daily news in Pharma, so if the result was really bad it would have to come out immediately.
      I would put my bet on : "nothing to show" unimportant result :-)…

  • My personal experience of Cladribine was pretty horrible. I had come off Tysabri, because of high PML risk. I went onto Gilenya seven weeks later and was doing pretty well on that. I came off it to have what turned out to be two full doses of Cladribine. A couple of months after that I had a horrible relapse, which had left me a lot more disabled than I was before. It felt like a rebound relapse, which the Cladribine did nothing to stop.

    • Klaus SchmiererSunday, March 05, 2017 9:39:00 pm
      "Why did you give up Fingolimod when you were doing well on it?"

      Why do you ask?

    • if it aint broken why fix it?

      So without knowing or wanting to know the circumstances

      A switch from fingo would either be because of safety/side-effects concerns, breakthrough relapsing disease or maybe disease was secondary progressive and one falls outside the NICE remit for prescription, if one is in UK anon may not be (please dont tell me as we should noy be discussing individual cases). Genric comments questions are best

      Based on the leist et al. Most relapses on oral cladribine were within the first three months of starting after a first demyelinating event.

      I presonally dont know much about fingolimod rebounds, but it it has a mechansism (anti-migration) akin to natalizumab then they are going to happpen. I have recently seen reports of a number of these.

      How to transition people off fingolimod will require more posts by ProfG. I'm sorry I dont have the answers and I am soory Claribine did not appear to work for you. No MS drug nor HSCT is 100% guarenteed to be effective

    • ps. to me it is not an obvious question to ask (but i'm not the original poster)

      to me, it is more obvious to ask HOW can people come off a drug before feeding them the drug (particularly gilenya – drug that was previously used by some to transition people off tysabri)…. but that's just me of course.

      here is 10 reasons off the top of my head:

      – they didn't wanna take gilenya
      – they wanted induction treatment/claradbine and were sick of the rest
      – they wanted to get pregnant at some point in the future
      – gilenya was giving them an evil look every time they took a dose
      – their neuro was getting kickbacks for gilenya prescription and the patient wasn't a fan of making their neuro richer….

      blah blah blah. i again say the WHY is less important than the HOW. the only time people seem more interested in the why people do things they do is when they can't tell them HOW to do things they want to do… and they try to change the topic.

    • The question posed was why did the person change from fingolimod when they were happy with the effect. If they weren't happy that is another matter.(ps to the original poster, we don't need to know. Too much personal detail).

      So now we accept one of the reasons from your rant.

      The question of how you transition from one drug to another and this is trial and sometimes error.

      We have seen alot of rebounds post natalizumab and slowly a picture emerges on how quick you introduce the changing drug.which changing drugs are more effective after certain drugs.

      There are numerous posts on this by profG so you can read for yourself.

      The change from fingolimod is less clear at the moment.

      We recently had a report of issues with alemtuzumab post fingolimod.

      25percent of people relapsed The explanation given is most likely to be wrong as alemtuzumab does get into lymph nodes. Does it get in enough? The better place to look is in the bone marrow.

      I have also seen data of people with persistent lymphopenia after fingolimod. This may because of an additional killing action evident in the cancer literature.

      There are a number of recent reports in rebounds post fingolimod. They prefer to call them re activation but manufacturers have created the mechanism that could me rebounds.

      Unfortunately the landscape for MS drugs has become complex and transitioning is a new bit of neurological art. That art comes from experience.

      PS we can always say how but how to do it safely is the key.

    • This why it is important to determine whether B memory cell activity has any predictive value as it has in other conditions. Maybe the original poster did not deplete the cells and needed more dosing..

    • PPS pharma has this data this is why Roche Merck Sanofi and lilly need to supply the results or the data

    • It is possible that the veracity of the original comment re cladribine may be doubted.
      Just sayin'

    • Yes, we tried to get the cladribine extension data published in 2013-2014 but it was rejected by two journals. To address the reviewer's comments required a massive investment of resource and time by Merck to get global comparative epidemiological data about cancer risk. This data/study has been completed and we are back playing ping-pong with the reviewers'. We are on our third round of comments. Getting papers published takes time, but the headline data has been in the public domain since 2013 via this blog; is that not enough?

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