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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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June 23, 2011

Cladribine Is Gone

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Posted by Derek

Multiple sclerosis therapy has been changing a lot in recent years, and one of the biggest events was the introduction of Gilenya (fingolimod). That's the first non-injectable for MS, and it's quite a story (as well as being quite a weird compound from a chemistry perspective).

Novartis has been racing ahead in selling that one, because they knew the Merck KgGa (Merck-Darmstadt) had another oral compound in the works, cladribine. That's a nucleoside analog with a different mechanism (targeting some lymphoctye subtypes and thus changing immune response), and it was already used in treatment of some forms of leukemia. It did show promising results in the clinic for relapsing MS, and there were high hopes.

Not now. Word has come that the company that they're withdrawing their application in Europe and the US, and taking the drug off the market in the only two countries (Russia and Australia) where it had been approved. The FDA had already said that it would not approve cladribine without more safety information, and Merck KgGa has decided that (1) the ongoing trials won't do the job, and (2) it's not worth it (risk/reward) to try new ones.

So that leaves the field open for Novartis, and German Merck (who have had several disappointments in recent years) in some trouble. . .

Comments (16) + TrackBacks (0) | Category: Regulatory Affairs | The Central Nervous System


COMMENTS

1. industry in trouble on June 23, 2011 9:41 AM writes...

Having to demonstrate that a new drug is actually safe and effective really puts a crimp in keeping the industry profitable, stopping downsizing.


Permalink to Comment

2. A Nonny Mouse on June 23, 2011 10:04 AM writes...

Keep an eye on Pleneva from BTG for an oral MS treatment; we were involved in the research to that compound. Seeing as it is a structured lipid it falls into the "GRAS" category which will make approval much easier (certainly all the tox studies were considerably accelerated). The initial trials with the natural lipid were very promising, but the problem was with the very large dose that had to be given (thus, a synthetic lipid with defined structure).

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3. law on June 23, 2011 10:29 AM writes...

Seems like you violated your confidentiality agreement, Nonny Mouse. Good job.

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4. Anonymous on June 23, 2011 10:40 AM writes...

More likely a stock tout that has no real hands-on to research background, and so no nondisclosure (or morals.)

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5. A Nonny Mouse on June 23, 2011 11:04 AM writes...

#3 & #4

I have been doing research for 28 years, and still actively do. And as for morals I won't even debate!

The information that I have given is in the public domain if you could be bothered to look it up. You will see that the PIIa trials will be up next month, which is when the "real" results will be available rather than the uncontrolled trials with the natural product. The information on the initial studies has been presented by the inventor (Lawrence Harwood, University of Greenwich) many times.

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6. sgcox on June 23, 2011 11:09 AM writes...

#3 not much violation :

http://clinicaltrials.gov/ct2/show/NCT01037907

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7. A Nonny Mouse on June 23, 2011 11:37 AM writes...

Sorry wrong Lawrence; should be Harbige (Harwood is at Reading and nothing to do with this!)

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8. cynical1 on June 23, 2011 12:58 PM writes...

As the spouse of a MS patient, a former researcher in MS, a former member of clinical teams for MS and a medicinal chemist; I am neither surprised nor disappointed in this news. Ablative therapy has its limits. MS isn't generally associated with a shorter lifespan so any longterm use of a chemotherapeutic, and the risks that go along with them, will necessarily limit chronic administration (c.f. mitoxantrone).

One of my big disappointments in MS research, as well as the other autoimmune diseases, is the general lack of effort towards immunotolerance towards putitive autoantigens. Granted, identifying those autoantigens in these diseases has been extremely difficult due to epitope spreading (MG being a notable exception). In the case of MS, they have beaten MBP as a putitive autoantigen into the ground so deep that I literally ignore any company/clinical trial that would target it as being hopelessly stupid. But the NMSS keeps funding work on it.

Approximately 5% of the world's population have an autoimmune disease. What do we have to show for it? Mostly immunosuppressants and chemotherapeutics. It's like using a hammer and anvil to repair a watch, in my opinion. Evidently the FDA saw cladribine as being more like a sledgehammer.

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10. Marc on June 23, 2011 3:55 PM writes...

#8: I agree on the frustrating lack of progress - I think our actual scientific understanding of autoimmune disease is really pretty comparable to that of CNS disease, even though on the surface it seems as though the immune system is better understood than the CNS. One point you don't raise, but which I think is important, is the utter uselessness of essentially all animal models for autoimmune disease. The RA models are hopeless & they are still better than those for SLE, or MS, or Scleroderma. Which puts us pretty much in the dark as to causes, and means the drugs end up being (at best, as in these MS oral treatments) folk remedies that turn out to actually work.

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11. Spike on June 23, 2011 9:18 PM writes...

There may be some misunderstanding of what GRAS relates to. Individual compounds can be defined as being GRAS. It doesn't apply to classes of compounds.
The definition from the FDA website is
"GRAS" is an acronym for the phrase Generally Recognized As Safe. Under sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act (the Act), any substance that is intentionally added to food is a food additive, that is subject to premarket review and approval by FDA, unless the substance is generally recognized, among qualified experts, as having been adequately shown to be safe under the conditions of its intended use, or unless the use of the substance is otherwise excluded from the definition of a food additive. For example, substances whose use meets the definition of a pesticide, a dietary ingredient of a dietary supplement, a color additive, a new animal drug, or a substance approved for such use prior to September 6, 1958, are excluded from the definition of food additive. Sections 201(s) and 409 were enacted in 1958 as part of the Food Additives Amendment to the Act. While it is impracticable to list all ingredients whose use is generally recognized as safe, FDA published a partial list of food ingredients whose use is generally recognized as safe to aid the industry's understanding of what did not require approval.

ItThe statement, "Seeing as it is a structured lipid it falls into the "GRAS" category which will make approval much easier (certainly all the tox studies were considerably accelerated)" is certainly provocative. Not sure how a substance being GRAS would accelerate the Tox studies or make approval easier. I'd love to be enlightened.

Would sure be interesting to see if the component or components of this drug are included in the FDA's Inactive Ingredient Database (i.e. used as a pharmaecutical excipient).

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12. anchor on June 24, 2011 5:47 AM writes...

@ Spike :

Thanks for that enlightenment on GRAS. A very lucid write up. Good job!

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13. A Nonny Mouse on June 24, 2011 7:05 AM writes...

#11

This was the MRC dealing with it, so I don't know if there is any difference with the FDA. It is also several years ago since the meetings, so anything could have happened in the meantime.

The belief was that, as the acids constituting the synthetic lipid were the same as those in natural oils which are consumed in large quantities (though not necessarily in the correct position in the lipid for the biological effect) then this would confer the safety onto the molecule.

As I say, I have lost touch with the project, so cannot say what the situation is.

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14. hypnos on June 24, 2011 10:08 AM writes...

Small correction: It is KGaA, not KgGa. (http://en.wikipedia.org/wiki/Kommanditgesellschaft_auf_Aktien)

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15. Bo Weers on July 20, 2012 3:17 AM writes...

Good article. It is quite unfortunate that over the last 10 years, the travel industry has already been able to to take on terrorism, SARS, tsunamis, bird flu, swine flu, and the first ever entire global recession. Through all of it the industry has really proven to be robust, resilient and dynamic, finding new solutions to deal with hardship. There are continually fresh troubles and chance to which the marketplace must yet again adapt and react.

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16. sterowniki dziwieku asus on September 11, 2013 8:06 AM writes...

Sweet site, super layout, real clean and utilize genial.

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