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PARP Inhibitors Come Through

PARP (poly ADP-ribose polymerase) inhibitors have had a rough time of it in the clinic. Sanofi had one (iniparib) fail, but it later turned out, embarrassingly, that it wasn’t really a PARP inhibitor at all (update: more on this here). AstraZeneca had a legitimate one fail as well (olaparib). Merck got out of the area and outlicensed their compound to a small company called Tesaro, and Pfizer spun their molecule off to another small outfit, Clovis (who have since had a wild ride of their own with other compounds). Meanwhile, Medivation recently acquired Biomarin’s PARP inhibitor, talazoparib.

So it’s been pretty messy, but the potential of PARP inhibitors has remained in the “unproven” category. Until today, that is. Tesaro announced that neraparib, the ex-Merck compound, showed very solid results in progression-free survival in three different genetic varieties of ovarian cancer in a 500-patient trial. This has their stock up over 100% as I write, and the other folks developing PARP compounds aren’t doing badly, either. We don’t measure stock in the mood of patients who are actually being diagnosed with ovarian cancer, but I would guess that if we could, that index would also be up, and good for them, because they need all that they can get.

Interestingly, the AstraZeneca compound, olaparib, has been approved in ovarian cancer, but only for patients with the BRCA mutation (its clinical performance was not enough in other patients, to the point that going back and looking at the BRCA subgroup was something of a rescue operation). Neraparib worked very well indeed in the BRCA patients, but showed significance in others as well. It’s not clear to me why these two should be this different, and this illustrates (once again) the value of so-called “me-too” compounds. Now, all these things have been under development more or less simultaneously, so it’s hard to call any of them a “me-too”, but to an outside critic of drug development, they certainly would be. So many companies in the same space! So wasteful!

It’s not a waste, and today’s results show why. It’ll be quite interesting to see the clinical results of the other PARP compounds in this light. You’d expect more differences to become apparent as they are tried in combination with other agents, too. This story is being written as we watch.

19 comments on “PARP Inhibitors Come Through”

  1. Lane Simonian says:

    Just from a mechanism perspective.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2438280/

    (although I would not at this point discount the peroxynitrite/PARP nexus in the development and progression of cancer).

  2. Anders says:

    Does anyone know if there are CNS active PARP inhibitors out there? Could have relevance in neurodegenerative diseases, perhaps.

    1. Ben B says:

      Hi, I believe veliparib crosses the blood brain barrier. It’s being looked at in brain tumours in the clinic.

    2. Andrew says:

      I think PARP inhibitors do have a potential role to play in treatments of ischemic stroke and cardiac infarction. MP-124 from from Mitsubisi Tanabe was developed for stroke but has been silent for more than 2 years. I consider it discontinued. JPI-289 from JEIL is still going, also for stroke. Both have used primate models but JEIL used a much larger primate and the MRIs look a lot more convincing in tersm of the accuracy of measuring volume of the ischema. The risk for increasing genetic instability in noprmal cells is very real, but I belive at the right dose and treatment duration, it is worth the risk.

  3. CMCguy says:

    The post and article only mention met PFS results as positive however saw nothing on the OS (overall survival) which is supposed the FDAs ultimate acceptance criteria. Does this mean may be looking at a potential complicated market approval, if even granted, that will be contingent on demo of OS in PIII & PIV studies?

    1. Biao Lu says:

      Good to know this interesting story.

    2. JPS says:

      The relevance of PFS (a measure of the time it takes for the tumour to grow) versus OS (overall survival, how long the patient lives) varies by cancer type. In cancers that are “relatively asymptomatic” (e.g., early metastatic breast cancer) the FDA is not particularly interested in PFS, because PFS improvements may have relatively little clinical significance. This is particularly the case if PFS improves but the treatment carries a high burden of toxicity. In other cancers, PFS can be a clinically relevant measure. Ovarian cancer falls into this category.

      1. CMCguy says:

        JPS thanks for clarification as reading Pazdurs statements on this did not seem to make such distinctions which I never really understood from practical view since as you mention the variety of cancer types means application of only a gold standard would seem to inhibit rather than encourage progress.

  4. ScientistSailor says:

    What about Abbott’s velaparib? Super ligand efficient mwt = 244, IC50 = 4nM.

    1. Dennis says:

      Veliparib may yet come through as well. There is currently a phase II clinical trial [NCT01514201] for its application in children with newly diagnosed diffuse intrinsic pontine glioma.

  5. usedtobeatirbm says:

    An historical comment. Niraparib was discovered at the Istituto di Ricerche di Biologia Molecolare (IRBM), the MRL site in Rome, Italy. Also discovered there were the first in class HIV Integrase inhibitor raltegravir and the HCV protease inhibitor grazoprevir. A wonderful little site that MRL closed in 2009 that now lives on as a CRO.

  6. I ask questions, I don't do chemistry says:

    After years of reading this blog, I just noticed that all those PARP inhibitors have names that end in parib. I now realize that there are patterns in drug nomenclature (and a Wikipedia article!).

    I had always thought of drug names as being generated by something like a FIPS 181 password generator — a random collection of 3 or 4 syllables that was pronounceable but meaningless 🙂

    1. Lars says:

      @I ask questions, I don’t do chemistry: Congratulations on this observation. Do note however, that there is a difference between compound names and trade names. Only compounds are named in this way. With benzodiazepines for example, we have two major groups, the -zepams and the -zolams. Diazepam has the trade name Valium, flunitrazepam is well known as Rohypnol. While the compounds are similarly named, the trade names are not alike at all.

      Oh and Derek: Maybe this is an idea for a blog entry? under Pharma 101…

      (and I don’t do chemistry either…)

    2. KevinH says:

      For a 187-page treatise on the use of “stems” (word fragments) in drug nomenclature, see “The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances” from the WHO–colloquially known as “the stem book”.

      http://www.who.int/medicines/services/inn/StemBook_2011_Final.pdf

      It makes for great bedtime reading. (*zzz*)

      While recently-assigned INNs tend to be pretty consistent and well-behaved, a lot of older names are more idiosyncratic and inconsistent. Some stems are more specific than others in what they imply; some describe function, or chemical structure, or both. Some stems can appear at the beginning, middle, or end, or some combination depending on the compound.

    3. tangent says:

      Yep, it’s fun!

      Also check out the naming of monoclonal antibodies.

  7. Breizh says:

    The differential effect might be due to parp trapping on DNA. This was highlighted by Yves Pommier’s group where equipotent parp inhibitors trap parp onto DNA with different affinities……

    http://www.ncbi.nlm.nih.gov/pubmed/23118055

  8. Anon says:

    PARP inhibitors have been around on the market for a while already:

    http://leftfieldwander.blogspot.ch/2013/07/gas-pass-blocker.html

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