New Drugs For Crohn’s Disease

crohnodrugsCD

Good news for IBD patients: there are many new drugs being developed for our diseases! A recent study reviewed those drugs, so now I have reviewed that study and found more info to help make sense of it. This posts focuses on drugs for Crohn’s Disease; in a post next week, I will address Ulcerative Colitis.

The study, by authors Aurelien Amiot and Laurent Peyrin-Biroulet, is “Current, new, and future biological agents on the horizon for the treatment of inflammatory bowel diseases” [Therapeutic Advances in Gastroenterology 8:2 (March 2015), available free so you can read the whole thing if you want to.] It focuses on biologics (the meds produced by genetically engineered cell cultures) but also includes handy charts for Crohn’s and Ulcerative Colitis drugs in the ‘pipeline’.

Here is the chart for Crohn’s drugs:

10.1177_1756283X14558193-fig1

If you can’t read the drug names, don’t worry: the information below is drawn from that chart and a heck of a lot of additional research. For each medicine in the chart, I include the following information:

drug generic name [drug info] (Brand Name – Manufacturer)*

An asterisk indicates a drug already approved for other uses – usually RA or MS. Many of these drugs are not, in fact, biologicals. It’s not clear where the authors got the chart, but it is also out of date, based on information I found on some of the drugs. I’ve added that info as notes, plus some additional cautions at the end.


 

Anti-TNF :

TNF is a signalling molecule in the immune system that can cause inflammation in the gut, among other things. TNF stands for ‘tumor necrosis factor’; one of the things the molecule does is cause cell death for some kinds of tumors. Anti-TNF drugs – like Remicade and Humira – block the TNF molecule, stopping the signal and preventing the inflammation. At least, that’s the theory. In practice, it’s still a bit of mystery precisely how these drugs work.

  • Approved: adulimimab (Humira – AbbVie);
    infliximab (Remicade – Jannsen/J&J);
    Certolizumab pegol (Cimzia – UCB)
  • Registration: thalidomide (Thalomid – Celgene)*;
    CT-P13 [infliximab biosimilar] (none – Celltrion)
  • Phase 3: HMPL-004 [extract of Andrographis paniculata] (none – Hutchison Medpharma)
  • Phase 1/2: TNF kinoid [vaccine against TNF] (none – Neovacs);
    lenalidomide [derivative of thalidomide] (Revlamid – Celgene)*;
    ozoralizumab (none – Ablynx)

Note: according to their website, Ablynx “is not pursuing this programme internally” – meaning they are not doing any more research on ozoralizumab. Ablynx have signed a licensing agreement to make the medicine available in China, and are looking for licensees in other parts of the world.


 

Anti-adhesion molecules:

Adhesion molecules allow white blood cells called ‘leukocytes’ to leave the bloodstream and enter gut tissue to cause inflammation. Anti-adhesion molecules prevent the leukocytes crossing over, thus interrupting the inflammatory process.

  • approved: natalizumab (Tysabri – Biogen)
  • registration: vedolizumab (Entyvio – Takeda)*
  • Phase 3: CCX282-B/Vercirnon (Traficet EN – ChemoCentryx)
  • Phase 1/2: TRK-170 ( none – Toray) ;
    alicaforsen (none – Atlantic/Isis);
    firategrast – (none – GlaxoSmithKline);
    PF-00547659 (none – Pfizer);
    AMG181( none – AstraZeneca/Amgen)

 

Downstream signaling blockade:

This class of drugs seeks to interrupt how cells transmit internally to activate DNA based on inputs from outside the cell. This pathway is called JAK/STAT, and there is evidence that its function is associated with IBD and other diseases.

  • approved: (none)
  • registration:(none)
  • Phase 3: tofacitinib (Xeljanz – Pfizer)*
  • Phase 1/2: semapimod (none – Cytokine PharmoSciences);
    doramapimod ( none – Boeheringer-Ingelheim);
    BMS-936557/eldelumab (none – Bristol-Myers Squibb);
    fingolimod (Gilenya –┬áNovartis)* ;
    GLPG0634/filgotinib (none – Galapagos);
    GED0301/mongersen (none – Celgene)

Note: Dorapimod was dropped by B-I because it had no efficacy and caused liver toxicity.


 

Immunomodulator:

While many of the drugs in this post could be called ‘immunomodulators’, this specific class affects how the immune system recognizes threats and activates a response.

  • approved: (none)
  • registration: (none
  • Phase 3: (none)
  • Phase 1/2: Abatacept (Orencia – Bristol-Myers Squibb)*;
    AM-3301 (none – Amalyte/Meiji);
    visilizumab (Nuvion – PDL/Facet/Abbott);
    NNC 0142-0000-0002 (none – Novo Nordisk);
    NI-0401 (none – Novimmune);
    laquinimod (none – Teva/Active Biotech)

Note: PDL terminated or withdrew clinical trials of visilizumab after poor results. The company then spun off its biologics division, which was acquired by Abbott (now AbbVie). AbbVie is not pursuing visilizumab, but has a similar drug called otelixizumab that was tested unsuccessfully in patients with Type I diabetes.


 

Cytokine:

Some of the drugs above seek to interrupt the immune system’s signals – that is, cytokines – to prevent inflammation. Another strategy is to introduce different signals, to tell the immune system to act in ways that do not produce inflammation. These drugs are all cytokines normally produced by the human body.

  • approved: (none)
  • registration: (none)
  • Phase 3: (none)
  • Phase 1/2: Low dose IL-2 (none – ILTOO);
    rhIL-11 (Neumega – Pfizer);
    rhIL-10 (none – none);
    IFN-B-1a (Avonex – Biogen; Rebif – Pfizer)*

Note: A study of IFN-B-1a Rebif in Crohn’s patients has been terminated for lack of efficacy, but a study of the similar moleculae Avonex in ulcerative colitis patients was recently completed.


 

IL-inhibitor:

One class of cytokines is called ‘interleukins’; in the above list, rhIL-11 stands for ‘recombinant human InterLeukin 11″. Some of the interleukins drive inflammation, and some do not. IL-inhibitors block the action of the interleukins that drive inflammation associated with Crohn’s disease, especially IL-12 and IL-23.

  • approved: (none)
  • registration: (none)
  • Phase 3: ustekinumab (Stelara – Centocor)*
  • Phase 1/2: AMG827/brodalumab (none – AstraZeneca/Valeant);
    vidofludimus (none – 4SC);
    FE-999301 (none – Ferring);
    PF0530900/ATR-107 (none – Pfizer);
    NNC0114-0006 (none – Novo Nordisk);
    BMS-954429/ALD-518/clazakizumab (none – Alder/Bristol-Myers Squibb);
    fontolizumab (none – AbbVie);
    olokizumab (none – UCB);
    PF-04236921 (none – Pfizer);
    tocilizumab (Actemra – Roche)*;
    STA-5326/Apilimod mesylate (none – Synta);
    AMG139 (none – Amgen/AstraZeneca);
    BI-655066 ( none – Boehringer-Ingelheim);
    SCH-099222/MK-3222/tildrakizumab (none – Schering Plough/Merck/Sun);
    briakinumab (none – AbbVie).

Notes: AMG827/brodalumab was originally developed by Amgen, which then partnered with AstraZeneca to bring it to market. After clinical trials showed ‘suicidal ideation’ in participants, Amgen bailed and left AstraZeneca with the drug; AstraZeneca then licensed it to Valeant. Pfizer discontinued work on PF0530900/ATR-107 in 2011 after 70% of subjects developed anti-drug antibodies. Clazakizumab was developed by Alder and licensed to Bristol-Myers Squibb. Alder regained rights and terminated a clinical trial for Crohn’s; they are now only testing the drug for rheumatoid arthritis and psoriatic arthritis. Fontolizumab was developed by PDL, later Facet, which was bought by AbbVie; there is no sign that AbbVie is pursuing the drug. A study of olokizumab for Crohn’s was withdrawn; the drug is currently being tested for RA. Apilimod is no longer in development after failing in clinical trials. Tildrakizumab was developed by Schering Plough, which was bought by Merck; the latter licensed the drug to Sun, but apparently stopped testing it for Crohn’s. Abbott (now AbbVie) withdrew its application for approval for briakinumab.


The good news is that lots of drugs are in development. Now the bad news: many of them will never make it to market. As you can see, even in a list published just this past spring, much of the information is already out-of-date. Some drugs have failed – or will fail – clinical trials. Even if they work, they might cause too many side effect to be marketable. Some drugs will be shelved by their manufacturers, even if they do work; it’s unusual for a company to sell more than one drug for a specific disease, because they are in effect competing against themselves – at least for those drugs that are still on patent. Sometimes manufacturers shelve a drug because the market is too crowded for that particular kind of treatment, as Ablynx did with ozoralizumab. That’s just how the business works.

But in the meantime, you can do something to help: many of these drugs are still in clinical trials. Before they can be brought to market, the drugs need to be tested on real live patients. You can help by volunteering for a clinical trial. It’s safe, free, and absolutely critical to bringing new IBD drugs to market. You can look for a trial near you at ClinicalTrials.gov.

I know there are drugs I missed. I will update this post (and the partner post for UC) every few months, so that it stays relevant.

Photo “Antibiotic Drugs” from Flickr user Global Panorama by CC license

 

 

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