New Drugs For Ulcerative Colitis

crohnoUCdrugs
Last week we did New Drugs For Crohn’s. This week the good news is for UC patients: there are a number of drugs on the horizon. A lot of this will be similar to the Crohn’s post, but there are important differences.

The two posts are drawn from a 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 UC drugs:

UCDrugs

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 It’s not clear where the authors got the chart, but it is also out of date, based on information I found on some of the drugs.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: CT-P13 [infliximab biosimilar] (none – Celltrion);
  • Phase 3: HMPL-004 [extract of Andrographis paniculata] (none – Hutchison Medpharma)
  • Phase 1/2: AG014 (none – ActoGenix/Intrexon)

Note: The chart above has ‘ActoGenix’ listed as a cytokine drug. In fact, ActoGenix is a company; its primary product for ulcerative colitis is AG014, an oral anti-TNF drug.


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: (none)
  • registration: vedolizumab (Entyvio – Takeda)*
  • Phase 3: (none)
  • Phase 1/2: alicaforsen (none – Atlantic/Isis);
    etrolizumab – (none – Roche);
    GLPG0974 – ( none – Galapagos);
    vatelizumab – (none – Genzyme/Sanofi);
    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: BMS-936557/eldelumab (none – Bristol-Myers Squibb);
    peficitinib – (none – Astellas);
    RPC-1063 (none – Receptos/Celgene);

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: DIMS-0150 (Kappaproct – InDex Pharm.)
  • Phase 1/2: Abatacept (Orencia – Bristol-Myers Squibb)*;
    AM-3301 (none – Amalyte/Meiji);
    rituximab (Rituxan/Mabthera – Biogen IDEC/Genentech)*;
    VB-201 (none – VBL Therapeutics);
    visilizumab (Nuvion – PDL/Facet/Abbott);
    SB-012 (none – Sterna);
    GSKL399686 (none – GlaxoSmithKline)

Notes: VBL Therapeutics stopped development of VB-201 after disappointing clinical trials. 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. GSKL399686 is not listed in GlaxoSmithKline’s current pipeline and may no longer be in development.


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);
    (ActoGenix was moved to anti-TNF, above)

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 IBD. For whatever reason, there are way fewer drugs in this category for UC, compared to the same category for Crohn’s.

  • approved: (none)
  • registration: (none)
  • Phase 3: (none)
  • Phase 1/2: Bertilimumab (none – iCo/IMMUNE);
    anrukinzumab (none – Pfizer;
    tralokinumab (none – AstraZeneca);

Notes: a 2013 document from Pfizer lists anrukinzumab as discontinued, probably due to poor clinical trials results. AstraZeneca is pursuing tralokinumab for asthma, but seems to have stopped testing it for ulcerative coiltis.


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. 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 Crohn’s) every few months, so that it stays relevant.

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

 

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