Posted by David Wohl on March 15, 2017
Come the end of the year, the Crohn’s and Colitis Foundation of America (CCFA) organizes Advances in IBD, a medical conference dedicated to topics in IBD research and care. The foremost clinically-oriented IBD meeting in the US, this conference attracts both adult and pediatric clinicians.
Per tradition, Advances in 2016 is held in Florida. And, that is how I found myself in the Magic Kingdom, rubbing shoulders not only with Mickey and Minnie but with the biggest names in IBD. As the parent of a 12 year old child living with Crohn’s disease, I was attending in the hopes of moving beyond the ‘IBD 101’ webinars and the usual CCFA-supported patient educational sessions to gain a higher-level understanding of the issues at the cutting edge of IBD management. If knowledge equals power, I needed to level-up and Advances seemed like the perfect place to do so. Unfortunately, I learned there is no clear path for parents or patients to register for this conference (co-production comes slowly in medicine). But, after some discussion with the good folks at CCFA, I was able to sign-on as a physician (having gone to medical school does come in handy), even though I am neither a gastroenterologist nor an IBD specialist. So, it was as a parent-mole that I sat among the sea of clinicians, feeling a bit like an imposter, and jotting down what I found of greatest interest from the perspective of a person affected directly by IBD. What follows are these observations – admittedly filtered by my personal experiences as #DadofkidwithIBD
Are Immunomodulators Dead? Should they be?
A topic that touches all kids with IBD and their families is the selection of treatment, and fittingly therapeutics dominated the conference. A theme threading through many of the drug therapy-focused presentations was the role of immunomodulators in IBD management. Although a mainstay of IBD treatment, the use of immunomodulators (e.g., azathioprine, 6-mecaptopurine, methotrexate) has become remarkably controversial with the advent of the more potent ‘biologic’ agents, like infliximab and adalimumab. These newer drugs target TNF - a chemical Paul Revere the body makes to announce, ‘Inflammation is coming! Inflammation is coming!’ They are potent but are inconvenient in that they have to be injected or infused; have some common, mostly mild side effects, and rarer serious ones, and are pricey. Despite these drawbacks, the effectiveness of biologics has some wondering whether immunomodulators are becoming the MySpace of IBD treatment.
To place this in context, it’s good to have some history. There have been a couple of main schools of thought about the use of immunomodulators and biologics. The first places immunomodulators as a biologic-sparing, front-line approach from which treatment aggressiveness could be Stepped-Up. In contrast, a more Top-Down strategy relegates immunomodulators to a secondary role to biologics – a sort of cherry on top of the anti-TNF sundae.
The ying-yang tension in these different treatment tactics is, in part, a testament to the ambiguity of the effectiveness of immunomodulators, and at the conference there was much skepticism heaped on to immunomodulators, with more than one speaker suggesting that these agents may even have vastly overrated intrinsic activity against IBD. Dr. Gil Melmed from Cedar-Sinai Medical Center laid out the spotty clinical research record of azathioprine and 6-mecaptopurine, highlighting the very mixed results for the efficacy of these two closely related medications when used alone for induction or maintenance therapy - especially in more recent trials of adults with Crohn’s disease or Ulcerative Colitis. Like other speakers, Dr. Melmed returned to the results of the SONIC Trial, a large study of adults with Crohn’s disease who were randomized to one of three initial therapies: azathioprine alone versus infliximab alone versus azathioprine plus infliximab together. More of those receiving the combination therapy achieved clinical remission, followed by those assigned infliximab alone. Well behind the other two was the azathioprine group.
While the higher rate of remission seen in the combination arm would seem to suggest activity of azathioprine, some hold that this agent acts mostly by raising the levels of the biologic – that is, enhancing the effect of the biologic and preventing production of anti-biologic antibodies that can sap them of their strength. Indeed, detection of anti-infliximab antibodies was rare in those on the combination regimen compared to those treated with infliximab alone.
If one were to follow this line of thinking, optimizing therapy with biologic agents, say through monitoring drug levels and then adjusting the dose to achieve desired levels, could render immunomodulators obsolete. As discussed in detail below, more than one presenter advocated for such an approach, although sparse are the supportive data, and expensive are drug and antibody level testing. Dr. Stephen Hanauer from Northwestern Hospital in Chicago hinted during a forceful presentation that there will be additional data presented at a major gastroenterology conference this year supporting the limited role of immunomodulators in IBD.
The Bottom Line: Re-evaluating the value of therapies, even those that have become steeped in traditional practice, is important and welcome. At this conference, there was a clear call by some to get clinicians to move away from, at least, azathioprine and 6-mecaptopurine as monotherapy and even as an adjunct to biologics. During the presentations, most lumped immunomodulators together and there was little differentiation between individual agents in this class of medications. While the data for azathioprine and 6-mecaptopurine may not look all that spectacular, there is stronger evidence supporting the use of methotrexate in Crohn’s disease, even as monotherapy. Any discussion of immunomodulators should recognize the differences between these agents. To be clear, not all experts agree with abandoning immunomodulators and the clinical research conducted to date has had major limitations. What is clear is that the use of immunomodulators in IBD is becoming a hotter topic and parents and patients will need to keep track of study findings to guide their treatment decision-making. Some may even consider joining clinical research studies within or outside of ICN that seek to settle this once and for all.
Top-Down vs Step-Up, also dead?
Related to the debate swirling around immunomodulator therapies, is the age-old question of whether it is best to hit IBD hard and early or softer and incrementally. At Advances, there was a drumbeat of presentations describing a new paradigm to replace this dichotomy. Atlanta IBD expert Dr. Doug Wolf described a sort of a ‘Top-Up For Some, Step-Down For Others’ approach based on assessing a patient’s disease severity and then matching the patient to a therapeutic approach (conservative or aggressive). In this more personalized model, those with moderate to severe disease, and perhaps those with higher risk of disease severity, would be treated with biologics and newer therapies targeting inflammation, while those with milder disease and more favorable prognostic factors could start with non-biologic agents, then ratchet-up the treatment potency as needed (see figure).
The Bottom Line: As clinical experience with the biologics increases and newer medications with potentially better safety and tolerability profiles become available, the pull to spare patients these drugs lessens. At the same time, the above-mentioned skepticism regarding immunomodulators also can also lead clinicians to be less reluctant to use the potent biologics earlier. On the other hand, these powerful (and expensive) drugs may be overkill for those with lower disease severity or risk. Additionally, for kids, in particular, there is a need for a long-term treatment strategy that preserves options and does not burn through powerful agents early. Thinking should be in terms of which therapeutic strategy to use rather than which drug to use.
At the heart of this discussion is also the assessment of disease severity and the risk for badness. Different tools are used to gauge severity of disease and risk. A more standardized approach based on evidence is needed and should also be studied in kids to determine their performance in pediatric populations.
Once a biologic agent is decided to be the way to go, the next question is which to choose. You’d think we know which one of the handful of agents available is best, or at least their relative merits and disadvantages based on head to head comparisons, but, we don’t. Instead we largely have studies where the biologic was compared to non-biologic controls. This is sort of like an Olympic swim meet where instead of doing the breaststroke alongside a half dozen other top swimmers, an athlete splashes down the lane alone, and at the finish her performance is compared to other competitors who also swam solo on different days.
Head-to-head comparisons provide a level playing field that allow us to fully assess which agent is best in terms of safety, efficacy, and patient reported outcomes. In the absence of good comparative data, we get marketing, faith-based perceptions, and anecdotal experience. Additionally, the lack of therapeutic drug monitoring and responsive adjustment that is increasingly being pursued in practice, as discussed next, has not been integrated into many clinical trials, leading paradoxically, to generally lower success rates in studies compared to real world practice.
Compounding these limitations is a lack of consensus on the study outcomes of greatest relevance to well-being. That is, the very definition of ‘winning’ is not consistent. There is a spectrum of outcomes used in studies spanning from histologic healing (under the microscope a biopsy of the lining of the gut looks fabulous) to mucosal healing (through the endoscope the lining of the gut looks fabulous) to semi-objective indices (survey says: “fabulous”) to self-reported outcomes (“I feel fabulous”). Experts argue about which of these is most important and should be the gold standard. The result is a muddle of data that can be hard to interpret and apply to patient care.
The Bottom Line: Over a million people in the US (that is 1 in 300) have IBD and we still don’t have the kinds of studies we need to make informed decisions about our care. Drug companies are not likely to organize and fund large head-to-head trials of their drug versus a competitor’s drug, although they could. This leaves the federal government to do what industry won’t, but flat (or worse, reduced) funding of the National Institutes of Health (NIH), which are very possible, does not bode well for any IBD ‘moonshot’.
At Advances, more than one presenter suggested that given the lack of consensus around a standard outcome for clinical research studies, patient-reported outcomes should matter the most. For this parent, that kind of talk signals a failure of the field to unify around the objective of therapy. How patients feel is certainly important but physicians don’t judge whether someone needs a coronary bypass operation based primarily on how they feel and no study comparing psoriasis treatments will bet the farm on a patient reported outcome instead of an assessment of the skin. Experts without relevant conflicts should get together in a room and establish a set of standards for the design of new agents for IBD that includes direct comparisons and meaningful outcomes. That would be a fair contest and we would all come out winners.
Therapeutic Drug Monitoring/Antibody Surveillance
There is considerable variability across practitioners in their habit of measuring infliximab and adalimumab drug and antibody levels. Guidelines have been issued to help clinicians but may be too conservative, according to Dr. Adam Chiefetz from the Beth Israel Deaconess Medical Center in Boston. Data (and a healthy dollop of common sense) support an association between levels of anti-TNF drug in the blood and durable activity of these medicines. Higher levels of drug also should reduce the risk of the body making antibodies against the anti-TNF agent. However, there is confusion among clinicians about when to order such testing, the benefits and disadvantages of the available assays, and the interpretation of the results.
As discussed above, the monitoring of drug levels could lead to adjustments that could, theoretically, preclude the use of immunomodulators if they act mostly as boosters for these biologics. There are some data, including results from a study of adults called the TAXIT Trial, that support the monitoring of the blood levels of biologics and the testing for the emergence of antibodies to these medications. Other work looking at kids with IBD shows that under-dosing with infliximab is not uncommon.
The Bottom Line: There are plenty of examples in medicine where optimization of drug levels has led to better responses. However, IBD is not exactly like diseases such as epilepsy or diabetes where there is a clear relationship between medication dose and response. In IBD, when the disease flares, more TNF is produced by the body and this can act like a sponge to sop up the anti-TNF medication, leading to lower levels. So, low levels of the drug may cause disease activity or disease activity may cause lower levels of the drug. For this reason and the not insignificant costs of the tests for drug levels and antibodies and the higher doses of medication, rigorous studies are absolutely required to justify drug and antibody monitoring becoming the standard of care.
The Biosimilars are Coming
Short of an adverse court decision, it appears that the first biosimilar for infliximab (Inflecta) will be available in early 2017 with an adalimumab biosimilar (Amjevita) coming along soon, thereafter. Biosimilars are drugs with a molecular structure that are very close to but still different than the original, and are purported to retain their activity and safety but at a much cheaper cost. Although the price of the biosimilars in the US has not been revealed, it is safe to say that insurers may well push for these to be used preferentially. Some computer modeling work presented at the meeting showed potentially large cost-savings even with modest price reductions in biologics.
Scientifically, most panel experts at the conference felt that initiating therapy with a biosimilar was not too concerning - all would prefer not to but were resigned that the data does not support more than a general sense of distaste. It is important to note that data on biosimilars is largely, but not exclusively, extrapolated from Rheumatoid Arthritis and Ankylosing Spondylitis. Slightly more concern was voiced about switching from a brand-name biologic to a biosimilar. Again, most felt that there would be little risk of failure with such a switch but they did not fancy messing with hard won and too fragile success.
The Bottom Line: We will likely have no choice. If these medications are approved for sale in the US there will be pressure to use them. For many of us, this move will save thousands of dollars of out-of-pocket costs, and, will be welcome. For others, there will concerns regarding effectiveness that will be paid in anxiety and angst. For a uniquely large IBD learning system like ICN, there will be a golden opportunity to look at what happens (or doesn’t) when kids switch or start biosimilars.
Of course, some exciting new drugs and targets for treating IBD were discussed at the conference. These include ustekinumab, approved in September 2016 to treat adults with moderate to severe Crohn’s disease, and a slew of agents in much earlier stages of development. Certainly, there was much buzz around ustekinumab, a blocker of the cytokine IL-12 and the p40 subunit of IL-23 (both part of the inflammatory cascade). Although this drug is intravenously administered, it seems better tolerated than older biologics and has a long half-life, which can mean less frequent dosing.
Other agents in various stages of development include the JAK inhibitors, which target IL-6, another pro-inflammatory cytokine. Newer drugs such and the Integrin Inhibitors, work by interfering with the trafficking of white blood cells from the blood into the gut, and some of these, including vedolizumab, look promising and safe.
The Bottom Line: For these and other the medications being studied, efficacy has to be weighed against observed and potential side effects, of which there can be many given the complexity of the immune system – the target of these drugs. It is heartening to see the attention being paid to developing newer and better treatments for IBD, even when they are developed foremost for other conditions. Perhaps some of these will render moot the arguments about how to use older therapies, by making them obsolete. Until then, we are left to make decisions based on the data we have and our understanding of them
Overall, as I headed home, with “It’s a Small World” stuck in my head, I was bugged by how much we still do not know about the diseases we place into the IBD bucket. Clinicians have increasingly powerful therapeutic tools at the beckoning call of their prescription pads but are still getting a grip on how best to use them. Studies provide only partial answers and into the data vacuum step experts, who share thoughtful, but at times conflicting opinions about what is best.
However, I was also very hopeful. It is clear that there is research being conducted that will provide answers. For parents of a kid with IBD, the answer-pipeline can never flow fast enough, but that is why we have to keep informed and understand the gaps in the data and fill them in with good advice, our keen judgement, and knowledge. And, that’s why next year, I will be back.
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