Monteleone G et al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn’s disease. N Engl J Med. 2015 Mar 19;372(12):1104-13.
There has been a lot of hype surrounding Mongersen (formerly GED-0301) for the treatment of Crohn’s disease so I thought I would go ahead and do a post discussing the recent phase 2 study published in the New England Journal of Medicine. Before, I proceed I want to make a few things clear. First, I am trying to write this using language that is accessible to as many as possible, so for healthcare professionals/scientists who may be reading this understand that this discussion is simplified and focused on CDAI and CRP results (although please help me answer several questions I have at the end of this post). Second, I will be focusing on the efficacy data and issues/disparities I see in those results as opposed to the safety/adverse events. I won’t pretend to have enough education to thoroughly understand the intricacies of adverse events. Lastly, after describing the study and results I am going to raise several questions which may make it seem like I am attacking this study but this is the time where drugs need to be carefully scrutinized. I too have a vested interest in seeing new drugs approved (I have exhausted the anti-TNF MABs and am less than thrilled about vedolizumab’s efficacy) so I am not trying to be a buzzkill instead I am more cautiously optimistic of drugs in the pipeline. Lastly, I am not a research authority by any means, just a guy who is interested in research.
Abbreviations/definitions used in the study and my discussion:
- CDAI = Crohn’s Disease Activity Index (patient reported scores range from 0-600 with increasing disease severity). CLICK HERE TO CALCULATE CDAI
- Clinical Remission = A CDAI value of <150 (patient reported)
- Clinical Response = A decrease in CDAI of 100 points (patient reported)
- CRP = C-reactive protein (a general marker of inflammation – blood test)
Study design: This was a double blind (neither the doctors nor patients knew their dose or if they were taking true medication), placebo controlled (Mongersen was compared to patients receiving a pill with no active drug in it), phase 2 trial (see the photo below) to determine if Mongersen could safely treat patients with active Crohn’s disease. Patients received three doses of oral Mongersen or placebo daily for 15 days, then studied at day 28 and day 84 following initiation of therapy. See photos below.
What were the investigators interested in (outcomes)? The proportion of patients achieving clinical remission after 15 days of therapy, 28 days after starting therapy and 84 days after starting. They also investigated the proportion of patients who achieved a clinical response at those same time points. See above for definitions of clinical remission and clinical response. Additionally, they investigated levels of CRP, IL-8 and TNF-a (blood tests) at different time points. Lastly, this study was designed to assess the safety of Mongersen (I won’t really be focusing on these results, I am more interested in the efficacy data).
Who was eligible to be in this study? Adults (18-75 years old) with moderate/severe Crohn’s based on CDAI values ranging from 220-400, patients with disease in the terminal ileum and/or right colon documented within 1 year of the study.
Who was excluded from this study? I won’t list them all but several notable groups of patients were excluded including those with fistulas, perianal disease, extraintestinal manifestations and those with Crohn’s colitis (transverse and left sided).
What did the study population look like (the demographics)? Data from table 1 and supplemental table 1: The majority of these patients were recruited from Italian sites with a handful from Germany. The 166 patients randomized to the different treatment groups (placebo, 10 mg, 40 mg, 160 mg) were rather similar based on age, sex distribution, body mass index etc which is desirable. Of note, the median CDAI and CRP levels at baseline were relatively low for each group (baseline CDAI by group: placebo=264, 10 mg=246, 40 mg=240, 160 mg=243) (baseline CRP by group: placebo=5.1, 10 mg=4.3, 40 mg=4.9, 160 mg=4.6). The proportion of patients taking glucocorticoids and immunomodulators at baseline did not exceeding 32% in any of the treatment groups.
What were the results?
- Crohn’s Disease Activity Index responses: The proportion of patients who achieved clinical remission and clinical response (measured by CDAI) by dose are shown below. Remember clinical remission was defined as a CDAI <150 at day 15 AND day 28, clinical response was any decrease of CDAI greater than or equal to 100. The number above each bar is the percent of patients who achieved clinical remission and response measured by CDAI.
- C reactive protein (CRP) results: Of the 166 patients who began treatment, 102 (61%) had an elevated CRP levels (>3 mg/L). The proportion of these patients with elevated CRP at baseline who achieved normalization of CRP after 15 days of treatment can be seen below.
The median CRP levels for the 102 patients measured at each time point are seen here.
In the results section the authors say that the rate of remission in patients with elevated CRP for the 160 and 40 mg groups were higher than the rate of the placebo group. However, in the text they do not explain that this definition of remission is based on CDAI, you need to look at supplementary figure 6 to see this.
Some thoughts and questions:
These CDAI based remission and response rates are obviously quite high which is encouraign. However there is a large disparity in between CDAI responses and CRP responses which I think is a problem. This is similar to the post I did on Cannabis in Crohn’s where there was significant improvement in CDAI and very little improvement in CRP levels. Although it would be more expensive, this drug will have to undergo more studies with harder endpoints like mucosal healing. I really would like to know why, when and how CDAI became a firm enough measurement to where it can serve as an inclusion criteria and an outcome measurement in clinical trials. From the limited amount that I know about it I think we need to start moving away from the CDAI toward more objective endpoints maybe based on imaging or scopes. They describe that these patients had moderate to severe Crohn’s disease but if you look at the baseline data in table 1 the CRP levels were only modestly elevated and the median CDAI levels were definitely on the low spectrum for their inclusion criteria. Personally I would have liked to see an analysis of CRP level by quartile. Here you could investigate the patients with the highest CRP levels and look at what happened to their CRP levels longitudinally. This would have been helpful to see if the patients who did achieve normalization of CRP were just the patients in the lower quartiles (low CRP levels at baseline). Another thing I would be interested in is the proportion of patients in this study who met each inclusion criteria. I want to know how many were included on CDAI alone versus imaging studies and those with a scope in the past year. A more general question I have is of the environment of the resected ileum. In patients with significantly altered ileum’s, would this pH sensitive capsule need to be tweaked or does the pH return to pre surgery levels. This brings up the point of whether this drug would be efficacious in patients with proximal disease, fistulas, and those with any extra-intestinal manifestations. Given the very low serum levels of drug (which come from other studies) I do not how if initiation of therapy w/ this drug would improve perianal disease, fistulas and other extra-intestinal manifestations.
I could go on but I’ll just leave it at that, if anyone has answers to these questions or different interpretations of the data please help me understand!