I want to discuss a phase 3 trial called GEMINI 2 that was published in the New England Journal of Medicine (NEJM) in 2013 about a promising new monoclonal antibody, vedolizumab, for the treatment of Crohn’s disease (CD) (A sister study, GEMINI 1, was published in the same issue that month and it examined the same drug in patients with ulcerative colitis) The GEMINI 2 aimed to determine the efficacy of vedolizumab NOW CALLED ENTYVIO in patients with CD. These are important studies because vedolizumab represents a new class of medication for the treatment of CD and UC, anti-integrin α4β7 (yes I know about XX but it has serious side effects) and they could be where I turn for my next therapy (I cannot speak for you all but do you just expect to fail therapies? I do, it isn’t fun). First I will describe how my doctor and I worked together using data from the GEMINI 2 study to have an EVIDENCE BASED approach to guiding my care. I WILL REMIND YOU THIS IS JUST A DESCRIPTION OF MY CASE, I AM NOT A DOCTOR. ONLY YOU AND YOUR DOCTOR CAN MAKE MEDICAL DECISIONS FOR YOU.
When Crohn’s Gets In The Way Of Your Life It Usually Wins
I had completed my job in early June ‘14 and was planning on taking June/July before school started to travel, relax and just prepare mentally. I was really pumped for this (I hadn’t done anything fun for basically 4 years as I just worked through all my summers and never took summer break trips or anything-you need money for those). I was going to travel to Puerto Rico to visit my best friend, his wife and brand new baby. I had it all planned and had been thinking about it all winter/sping. Well Crohn’s had other plans and I feel like whenever things are going well in my life and I’m happy my disease has to rear its ugly head just to have the satisfaction of disappointing me.
June rolled around and it brought with it my lovely Crohn’s symptoms; intermittent pain and chills throughout the day (does anyone get else get chills? I feel like I have them chronically), dark bloody diarrhea 7-10 times per day, and a feeling of incomplete emptying (do you all get this? It drives me crazy). This was just par for the course for my disease, however what was troubling to me was that now upon injecting my Humira pen I would get a FEVER (I hardly ever get fevers so knew something was wrong), chills and nausea for several days. Well I learned later that this is basically the definition of serum sickness. To make a long story short I was tested using the Prometheus Anser ADA test (THIS TEST IS WORTHY OF DISCUSSION-GIVE ME A BIT OF TIME). I had developed anti-bodies to the Humira means that my body was recognizing the Humira as a foreign substance and mounting an immune response thus causing the serum sickness.
It was clear that I needed to change medication. At this point I had failed the following drugs: the 5’ASA’s (pentasa), 6-MP, Remicade and now Humira. My options were Cimzia alone, Cimzia with 6-MP (or methotrexate) or ENTYVIO (VEDOLIZUMAB – the new kid on the block). My doctor and I were never seriously considered Cimzia alone as I had failed two anti-TNFa mono therapies). I feared that given my two previous failures I would have a much greater probability of subsequent development of anti-bodies (or have cross reactivity) to the Cimzia if I alone as I had with Remicade and Humira. So the next decision was between the Cimizia+6MP and entyvio. Here I had to weigh the known side effect of Cimizia+6MP causing a kind of blood cancer to the possibility of abandoning the anti-TNFa drugs….So we turned to the data.
GEMINI 3- Boom or bust for the anti-integrin?
This publication reports phase 3 data collected from 2008 until 2012 from almost 300 medical centers across 39 countries (serious stuff). Patients who were 18 to 80 years old with “moderately to severely active” Crohn’s disease were eligible (there is extensive inclusion/exclusion- see PDF linked at below). These patients were sick for sure but they seemingly had stable disease from what I could tell. Importantly, only 50 % of the patients were allowed to have previous anti-TNF drugs (this is the group that I would have belonged to).
The study had 2 “arms” which are essentially routes patients could be randomized to and these the patients are termed cohort 1 and cohort 2. Cohort 1 underwent a 6 week “induction” phase (2 infusions before the other group) followed by a 46 week maintenance therapy. Cohort 2 simply underwent the maintenance phase starting when cohort 1 finished its 6 week induction phase and finishing 46 weeks later. During the maintenance phase, patients were randomized to receive infusions every 4 or 8 weeks. As patients who have failed various anti-TNF regimens we are naturally most curious about the new therapies effectiveness so lets work through the results together.
The primary objective was to determine the effect of vedolizumab on remission at 6 weeks in cohort 1. For the maintenance phase the primary objective was determining the effect of vedolizumab on clinical remission at 52 weeks. I am not going to discuss the various secondary objectives or the comparison of 4 versus 8 week dosing. For detail regarding all the definitions or anything your heart desires please read the article by clicking the link below. I am purposefully leaving alot of information out to try and show that research articles can be interpreted rather simply if you have some patience with them.
One thousand one hundred and fifteen patients with an average age of 36 years old were included in this study. An interesting bit of data I thought was that the patients had been aware of their diagnosis an average 9 years. Additionally, 27% of the patients were current smokers (Why does this matter? See previous journal club post on smoking!)
The primary outcome for cohort 1 is represented in figure A (right). The 220 patients who were randomized to receiving induction therapy with vedolizumab had significantly higher rates of clinical remission at 6 weeks compared to those who received placebo but the CDAI-100 responses were no different after 6 weeks between the groups. At 6 weeks of induction therapy there was no difference in C-reactive protein (CRP-a marker on inflammation that is detected in blood) levels between patients who induction therapy as compared to placebo (Panel B).
The primary outcome of patients randomized to the maintenance arm is shown in the figures below. Panel A shows that following 46 weeks of therapy, the rate of clinical remission among patients who received vedolizumab (39% and 36% for patients who received infusions every 8 and 4 weeks respectively) was significantly higher than patients who received 46 weeks of placebo. CDAI-100 response rates in this arm were 44% and 46% for patients who received infusions every 8 and 4 weeks respectively which was significantly higher than patients taking placebo who had a CDAI-100 response.
Patients treated with vedolizumab were more likely than those receiving placebo to achieve clinical remission after 6 weeks of induction therapy. After 46 weeks of maintenannce therapy, patients who took vedolizumab had significantly higher rate of clinical remission. The rate and overall number of individuals who achieved remission between the 4 week and 8 week dosing arms were similar.
The Bottom Line and My Clinical Decision
These rates of remission after maintenance therapy are low, particularly the clinical remission. While the group that received the drug had significantly higher rates of response after maintenance it was still below 40% which honestly sucks a lot, I was hoping for higher response rates. I would be curious to see the rates of remission among patients who were not quite as sick to begin with and also in combination with existing therapies.
What my doctor and I decided to do
I decided that taking Cimzia and 6-MP combination therapy was the better option for me. Although I had failed 6MP once before I would have the backup of methotrexate injections if I needed it. Theoretically, the purpose of the combination therapy for me was to hopefully have the Cimzia doing the leg work in getting me into remission while the other drug would help prevent antibody formation to Cimzia (as I seem to have a unfortunate predilection to doing) I did not want to abandon the anti-TNF family completely because I feel like for me I should delay using the anti-integrin as long as possible. I have no idea what medications I will be using once I recover surgery, my fistula closes and get back on immunosuppression for maintenance.
Have any of you taken Entyvio yet? Do people have experience with this drug and care to share what its like?
Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, Lukas M, Fedorak RN, Lee S, Bressler B, Fox I, Rosario M, Sankoh S, Xu J, Stephens K Milch C, Parikh A; GEMINI 2 Study Group. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 2013 Aug 22;369(8):711-21.