New FDA Approval: Zinplava
Drug
Bezlotoxumab [Zinplava]
Indication
To reduce the recurrence of Clostridium difficile infection (CDI) in patients 18 years and over. Patients must also be receiving concurrent antibiotic therapy, and be considered "high risk" for recurrence.
How it Works
Zinplava is not an antibiotic.
It is a monoclonal antibody that binds to Toxin B, (one of the major toxins produced by C. diff). Toxin B is at least partly responsible for the disruption of your intestinal epithelium that we all know and love.
Visual representation of "horrible, watery, sometimes bloody, and very, very frequent diarrhea" (Image)
Of course, by "disruption of intestinal epithelium" I mean horrible, watery, sometimes bloody, and very, very frequent diarrhea. It even has a distinctive smell, which is often described by nurses as "moldy bread, "mildew," or "decaying roadkill." (I'm not sure what sort of people go around and smell decaying roadkill).
So the thought with Zinplava, is that if you give it with standard CDI antibiotics (metronidazole, vancomycin, and fidaxomicin are the main ones), that you can kill off most of the bacteria and remove its toxin.
It's given as a single 60 minute infusion that can be given at any time during antibiotic therapy for CDI.
Notable Adverse Effects
The biggest thing to watch out for with Zinplava is worsening heart failure. But the risk seems to mostly pertain to patients with existing heart failure. In patients with a history of heart failure, 12.7% patients (15/118) in the Zinplava group versus 4.8% (5/104) in the placebo group experienced the major adverse event of heart failure.
That's just shy of 3x the rate compared to placebo, and this was only in a 12 week study period. It was enough for the FDA to require warnings about worsening heart failure in the labeling for Zinplava.
For more about heart failure, check out our 3 part series which breaks down the pathophysiology, the signs and symptoms, and the pharmacotherapy. It was written by J. Nile Barnes, PharmD, BCPS; a professor from the University of Texas at Austin College of Pharmacy and it's real good. I promise you'll learn something.
There was also an increased rate of death in the Zinplava group (19.5% vs 12.5%) although the causes of death were multifactorial and not all related to the treatment group.
Many of the adverse effects associated with infusion reactions are similar to those cause by CDI infection itself, so it's difficult to distinguish between the two. There are fevers, nausea, fatigue, and headache. There was a slightly higher occurrence in the Zinplava group (10% vs 8%), but in my opinion at least, that's pretty mild.
Current Place in Therapy
And so we get to the crux. Where does Zinplava fit in?
For starters, how prevalent is CDI?
The most recent "solid" numbers are from 2011, but the CDC is pretty alarmed about them. They have termed CDI one of the highest threats to antibiotic resistance in the US. They've also named CDI an "urgent threat" and called for increased measures to prevent infection.
Anyway, there were over 500,000 cases of CDI in 2011, resulting in 29,000 deaths within the first 30 days of infection. About 83,000 patients who develop CDI will experience at least one recurrence. And once you've had one recurrence, you're considerably more likely (i.e. 50% more) to have more recurrences. (All of the preceding stats come from the CDC link above).
Those numbers are somewhat skewed to certain patient populations. For example, up to 90% of deaths from CDI occur to patients older than 65 years old. But no matter how you slice it, you're seeing billions of dollars of medical spending per year on CDI. The cost has been estimated to be as high as $29,000 per episode.
So, if we're looking at 83,000 recurrences per year (and rising) of CDI, additional pharmacologic help is certainly warranted.
Does Zinplava do that? According to Merck it does. But let's ignore my healthy skepticism and dig in.
Zinplava was approved based off the MODIFY I and MODIFY II trials. Merck also developed an antibody to Clostridium difficile Toxin A (actoxumab), but it provided no additional benefit over Zinplava and was eventually dropped.
If you drill in to the numbers, you see a significant decrease in CDI recurrence with the Zinplava group (15.7% vs 25.7% with a one sided p=0.0003). That's an absolute risk reduction of 10%, but there are some caveats.
The results were carried by certain patient populations considered to be "high risk" for recurrence. This includes:
Patients over the age of 65
Immunocompromised patients
Patients with previous recurrence
Patients with the BI/NAP1/027 strain of C. diff
Patients with severe CDI (albumin < 3.0 PLUS abdominal tenderness or WBC > 15,000)
So the FDA approval is specifically for these high risk patients. It's also worth mentioning again that the study follow up period was 12 weeks. It is certainly possible to experience recurrent infection later than 12 weeks, but it's less likely. Current GI guidelines consider it recurrent CDI if it occurs within 8 weeks of previous antibiotic therapy.
And as always, you have to take into consideration the cost. Unfortunately, the pricing for Zinplava has not yet been reported (at least not anywhere that I can find).
I've thrown a lot of numbers at you. When Zinplava becomes available next year, should you use it or not?
A 10% absolute reduction in CDI recurrence (which was 40% relative risk reduction) is significant. Considering the overall incidence and costs associated with CDI, that is something to be intrigued about.
The challenge will be not to get trigger happy and start giving everyone with CDI Zinplava. It's real benefit shined in the "high risk for recurrence" patients. If we start giving it to everyone then we'll just ramp up the cost (and complications) of our current CDI management.
Also, the MODIFY trials only included a little over 1000 people. As we saw earlier, CDI is not exactly a rare disease. What happens when we 9x the patient population up to 89,000 patients (using 2011 numbers)? I suspect we'll see an even higher incidence of heart failure complications. There may be more infusion reactions. Or even some adverse effects we don't even know about yet.
So, my final recommendation would be to consider using this only in high risk patients with no history or risk factors for heart failure....depending on the cost.
Because if Merck goes all sofosbuvir with the price, then I don't think the ends justify the means.