I’m in the taxi leaving #NKFClinical (or at least I was when I started writing this) and if it wasn’t the first in-person meeting that most of us have been to since the onset of the pandemic, it would be remembered as “the one where Korsuva was launched.”
During the meeting there was a buzz about this drug. And the buzz was around the two phase-3 trials, KALM-1 and KALM-2. The buzz is around the decreased effect size from KALM-1 to KALM-2. Difelikefalin met it’s primary endpoint to reduced severe itching in KALM-2, but the effect size is notably smaller than in KALM-1.
The effect size could have been larger, the same, or smaller than KALM-1. I’m not sure how much shade should be cast that it turned out to be smaller, especially as it remains better than placebo.
But my primary concern is that focusing on effect size misses the point.
We are used to prescribing invisible drugs; drugs that move a magical end point like cholesterol or blood pressure. Lowering cholesterol does not make patients feel better it just loads the dice so that when fate rolls them every year your patient is less likely to have an acute MI. Same with antihypertensives, SGLT2 inhibitors and almost everything we use except for pain killers. If the patient asks the doctor if the drug is working it is an invisible drug. If the doctor asks the patient if the drug is working it is a visible drug.
I was a sight PI on KALM-1, which means I am one of the few nephrologists who has real world experience with the drug. During KALM-1 I saw people have remarkable response to study drug and I saw people people have no response to study drug. Since I was blinded, I assumed that everyone having a good outcome was on drug and everyone without a response was on placebo. That is always a fairy tale and I now know that wasn’t true. Both KALM trials showed a big placebo effect (not as big as difelikefalen, but big). The placebo effect was large enough to convince me that all the success I have seen with diphenhydramine, gabapentin, steroid creams (none of which have robust supportive data), was likely just placebo effect. And now we are about to get the opportunity to switch everyone who has failed placebo to start an effective drug. But the wonderful thing is we do not have to just hope the drug is working, we can just ask our patients. Use it for a few months and ask people if they are better. No need to worry about the statistical effect size, all we need to do is assess the effect size in the patient in front of us. If the drug is not working stop the drug. However, be aware, a few weeks later the patient may tell you how much they liked it and that it was helping more than they recognized. My study patients were most vocal after the study concluded and everyone stopped study drug and went back to usual care. Multiple patients begged to enroll in extension studies, different investigations, anything to get access to difelikefalin…because uremic pruritus is miserable.
Difelikefalin is the first drug we have in nephrology whose specific purpose is to alleviate symptoms. This is a different type of drug and we need to retrain ourselves to shift our view on effect side.
After I wrote this, I was made aware of two other anti-itching drugs that I was not aware of. I have no experience with them, but I thought I would list them here:
Nalfurafine a K-opioid-receptor agonist which is approved in Japan (2009) and South Korea (2013).
Nalbuphine, a mixed k-opioid-receptor agonist and partial-opioid antagonist. It has central nervous system effects and may cause dysphoria. It has abuse potential, though it was initially a schedule II drug, it no longer is.
COI: I was a site PI for KALM-1. I recorded a video testimonial for difelikefalin a few years ago. I have attended an advisory board with Cara, the company who developed the drug. I have participated in these because I have seen the product relieve suffering. I would not support a product I did not believe in.