Pam Vig, PhD, Head of Research and Development at Mirum Pharmaceuticals, highlights some of the clinical data on progressive familial intrahepatic cholestasis (PFIC) and Alagille syndrome presented at the North American Society For Pediatric Gastroenterology, Hepatology & Nutrition (NASPGHAN) meeting.
Transcription:
What we’re showcasing at the NASPGHAN conference this week is 15 abstracts. We’re working very hard to get all those posters done. I’d say the first presentation we’re very proud of, we won the Gerard Odell Prize for excellence in pediatric hepatology.
That was for a study presented by Dr. Alex Miethke. It is our phase 3 study in PFIC patients showing very significant differences between those receiving Livmarli or maralixibat, and those receiving placebo, with reductions in pruritus, reductions in serum bile acid, improvements in bilirubin, and improvements in growth. Very strong, robust data for six months.
What we’re also showing for PFIC is really what happens in some of the subtypes. We have data on FIC1 patients, for example. There are genetic types under the PFIC umbrella, and sometimes they vary in their natural history. We’re really working hard to parse through each of those subtypes of patients, those genetic types of patients, so that we can understand more. Our goal is to move the field forward. We have this great data set, and we keep collecting data on these patients.
A few other notes for the PFIC space that are meaningful is that we have a poster on bilirubin reduction. Bilirubin is a marker of disease progression. When these patients start to have increased bilirubin, you know that they’re headed towards disease progression. Now, on aggregate, we saw reductions in patients treated with maralixibat versus placebo patients, and that was statistically significant. We dug a little deeper to find who are the patients that came in with abnormal bilirubin? Because they don’t all have abnormal bilirubin at the start of the study. The patients progress at different times.
We looked at those groups of patients with abnormal bilirubin at baseline. Of those, 40% of maralixibat-treated patients have normalized. They went from abnormal to normal. This is clinically meaningful. 30% of placebo patients went from normal to abnormal; they got worse. That delta between the two groups at the end of 26 weeks is meaningful. It was quite a surprise for us because we would not have necessarily expected bilirubin to change that quickly, and that perhaps maybe it would take more time. These data are really driving home the fact that we’re altering the underlying health of the liver.
For the Alagille program, Livmarli was approved in now exactly two years for cholestatic pruritus for Alagille syndrome, age three months and older in the US. We’ve been busy gathering real-world data. We have a program called MAP, Mirum Access Plus, and that is a single-source specialty pharmacy and educational program for patients to help them with insurance coverage assistance, to help them with medication delivery, to help answer questions they can opt in for us to gather data.
We wanted to understand the persistence and adherence of maralixibat in this population, understanding that this is a chronic disease that requires chronic dosing. Because you constantly need to keep those bile acids out of the hepatocytes. We found that 94% of patients have insurance coverage. That is really telling of how debilitating the disease is and how you really don’t want to unnecessarily get a liver transplant for a symptom. Removing bile acids through pharmacology is very important.
93% of patients had no dose reductions, so they’re able to get to the top dose and stay there. I think the adherence is very, very strong. This is quite important given that the minute you take maralixibat away or you stop inhibiting the IBAT or you take away the IBAT inhibitor, I should say, that’s when you see the rebound of the pruritus and the bile acids come right back. We’ve seen that in our studies. Adherence is very important to keep those symptoms at bay. We’ve seen in our studies, significant improvements in quality of life in pruritus that pulls into the way that kids sleep.
We also see patients starting to grow. Maybe that’s because of nocturnal growth hormones because they’re able to sleep. Maybe it’s because of a better bile acid homeostasis and the ability to absorb fat-soluble vitamins and lipids more readily. These are some of the theories of why we think we’re seeing a catch-up growth in these patients as well.
Another couple of data points on the real-world evidence is the concomitant medication use. This is another analysis that was conducted through the MAP program where we looked at 116 patients. There’s a polypharmacy for these children. They’re on tons of nutritional and vitamin supplements. As I mentioned, they have failure to thrive, so they need to be on these supplements. They also have antipyretic medications before they start maralixibat. In our trial, those antipyretic medications were allowed, they’re off-label. Despite that, they still have significant pruritus. So then in the study, you add maralixibat on top of that.
Now in the real world, what we’re seeing is when you’ve added maralixibat or Livmarli into the mix, a third of patients are dropping medication, so they have at least one or more medications being dropped. One out of five have dropped two or more medications. I think most interesting, or also interestingly, is the nutritional supplement has decreased by about 20% in this group that we looked at. I think indicating better liver health, better growth.
I guess I would be remiss to mention that we have a poster on two patients that came off the transplant waiting list because of this significant reduction in pruritus, improvement in quality of life. One patient was entirely delisted from the transplant setting and the other has been delayed.
It’s hard to explain 15 abstracts succinctly, so apologies for being very wordy. All in all, in these diseases where bile acid is the problem, is the driver of poor outcomes, is the driver of the symptoms, removing those toxic bile acids is really what you need to do to improve quality of life, to improve symptomology, to improve family dynamic, to improve sleep, and to extend long-term outcomes.
In the past, we have done an analysis where we looked at natural history comparison. What we found is that there’s a 70% risk reduction for patients treated with Livmarli over the standard of care, meaning they are going to transplant less frequently over time because of really driving what is the down, what is the driver of bad outcomes, which is bile acids.
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