Earlier this week, the FDA approved
Kanuma (sebelipase alfa) for the treatment of patients with lysosomal acid lipase (LAL) deficiency.
LAL deficiency is a rare lysosomal disorder in which the body does not produce enough active LAL enzyme. Common symptoms vary greatly but may include vomiting, diarrhea, abdominal distention, weightless and hepato-splenomegaly. For patients who begin to show symptoms in infancy, the outcomes can be severe and most will die in the first year if untreated.
In the older children and adults, it's a much more highly variable condition with varying age of onset and rate of progression. Regardless, the significant dyslipidemia that develops can lead to a host of hepatic and cardiovascular problems that create significant morbidity and premature mortality.
The approval of Kanuma provides these patients with an enzyme replacement therapy that may attenuate the progression of the disease. The drug’s approval was based partly on clinical trial data led by Barbara Burton, MD, Northwestern University Feinberg School of Medicine in Chicago, Illinois.
We talked with Dr Burton about the trial and what the approval of Kanuma means for these patients.
Rare Disease Report: Can you briefly describe the clinical data that led to Kanuma’s approval by the FDA?
There were two sets of data. In the infants there was an open label study that showed very significant survival benefit for infants with 6 out of 9 enrolled infants surviving beyond one year of age, and one now as old as five years of age and in very good shape. So dramatically different than the natural history of the disorder. Also improvements in weight gain and nutrition and so on in the infants.
And then in the ARISE Trial, which is the one that I was involved with in the older children and adults, which was a multicenter double-blind placebo-controlled trial, it showed significant improvements in all of the major biochemical hallmarks of the disease in the elevated transaminases, in the lipids, all of the abnormal lipids, HDL, LDL, triglycerides. Also decrease in liver fat content, a decrease in liver volume, decrease of spleen enlargement. So all of these things showing real improvements, in some cases, normalization of the key biochemical parameters.
We expect that will translate into decreased progression of the liver disease if the fat can be cleared out of the liver. And with the correction of the dyslipidemia, certainly it will improve the cardiovascular risk that exists in this disease.
It almost sounds like a wonder drug.
Well it is dramatically effective in terms of altering these biochemical parameters. Of course we don't have long-term data on survival in the older children and adults, or in clinical outcomes because the time course of the disease is so much longer.
But it is dramatic how quickly liver enzymes drop and how quickly lipid abnormalities change. By as early as two weeks of treatment, you see a pretty significant decline in the ALT, for example. And with the lipids, certainly by eight weeks of treatment very significant decrease in the LDL, increase in the HDL.
So it is pretty amazing, although not totally surprising when you think about the tissues that are most affected in LAL deficiency, the liver, the spleen, macrophages that impact the vessel wall, vascular system, those are some of the easiest tissues to get to with enzyme replacement therapy.
What other clinical trials are being conducted with Kanuma?
There are a couple of ongoing trials. I'm involved in one of them which is a trial for patients who did not qualify for the pivotal trial for the ARISE trial. Either they didn't meet the inclusion criteria for one reason or another or had some exclusions that kept them out of that trial. So I'm participating in that one. And they have an ongoing extension trial with the infants and there is an ongoing extension trial with ARISE as well.
How will approval of Kanuma change these people's lives?
I think it's really transformative therapy. I think it's going to dramatically change their lives in the long term. The thing that's a little tricky about LALD, except in the infants, in the older children and adults is that it's a silent killer. Until the patients get really endstage liver disease or until they have a heart attack or stroke, they look good and they feel fine for the most part. Liver disease is very insidious and so they don't feel bad while their liver is becoming cirrhotic. And similarly the dyslipidemia doesn't really cause any symptoms, only when they're atherosclerosis gets to the point that they have a cardiovascular event. So it really is a silent killer. I think it will prolong survival and I think it's going to change their lives, but it's not, you know, in an immediately obvious way.