New FDA approval for rare condition CTX offers better support for patients

Ernst J. Schaefer, MD, chief medical officer and laboratory director at Boston Heart Diagnostics and professor of medicine at Tufts University School of Medicine, spoke with Rare Disease 360 about the recent FDA approval of the treatment Ctexli™ (chenodiol) for adult patients with cerebrotendinous xanthomatosis (CTX), an important advancement for patients with this rare genetic condition.

Question:

The FDA recently approved the first treatment specifically for cerebrotendinous xanthomatosis (CTX) in adults. What is your reaction to the approval of Ctexli (chenodiol)?

Ernst J. Schaefer, MD:

Yeah, it’s long overdue. CTX, or cerebrotendinous xanthomatosis, is a disease where it’s really important to replace the major bile acid that these people don’t make. The bile acid is called chenodeoxycholate. The trade name is Chenodiol, and patients take it at a dose of 250 mg 3 times a day. It literally is critical to prevent them from progressing on to severe neurological disease and death.

This is a therapy that was originally FDA approved many years ago for dissolving gallstones. But of course, doctors don’t wait for gallstones to dissolve. If somebody is having a gallbladder attack, now you can do a laparoscopy, and just snip out the gallbladder and tie it off. That’s the end of it. Takes a fairly short period of time.

Anyway, it’s long overdue. The FDA really, unfortunately, dragged their feet for quite a number of years. They did approve another drug for CTX, which is the other major bile acid, cholic acid, but that mainly was used in children, whereas chenodeoxycholate is really the one that’s most important, and it’s the one that we use almost entirely in adults.

Question:

The approval was based on results of the phase 3 RESTORE study. What did that study find?

Ernst J. Schaefer, MD:

What the FDA wanted the company to do… The company, now it’s Mirum Pharma. Before, it was Travere that actually did the study. They wanted them to document that chenodeoxycholate, or Chenodiol, had beneficial effects on the biochemistry and would also have some effect on the symptomatology. The problem with it was that many people in the field felt it was somewhat unethical to withhold therapy from these people, but it was only a 4-week period of time where the people were off Chenodiol. What they did is they took people who were either new to therapy, or they took people who had been on therapy for a long period of time, and they had a run-in period where they were on the active drug. Then they had a washout period. Then they had a period where they were on placebo. During that placebo period, which was 4 weeks, it was a short period of time, if people had symptoms, they could have rescue therapy.

What the study actually showed was that, first of all, the drug did all the expected things that had major effects on cholestanol, the abnormal substance that builds up in these patients when you don’t make the bile acid. Giving the bile acid suppresses the production of abnormal substances in the blood, including cholestanol and other substances that can build up in the brain. They can also build up on the tendons. This is a disease that it presents in childhood often with diarrhea, but then in the teens it often presents with cataracts. When you see a cataract in a 14-year-old, it often can be this disease. Then, of course, they also have intellectual impairment over time. They also, in their 20s and 30s, they develop neurologic disease to the point where they can’t walk, or they have unsteady gait, or they have lots of neurological problems. This therapy is really critical for these patients.

In the study, they showed that the medication normalized the abnormal biochemistries in these patients. In some cases, they couldn’t stay off drug for 4 weeks. They had to have rescue therapy, because they developed symptomatology. They developed headaches, neurological symptoms, and they had to go back on drug.

Question:

How might this FDA approval for CTX impact patients’ lives and physician’s ability to better manage their condition?

Ernst J. Schaefer, MD:

Well, look, I manage 8 of these patients because Dr. Gerald Salen, before he passed away, asked me to follow some of his patients. I referred some of them to Dr. Ginsberg in New York. He follows some of them now. I had 1 patient myself, who actually led a fairly normal life and died at 74 of ovarian cancer, totally separate from CTX. What would happen is, you’d have to, every year, get a prior authorization from the insurer. They would always make you jump through all these hoops. I still have to do it today. Usually, I’ll have to write a letter. I’ll have to spend an hour on the telephone with somebody, who often is very uneducated, and you just have to make sure you answer all their questions and fill in all their boxes.

One of the things that was a little bit not ideal about it was, you had to sort of say, “Well, I’m using this bile acid to dissolve gallstones,” even though the patient may not have had gallstones for a long period of time. But because this therapy was so important for neurological disease, I, as a doctor, would do anything I could to make sure I got these patients on therapy. I mean, I never billed insurance for it. It was basically, we’re trying to help these people. Now, with FDA approval for CTX, would just say, “Yeah, this patient has CTX.”

We have a lab here where we measure some of these things, but the best lab in the country for the diagnosis of this disease is out at the Oregon Health Sciences University. A woman named Dr. Andrea DeBarber runs an excellent lab, where she not only measures cholestanol, but also urinary bile alcohols and bile acids and other things that only a specialty lab can run.

Worldwide, there’s a lot of recognition that chenodeoxycholic acid is the best therapy for this disease. The question that I’ve always had since I worked with Dr. Salen before he died was, “Well, what about giving them the other bile acid, which has also been approved for this disease, which is cholic acid?” Because some of these patients, even when they’re on chenodeoxycholate, they still sometimes progress a bit, especially if you catch them later on in life. The question I’ve always had is, “If you put them both together, will the patients do even better?” I don’t know the answer to that, but that’s something that hopefully will be investigated down the line, because the defect causes a lack of production of both bile acids, not just chenodeoxycholate, but also cholic acid. It’s a cytochrome P 450 defect in an enzyme. These are either homozygous, which case the parents often were first cousins, or something, or they’re compound heterozygous and it’s just really bad luck that 2 people got together that had mutations at this gene loci that caused it to have a phenotype of being a homozygote, but even though they had two separate mutations.

Question:

What’s on the horizon for CTX research and care?

Ernst J. Schaefer, MD:

The question is, should we have newborn screening for this disease? That’s a tough call, because it’s fairly rare. But certainly, I was very happy to see Dr. Friedman and others published a paper about premature cataracts. I think if you see a patient with cataracts in their childhood or teens, you have to think of this disease. I mean, there are other causes. That’s number 1 we need to screen. Number 2, if you see a patient with abnormal deposits on their knuckles, like xanthomas, think of this disease. Number 3, I think really it’s important now to begin investigating. Since you have 2 drugs approved now for CTX, let’s compare each drug alone with the combination. My bias, and not everybody certainly agrees with me, is that the combination would work even better. If you can diagnose this disease in childhood or in teens and give patients both bile acids, I think my bias is that they would lead a fairly normal life.