'It can be really bad': Vascular Ehlers-Danlos syndrome treatment options remain limited
Ehlers-Danlos syndrome can be a devastating disease in patients who are severely affected — a situation made worse by the current scarcity of treatment options.
“The life expectancy for those patients is really diminished, perhaps around 50 to 51 years of age, depending on what form they have,” David R. Deyle, MD, medical geneticist at the Mayo Clinic in Rochester, Minnesota, told Healio. “For those who are severely affected, it can be really bad.”
The FDA in December granted orphan drug designation to enzastaurin (AR101, Aytu Biopharma) for the treatment of Ehlers-Danlos syndrome. Aytu Biopharma is undertaking the PREVEnt trial to study the effectiveness of enzastaurin in preventing cardiac or arterial events in patients with vascular Ehlers-Danlos syndrome confirmed to have COL3A1 gene mutations.
Healio spoke with Deyle about vascular Ehlers-Danlos syndrome and the FDA’s recent orphan-drug announcement.
Healio: What causes vascular Ehlers-Danlos syndrome?
Deyle: We know that variants or changes in the COL3A1 gene, type 3 collagen, lead to vascular Ehlers-Danlos syndrome. Type 3 collagen is primarily in tubular structures — so, arteries. It is also in the intestine and uterus. This is where we see many of the complications from vascular Ehlers-Danlos syndrome.
One way it can happen is that abnormal collagen incorporated into the triple helix, where three proteins come together, is then going on to cause problems. In subgroups of patients with vascular Ehlers-Danlos syndrome, mutations may lead to a loss of collagen production. There are two ways that can happen. One, an error can create technically the right amount of collagen, but it may not be getting out, or the collagen may be not quite right. Or, you may only make half as much collagen, and that’s what we know leads to vascular Ehlers’s Danlos syndrome.
Healio: What are symptoms of Ehlers-Danlos syndrome and how is it diagnosed?
Deyle: That depends sometimes on the particular mutation. Patients who only make half as much collagen tend to have milder cases than patients who make an altered copy. In milder cases, the main criteria for diagnosis are arterial ruptures, spontaneous arterial ruptures, spontaneous intestinal ruptures and spontaneous uterine ruptures.
In more severe cases, you might also see thin, translucent skin, where you can really see all the underlying veins, particularly in the chest and sometimes even in the arms. The hands may look older than they should. Some patients may have a small nose, a small pointy chin or thin lips. Some patients can have flexible joints.
Something that we see first and foremost is unusual bleeding or bruising. Patients may also have hemothorax, a hole in the lung, just spontaneously — no reason why. People who have hypermobility can have joint subluxation dislocation.
Healio: When do symptoms manifest?
Deyle: The more severe cases can happen in childhood. Although vascular Ehlers-Danlos syndrome can present at any age, some children can have arterial rupture, but mostly we see intestinal rupture first.
The statistics are that at roughly age 25 years, 50% of patients will have had a major event, including arterial rupture, intestinal rupture or uterine rupture. In patients approximately 40 years old, 85% of them will have had an event of some sort. Every year thereafter, the percentage gets closer to 100%.
Patients who only make half as much collagen and may not present until later in life primarily have vessel issues, either arterial dissection or rupture, but they may not have some of the physical findings. You couldn’t really pick them out from anybody else. They tend to live longer, so they can have more normal lifespans because their symptoms are milder and they don’t present until later. But we still see a lot of patients who have significant complications in their 20s and 30s.
Healio: How is Ehlers-Danlos syndrome treated?
Deyle: There are no treatment options currently for vascular Ehlers-Danlos syndrome. Treatment is about empowering our patients with knowledge of the underlying condition because there are certain things they should avoid, primarily anything that can lead to trauma.
These patients have very fragile vessels so we do not recommend elective surgery, because that can be lethal. Particularly for cardiovascular surgery, if you can’t put the vessel back together it can be catastrophic. We also recommend that patients keep an emergency letter with them and wear a MedicAlert bracelet, because one of the things to avoid is any kind of instrumentation within the vessel, which can lead to more damage. Instrumentation can rip the vessels. So, it’s really about avoiding situations that can lead to more damage.
We also don’t recommend patients have colonoscopies routinely because that blowing up of the colon can cause a rupture. We do recommend screening of the vessels, looking at what the arterial system looks like, but we do not currently have any kind of therapeutic and surgery can be fraught with problems.
With surveillance, we look at changes in the arterial system or whether there has been a dissection. If somebody has abdominal trauma, you want to know what the arteries looked like before, compared with after, but there are no active therapeutics, no medication.
Healio: The FDA recently gave the drug enzastaurin orphan drug status for the treatment of Ehlers-Danlos syndrome. How do you see this new medication changing the treatment paradigm, if at all?
Deyle: It would be great if it works, but I want to see the data after patients are treated. Does the mechanism work in patients who are only making 50% of the collagen they are supposed to be making, but still have normal collagen? We need to see how it affects people. Does the dose lead to side effects that people cannot tolerate? The bigger thing is to see how it works, but if it does, fantastic.
References:
- Aytu BioPharma announces FDA clearance of investigational new drug (IND) application for AR101/enzastaurin in vascular Ehlers-Danlos syndrome. https://irdirect.net/prviewer/release_only/id/4970094. Published Dec. 13, 2021. Accessed Feb. 7, 2022.
- Aytu BioPharma receives orphan drug designation from FDA for AR101 for treatment of vascular Ehlers-Danlos syndrome. https://irdirect.net/prviewer/release_only/id/4965670. Published Dec. 8, 2021. Accessed Feb. 7, 2022.
For more information:
David R. Deyle, MD, can be reached at Deyle.David@mayo.edu.
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