Research News

A clinical trial has demonstrated that the immunomodulatory drug pomalidomide is safe and effective in treating hereditary hemorrhagic telangiectasia (HHT), a rare bleeding disorder that impacts more than 1 in 5,000 people worldwide. The trial, supported by the National Institutes of Health, was stopped early because of these successful findings, and has been published in the New England Journal of Medicine.

The impetus for this trial was a single patient. About 15 years ago, Cleveland Clinic’s Keith McCrae, MD, saw a patient presenting with HHT symptoms — or at least what he thought were HHT symptoms. There was little information about the disease at the time, says Dr. McCrae, a hematologist and scientist. HHT, also known as Osler-Weber-Rendu Syndrome, is characterized by serious defects in blood vessel formation. Blood vessels in HHT become unusually tangled and twisted, instead of growing linearly. Disordered blood vessels are prone to leaking, causing the excessive nosebleeds that hallmark the disease. HHT also causes gastrointestinal tract bleeding, and the abnormal vessels can produce complications in the lung, liver and brain. Bleeding episodes worsen with age, affect quality of life and can cause anemia and other life-threatening conditions.

Dr. McCrae’s patient was experiencing nosebleeds and severe GI bleeding. He was requiring several blood transfusions and multiple doses of concentrated blood plasma clotting factors, which were very expensive, every week.

The patient, who was in his 50s at the time, had been told that his only option was surgery to remove the diseased bowel. He would then need to be fed intravenously to maintain nutrition. Dr. McCrae was determined to find another solution.

Dr. McCrae says being both a researcher and a physician influences how he approaches patient problems. Working with rare diseases requires a creative approach because there is often very little data and a small patient pool, he explains.

“In the lab, you must think critically, analyze every experiment and challenge yourself to make sure you’re doing good work and what you’re spending your time on is worthwhile,” he explains. “I look at every patient as a puzzle. There are so many things we don’t understand about a patient, particularly in my specialty of classic hematology, so you need to try to think of new and mechanistic approaches to these disorders.”

Trying a new approach

Dr. McCrae began his search for new options for his HHT patient and found that a cancer drug called thalidomide had shown positive outcomes in a few patients with similar clinical manifestations. He treated his patient with a low dose of thalidomide and the bleeding almost completely stopped within 2-3 weeks. Dr. McCrae tried thalidomide with other patients showing similar HHT symptoms and they also responded positively.

“It was amazing,” Dr. McCrae recalls. “I had rarely seen anything quite like that in my clinical experience, and I thought, ‘we have to study this.’”

Thalidomide primarily treats multiple myeloma, but became infamous for causing severe birth defects in babies when prescribed to pregnant women in the 1950s for morning sickness. Due to these side effects and others, thalidomide is used much less commonly currently, and instead of pursuing large-scale research with thalidomide, Dr. McCrae used a drug with a similar chemical structure called pomalidomide. He performed a pilot study with pomalidomide, and the drug appeared effective and safe.

“It’s been an interesting journey over the last 15 years,” Dr. McCrae says.

From idea to clinical trials

To test pomalidomide researchers enrolled 144 adults with HHT at 11 U.S. medical centers between November 5, 2019, and June 27, 2023. CureHHT, a patient advocacy organization, actively supported enrollment in this trial. All participants had moderate to severe nosebleeds requiring iron infusions or blood transfusions. The study utilized RTI International, in North Carolina, as the data coordinating center.

Researchers observed that HHT patients taking an oral medication saw a marked decrease in nosebleed severity, required fewer blood transfusions and iron infusions and experienced an improved quality of life. In June 2023, an interim analysis found pomalidomide had met a prespecified threshold for efficacy and the trial was closed.

Researchers speculate that pomalidomide worked by blocking the growth of abnormal blood vessels. “The drug may cause the blood vessels to have a more normal structure or thicker walls so they are less fragile,” Dr. McCrae says, but further study is needed.

“Finding a therapeutic agent that works in a rare disorder is highly uncommon, so this is a real success story,” said Andrei Kindzelski, MD, PhD, program officer in the Division of Blood Diseases and Resources at the National Heart, Lung, and Blood Institute, part of NIH. “To date, there has been no positive trial of a therapeutic for treating HHT.”

Dr. Kindzelski said the finding has broader, life-saving implications for people with more severe forms of HHT. In those cases, malformed blood vessels can also develop in organs such as the lung, liver and brain, which can lead to hemorrhagic stroke, bleeding in the lungs or heart failure.

Though researchers did not follow participants after the trial ended, Dr. McCrae said some of his patients who were enrolled in the study have gone 4-6 months without nosebleeds recurring, even though they had stopped the medication. This suggested that the drug may have promise as a long-term or intermittent treatment, he said.

Even after finding a successful treatment for this rare disease, much is still unknown about the mechanisms of HHT itself. Dr. McCrae is hoping to obtain additional funding to continue studying HHT, clarifying the mechanisms behind the disease and how pomalidomide and other drugs influence them.

"I'm optimistic that learning more about the mechanisms of how this treatment works will make a great impact in hematology and our understanding of vascular malformations," he says. "There are many idiopathic GI bleeding disorders or other vascular malformations, that aren’t necessarily HHT, and this drug or family of drugs may actually be effective in treating those as well.”

Dr. McCrae is up to the challenge, as solving this type of puzzle is one of his specialties.