Beth Drolet, President of Department of Dermatology at the University of Wisconsin School of Medicine and Public Health, is motivated by the stories of pain and disfigurement experienced by some of her patients.
It treats patients with vascular abnormalities, which are the result of abnormal development of blood and lymphatic vessels, and sometimes accompanied by overgrowth of bones and soft tissues. Over time, patients with these abnormalities may experience pain and loss of function due to multiple factors, including blood clots, bleeding, and gradual growth of blood vessels.
Despite advances in gene discovery, treatment remains primarily procedural through surgery and other invasive procedures. Most of the time, relief from these treatments is temporary.
Drolet is trying to change that by advancing an early phase clinical study to provide more lasting help to his patients and others like them. The multi-site trial at UW – Madison is in its first phase and is testing a personalized topical drug in gel form as a way to treat vascular abnormalities.
“This trial is truly the epitome of precision medicine,” says Drolet. “We assess each patient before they enter the trial to determine which gene is mutated within their malformation. Once we have this data, we use a drug developed to target the specific pathway that the mutated gene has altered. “
The topical gel, called VT30 topical gel, allows Drolet and other researchers in the trial to deliver the drug directly to the affected tissue through the patient’s skin, which also limits exposure of the drug to healthy tissue. .
“Getting the right medication to the right patient and delivering it precisely to the tissues that need it will increase effectiveness while reducing the risk of unintended side effects – precision medicine,” says Drolet.
The phase 1/2 study recruited patients with venous, lymphatic and venolymphatic malformations, which are tumor-like lesions combining venous and lymphatic vascular structures. The study assesses the safety of the drug and patients’ tolerance to its use.
The majority of these vascular malformations are caused by mutations in the genes that govern the formation of the vessels, called PIK3CA and TEK, resulting in overactivation of the pathways involved in their development.
Drolet says the idea of creating a drug to treat vascular abnormalities came to him in a dream. And now he’s taken off.
“We had a network of 16 institutions to find out which genes were causing vascular abnormalities and once we and others found the genes, the industry became interested in reusing cancer drugs for the treatment of this rare disease. », Explains Drolet. “This is the world’s first trial offering targeted gene therapy in a cream for vascular abnormalities. It’s transformational. “
From the start, Drolet worked with a pharmaceutical company, BridgeBio Pharma, Inc. and its subsidiary Venthera, to engage patient organizations and national experts to help gather feedback on clinical trial design and the design of the clinical trial. administration of drugs. The company is focused on developing new treatment options for patients with rare vascular abnormalities.
“It’s a big deal,” says Drolet, who has been a consultant for Venthera and on its medical advisory board.
Sara King, a schoolteacher in Wauwatosa, Wisconsin, agrees.
She met Drolet when Drolet was at the Wisconsin Children’s Hospital, as the Medical Director of Birthmarks and Vascular Anomalies (where she also established the Center for Birthmarks and Vascular Anomalies).
When the doctor joined UW – Madison in 2019, King followed her for treatment.
King has Klippel-Trenaunay syndrome, which has three characteristics: a red birthmark called port wine stain, abnormal soft tissue and bone growth, and venous malformations. It is a rare genetic disease apparent at birth that affects approximately 70,000 people in the United States.
But King was not diagnosed right away. In fact, she remembers, “When I was born, the doctors told my parents that my birthmark would be gone when I was 3 or 4 years old.”
Few people knew at the time that his birthmark, which stretches from his hip to his big toe on his left foot, was the hallmark of a rare disease. Forty-four years later, the birthmark has not disappeared.
King was not even diagnosed with Klippel-Trenaunay syndrome until she experienced a blood clot during her third pregnancy.
Besides making her more prone to clots, the syndrome causes varicose veins and another condition called arteriovenous malformation, which King says is very painful. She wears a compression bandage on her leg for pain relief and has tried many treatments, including venous stripping, to remove varicose veins; sclerotherapy, used to narrow blood vessels; and stent placement, to help with blood flow.
Last December, she learned about the clinical trial and, after an assessment, was invited to participate. The study focuses largely on patients with mutations associated with Klippel-Trenaunay syndrome and another syndrome marked by vascular abnormalities, called PHACE, which affects fewer than 5,000 people in the United States.
King’s treatment in the trial targeted an area 10 x 10 centimeters of his birthmark. She applies the gel once a day. In phase 1, King started with a low dose of the drug, and after two weeks she returned to the clinic. There, the researchers used a special camera to photograph and measure any changes in redness and volume in the treated area of his birthmark. She was sent home to start an increased dose for another two weeks.
King recently completed Phase 1 and wants to continue Phase 2 of the trial, which includes a 12-week, randomized, double-blind, placebo-controlled treatment focused on the safety and effectiveness of the topical drug.
Although this is a nationwide study, UW – Madison and UW Health were effective in recruiting the first patient to the trial and currently have the most patients enrolled. This is in part due to another study conducted by Drolet at UW which receives vascular samples from 16 sites around the world. With approximately 300 patients enrolled in this study, she can consult this list and identify patients who may have the mutations targeted by the gel.
“The patients are amazing,” says Drolet. “They want to help science and help people feel better.”
King’s motivation to join this first clinical trial is multiple.
“Of course, there is the potential for personal benefits,” King says. “But also, it’s cutting edge and I’m delighted to be one of the first people in the world to try this treatment. These doctors are some of the best in their field and it is exciting to see them take care of me.
King adds that having a rare disease can be isolating.
“It helps me to know that there are other people I connect with through a study like this, people from across the country,” she says. “I’m also a teacher and it’s gratifying to know that as a middle aged woman, maybe I could do something that could impact the children and their families. Some of the things I have faced because of my condition have been scary and painful and if I can take that down for someone else it really makes me feel good.
For Drolet, the experience was also profound.
“I never imagined how moving it would be to see the first patient apply the drug,” says Drolet. “I have been discussing with some of my patients the potential of this type of treatment for over five years… It is a dream come true.”
For more information on the trial, which is still recruiting patients, visit: Clinicaltrials.gov/ct2/show/NCT04409145.