Clinical Trial for Rare Blood Disorder Brings Dallas Mom to UAMS

By Susan Van Dusen

With 14 years on the job, she has seen her share of both typical and unusual medical cases.

“Being a nurse for so long, you feel like you have a lot of knowledge about health care and the needs of patients,” said Shield, who has served as manager of the Hematology/Oncology Unit at Methodist Dallas Medical Center for nine years.

That confidence was turned on its head in October 2017 when Shield suddenly found herself in the role of patient and her colleagues searching for answers to a set of overwhelming and unusual symptoms.

What started with back pain and nausea, quickly progressed to uncontrollable vomiting. A prescription for antibiotics got the symptoms under control for about 12 hours, when they returned in full force.

“As that point, I decided to go ahead to the hospital where I work,” she said. She was admitted and put on more antibiotics, but after a weekend stay followed by two days at home, Shield was back at the hospital, where her symptoms took an unexpected and frightening turn.

“I became very confused, and my pain was uncontrollable,” she said.After her symptoms subsided a few days later, Shield returned to work and hoped for the best.

However, it was only one month later when the cycle repeated itself again … and again … and again.

“These repetitive attacks, as we called them, happened four times. I was admitted to the hospital five or six times over the course of four months and was tested from head to toe,” she said.

All test results came back normal, leaving Shield and her family frustrated and scared.

It seemed like there was no end in sight to these strange and extreme symptoms, when one of the oncologists she works with had an idea.

“After I returned to work following my fourth attack, she came to my office so we could talk. I walked her through all of my symptoms, and she asked if anyone in my family had ever had porphyria. I had never even heard of porphyria, and I’ve been a nurse for a long time,” Shield said.

According to the National Institutes of Health, porphyria is an extremely rare group of genetic disorders caused by abnormalities in the chemical steps that lead to heme production. Heme is an essential component of hemoglobin, the protein in blood that carries oxygen throughout the body.

With the type of porphyria known as acute hepatic porphyria (AHP), potentially life-threatening, debilitating and seemingly unconnected symptoms can include severe abdominal pain, fatigue, paralysis, weakness, confusion, anxiety, hallucinations, vomiting and others.

Shield’s colleague had seen one porphyria case during her fellowship training, and the memory stuck with her. She set up an appointment for Shield to undergo what is known as a spot urine test. This specialized test is used to diagnosis porphyria by detecting elevated levels of the neurotoxins that build up in the blood and affect the body, both mentally and physically.

On her daughter’s second birthday, Shield’s test results arrived. Just as her colleague suspected, she was living with AHP.

“It was scary, but also reassuring that we had an answer and could get some direction about where to go from there,” she said.

Shield quickly made an appointment with a specialist at UT Southwestern Medical Center in Dallas who told her about a clinical trial for a new drug called givosiran. Instead of treating AHP attacks when they occur, givosiran is designed to prevent attacks from happening in the first place.

Clinical trials are research studies in which people help doctors find new and better ways to prevent, diagnose and treat disease. Although there is no guarantee a patient will benefit from participating in a clinical trial, the results of many trials have allowed people to live much longer and more productive lives.

Although the trial of givosiran– called ENVISION — was not available in Dallas, it was offered just a short plane ride away at UAMS in Little Rock.

Plus, the doctor at UT Southwestern told Shield he had a friend at UAMS – Appalanaidu Sasapu, M.D. – who would take excellent care of her, she said.

Appalanaidu Sasapu, M.D.

Appalanaidu Sasapu, M.D.

Shield didn’t hesitate. She registered for ENVISION online, made her first appointment with Sasapu and started the trial in July 2018.

“Because AHP is so rare, there only a handful of patients in each state. UAMS was one of very few centers that offered ENVISION, and we had two patients enroll within the first week,” Sasapu said, adding that he knows of only six porphyria patients in the entire central Arkansas area.

Sasapu is a hematologist/oncologist at the UAMS Winthrop P. Rockefeller Cancer Institute and serves as assistant professor in the UAMS College of Medicine Department of Internal Medicine.

The ENVISION trial was in Phase 3, meaning it had already been through years of testing to determine its safety, possible side effects and dosage.

The Phase 3 trial provided half of the enrolled patients with givosiran, while the other half received a non-therapeutic placebo. Called a double-blind trial, neither the doctor nor the patient knew whether they were receiving givosiran or the placebo. By comparing the results of the two groups, researchers could determine whether givosiran did indeed prevent attacks as intended.

As an incentive to enroll, all participants were promised access to givosiran free of charge for 29 additional months following their six months in the trial.

Shield describes her experience during ENVISION as a “rocky road.” Although she traveled to Little Rock once a month for six months to receive the injection, her intermittent attacks continued.

It wasn’t until November 2019 when the trial was “unblinded” that she discovered she was in the placebo group and therefore did not receive any possible benefits from the drug during the trial period.

A total of 94 patients in 18 countries participated in ENVISION. Results of the trial, which were presented in April 2019 at the European Association for the Study of the Liver 54th Annual International Liver Congress, found a 74% mean reduction in porphyria attacks in those who received givosiran versus those who received the placebo.

“This is a tremendous improvement for patients and led to givosiran’s approval by the FDA in November 2019,” Sasapu said.

Since starting her monthly dose of givosiran in January 2019, Shield has seen positive results.

“It’s been a roller coaster, but I think I’ve seen benefits. I am still having attacks here or there, but since I’m still fairly new to this disease it’s hard to know if the results are significant yet,” she said.

Because AHP is such a rare disease, it is often misdiagnosed, sometimes for 10 or more years.

“Many people with AHP first go the emergency room with severe abdominal pain. The doctors will suspect pancreatitis or appendicitis or gall bladder issues, but all the test results will be normal. Some people even have their gall bladder or appendix removed, only to discover that was not the cause of their pain,” Sasapu said.

Because AHP also causes symptoms such as confusion, anxiety and hallucinations, some patients are diagnosed and treated for psychiatric conditions. Others are thought to be seeking access to drugs after all test results come back normal, leading doctors to believe there is no physical cause for their pain.

If left untreated, however, AHP leads to serious consequences. Sasapu has seen patients with AHP develop extreme, chronic pain and one who was placed on a ventilator due to respiratory paralysis.

“I am fortunate that I was diagnosed fairly quickly and have been able to continue working and being an active mom. Many people live for years without knowing what is happening to their body,” Shield said.

Sasapu added that although AHP is a genetic condition, simply having the gene mutation doesn’t mean you will develop symptoms. It is often a secondary trigger – such as stress, alcohol or prolonged starvation, such as can follow a major surgery – that causes the symptoms to manifest.

“Only about 10% of people of people with the gene defect ever show symptoms. But for those who do, we need to greatly increase awareness about AHP so people are diagnosed more quickly and can maintain their normal lives for as long as possible,” Sasapu said.