On a recent fall day, 80-year-old Gail Delente rolled her motorized scooter through the door of the retirement home she shares with her husband in Adamstown, Maryland. Winding through the kitchen to the living room, she spied her 7-foot Steinway Model B grand piano—“one of the most beautiful pianos there ever was,” she says.

It’s a memento to the long career she held as a university professor and concert pianist. She performed widely in the United States and France, where she founded a piano festival to promote the authentic performance of French piano music worldwide. In recognition of her efforts, the French government knighted Delente in 2000.

But these days, playing the piano is a distant memory. Six years ago, Delente noticed a bothersome tingling in her fingers, which gradually stopped working the way she’d always expected them to and began throbbing with pain. A crippling numbness began spreading from her toes to just above the knee, making it impossible for her to walk.

Desperate for a diagnosis, Delente saw a string of specialists before she landed at Johns Hopkins and underwent numerous tests. In February 2017, she got a long-awaited answer: She suffered from transthyretin amyloidosis, also known as hATTR amyloidosis, a disease in which abnormal protein deposits build up in the nerves, heart or both.

“When given my test results, the first thing they said was that they finally had a diagnosis,” she remembers. “They then added that it’s fatal.”

Indeed, until recently, patients like Delente with hATTR amyloidosis have had few options to treat this progressively disabling and deadly condition. But two clinical trials, both of which took place recently at Johns Hopkins, are giving new hope for patients. These drugs not only offer the potential to save lives but to possibly reverse the course of this devastating disease—something that patients and their doctors have long thought to be an impossible feat.

A Dreaded Diagnosis

Johns Hopkins neurologist Michael Polydefkis is one of the few neurologists in the United States who specializes in treating hATTR amyloidosis. This disease, caused by one of 120 different point mutations—a one-letter swap in a person’s genetic code—affects a protein known as transthyretin (TTR). Its job is to ferry thyroid hormone and vitamin A in the body.

TTR usually exists as a tetramer, Polydefkis explains, a shape like a four-leaf clover. But it can also separate into individual leaves. For people with an amyloidosis-causing TTR mutation, these leaves can misfold and aggregate, forming amyloid, which collects in tissues and ultimately causes dysfunction.

Amyloid is a generic term for proteins that fold abnormally and clump together, causing diseases as wide ranging as Alzheimer’s disease or other conditions that affect the kidneys or liver.

In the case of hATTR amyloidosis, Polydefkis adds, these protein aggregates can collect in the heart, making it too stiff to beat effectively, eventually resulting in heart failure. Sometimes amyloid collects in peripheral nerves, affecting sensation and motor abilities or causing diarrhea or constipation when it acts on nerves in the gastrointestinal tract. Most patients have components of both cardiac and neurologic manifestations.

Although the exact prevalence of this condition is unknown, estimates suggest that about 50,000 people are affected worldwide, with about 5,000 in the United States. The median age of onset is about 39, but some patients start showing symptoms as early as their 20s.

“Once the process starts, it’s a progressive decline, which translates into increasing disability and eventually death,” Polydefkis explains. “[Until recently], I dreaded delivering these diagnoses because I knew what was in store for these patients.”

Because this condition can be genetic, Polydefkis adds, many patients he saw also knew what was to come once they received their diagnosis. They’d seen their parent, aunt, cousin or other relatives slowly degenerate, trapped in a dysfunctional body wracked with pain.

Until recently, patients with this diagnosis had been relatively rare in Polydefkis’ practice, he says. That’s because many already knew there was relatively little to offer. For those who did end up seeing him anyway, there were only a handful of options that he and his nurse practitioner, Kathleen Burks, could suggest.

One potential way to treat hATTR amyloidosis is through a liver transplant, says Burks, since that’s the major source of TTR. But, depending on the mutation that causes a patient’s condition, TTR produced by the new liver may also misfold and continue the disease’s progression.

A drug called tafamidis, which stabilizes the tetramer form of the protein and prevents it from separating and misfolding, was approved in Europe after testing at multiple clinical trial sites, including Johns Hopkins—but it wasn’t approved in the U.S. because it produced only mildly improved outcomes. Researchers found that a generic nonsteroidal anti-inflammatory drug called diflunisal had similar properties. It’s often used in the U.S. to slow disease progression, but it can cause serious side effects, such as renal toxicity, and it can complicate the management of heart conditions.

“It’s been depressing for patients to hear that there are no real options for treatment, that we can’t undo what’s happened and that we can’t stop it from progressing,” says genetic counselor Emily Brown, who works in the Division of Cardiology educating and advising patients with cardiac or combined manifestations of this disease.

Patients are often referred from cardiology to Polydefkis’ practice based on their symptoms. “While we could treat the symptoms,” Brown adds, “we previously couldn’t treat the underlying disease. Consequently, a lot of our patients felt hopeless.”

‘Unprecedented’ Improvement

But those conversations started to take a turn several years ago, says Polydefkis. That’s when two clinical trials launched at Johns Hopkins and selected sites across the globe for new drugs to treat hATTR amyloidosis.

The trials, run by two different drug companies, offered separate strategies for those whose condition had manifested neurologically. One trial, administered by Boston-based Alnylam Pharmaceuticals, tested a drug called patisiran. Delivered by infusion every three weeks, patisiran uses a phenomenon called RNA interference to restrict cells’ ability to make TTR. The drug binds to messenger RNA—instructions that the cell prints from DNA to make proteins—and marks it for degradation.

The other trial, by Carlsbad, California-based Ionis Pharmaceuticals, tested a drug called inotersen. This drug, which falls into a category known as antisense oligonucleotide therapeutics, takes a different but related tack to inhibit TTR production. An injection that patients self-administer once a week, inotersen binds to messenger RNA to make it ineffective at producing proteins.

Preclinical testing in animal models showed that both of these drugs could greatly reduce the amount of TTR circulating in the blood, which in turn reduced the ability of misfolded proteins to aggregate and form amyloid deposits. But, until the clinical trials, no one knew exactly what would happen when patients with hATTR amyloidosis took these drugs.

For both medications, Burks says, study volunteers were split 2-to-1—for every two patients who received the real drug, one took a placebo. Neither the medical team who administered the drugs and cared for these patients nor the patients themselves knew who was on which regimen.

“I’ve worked on a lot of clinical trials, and it’s nearly impossible to tell who’s on the drug and who’s on the placebo. Clinical trials only rarely succeed, so you don’t often see patients improve,” Burks says. “You’re not supposed to guess, but here, we started to notice some differences among patients.”

Some patients continued the precipitous decline that’s characteristic of this disease over the next few months, she says. But other patients gradually stalled in their disease state. Rather than developing progressively more sensory and motor dysfunction, their progression stopped. A few on patisiran, she says, even improved slightly the longer they were on the drug.

“For this disease,” says Polydefkis, “this is unprecedented. We hadn’t thought of hATTR amyloidosis in terms of improvement. Never.”

The trials were so successful that after two years, both drug companies switched from an investigation phase into an expanded access program where newly diagnosed patients could receive the drug instead of the placebo.

Pham Hung, a 68-year-old physics professor from the University of Virginia, joined the expanded access program in January 2018. Hung’s hATTR amyloidosis involves combined cardiac and neurologic symptoms. Nearly three years ago, progressive difficulty in walking and then an irregular heartbeat brought him to a series of specialists, seeking an answer. A genetic test confirmed his diagnosis in 2017. Afterward, Hung had surgery to receive an implanted cardioverter defibrillator. It also gathers data, downloadable by physicians, on heartbeat rhythm patterns. As walking got harder and harder, Hung began using a set of hiking sticks instead of a cane.

After six months on patisiran, he improved enough to stop using his walking sticks entirely. Data from his implantable cardioverter defibrillator show that episodes of irregular heartbeats have reduced from about 200 over three months to just five. Gastrointestinal problems that had plagued him for years disappeared. A blood test showed that the amount of TTR protein circulating in his bloodstream had decreased from a range of 18 to 38 milligrams per deciliter—typical for healthy patients and those with hATTR amyloidosis alike—to less than 3.

“I’m a physicist, so it usually takes seeing some numbers before I believe in something,” Hung says. “To me, it’s like science fiction that this drug has caused so many measurable improvements.”

One of Polydefkis’ areas of research is using punch skin biopsies—clinical tests in which small skin samples can shed light on various factors of patients’ health—to track various forms of neuropathy. His lab pioneered a way to track amyloid in the skin’s nerves as a way to follow the progress of hATTR amyloidosis. He incorporated these biopsies into Johns Hopkins’ clinical trials.

“These tests showed us what patients were already telling us,” Polydefkis says. “We could physically see that amyloid accumulation had stopped. And in some patients, it reversed.”

More in the Works

Patisiran was approved by the FDA in August 2018. Inotersen was approved in October 2018.

As trials continued for both drugs, word spread like wildfire among the hATTR amyloidosis community. Nearby Hagerstown, Maryland, is a hotspot for this disease, explains Polydefkis. Many members of the same family have passed on their mutant gene to descendants. As patients told their relatives about the two trials, Polydefkis and his colleagues began to see an influx of new patients, all with new hope about what could be done for their condition. There were so many that he set up a registry of local patients—many of whom are related to each other, and others who aren’t—which now totals 100 individuals who Polydefkis tracks and frequently treats.

Delente, who’s on Polydefkis’ registry but isn’t related to the Hagerstown clan, has also made modest gains on patisiran. Although she still can’t walk distances more than 5 to 10 feet and has trouble using her hands, her motor decline has stopped. Gastrointestinal symptoms that long bothered her have disappeared.

Now that the trial is over, Delente is nearing the end of her free doses—a time that she’s feared since her first infusion in early 2017. The estimated price for a year of patisiran is $450,000, an amount that’s untenable for nearly all the patients who need it. Since the drug has only recently gained FDA approval, most insurance companies don’t automatically cover it yet, and it’s unclear how and when insurance approvals will come through. Burks and her colleagues are currently working on helping the 40 patients currently using this drug or inotersen at Johns Hopkins to find options to continue the medication once they exit these trials.

In the meantime, Polydefkis says, more pharmaceuticals for treating hATTR amyloidosis are in the works. Although the patisiran and inotersen trials focused on the neurologic manifestations of this disease, other trials currently running are using variations of these drugs to treat the cardiac manifestations of hATTR, as well as a mechanistically identical TTR amyloidosis that is not inherited, called wildtype TTR amyloidosis.

“I went into neurology because it contains so many difficult diseases that we’re just beginning to understand from a mechanistic standpoint,” Polydefkis says. “I’m seeing this dramatic change for the first time in my career. It’s transformed those tough discussions with these patients into optimistic ones.”