The patients are young adults, often in their 30s. The disease, known as TTR-FAP, starts with tingling in the feet. Then it moves up the body, destroying nerves and killing within a decade.
Pfizer Inc., the world’s largest drugmaker, has a pill called tafamidis meglumine that may stem the tide of the rare genetic illness, keep patients’ bodies from wasting away and give them a chance at a full life. TTR-FAP, or Transthyretin Familial Amyloid Polyneuropathy, was first detected near a village in Portugal, where it has ravaged families. Clusters also have been found in Japan and Sweden.
For the estimated 8,000 patients worldwide like 34-year-old Kevin Mui, Pfizer’s medicine may be the best hope for a therapy. In the three years since his symptoms surfaced, TTR-FAP has cost him 100 pounds and most of his mobility. The disease killed his mother and uncle at age 47. His brother, 45, also has it.
“We have this kind of magic number in our heads where we wonder whether we’ll make it past our 47th birthday,” said Mui, who was a technology analyst at the Bank of New York in Manhattan before his illness forced him to stop working. “Even though I saw my family members go through it, it was a surprise how quickly it came on.”
The U.S. Food and Drug Administration is scheduled to decide by June 16 whether to approve tafamidis. An approval would make it the first drug for sale to treat TTR-FAP, which New York-based Pfizer estimates affects 3,000 people in the U.S.
In a report dated May 24, the FDA said the studies didn’t support approval “based on inadequate evidence of effectiveness.” A panel of outside advisers voted 13-4 to recommend the drug, saying data from Pfizer suggested a benefit.
The medicine was approved with the name Vyndaqel in November in Europe where the disease is concentrated around the Portugese town of Póvoa de Varzim. It was first described there in 1952, and the largest treatment center is at a local hospital. Póvoa de Varzim, once a fishing village, is now a suburb about 30 kilometers (19 miles) north of Porto.
Around Póvoa de Varzim, as many as one in 1,000 people have TTR-FAP. “In some regions, it’s not a rare disease,” said Teresa Coelho, a doctor at Hospital Santo Antonio in Porto. Coelho led the trials of Pfizer’s (PFE) drug at the hospital.
“It runs in families,” Coelho said in a telephone interview. “If you are a carrier, the likelihood you will develop the disease is very high.”
Lou Gehrig’s Disease
TTR-FAP resembles the better-known amyotrophic lateral sclerosis, or Lou Gehrig’s disease. It’s also a neurodegenerative disease characterized by loss of use of the limbs. TTR-FAP, though, often strikes people at younger ages than ALS, which usually develops in 40- to 60-year-olds, according to the National Institutes of Health. TTR-FAP attacks the digestive system while ALS patients often die from respiratory failure.
In the Porto region, children of families with a history of TTR-FAP have genetic testing at age 18, then counseling and monitoring after that.
The signs are easy to identify. “One year they come in and say, ‘I’m feeling something strange in my feet. I have neuralgic pain, I can’t feel hot water the way I used to,’” Coelho said.
The loss of bowel control can force many to use a colostomy bag. Eventually, they are paralyzed.
“What you have is a picture of progressive, relentless, debilitating symptoms that invariably lead to death,” said Ilise Lombardo, Pfizer’s lead clinical developer of the drug.
Protein Breaks Up
Pfizer’s pill targets transthyretin, a protein which carries thyroid hormone and retinol. In those with the rare genetic mutation that causes TTR-FAP, the protein breaks apart and clumps into plaques called amyloids.
Toxicities from the plaque attack the body’s longest nerves first. Patients lose sensation in their feet, genitals and digestive system. To slow damage, Pfizer’s drug puts a lock on the problem protein, stopping it from breaking apart and reforming into the toxic clusters.
The current treatment is a liver transplant -- the organ produces the problematic protein and a new one can extend patients’ lives. Alnylam Pharmaceuticals Inc. (ALNY), based in Cambridge, Massachusetts, also has a drug in early trials. Isis Pharmaceuticals Inc. (ISIS), based in Carlsbad, California, and London- based GlaxoSmithKline Plc (GSK) have teamed to develop a treatment.
Analysts haven’t estimated a market for the medicines. Pfizer declined to comment on its European or potential U.S. sales.
The Alnylam and Isis therapies stop the production of the transthyretin protein, said Rodney Falk, director of Brigham and Women’s Hospital’s program for cardiac amyloidosis, a related disease where patients’ heart muscles are damaged. The hospital is based in Boston.
“I don’t think they’re necessary rivals to tafamidis,” Falk said in a phone interview. “My prediction is that none of these drugs will be perfect, and we’ll end up using a combination.”
Bill Hanshaw, 62, lives in Tallmadge, Ohio, and was diagnosed in 2007 -- older than many patients in Portugal. He retired onto disability because the disease has made work too difficult. Like others, he has relatives who’ve died from TTR- FAP.
“A lot of people were dying undiagnosed,” he said of his family. Tipped off by a cousin about the family’s history, he went for a test that confirmed TTR-FAP.
The plaque began to harden the walls of his heart, dropping Hanshaw’s blood pressure and leaving him constantly short of breath and fatigued. While he has nerve damage that makes walking difficult, he was able to get into the trial for tafamidis and said it’s stalled the progress of the disease.
“I watched my father slowly die. I watched my brother slowly die. So I had an idea how this disease progressed,” Hanshaw said. “As I looked at how I’ve progressed, my symptoms have slowed down.”
Hanshaw’s family has been tested, and more than half of his siblings have the gene. His children are luckier.
“My son and my two grandsons are OK,” Hanshaw said. “For my family, it stops with me.”
Mui, the former New York analyst, said he’s hopeful Pfizer’s drug can give him more time. “I have to just keep on fighting and not give up.”
After his symptoms started, a test confirmed Mui had the gene that causes the disease. He jogged and worked with a trainer at the gym, trying to build up muscle and balance in his legs. Three years later, he rarely gets around without a cane.
Mui does yoga and tai chi to help his balance. He gets looks at the gym, after losing 100 pounds in the first year of symptoms, leaving just 115 pounds on his 5-foot-11-inch frame. He started a nonprofit called “Living with Amy” to raise awareness about the disease.
“My friends are trying to figure out how they can help me,” he said. “I have to keep being active to keep things going.”
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