ST. LOUIS — A rare genetic liver disease that afflicts 100,000 Americans has evaded treatment by scientists and doctors for decades.
Now, after 29 years of research, a St. Louis University scientist and his team are on the cusp of a solution.
A breakthrough drug developed by the team of researchers and pharmaceutical companies is entering the final trial before potential approval by the U.S. Food and Drug Administration. It could be one of the first treatments for people with liver disease caused by the condition. Now, the only option is a liver transplant.
“When we started on it we didn’t even know how the disease worked,” said researcher Jeffrey Teckman, a professor of pediatrics and biochemistry at St. Louis University. “And we’ve come all the way to being able to heal peoples’ livers, which is remarkable.”
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The disease starts with something of a genetic malfunction.
When the human body fights lung infections, it dispatches troops of white blood cells that wield powerful chemicals to kill invaders. They’re so powerful that they can damage lung tissue if the tissue isn’t protected by a specific protein: alpha-1 antitrypsin. This protein, a type of building block molecule produced in the liver, deactivates the chemicals before they can harm the lungs.
That makes alpha-1 antitrypsin, “a shield for your own tissues,” Teckman said.
But some people are born with a genetic mutation that turns the shield into a weapon.
The mutation leads the body to produce deformed copies of alpha-1 that the liver can’t send to the lungs. Instead, the protein simply builds up in the liver and scars it, a condition called fibrosis. In severe cases, the scarring can lead to permanent damage. Meanwhile, the lungs are left without their shield.
But, in 2011, Teckman found a tool that seemed to cure the disease in his lab.
Teckman was using a type of genetic code called silencing RNA, which the body naturally uses to shut down protein building when proteins aren’t needed.
He’s been working with scientists and pharmaceutical companies ever since to advance the treatment.
Scientists have since honed in on a specific strand of RNA that stops the production of alpha-1 antitrypsin, leaving the liver free to heal by ridding itself of the buildup of damaging proteins.
The breakthrough drug is called fazirsiran.
In June, the scientists and companies published a study of a trial of the drug with 16 patients. Teckman was the senior author.
And the work showed promising results:
The injection of fazirsiran reduced the amount of deformed protein in the liver of all the patients, the study showed. The median reduction in concentration of the protein was 83.3%.
Seven of the 15 patients who started the trial with fibrosis had the condition recede.
“It takes a long time to go from curing something in the lab to curing in a person,” Teckman said. “And that’s what we’ve done.”
Souvik Sarkar, a national medical adviser for the American Liver Foundation who was not involved in the trial, praised the study as well planned with solid conclusions.
“This is definitely a landmark paper for advancing the field both in the disease treatment for alpha-1 antitrypsin and for liver disease in general,” Sarkar said.
A key component of the trial was that the drug allowed patients’ livers to heal, he said, in addition to reducing the build up of the deformed protein.
The larger group of patients and years of treatment in a phase three trial will be important for ensuring the injection is safe, he said.
Fazirsiran is being developed by Arrowhead Pharmaceuticals and Takeda Pharmaceutical Company. Takeda is currently organizing a phase three trial, the last of a series of trials required by the FDA before the companies can submit an application for market approval.
Arrowhead and Takeda will split U.S. profits in half if the drug is approved, the companies said.
Fazirsiran received a breakthrough therapy designation from the FDA in 2021, which is granted to accelerate the development and review of treatments for life-threatening conditions. It’s speeding up the organizing process for the phase three trial and may make the drug eligible for accelerated approval, said Javier San Martin, Arrowhead’s Chief Medical Officer.
The scientists will use the phase three trial to fine tune what dosage of the drug to use and the length of time people need to be treated, in addition to gathering safety data, Teckman said.
He hopes the trial will begin before the end of year.
“I’m very anxious to make it so that no one with this disease ever needs a liver transplant ever again,” he said. “And I think we’re gonna get there. But we’re not there yet. We got a little more work to do.”