Aspen Webinar 2021 Part 7 -Cystic Fibrosis Liver Disease

More from Aspen Webinar 2021. This blog entry has abbreviated/summarized several presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well. Great lecture from Jim Squires.

Key points:

  • Cystic Fibrosis Liver Disease (CFLD) is variably defined
  • Risk factors include male patients, DeltaF508 mutations, meconium ileus and SERPINA1 Z allele
  • Two main phenotypes: Classic “Focal Biliary Cirrhosis” and Obliterative Portal Venopathy (increasingly recognized)
  • Intestinal microbiome and gut permeability/endotoxins may influence liver disease
  • Treatments: ursodeoxycholic acid may be helpful but overall evidence is low quality. Cochrane review does NOT recommend its routine use
  • Treatments: liver transplant (thorough review: Freeman et al. Liver Transpl 2019; 25: 640-657)
  • Treatments: CF Modulators: potentiators (Ivacaftor), correctors (Lumacaftor, Elexacaftor, Tezacaftor)
  • Treatment: Trikafta has been a game changer for CF lung disease. Its effects on the liver are not clear yet

Some of the slides:

Related blog posts:

SAVE THE DATE for next year’s conference: July 11-15, 2022 in Snowmass Village, CO

In the News: Big Therapeutic Advance for Cystic Fibrosis

Washington Post: Long-Awaited Drug Could Turn Deadly Disease into Manageable Condition

An excerpt:

A new cystic fibrosis therapy dramatically improved patients’ lung function and showed clear signs of targeting the genetic root of the disease, instead of just alleviating symptoms — a breakthrough so long-sought that many doctors and patients are moved to tears when talking about it.

The data, being unveiled Thursday at a national conference in Tennessee and simultaneously published in two leading medical journals, was so persuasive that the Food and Drug Administration last week approved the three-drug combination, called Trikafta — five months ahead of the agency’s deadline. The drug could benefit 90 percent of patients with the disease, a major advance over previous drugs that worked in a tiny fraction of the people with the disease or had more modest effects

Sarah Carollo, 28, a special needs teacher in Lee’s Summit, Mo., started Trikafta through a clinical trial in late 2018. Carollo… couldn’t walk down a hallway without stopping to rest and catch her breath…

A few days after she began taking the pill, her doctors tested her lung function and were so stunned at the improvement that they had to check whether they were really looking at the results from the right patient. Two weeks ago, Carollo ran a 5K race with another patient, Laurana Blackburn, who was also taking the drug through the clinical trial…

There are more than 1,700 gene mutations that can cause the protein to malfunction, but in the most common mutation, the protein is misfolded and can’t reach the right spot in the cell — and even if it does reach that spot, it doesn’t work properly. The new combination therapy includes one drug that corrects the misfolded protein and two that activate the correctly folded protein when it reaches the right spot in the cell.

In the largest trial, reported in the New England Journal of Medicine, 403 patients who had at least one copy of the most common gene mutation underlying cystic fibrosis received either Trikafta or a placebo. There were improvements in objective tests of lung function, decreases in lung problems and hospitalizations and an increase in people’s quality of life…

It also remains to be seen whether patients have an easy time gaining access to the drug, which will cost $311,000 a year. While that is a tremendous amount, orphan drugs for small patient populations typically carry very large price tags, and physicians are optimistic that insurers will cover the drug.

The NY Times reported on the FDA approval (October 2019), Studies Yield ‘Impressive’ Results in Fight Against Cystic Fibrosis, and noted that the “Institute for Clinical and Economic Review, which evaluates the cost-effectiveness of drugs, found that the cystic fibrosis drugs the company sells should cost as much as 77 percent less. ”