Vertex Pharmaceuticals In The News Today -- March 4, 2024

Locator: 46673CF.

Cystic fibrosis:

Cystic fibrosis is a genetic condition that affects a protein in the body. 

People who have cystic fibrosis have a faulty protein that affects the body’s cells, its tissues, and the glands that make mucus and sweat. The protein: cystic fibrosis transmembrane conductance regulator (CFTR).

Normal mucus is slippery and protects the airways, digestive tract, and other organs and tissues. Cystic fibrosis causes mucus to become thick and sticky. As mucus builds up, it can cause blockages, damage, or infections in affected organs. 

Cystic fibrosis used to cause death in childhood. Survival has improved because of medical discoveries and advances in newborn screening, medicines, nutrition, and lung transplants. Nearly 40,000 children and adults in the United States and more than 100,000 worldwide are now living with cystic fibrosis. Children born between 2018 and 2022 who have cystic fibrosis are expected to live an average of 56 years. 

On average, half of babies born in 2021 with cystic fibrosis are expected to reach the age of 65 or older.

Medical therapy: modulators. Now being prescribed with "triple" combos:

A class of drugs called CFTR modulators target specific defects in the CFTR protein so that the protein can work properly. CFTR modulators do not fully restore chloride flow, but they do improve the flow enough to help lessen CF symptoms. There are currently 3 types of CFTR modulators:

• potentiators (ivacaftor) 
• correctors (lumacaftor, tezacaftor, and elexacaftor) 
• amplifiers

The three different types of CFTR modulators work on distinct parts of the CFTR protein to help it work better. 

The CFTR protein is shaped like a tunnel with gates that open and close, offering access out of the cell. 

Potentiators 

Potentiators help chloride move through the CFTR protein, providing a channel to the cell surface. Potentiators hold the gate open. Potentiators work on gating, conduction, residual function, and splice mutations. Ivacaftor (brand name Kalydeco) has been approved for use in the U.S.

Correctors

Correctors help the CFTR protein form the right shape so that it is able to move to the cell surface and stay there longer. Two correctors, lumacaftor (brand name Orkambi) and tezacaftor (Symdeko), have been approved for use in the U.S. These correctors are used in combination with the potentiator ivacaftor to increase their effectiveness. 

Both lumacaftor and tezacaftor are first-generation modulators. 

This means they were the first modulators used to treat CF.

Elexacaftor is a “next-generation” modulator. This means it may be more effective than previous modulators.  

Elexacafor is combined with tezacaftor and the potentiator ivacaftor to form the brand name Trikafta. This triple combination drug allows more people with CF a variety of treatment options.

So, the "triple combo" has a potentiator and two correctors, but no amplifier.

Amplifiers

One amplifier, PTI-428, is currently being tested so this drug is not yet available. Amplifiers increase the amount of CFTR protein that a cell makes, which should help those people with CF who do not produce enough CFTR protein. The theory is that if the cells make more CFTR protein, the potentiators and correctors could allow more chloride to flow through the cell membrane. Research continues on many other next-generation CFTR modulators.

So, as I understand it, Trikafta is the "gold standard," against which new modalities are compared.

Now, a new "triple combo" in phase III trials. Link here.

Phase III trials have found CFTR modulator vanzacaftor/tezacaftor/deutivacaftor (vanza triple) to be non-inferior to TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor and ivacaftor) in improving cystic fibrosis lung function.

Vertex Pharmaceuticals: Trikafta

Vertex Pharmaceuticals: vanza triple

Vanza Triple has now been approved for Phase III trials.

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