New Mutation-Specific Targeted Therapy for Cystic Fibrosis

New Mutation-Specific Targeted Therapy for Cystic Fibrosis

By Soo Jung Kim

Cystic fibrosis (CF) is a life-threatening, genetic disease caused by genetic mutations that induce protein misfolding. Cystic Fibrosis affects about 30,000 people in the US and over 75,000 people worldwide. It is the most common fatal genetic disorder in the Caucasian population, occurring in approximately 1 in 3,500 in the US and 1 in 2,500 in the EU. The median predicted age of survival for CF patients is 41 years.

What Causes Cystic Fibrosis?

Cystic fibrosis is caused by inherited mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, resulting in dysfunction of the CFTR protein. CFTR is an ion channel residing in the apical membrane of secretory epithelial cells, and is important for fluid- and electrolyte-homeostasis in the lungs and pancreas.

Defective or lack of functional CFTR impairs Cl and bicarbonate secretion, and at the same time enhances Na+ absorption, resulting in dehydration and accumulation of viscous mucus in the air ways and digestive tract. As a consequence, a recurrent cycle of infection and inflammation occurs, which ultimately leads to fatal lung damage.

Is Cystic Fibrosis Treatable?

The majority of cystic fibrosis therapies have been focused on treating symptoms, such as clearing mucus from the lungs, treating infections, pancreatic enzyme replacement therapy (PERT), and prescribing the mucolytic agent, dornase alfa (Pulmozyme; Genentech/Roche).

These treatments aim to lessen cystic fibrosis symptoms, and do not act on the fundamental cause of this disease. However, several companies took a different approach and focused on improving defective CFTR function as a novel way of treating cystic fibrosis.

Cystic Fibrosis Modulators: A New Class of CF Mutation-Specific Drugs

To date, more than 2,000 CFTR mutations have been identified. CF mutations are classified into 6 different classes according to their biological defect.

Class I – mutations that introduce a premature stop codon, resulting in almost no CFTR expression

Class II – mutations that lead to CFTR misfolding and degradation before it reaches the cell surface

Class III – mutations that impair CFTR gating by reducing open probability

Class IV – mutations that affect CFTR channel conductance

Class V – mutations that do not disrupt CFTR folding, but decrease its expression level

Class VI – mutations that destabilize CFTR in post-ER compartment and/or at the cell surface

Ivacaftor (VX-770, Kalydeco), developed by Vertex Pharmaceuticals as part of a collaboration with the Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT) directly targets the gating defect of the class III mutation, G551D-CFTR. This compound was approved by the US Food and Drug Administration (FDA) in 2012 as the first medicine to treat the underlying cause of CF. The FDA approval of Ivacaftor was further extended to another 8 class III mutations (G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, and G1349D) and 1 class IV mutation (R117H).

The most prevalent CFTR mutation is Phe508del, a class II mutation, which is found in ~90% of CF patients. Lumacaftor (VX-809) partially restored Phe508del-CFTR expression, resulting in up to 15% of wild-type channel activity in vitro, but failed to show significant benefit in the clinical trial.

However, the combination of Lumacaftor, which is designed to increase CFTR level on the cell surface and Ivacaftor, which is designed to enhance channel function once CFTR reaches the cell surface, showed significant clinical benefit. This combination drug (Orkambi; Vertex Pharmaceutical/CFFT) was approved by the FDA in 2015 to treat cystic fibrosis patients with two copies of the Phe508del mutation.

For class I mutations, Ataluren (PTC124) was developed by PTC Therapeutics as a drug that induces ribosomal read-through at the premature stop codon. Ataluren partially restored class I mutation, G542X-CFTR expression in vivo, but failed to reveal significant benefit in a recent phase 3 clinical trial.

CF Drug Market

Based on a 2014 report (IMS Health, IMS Midas), the cystic fibrosis drug market is ~$1.6 billion worth. Among this, anti-infectives including tobramycin (Tobi; Novartis) showed the biggest sales in the US, accounting $626 million, followed by mucolytics such as Dornase Alfa with sales of $530 million. PERT including Pancrelipase (Creon; AbbVie) generated $288 million and the CF modulator, Ivacaftor accomplished $168 million.

The cystic fibrosis drug market is predicted to increase to $3.9 billion by 2019 due to potential new drug development and the increasing number of CF diagnosis in non-Caucasian populations as well as Caucasian populations.

Although earlier diagnosis and better treatment have significantly improved the prognosis over the years, there is still a serious demand for more efficient treatments that will substantially increase the life expectancy of CF patients. Emerging cystic fibrosis therapies that directly target biological defects caused by mutations will undoubtedly contribute to more efficacious CF treatment.

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