A Crucial Need for Symptomatic Treatments Still Exists for Cystic Fibrosis Patients

December 5, 2016
By Pavan Kottamasu, BioSpace.com contributor

A point of emphasis at the recent North American Cystic Fibrosis Conference (NACFC) in Orlando, Florida was leaving no cystic fibrosis (CF) patient behind.

While cystic fibrosis transmembrane conductance regulator (CFTR) modulators continue to advance the CF drug market in transformative and personalized ways, a number of CF patients are still left without a curative option, as the modulators only work in patients with specific mutations.

There are over 2,000 genetic variants associated with CF, rendering theratyping and personalized medicine complex and challenging. Therefore, a vital need still exists to develop additional symptomatic respiratory treatments that help CF patients irrespective of genotype, both now and in the future.

CF is an inherited, autosomal recessive disorder that causes persistent lung infections and impairs breathing ability over time, and affects more than 70,000 people worldwide. Characterized by a loss of function in the CFTR protein, CF causes abnormally thick, sticky mucus production that can lead to airway obstruction and lung infections and can eventually lead to pancreatic insufficiencies due to mucous blockage of the pancreatic duct.

Currently, there are six different classes of CF that categorize more than 2,000 different CFTR mutations. The F508del mutation is the most prevalent CF mutation, a Class II mutation that accounts for approximately two thirds of CF cases worldwide.

CFTR modulators are drugs designed to correct the function of defective CFTR protein translated from a mutated CF gene. Different CF mutations cause different defects in the resulting protein, thus, drugs that have been developed and marketed so far are effective only in populations with specific mutations.

Vertex Pharmaceuticals ’ Kalydeco (ivacaftor) was the first CFTR modulator approved in the US and EU in 2012. Initially approved for CF patients with the G551D mutation, Kalydeco has since received label expansion for patients with either the R117H mutation or one of many gating mutations, including G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, and S549R. According to the Cystic Fibrosis Foundation (CFF) Patient Registry, Kalydeco is approved to treat approximately 8.3 percent of the total CF population in the US.

In 2015, Vertex Pharmaceuticals’ Orkambi (ivacaftor/lumacaftor) became the second CFTR modulator approved in the US and EU. Its target population is CF patients aged six years and older with two copies of the F508del mutation, accounting for 46.5 percent of the total CF population in the US.

In addition to Kalydeco and Orkambi, Vertex has another drug in its late-stage pipeline, a combination drug of ivacaftor and tezacaftor, which is expected to target CF patients with one copy of the F508del mutation and another CFTR mutation, a population comprising 36.2 percent of the total US CF population.

Therefore, 5 percent of US CF patients are left without a CFTR modulating therapy.

Dr. Eric Sorscher, Director of the Gregory Fleming James Cystic Fibrosis Research Center at the University of Alabama at Birmingham, made a presentation in October at the NACFC that emphasized that even though a large portion of the CF population can be treated by CF modulating therapies, significant gaps still remain for patients who are homozygous and heterozygous for the F508del mutation.

According to Dr. Sorscher, the clinical effectiveness of current pipeline candidates and marketed drugs towards homozygous and heterozygous F508del mutations is relatively much lower than that of ivacaftor’s efficacy in treating CF patients who harbor the G551D mutation. Despite the variability of CF modulating therapies targeting the F508del CF population, patients still require additional drugs to treat inflammation, infection, and airway obstruction related to CF.

International consortia continue to place personalized therapeutics as a mission priority, as such therapies have the potential to significantly restore the CFTR protein and cure CF. However, according to the CFF Patient Registry Team, in five years’ time, symptomatic therapies will still be needed for approximately 70 percent of the CF population, and in 10 years, 51 percent of the CF population.

“As more CF genotypes are treated with better modulators at younger ages, the health of the CF population will shift dramatically. A smaller proportion of individuals will have need for downstream therapies. However, there will still be a need for those therapies,” Sorscher said.

Symptomatic therapies that treat chronic infections, inflammation, and mucociliary obstruction are as equally important to some patients as modulator therapies. Even though ivacaftor markedly reduces counts of sputum Pseudomonas aeruginosa, the most common bacterial infection presented by CF patients, infections remain and the bacterial burden may increase after a year.

This emphasizes the need for a robust pipeline to address infection and inflammation in a post modulator era. Pharmaceutical companies are advised to continue seeking better means for both symptomatic and curative CF treatments.

Pavan Kottamasu, MSc, MBA is a Healthcare and Pharmaceutical Analyst at GlobalData in Boston. He gained experience in all stages of drug and therapy development within academia, the pharmaceutical industry, and the NHS. Prior to joining GlobalData, he was a lead investigator at the Brigham and Women's Hospital, working in the Laboratory for Tissue Engineering and Regenerative Medicine within the neurology, cardiovascular, renal, pulmonary, and immunology disease therapy areas. Pavan received an MSc in the Biomedical Sciences from the Tufts University School of Medicine and an MBA in Healthcare Administration and Management from Brandeis University, after completing a BA in the Biological Sciences at Cornell University.