QBW251 is an experimental therapy developed by Novartis for cystic fibrosis (CF). Clinical studies of QBW251 are currently underway, but early results have demonstrated that the drug is safe and well tolerated in CF patients.
The drug is known as a potentiator, which facilitates the opening of the cystic fibrosis transmembrane conductance regulator (CFTR) channel.
History of QBW251
Preclinical results showed that when QBW251 is combined with lumacaftor, its effectiveness is superior to ivacaftor (Kalydeco) in sustaining F508del mutation membrane expression and function. Kalydeco was FDA approved in 2012 for CF patients with other mutations but was shown as ineffective alone for patients with the F508del mutation.
QBW251’s promising preclinical results led to a Phase 2 study (NCT02190604), which began in 2012 and ended in 2015. The study aimed to evaluate the safety, tolerability, pharmacokinetics (how drugs move in the body), and preliminary pharmacodynamics (effect and mechanism) of QBW251.
The study enrolled 118 participants from the U.S., Belgium, Germany, Ireland, Romania and the U.K. The first clinical study for QBW251, a proof of concept study, consisted of four parts. Parts 1 and 2 involved healthy volunteers and Parts 3 and 4 included only CF patients. Some of the outcomes have been released.
The study found:
- QBW251 was safe and well tolerated in CF patients who received the therapy twice a day (doses of 150mg and 450 mg);
- CF patients who received QBW251 (dose of 450 mg) showed increased lung function (similar to ivacaftor);
- QBW251 provided as a monotherapy (without being combined with Kalydeco) showed no effect in CF patients with two copies of the F508del mutation (affects the amount of CFTR proteins that reach the cell surface).
In Europe, the study (2011-005085-37) is still ongoing.
The trial program for QBW251 also includes other indications for the drug, such as a Phase 2 (NCT02449018) study currently enrolling patients with chronic obstructive pulmonary disease (COPD). The study aims to evaluate the effectiveness, safety, and tolerability of multiple doses of QBW251 compared to a placebo. Changes in the airway function, lung volume, and quality of life of COPD patients will be evaluated. Final data is expected in 2017.
How QBW251 works
QBW251 belongs to a class of drugs referred to as potentiators. It is particularly targeted for CF patients carrying class 3 or class 4 mutations. In these types of mutations, a full CFTR protein is produced but the chloride ion transport is reduced, either because the channel doesn’t open properly (class 3) or its conductance is altered (class 4) [2, 3]. The passage of the chloride ion plays an important role in the movement of water in tissues. The overall result is the production of a thin mucus that protects and lubricates internal epithelial surfaces. The mucus prevents disease by trapping potential invaders into organs such as the lungs and pancreas, or tissues. If the passage of the chloride ion is compromised, thick mucus is created.
Normal CFTR proteins act like a channel on the surface of the cells. They open and close to let chloride ions move in and out of the cell—a process called “gating.” This helps maintain a healthy balance of salt and water in the tissues.
Like ivacaftor, the main mechanism of action of QBW251 is to open the CFTR channel, facilitating the transport of chloride. As a result, CFTR activity is improved and thin mucus is produced.
Next steps for QBW251
The Phase 2 study (NCT02449018) is currently recruiting COPD patients.
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 Shamsah K, Jose A, Laurie D, et al. QBW251 is a safe and efficacious CFTR potentiator for patients with cystic fibrosis. Am J Respir Crit Care Med. 2016;193:A7789.
 Schmidt BZ, Haaf JB, Leal T, Noel S. Cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis: current perspectives. Clin Pharmacol. 2016;8:127-140.
 Lopes-Pacheco M. CFTR Modulators: Shedding light on precision medicine for cystic fibrosis. Front Pharmacol. 2016;7:275.