Positive data from preclinical and Phase 2a studies evaluating the investigational cystic fibrosis (CF) treatment RPL554 were presented at the 2018 North American Cystic Fibrosis Conference (NACFC) in Denver, Colorado (Oct. 18-20).
RPL554, developed by Verona Pharma, is an inhaled potential therapy for CF and chronic obstructive pulmonary disease (COPD). It is the first drug of its kind designed to inhibit both phosphodiesterase 3 and 4, which results in strong bronchodilatory and anti-inflammatory actions.
In CF, mutations in the CF transmembrane conductance regulator (CFTR) gene results in a defective CFTR ion channel causing the accumulation of mucus. Previous studies have shown that RPL554 can stimulate CFTR function and reduce airway obstruction by clearing the mucus.
Multiple CF-causing mutations in the CFTR gene have been identified, and they are classified into six categories depending on the defect they cause in CFTR protein production and function. Of note, class III and IV mutants are unable to transport ions across the cell membrane.
Preclinical data presented at NACFC 2018 show that RPL554 was effective in stimulating, by itself or in combination with other treatments, several CFTR mutants, including those of class III and class IV.
Researchers showed that RPL554 alone enhanced the CFTR activity in cells expressing T338I and R334W CFTR mutants — enhanced CFTR activity in cells with such mutations indicated improved ion exchange ability.
Also, pretreatment of cells expressing S549R and G551D CFTR mutants with Orkambi (lumacaftor/ivacaftor) for 24 hours followed by RPL554 treatment had an additive effect on the enhancement of CFTR activity.
“The potential for RPL554 to stimulate numerous rare class III and IV CFTR mutations is an important advancement for CF patients as it highlights RPL554 as a novel therapeutic. Current FDA-approved therapies are limited in their ability to address this need for patients,” Mark Turner, PhD, said in a press release. Turner is a postdoctoral research fellow at Cystic Fibrosis Translational Research Centre, McGill University in Canada, and presenter of the preclinical data at the NACFC.
Furthermore, results of Phase 2a clinical trial (NCT02919995) conducted at the Papworth Hospital in the United Kingdom, evaluating the effectiveness of RPL554 in CF patients, also were presented at the meeting. In this trial, 10 CF patients received a single dose of nebulized RPL554. The study assessed the pharmacokinetics — the way a drug reacts within the body — of RPL554 and its ability to improve lung function.
The pharmacokinetic profile of RPL554 was found to be consistent with previously reported data in COPD patients. Also, treatment with 1.5 mg or 6 mg of RPL554 at four-, six-, and eight-hour time points significantly improved lung function, as indicated by a marked increase in forced expiratory volume in one second (FEV1).
“We are encouraged by the positive data being accrued from pre-clinical and clinical studies with RPL554 in both CF and COPD,” said Jan-Anders Karlsson, PhD, CEO of Verona Pharma.
“RPL554 has been well-tolerated and demonstrated bronchodilator and anti-inflammatory activity in our extensive COPD clinical trial program, and we are encouraged that this dual effect also shows promise in CF. There remains a high unmet need among CF patients to address inflammation which is known to cause disease progression and can lead to worsening of symptoms as well as pulmonary exacerbations,” Karlsson concluded.