Respiratory diseases: Interim results from new RPL554 trial demonstrates excellent drug tolerability even at highest dose

Verona Pharma plc, the drug development company focused on first-in-class medicines to treat respiratory diseases, has announced encouraging interim results from the first part of a 120 subject Phase I/II clinical trial with RPL554, using a new proprietary nebulised formulation. RPL554 is a novel PDE3/4 inhibitor, which is currently in development as a nebulised treatment for acute exacerbations in COPD patients in a hospital or home-care setting.

The trial is being performed at the Medicines Evaluation Unit in Manchester by lead investigator Professor Dave Singh.

In the first part of this study, which was successfully completed ahead of schedule, 50 healthy volunteers were enrolled in a single ascending dose study with the new drug formulation. Five dose levels were tested with the pre-specified highest dose being approximately 16 times greater than the dose tested in earlier reported clinical studies, using the previous formulation of RPL554.

The results from this study showed that the drug was well tolerated across all doses and no maximum tolerated dose could be defined. Importantly, there were no changes in subjects' cardiovascular parameters and there was complete absence of nausea or vomiting at all doses.

Pharmacokinetic data showed lower peak plasma levels of the drug and a plasma half-life of 11-12hr, significantly longer than that of historically published data of similar doses, using the previous formulation. This suggests that the new formulation results in a longer residence time for RPL554 in the lung and slower release into the blood stream. Pulmonary residence time is an important factor in determining duration of effect.¹ These results support the potential for RPL554 to be a drug administered twice-a-day and this will be further verified in the second part of the trial, which is now being initiated.

In the next part of the study, multiple ascending doses given for five consecutive days will be investigated in both healthy volunteers and patients with chronic obstructive pulmonary disease (COPD). The primary objective of this study is to further confirm safety and tolerability, as well as to investigate bronchodilation in COPD patients. In studies with the previous formulation, RPL554 generated significant bronchodilation that appeared to be at least similar in effect size to that seen with salbutamol,² a commonly used drug in the treatment of COPD. Results from this new study are expected to be available in the second half of 2015.

Dr Ken Newman, Chief Medical Officer of Verona Pharma, commented:
"These initial results are very encouraging and confirm that the new formulation of RPL554 has excellent tolerability and has a significantly improved profile in comparison to the previous formulation. This has allowed doses of RPL554 to be assessed that are many multiples higher than doses tested in the clinic to date that have already demonstrated a robust bronchodilator effect. It is important to note that even at the highest dose now evaluated we have seen no impact on subjects' cardiovascular parameters. No vomiting or evidence of nausea has been reported. Additionally, the initial pharmacokinetic data suggests a profile that we tentatively believe could make RPL554 amenable to twice-a-day dosing. We look forward to reporting data from the second part of this trial in the second half of 2015, which we expect will confirm the potent bronchodilator potential of this drug in COPD patients."

Dr Jan-Anders Karlsson, Chief Executive Officer of Verona Pharma, said:
"We are very excited by this first set of clinical data generated with our new proprietary formulation for nebulised RPL554, which is consistent with the expected profile based on preclinical studies. We have already demonstrated in earlier trials that RPL554 has the unique ability to combine potent bronchodilation with broad anti-inflammatory activity in a single molecule. The studies we are now commencing, thanks to the excellent tolerability of our new formulation, will allow us to assess markedly higher doses of the drug than those used in our studies in COPD patients to date and seeks to maximise the clinical impact of the drug. We look forward to reporting data from this important clinical study later in the course of 2015.

"We are initially developing nebulised RPL554 as a treatment for acute exacerbations in COPD, where we believe it has significant market potential. We continue to believe that the emerging profile of RPL554 suggests that it could potentially become an important addition to available treatment options both as a monotherapy and, as a result of its unique mechanism of action, as a combination partner for existing drugs for COPD."

Phase I and Phase II proof of concept studies with RPL554 in its previous nebulised formulation were successfully conducted in over 100 subjects. Results collectively showed that the drug is a very potent bronchodilator with the ability to elicit a unique anti-inflammatory response. At the doses previously tested, RPL554 had a benign side effect profile, which compared favourably with existing standard treatments. The original nebulised formulation of the drug used in these initial studies was devised to provide proof-of-concept data, before developing the new formulation suitable for commercial scale-up.

It is expected that the new formulation of RPL554 will result in a significantly improved therapeutic index in patients, implying that they should be able to inhale higher doses with prolonged effect, offering potential for improvements in convenience and compliance, as well as health economic benefit. In addition, the commercial viability of the new formulation is underlined by significantly improved stability compared to the previous formulation.