Achieved statistically significant and clinically meaningful additional improvement in peak lung function and faster onset-of-action in COPD patients with RPL554 when added to tiotropium
LONDON, May 21, 2018 (GLOBE NEWSWIRE) -- Verona Pharma plc (AIM:VRP) (Nasdaq:VRNA) (“Verona Pharma” or “the Company”), a clinical-stage biopharmaceutical company focused on developing and commercializing innovative therapies for respiratory diseases, today presented Phase 2a and pharmacokinetic data from two clinical trials evaluating its lead product candidate, RPL554, in chronic obstructive pulmonary disease (COPD) at the American Thoracic Society International Conference (ATS 2018), in San Diego. Results from these trials were previously reported by Verona Pharma on September 7, 2017 and September 27, 2017, respectively.
RPL554 is a first-in-class, inhaled, dual inhibitor of the enzymes phosphodiesterase 3 and 4 designed to have anti-inflammatory as well as bronchodilator properties, and is currently in development for the maintenance treatment of COPD and for the treatment of cystic fibrosis.
The poster, titled, “RPL554, A First-In-Class Dual PDE3/4 Inhibitor, Causes Rapid Additional Bronchodilation When Dosed with Tiotropium in COPD Patients,” provided a review of the positive data from Verona Pharma’s Phase 2a clinical trial, in which RPL554 was dosed in addition to tiotropium (Spiriva®), one of the most commonly used drugs to treat COPD. In summary, the data from this Phase 2a trial demonstrated significantly improved peak lung function when RPL554 was added to tiotropium in patients with moderate-to-severe COPD.
This was a double blind, placebo-controlled, three way cross-over trial in 30 subjects with COPD and included two different doses of RPL554, 1.5 mg and 6 mg, or placebo, dosed twice-daily for three days, in addition to tiotropium, a long-acting anti-muscarinic (LAMA) bronchodilator, dosed once-daily (ClinicalTrials.gov Identifier: NCT03028142). The primary outcome measures for the trial were peak forced expired volume in one second (FEV1) on the third day of dosing and the average FEV1 on the third day of dosing, representing measures of lung function and duration of effect. A number of secondary outcome measures were also recorded. Of note, the 6 mg dose of RPL554 achieved statistical significance, compared to placebo, on all primary and secondary outcome measures. The data confirmed dose dependency between the two RPL554 doses.
- Primary outcome measures1:
-- RPL554, compared to placebo, produced a statistically significant (1.5 mg, p=0.002; 6 mg, p<0.001) and a clinically meaningful (>100 ml) peak FEV1 on the third day of dosing (additional bronchodilation) when administered on top of the standard bronchodilator, tiotropium (Spiriva®)
-- Average FEV1 on the third day of dosing (0 - 12 hours) of RPL554 when added on top of tiotropium was larger than that of tiotropium alone (1.5 mg, p=0.099; 6 mg, p<0.001)
- Secondary outcome measures:
-- Both doses of RPL554 produced a statistically significant faster onset of action2 (1.5 mg, 4.2 min; 6 mg, 4.6 min) when added to tiotropium compared to tiotropium alone (37.6 min; p<0.001)
-- The administration of RPL554 as an add-on treatment to tiotropium caused a marked reduction in Functional Residual Capacity (1.5 mg, p<0.01; 6 mg, p<0.05) and in Residual Volume (1.5 mg, p=0.07; 6 mg, p<0.01), both measures of trapped air in the lung, as compared to tiotropium alone
- Suggesting that RPL554 treatment may reduce dyspnea, a major debilitating symptom of COPD3.
- Both doses of RPL554 were well tolerated as add-on treatments to tiotropium:
-- Adverse reactions were consistent with previous studies with RPL554 and tiotropium. No cardiovascular-related or gastrointestinal related adverse reactions were reported.
1 In the study, a p-value<0.05 is regarded as statistically significant
2 Defined as FEV1 improvement by ≥10%
In addition, Verona Pharma presented data at ATS from its pharmacokinetic trial with RPL554 in a poster titled, “Low Oral Bioavailability of RPL554, a First-in-Class Dual PDE3/4 Inhibitor, Demonstrates that its Nebulized, Inhaled Formulation is Appropriate for Delivering Optimal Pulmonary Dose,” which showed that inhaled RPL554 is an appropriate form of administration for patients with COPD and other respiratory disorders.
This complete block two-way crossover trial evaluated a single dose of RPL554 in 12 healthy volunteers to determine the process of bodily absorption, distribution, metabolism and excretion of this novel therapy, including the swallowed portion of the nebulized dose. The trial was conducted under an Investigational New Drug application accepted by the U.S. Food and Drug Administration in June 2017.
With any inhaled or nebulized medication, a portion of the substance is deposited in the mouth and then swallowed by the patient. These results showed that in the study subjects, only 10.4 percent of the inhaled dose entered the bloodstream via the gastrointestinal tract. The low oral bioavailability of nebulized RPL554, as demonstrated in the study, is consistent with optimal inhaled delivery of medications for the treatment of COPD and asthma. Therefore, the results from this study confirmed that inhaled RPL554 is an appropriate form of administration for patients.
Dave Singh, M.D., Professor of Clinical Pharmacology and Respiratory Medicine, Medicines Evaluation Unit, University of Manchester, presented the RPL554 with tiotropium data at ATS and commented, “These encouraging data warrant further investigation of RPL554 to meet the urgent need for drugs with novel mechanisms of action that can be used in addition to current therapies, in order to provide further treatment of both COPD symptoms and exacerbations.”
“These positive data are further evidence of RPL554’s promising therapeutic potential for the treatment of COPD patients, further supporting Verona’s ongoing clinical development program,” said Jan-Anders Karlsson, PhD, CEO of Verona Pharma. “We look forward to advancing development of this first-in-class treatment this year by initiating in the third quarter a Phase 2a clinical trial to evaluate RPL554 when dosed in addition to LAMA/LABA therapy or triple therapy, compared to placebo. We also plan this year to complete pre-clinical studies for RPL554 delivered as both pressurized metered dose inhaler and dry powder inhaler formulations, followed by clinical trials in healthy subjects or patients with COPD targeted to commence in the first quarter of 2019.”
In March 2018, the Company reported positive top-line results from a Phase 2b trial for the maintenance treatment of COPD. The study met its primary endpoint, with RPL554 producing a clinically and statistically significant improvement in FEV1 at four weeks in patients with moderate-to-severe COPD compared to placebo. Furthermore, the peak FEV1 was significantly improved at all time points over the four weeks of dosing. Secondary endpoints measuring 12 hour average FEV1, progressive improvement in COPD symptoms and Quality of Life were also met and support the potential clinical benefits of RPL554 for the treatment of COPD. RPL554 was well tolerated at all doses with an adverse event profile similar to placebo.
3 Dyspnea (shortness of breath) in COPD patients is often associated with hyperinflation of the lungs resulting from a higher residual volume of air
Chronic obstructive pulmonary disease (COPD) is a progressive and life-threatening respiratory disease for which there is no cure.1 The condition damages the airways and the lungs, leading to persistent breathlessness, impacting a person’s daily life and their ability to perform simple activities such as walking a short flight of stairs or carrying a suitcase.1 Although COPD is thought to be underdiagnosed, globally, around 384 million people suffer from the disease.2 This number, according to the World Health Organization (WHO), is likely to increase in coming years, with estimates that COPD will become the third leading cause of death worldwide by 2030.1,3 Current COPD therapies focus on reducing and controlling symptoms. Yet, despite the wide availability of these treatments, many patients continue to suffer acute periods of worsening symptoms known as exacerbations. These exacerbations often lead to emergency department visits or hospital admissions and are also associated with high mortality.4 In the United States alone, the 2010 total annual medical costs related to COPD were estimated to be $32 billion and are projected to rise to $49 billion in 2020.5
About Verona Pharma plc
Verona Pharma is a clinical-stage biopharmaceutical company focused on developing and commercializing innovative therapies for the treatment of respiratory diseases with significant unmet medical needs. Verona Pharma’s product candidate, RPL554, is a first-in-class, inhaled, dual inhibitor of the enzymes phosphodiesterase 3 and 4 that acts as both a bronchodilator and an anti-inflammatory agent in a single compound. In clinical trials, treatment with RPL554 has been observed to result in statistically significant improvements in lung function as compared to placebo, and has shown clinically meaningful and statistically significant improvements in lung function when administered in addition to frequently used short- and long-acting bronchodilators as compared to such bronchodilators administered as a single agent. Verona Pharma is developing RPL554 for the treatment of chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and potentially asthma.
This press release contains forward-looking statements. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including, but not limited to, statements regarding the value of the results from the Phase 2a and pharmacokinetic clinical trials, RPL554 as a new complementary treatment for patients with COPD, projected annual medical costs related to COPD, the results of the Phase 2a and pharmacokinetic trials supporting later stage development of RPL554, the future clinical development and positioning of RPL554, and the treatment potential for RPL554.
These forward-looking statements are based on management's current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from our expectations expressed or implied by the forward-looking statements, including, but not limited to, the following: our limited operating history; our need for additional funding to complete development and commercialization of RPL554, which may not be available and which may force us to delay, reduce or eliminate our development or commercialization efforts; the reliance of our business on the success of RPL554, our only product candidate under development; economic, political, regulatory and other risks involved with international operations; the lengthy and expensive process of clinical drug development, which has an uncertain outcome; serious adverse, undesirable or unacceptable side effects associated with RPL554, which could adversely affect our ability to develop or commercialize RPL554; potential delays in enrolling patients, which could adversely affect our research and development efforts; we may not be successful in developing RPL554 for multiple indications; our ability to obtain approval for and commercialize RPL554 in multiple major pharmaceutical markets; misconduct or other improper activities by our employees, consultants, principal investigators, and third-party service providers; material differences between our “top-line” data and final data; our reliance on third parties, including clinical investigators, manufacturers and suppliers, and the risks related to these parties’ ability to successfully develop and commercialize RPL554; and lawsuits related to patents covering RPL554 and the potential for our patents to be found invalid or unenforceable. These and other important factors under the caption “Risk Factors” in our Annual Report on Form 20-F filed with the Securities and Exchange Commission (“SEC”) on February 27, 2018 relating to our Registration Statement on Form F-1, and our other reports filed with the SEC, could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management's estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this press release.
1 World Health Organization. Chronic Obstructive Pulmonary Disease. http://www.who.int/mediacentre/factsheets/fs315/en/. Accessed September 2017.
2 Adeloye D, Chua S, et al. Global and regional estimates of COPD prevalence: Systematic review and meta–analysis. J Glob Health 2015; 5(2): 020415.
3 World Health Organization. Burden of COPD. http://www.who.int/respiratory/copd/burden/en/. Accessed September 2017.
4 COPD Foundations. Characteristics of COPD Patients Using United States Emergency Care or Hospitalization. https://journal.copdfoundation.org/jcopdf/id/1103/Characteristics-of-COPD-Patients-Using-United-States-Emergency-Care-or-Hospitalization. Accessed September 2017.
5 Centers for Disease Control. Increase Expected in Medical Costs for COPD. https://www.cdc.gov/features/ds-copd-costs/. Accessed September 2017.
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