Chronic obstructive pulmonary disease (COPD) has an enormous global impact, thought to affect up to 10 percent of adults in countries where its epidemiology has been studied, according to Cortellis Disease Briefings. Although the underlying mechanisms aren't completely understood, COPD generally is triggered by damage to the airway epithelium by smoke or other noxious elements, causing a cascade of detrimental inflammatory and immunological processes that culminate in progressive remodeling of the small airways, destruction of lung parenchyma and consequent loss of elastic recoil. In short, individuals with the disease face slow, progressive decline in lung function characterized by increased mucus production, cough and dyspnea.
Despite the high prevalence, treatments for COPD – mainly beta2-adrenoceptor agonists, muscarinic receptor antagonists and corticosteroids – have not changed markedly over the years, save the introduction of combination products. But some biopharmas are seeking to change the standard of care, both in timing of treatment – targeting of early disease (GOLD stage II) to prevent exacerbations and progression – and advancement of agents with new mechanisms of action.
"In COPD, you have many patients – 380 million or more worldwide – who are normally treated either with bronchodilators, which are short- or long-acting but basically the same, or anti-inflammatories, which are the steroids," said Jan-Anders Karlsson, CEO and executive director of Verona Pharma plc. Although widely prescribed, questions have arisen in recent years about their usefulness in treating the disease, he said, since hundreds of thousands of patients are hospitalized annually for exacerbations of the disease.
Apart from Astrazeneca plc's PD4 inhibitor, Daliresp (roflumilast), which gained FDA approved in 2011 only to treat the most severely affected COPD patients, innovation in drug development hasn't kept pace with the medical need, he said.
"Over the last 50 years, we've had the same three mechanisms," Karlsson told BioWorld Insight. "The innovation has been from many times a day to once a day and from many inhalers to one inhaler. That's all fantastic for convenience and compliance, but I don't think that is the right way to treat patients who need a different type of medication for their symptoms and their underlying inflammatory disease."
The proof, he said, is that even with the arrival of newer COPD treatments, sometimes in combination with older compounds, "there doesn't seem to be a change in the lives of these patients. In the end, patients really need a new mode of action."
Market size 'a lot to chew on'
Verona's VMX-554, a dual phosphodiesterase (PDE) 3/4 inhibitor, grabbed the spotlight in 2016 when a phase IIa study in individuals with moderate to severe COPD showed 60 percent additional bronchodilation on top of standard-of-care bronchodilators. While only a 30-patient study, RPL-554 generated highly significant (p ≤ 001) and clinically meaningful bronchodilation in patients treated initially with the beta2-agonist salbutamol or the antimuscarinic ipratropium bromide. (See BioWorld Today, May 11, 2016.)
Verona, based in London, is developing '554, which has both bronchodilator and anti-inflammatory properties, initially as a nebulized treatment for exacerbations of COPD. A fully enrolled randomized, double-blind, placebo-controlled, dose-ranging phase IIb study in 400 individuals with moderate to severe COPD is expected to report top-line data early in the second quarter. The study is investigating the effect of four weeks of twice-daily treatment across four doses of the study drug in patients who discontinued background treatment, with change from baseline in peak forced expiratory volume in 1 second (FEV1) as the primary outcome measure.
"The expectation is that we will see a dose-dependent effect and, of course, also a clinically meaningful effect during this treatment," Karlsson said. "This is a new mode of action, and we really wanted to understand well how the compound behaves in these patients."
Verona also is advancing VMX-554 in cystic fibrosis (CF), reporting earlier this month that a single dose improved lung function in CF patients. (See BioWorld, March 5, 2018.)
The size of the COPD market is "a lot to chew on" for a small company, Karlsson conceded. But starting with a nebulized formulation in the U.S. would allow a company like Verona to tap into an existing infrastructure to treat very severe patients, where he said the greatest unmet need exists. That population represents only a small fraction of the COPD market. To move upstream and treat the dramatically larger group of patients in earlier stages of the disease, the company also has pressurized metered dose and dry powder inhaler formulations of its drug in preclinical development.
"After we've done clinical trials and if it works the same as the nebulizer, we would need to license that to a larger pharma or another big player for phase III studies and commercialization," Karlsson said.
New LAMA developed to be 'lung selective'
Before either of those scenarios plays out, a COPD drug from a company with a legacy in respiratory disease is likely to enter the market. The new drug application for revefenacin (TD-4208), a once-daily, nebulized long-acting muscarinic antagonist (LAMA) discovered and developed by Theravance Biopharma Inc., is under review by the FDA, with a Nov. 13 PDUFA date.
Theravance Biopharma is the spin-off from Theravance Inc. (now Innoviva Inc.), long partnered in the respiratory field with London-based Glaxosmithkline plc (GSK). Although revefenacin falls into the same class as Spiriva (tiotropium bromide), the blockbuster COPD drug from Boehringer Ingelheim GmbH, important distinctions offer the opportunity for a differentiated and improved profile, according to Rick Winningham, Theravance CEO.
Revefenacin was developed to be "lung selective: to go into the lung, to bronchodilate and, once it got into the circulation of patients, to fall apart," Winningham explained. In that respect, revefenacin offers a major advantage over Spiriva, which is absorbed into the bloodstream through the lungs and, to a smaller extent, the stomach, since it "sticks to muscarinic receptors wherever they are in the body, and they're everywhere," he said.
Consequently, COPD patients who use Spiriva and other agents in the class are subject to side effects such as urinary retention, dry mouth and ocular issues. From the get-go, revefenacin was developed to stand apart from the crowd.
Theravance also took the nebulizer route with revefenacin, offering another divergence from Spiriva.
"There was nothing available for patients who use nebulizers," who represent about 9 percent of those with COPD, Winningham told BioWorld Insight.
The fact that revefenacin was designed for once-daily use added a convenience factor, as well.
In 2015, Theravance, based in Dublin but with operational headquarters in South San Francisco, partnered with Mylan NV to develop and commercialize revefenacin to treat COPD and other respiratory diseases. The deal included an initial payment of $15 million in cash and a pledge from Mylan to make a $30 million equity investment in Theravance. Mylan also footed the bill for phase III studies, conducted by Theravance, and is responsible for ex-U.S. development and commercialization.
Theravance is eligible to receive up to $220 million in development and sales milestone payments, as well as a profit-sharing arrangement with Mylan on U.S. sales and double-digit royalties on ex-U.S. sales. Additionally, Theravance kept worldwide rights to revefenacin delivered through other dosage forms, such as a metered dose inhaler or dry powder inhaler, and the rights to nebulized revefenacin in China, where COPD is becoming a leading cause of death.
In 2016, the companies reported that revefenacin met the primary endpoints in twin randomized, double-blind, placebo-controlled, parallel-group phase III studies, showing statistically significant improvements from baseline over matched placebo in trough FEV1 after 12 weeks of dosing for each of two doses studied, 88 mcg and 175 mcg.
The U.S. studies enrolled more than 1,250 patients across a range of disease severity, from moderate to very severe COPD. To assess the potential add-on benefit of revefenacin, Theravance allowed participants to continue use of long-acting beta agonist (LABA) and/or LABA/inhaled corticosteroid (LABA/ICS) treatments – something 38 percent of the studied population did. (See BioWorld Today, Oct. 21, 2016.)
'We're quite committed to this space'
As the partners prepare for commercialization, Theravance is set to take revefenacin into acute-care facilities while Mylan, which is leading the effort, plans to work with providers in ambulatory and home health care settings.
"About 900,000 patients a year are admitted to U.S. hospitals based on significant worsening of their COPD," Winningham pointed out. Although most of those patients receive nebulized treatment in the hospital, the only way to receive the same treatment when they return home is through multiple daily visits by a respiratory therapist.
"With revefenacin, our plan is to deliver the medicine into hospitals, where patients would only have to take it once a day, then have them discharged with revefenacin with a prescription for nebulization and have Mylan pick up the work once patients leave the hospital," Winningham said.
Theravance also has done initial work to examine COPD patients by severity, or GOLD stage, to determine those best matched with revefenacin.
"We see an exciting opportunity to look more deeply at GOLD stage 3/4 patients with low peak expiatory flow," Winningham said. A prospective study of 200 patients conducted by the company showed that revefenacin offered clinically relevant benefit compared to hand-held devices – a finding that's especially significant considering compliance issues that many older adults face when using such devices.
And revefenacin is not the end game for Theravance. The company is working on an inhaled Janus kinase (JAK) inhibitor that it hopes to move into the clinic by year-end to treat patients with asthma and severe COPD.
"We're quite committed to this space," Winningham said.
Last month, Theravance flexed its muscles with another JAK inhibitor, inking a potential $1 billion global co-development and commercialization deal with Janssen Biotech Inc., a subsidiary of New Brunswick, N.J.-based Johnson & Johnson, for TD-1473. The oral, intestinally restricted pan-JAK inhibitor targets inflammatory intestinal diseases, including ulcerative colitis (UC) and Crohn's disease. (See BioWorld, Feb. 8, 2018.)
'We've not been able to reduce mortality'
Plenty of other companies are active in the COPD space, of course. Cambridge, U.K.-based Astrazeneca is testing its approved anti-IL5R, Fasenra (benralizumab), in the indication, with phase III data due in the second half of the year. Cytokinetics Inc. and partner Astellas Pharma Inc. have reldesemtiv (formerly CK-2127107), a next-generation skeletal muscle activator, in a phase II study in COPD that's also scheduled to report data in the second half.
And, although clinical COPD programs remain dominated by big pharma, Cortellis cites two dozen preclinical efforts by smaller companies such as Proteostasis Therapeutics Inc., Pulmatrix Inc., Synspira Inc. and Therabron Therapeutics Inc.
COPD isn't an indication that will be solved overnight, Karlsson acknowledged.
"The disease is well-described," he said, "but we don't really understand the underlying cause, except for the environmental pollution, etc. We have little understanding of the genetic defects that are specifically involved in disease progression. And obviously, with all the treatments we have today, we've not been able to reduce mortality and not really been able to reduce the decline in long-term lung function."
The COPD therapeutic space remains well behind those of many cancer indications, Karlsson added, noting that more people in the U.S. and Europe now die from COPD than from breast and prostate cancer combined. The reason, he said, is that individuals with advanced breast and prostate cancer have a choice of treatments with different mechanisms of action, and some patients respond very well. Individuals with advanced COPD, in contrast, have exhausted current treatment options and still have declining lung function along with diminished quality of life as they're forced into the last resort of oxygen therapy at home.
"This is a big group of patients that needs different medication," Karlsson said. "Today, we have nothing for them."
He's optimistic that Verona can help change that situation.
"Maybe one day most of the patients who enter this final stage will come to a point where they're eligible for treatment with '554," he said, "assuming it comes to market, of course."