Chronic Obstructive Pulmonary Diseases:Journal of the COPD Foundation

Running Head: COPD Pipeline XXXV

Abbreviations: long-acting muscarinic antagonist, LAMA; forced expiratory volume in 1 second, FEV1; whole-body vibration training, WBVT; CXC chemokine receptor, CXCR2; muscarinic antagonist-beta2-agonist, MABA

Citation: Gross N. The COPD Pipeline XXXV. Chronic Obstr Pulm Dis. 2017; 4(3): 247-251. doi: http://doi.org/10.15326/jcopdf.4.3.2017.0154

Introduction

Dealmakers in biopharma ended April with much disappointment and grumbling. This was the year that Mergers and Acquisitions were supposed to take off, with a new president bullishly asserting plans to reform taxes in a way that would free up billions in “big pharma” cash held overseas. As one trade journal states: “Didn’t happen. Donald Trump is so far bogged down on Obamacare reform and not able to deliver a much-ballyhooed tax reform pledge — for now.”1 Most people are disappointed with the pace of mergers and acquisitions. In the first quarter, pharmaceutical dealmakers were down 13% compared to the same period a year ago.1

Revefenacin

Revenfancin is a long-acting (24 hour) muscarinic antagonist (LAMA) being developed for COPD by Mylan and Theravance. Phase III studies, recently completed, show meaningful efficacy in terms of increased forced expiratory volume in 1 second (FEV1) versus placebo (NCT03064113).2 Adverse events included dry mouth in less than 0.5% of participants.3 There were no reports of vision impairment, narrow-angle glaucoma or worsening of urinary symptoms. One’s unique interest in this agent is that it will be the first nebulized once-daily LAMA for COPD patients who, for a number of potential reasons, need or prefer to get their bronchodilator by nebulization. It is estimated that about 9% of patients who use a long-acting agent use it by nebulization.3 One expects that a combination of Revefenacin with a nebulized long-acting beta-agonist will shortly be developed.

Whole-Body Vibration Training

Whole-body vibration training (WBVT) is a physical treatment consisting of the administration of vibrations delivered to the whole body. Physical retraining is a recognized goal of rehabilitation in COPD, however it is rarely practiced correctly or in full. Whole-body proponents opine that “vibration training could be a new and time-saving exercise approach aimed at increasing exercise performance in patients with COPD.” 4 Participants in a randomized placebo controlled clinical trial with chronic bronchitis received 2 treatments of WBVT per month for 3 months. Whole body vibrations were delivered while standing on a vibrating platform. The control group received “relaxation and breathing retraining in combination with calisthenics exercises.” 4 Participants who received vibrations experienced statistically improved results on the St George’s Respiratory Questionnaire, 6-minute walk tests, sit-to-stand tests, peak force and Berg balance tests. The control group experienced no changes. Unavoidably, the trial was not double-blinded. Clinicaltrials.gov shows 76 studies of “whole body vibration training,” 10 of which were for “pulmonary” studies, mostly of a bronchitic nature.

The Gala Airway Treatment System is somewhat similar in nature but more intense. High frequency vibrations are delivered to the lungs via a proprietary catheter through a bronchoscope under general anesthesia.5 Treatments last about 60 minutes and there are just 2 treatments in total, 1 for each lung. A device-based, energy delivery system delivers high frequency short duration energy to the airway epithelium and sub-mucosal tissue layers. The energy is delivered via a proprietary catheter through the bronchoscope. Three months after treatments, bronchoscopy will be performed to obtain tissue for histology. A clinical trial will enroll 12 participants, the primary outcome being safety (NCT03107494).5

Chiesi

Chiesi has several agents in development. CHF6001 is a phosphodiesterase type 4 inhibitor that has or shortly will be in 7 trials for COPD. Trial NCT02986321 the most recent, is a dose-ranging study called PIONEER.6

Chiesi also has a p38 MAP Kinase inhibitor in phases 1 and 2, CHF-6297, which, if I am not mistaken, is aimed at addressing the acute exacerbation itself (NCT02815488), a novel and interesting approach to COPD management.7

Clinicaltrials.gov shows that Chiesi has or had 59 clinical trials limited to “pulmonary” in phases I, II, or III in recent years.

RPL554

On the subject of phosphodiesterases for COPD, the dual phosphodiesterase 3/4 inhibitor RPL554, a Verona Pharma agent, is in 2 trials for COPD (NCT02542254 and 03028142)8,9 as well as one trial in asthma and another in cystic fibrosis. The drug stimulates the cystic fibrosis transmembrane conductance regulator and ciliary beat frequency in primary cultures of bronchial epithelia.10 Both PDE3/4 COPD trials are in Phase II, the primary objective being FEV1 over the first 8 hours of administration.

Danirixin

Danirixin is a selective CXC chemokine receptor (CXCR2) antagonist being developed as a potential anti-inflammatory agent for the treatment of COPD. A phase II trial will evaluate several dosages, the primary outcome being the change from baseline in clinical outcomes as measured by the E-RS tool, a component of the EXACT tool (NCT03034967).11 As previously published,12 a limitation of the anti-inflammatory approach by CXCR2 antagonists has been a decrease in circulating neutrophils that can be severe.

Batefenterol

Batefenterol, GSK961081, is a potent dual pharmacophore, or muscarinic antagonist-beta2- agonist (MABA), that demonstrates both antimuscarinic and beta-agonist pharmacology.13 In preclinical studies, both pharmacologies were functional and of long duration. If reproduced in man, GSK961081 has the potential to deliver a medicine that can be given once daily. The primary outcome of the latest trial (NCT00674817) will be bronchodilatation after inhalation of single doses of GSK961081 alone and in the presence of salbutamol and/or ipratropium.13 Any residual bronchodilatation post-inhalation of GSK961081 may provide an indirect assessment of the beta-agonist and antimuscarinic components of this agent. In a phase II trial of the same MABA, the primary outcome is the change in FEV1 at 7 weeks, versus umeclidinium/vilanterol fixed combination (NCT02570165).14

The status of this agent, GSK961081, is unknown as the clinicaltrials.gov site has not received updates for more than 2 years.

Eosinophilia with COPD

Eosinophilia with COPD is a topic of interest in which pharmaceutical companies are trying to determine the frequency of blood eosinophilia in patients with COPD (NCT03018808).15 Besides being of concern in asthma patients, the topic has become one of interest for pulmonologists treating COPD.16 If this research shows a connection between eosinophilia and acute exacerbations of COPD, no doubt we will be using IL-5 inhibitors in the latter.

Lungpacer Medical, Inc

Lungpacer Medical, Inc., is a medical device company developing an intravenous catheter-based phrenic-nerve-pacing system. The company announced recently that it has received an Expedited Access Pathway designation for this device from the Food and Drug Administration. Lungpacer Medical states its system “is a novel therapeutic solution for preserving the integrity and strength of the diaphragm muscle in critically ill patients who require mechanical ventilation. The proprietary Lungpacer system is designed to activate the diaphragm using a temporary, minimally invasive, transvascular nerve stimulation approach that is expected to save many lives, improve surviving patient outcomes and greatly reduce hospital care costs.”17 Ongoing trials are NCT03096639 (RESCUE2)18 and NCT03107949 (RESCUE1).19 The protocol indicates that diaphragm pacing intervention will be conducted 3 times a day using the Diaphragmatic Pacing Therapy System. A control group will receive no pacing.

Tetomilast

Tetomilast--what happened to it? It was a promising phosphodiesterase 4 inhibitor that was in 2 phase II studies for COPD and 5 studies for ulcerative colitis. Nothing since 2015.20

N1,N3-bis(2-Mercaptoethyl) Isophthalamide (NBMI)

Emiramide is an antioxidant and metal chelator that is in its first clinical trial exploring safety for COPD. The study is a randomized, 2-arm, double-blind, placebo-controlled, cross-over trial. Participants will receive 14 days of administration and observation; the method of administration is not mentioned (NCT03123692).21 Many antioxidants, e.g., CoQ10 and N-acetylcysteine, have been tested in lung diseases before and found not to be very effective.

Colistin

Colistin, also known as polymyxin E, is an antibiotic produced by certain strains of the bacteria Paenibacillus polymyxa. It belongs to the class of polymyxins and is effective against most Gram-negative bacilli. An old drug, it fell out of favor in human medicine due to kidney toxicity. A double-blind placebo controlled trial is in phase III. A total of 264 participants with non-cystic fibrosis bronchiectasis will be enrolled. The primary outcome is time to first exacerbation (NCT03093974).22

Acknowledgements

Some information in this report was obtained through the generous contribution of Johan Karlberg, MD, PhD, Director of Humanity and Health Research Centre and Editor of the Clinical Trial Magnifier Newsletter.

1. Carroll J. Don’t let a slump in biopharma deals get you down — yet; The controversy on drug prices is taking a toll. Endpoints News website. Published April 21, 2017. Accessed June 2017. https://endpts.com/thumbs-dont-let-a-slump-in-biopharma-deals-get-you-down-yet-the-controversy-on-drug-prices-is-taking-a-toll

2. National Institutes of Health. Effects of TD-4208 on FEV1 in subjects with chronic obstructive pulmonary disease (COPD). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/record/NCT03064113 Published January 2017. Updated February 2017. Accessed June 2017.

3. Theravance biopharma and Mylan report additional Phase 3 data for Revefenacin (TD-4208) in several presentations at 2017 ATS [news release]. Dublin, Hertfordshire, England and Pittsburgh, Pennsylvania. Mylan Pharmaceuticals. May 23, 2017. http://newsroom.mylan.com/2017-05-23-Theravance-Biopharma-and-Mylan-Report-Additional-Phase-3-Data-for-Revefenacin-TD-4208-in-Several-Presentations-at-2017-ATS Accessed June 2017.

4. Spielmanns M, Boeselt T, Gloeckl R, et al. Low-volume whole-body vibration training improves exercise capacity in subjects with mild to severe COPD. Respir Care. 2017;62: 315-323. doi: https://doi.org/10.4187/respcare.05154

5. National Institutes of Health.Gala FIH feasibility study for the treatment of chronic bronchitis. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03107494 Published March 2017. April 2017. Accessed June 2017.

6. National Institutes of Health. A 24-wk dose ranging study to evaluate the efficacy and safety of 4 doses of a new pde4 inhibitor in patients with COPD (PIONEER). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02986321 Published November 2016. Updated December 2016. Accessed June 2017.

7.National Institutes of Health. A study to investigate safety, tolerability, pharmacokinetics and pharmacodynamics of single and repeat doses of CHF6297 in healthy subjects and patients withCOPD (CHF6297 FIH). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02815488 Published May 2016. Updated October 2016. Accessed June 2017.

8. National Institutes of Health.The effects of RPL554 on top of standard COPD reliever medications. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02542254 Published August 2015. Updated September 2016. Published 2017.

9. National Institutes of Health.The effects of RPL554 in addition to tiotropium in COPD patients. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT03028142 Published January 2017. Accessed June 2017.

10. Turner MJ, Matthes E, Billet A, et al. Am J Physiol Lung Cell Mol Physiol. 2016;310(1):L59-70. doi: https://doi.org/10.1152/ajplung.00324.2015 .

11. National Institutes of Health. Danirixin dose ranging study in participants with chronic obstructive pulmonary disease (COPD). ClincialTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT03034967 Published January 2017. Updated June 2017. Accessed June 2017.

12. Gross NJ, Barnes PJ. New therapies for asthma and COPD. Am J Respir Crit Care Med. 2017;195:159-166.

13. National Institutes of Health. An investigation of the interaction ofGSK961081 with inhaled beta-agonist and anti-muscarinic drugs. ClincialTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT00674817 Published April 2008. Updated April 2017. Accessed June 2017.

14. National Institutes of Health. Dose-finding study of batefenterol (GSK961081)via dry powder inhaler in patients with chronic obstructive pulmonary disease (COPD). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02570165 Published October 2015. Updated February 2017. Accessed June 2017.

15. National Institutes of Health. Prevalence of chronic obstructive pulmonary disease(COPD)and eosinophilia among primary care patients. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT03018808 Published January 2017. Updated May 2017. Accessed June 2017.

16. Calverley PMA, Tetzlaff K, Vogelmeier C, et al. Eosinophilia, frequent exacerbations, and steroid response in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2017; In press. doi: https://doi.org/10.1164/rccm.201612-2525LE

17. Lungpacer Medical. Lungpacer Medical, Inc. The WEANING SOLUTION® for mechanically ventilated patients. Lungpacer Medical website. http://lungpacer.com/ Published 2017. Accessed June 2017.

18. National Institutes of Health.Percutaneous temporary placement of a phrenic nerve stimulator for diaphragm pacing(RESCUE2). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03096639 Published March 2017. June 2017.

19. National Institutes of Health.Percutaneous temporary placement of a phrenic nerve stimulator for diaphragm pacing(RESCUE1). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03107949 Published March 2017. Updated April 2017. Accessed June 2017.

20. Mulhall AM, Droeger CA, Ernst NE, Panos RJ, Zafar MA. Phosphodiesterase 4 inhibitors for the treatment of chronic obstructive pulmonary disease: a review of current and developing drugs. Expert Opin Investig Drugs. 2015;24(12):1597-1611. doi: https://doi.org/10.1517/13543784.2015.1094054

21. National Institutes of Health. Clinical study on COPD (Emera003COPD). ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03123692 Published April 2017. Accessed June 2017.

22. National Institutes of Health. Trial in non-cystic fibrosis bronchiectasis patients with chronic lung infections treated with colistimethate sodium(PROMIS-I). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03093974 Published March 2017. Accessed June 2017.

Posted in: The COPD Pipeline, Volume 4 | Issue 3

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