Chronic Obstructive Pulmonary Diseases:Journal of the COPD Foundation

Running Head: COPD Pipeline

Abbreviations: Food and Drug Administration, FDA; Centers for Drug Evaluation and Research, CDER

Citation: Gross N. Pipeline XXXI. Chronic Obstr Pulm Dis. 2016; 3(2): 589-593. doi: http://doi.org/10.15326/jcopdf.3.2.2016.0140

New Drugs in 2015

A recent Food and Drug Administration (FDA) report begins: “FDA’s Center for Drug Evaluation and Research (CDER) supports the pharmaceutical industry at every step of the process.”1 The FDA approved 45 new drugs last year, substantially more than the usual 25 – 30 new entities (“me-toos,” of which hundreds are approved each year, are not included here). Sixteen of the 45 novel drugs were considered to be First-in-Class, and 21 of the 45 approvals, almost half, were for orphan drugs. Only 3 of the 45 new molecular entities were for pulmonary disorders. One of them, the fixed combination of lumacaftor/ivacaftor (Okambi) was approved for cystic fibrosis due to homozygous F508del mutations,1,2 the most common cause of cystic fibrosis. Okambi is designated as an orphan drug. Mepolizumab (Nucala, a First-in-Class drug) was approved “for use with other asthma medicines for the maintenance treatment of asthma in patients aged 12 years and older.”1 It is a humanized, interleukin-5 antagonist monoclonal antibody. The third pulmonary approval was for selexipag (Uptravi),1 to treat pulmonary arterial hypertension. It is an oral prostacyclin receptor agonist. No new molecular entities for COPD were approved by the FDA.

An updated summary of the FDA’s current drug development and approval process was published in January of this year.3

Treprostinil

Treprostinil, a prostaglandin analog, 4 was approved for the treatment of pulmonary artery hypertension (WHO group I) in 2002. It is now or has been in 81 trials for a variety of indications and formulations as Tyvaso™. The latest trial, just initiated (NCT02633293),5 is a phase 2/3 multicenter, open-label, 2-year trial to evaluate the safety and efficacy of inhaled treprostinil in individuals with pre-capillary pulmonary hypertension associated with interstitial lung disease including combined pulmonary fibrosis and emphysema, comorbidities that are presently outside the Tyvaso indication.

BI 1026706

A new Boehringer Ingelheim agent, BI 1026706, seems to be looking for an indication. In 5 completed trials it has been tested as an antifungal agent, as an anti-epileptic, as an analgesic and as a non-steroidal anti-inflammatory.6 The present study is its first trial in COPD patients. It is a dose-response study in Phase I and the primary outcome is safety and tolerability. A total of 120 individuals with COPD will be enrolled into a 4 week study (NCT02642614).7 There is no public information about the action of this agent but one presumes the trial is to test its anti-inflammatory activity in COPD patients.

PT003

Pearl Therapeutics has a new glycopyrronium/formoterol (14.4/9.6gm) fixed combination, PT003. It will employ Pearl’s “…proprietary formulation technology that uses lipid-based porous particles to create stable cosuspensions with drug crystals in HFA propellants, and high performance aerosols upon actuation.” 8A trial will enroll 20 COPD individuals in a placebo controlled 2-week, cross-over Phase III study. The outcomes will be lung volumes and resistance as determined by imaging (NCT02643082).9

CHF5259

CHF5259is Chiesi’s glycopyrronium bromide dry powder inhaler. Currently, a randomized, double blind, placebo-controlled, 3-way cross-over study of doses from 6.25 to 25 mg twice daily to evaluate efficacy and safety in individuals with moderate to severe COPD is being conducted. In this phase II trial 300 individuals will receive treatments of 4 weeks duration over 3 periods. The primary outcome is forced expiratory volume in 1 second, area under the curve from 0 – 12 hours at the end of each study period (NCT02680197).10

Philip Morris P3L Nicotine Delivery Device

Two new trials are being tested for Philip Morris’ P3L nicotine delivery device. The first trial, NCT02643693, will assess the safety and tolerability of Philip Morris’s “…Nicotine Lactate Delivery System (P3L) after ad libitum use and the ability of combustible cigarette smokers to use P3L to maintain their customary nicotine intake.”11 A second trial, NCT02649556, known as the ZRHR-ERS-09-EXT-US study, has the objective of further assessing the effect of the Tobacco Heating System 2.2 (THS 2.2), compared to conventional cigarettes, on the components of the smokers' health profile for a prolonged period of 26 weeks.12 This will provide additional information to the results of the original study ZRHR-ERS-09-US of 26-week exposure (NCT02396381). In total, the ZRHR-ERS-09-EXT-US study will extend the exposure period to 52 weeks. Neither study states a phase number.

Vismodegib

Vismodegib byErivedge® is a drug that was approved for basal-cell carcinoma in 2012. It has since been tested in over 60 trials for a wide variety of diseases mostly associated with malignancies of the prostate, colorectal, ovaries, stomach, lymphomas and several more. It is the first hedgehog signaling pathway-targeting agent to gain FDA approval. Initially developed by Genentech, it is now undergoing a small, single-arm phase I safety and tolerability trial of the drug in combination with pirfenidone in patients with idiopathic pulmonary fibrosis (NCT02648048).13

Batefenterol

Batefenterol, a GlaxoSmithKline molecule, has just entered 2 phase 1 trials. It is “..a bifunctional bronchodilator that is being developed for the treatment of COPD. Absorption, metabolism and excretion of batefenterol have been studied in animals, in vitro, and in previous clinical studies; however, the elimination routes and metabolic pathways of batefenterol have not been fully elucidated in humans.”14,15 Like some other emerging bi-functional molecules for COPD, its action consists of anti-muscarinic and beta-adrenergic pharmacophores joined by an inert spine. In the 2 phase 1 safety studies, 6 and 48 healthy individuals will receive the agent by intravenous infusion, orally, or by inhalation of the dry powder (NCT02663089 and NCT02666287).

GSK2269557

GSK2269557 is a potent and highly selective inhaled phosphoinositide 3-Kinase delta inhibitor being developed as an anti-inflammatory and anti-infective agent for the treatment of inflammatory airway diseases, according to its developer, GlaxiSmithKline (NCT02691325).16 Additional information about this new molecule is available from Expert Opinion on Therapeutic Patents. 17

Moracin M

The moracins are 2-arylbenzofuran derivatives that are derived from an oriental tree bark. They have been found to inhibit interleukin-6 production from IL-1β-treated lung epithelial cells.18 Among the several moracin molecules, moracin M shows the strongest inhibitory effect. Downregulation of IL-6 expression by moracin M was mediated by interrupting the JNK/c-Jun pathway. Its action includes selective inhibition of PDE4D2 and PDE5A2, interfering with NF-kB activation, and inhibition of inducible nitric oxide synthase (iNOS)-catalyzed NO. When orally administered to mice, moracin M (20 - 60 mg/kg) showed comparable inhibitory action to dexamethasone (30 mg/kg) against LPS-treated lung inflammation. The interference with activation of NF-κB inhibition of inducible nitric oxide synthase (iNOS) is seen both in vitro and in vivo. The moracins, in particular moracin M, might have therapeutic potential in treating lung inflammatory disorders, as has been suggested (F), but trials of moracins have not yet been registered in clinicaltrials.gov.

GLPG1837

TheS1251N mutation of cystic fibrosis is one of the earliest to have been identified19 and one of the more common ones of the hundreds of known mutations. A trial of a treatment for patients with CF due to that mutation is about to begin (NCT02690519).20

New Lipid Formulation Trial

NCT02646995describes a clinical trial of a novel lipid formulation aimed at increasing the bioavailability of fatty acids in cystic fibrosis patients.21

Acknowledgement

Many of the items in this report are due to the generous support of Johan Karlberg, MD, PhD, via his e-publication Clinical Trials Magnifier Weekly.

1. Food and Drug Administration. Novel drug approvals for 2015. FDA website. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm430302.htm Updated April 2016. Accessed April 2016.

2. FDA approves new treatment for cystic fibrosis [news release].Silver Spring, MD: FDA; July2, 2015. .http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm453565.htm Accessed April 13, 2015.

3. U.S. Food and Drug Administration. Novel drugs summary 2015. FDA website. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm474696.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery Published January 2016. Accessed April 2016.

4. Jing ZC, Parikh K, Pulido T, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension a randomized, controlled trial efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension a randomized controlled trial. Circulation. 2013; 127:624-33. doi: http://dx.doi.org/10.1161/CIRCULATIONAHA.112.124388

5. National Institutes of Health, National Library of Medicine. An open label extension study to evaluate inhaled treprostinil in adult PH with ILD including CPFE. Clinical Trials.gov website. https://clinicaltrials.gov/ct2/results?term=NCT02633293&Search=Search . Published March 2016. Accessed April 2016.

6. National Institutes of Health, National Library of Medicine. 9 studies for BI 1026706. Clinical Trials.gov website. https://clinicaltrials.gov/ct2/results?term=+BI+1026706&Search=Search. Updated April 2016. Accessed April 2016.

7. National Institutes of Health, National Library of Medicine. Safety, tolerability and pharmacokinetics and effect on inflammation of oral BI 1026706 in patients with COPD. Clinical Trials.gov website. https://clinicaltrials.gov/ct2/show/NCT02642614?term=BI+1026706&rank=6 Updated: April 2016. Accessed 2016.

8. Pearl Therapeutics. Pipeline and platform: Pipeline overview- Pearl proprietary particles. Pearl Therapeutics website. https://www.pearltherapeutics.com/proprietary-platform-technology Published 2015. Accessed April 2016.

9. National Institutes of Health, National Library of Medicine. A study to assess the effects of PT003 and placebo MDI on specific image based parameters in subjects with moderate to severe COPD. Clinical Trials.gov website. Published February 2016. Accessed April 2016.

10. National Institutes of Health, National Library of Medicine. Study to evaluate efficacy/safety of 4 doses of CHF5259 via dry powder inhaler (DPI) in patients with COPD (glyconext). Clinical Trials.gov website. Published February 2016. Accessed April 2016.

11. National Institutes of Health, National Library of Medicine. User Acceptability of P3L. Clinical Trials.gov website. https://clinicaltrials.gov/ct2/show/NCT02643693 . Published February 2016. Accessed April 2016.

12. National Institutes of Health, National Library of Medicine. A 26-week extension of the ZRHR_ERS-09-US study evaluating biological and functional changes in healthy smokers after switching to THS 2.2 Clinical Trials.gov website. https://clinicaltrials.gov/ct2/show/NCT02649556?term=NCT02649556&rank=1 Published January 2016. Accessed April 2016

13. National Institutes of Health, National Library of Medicine. A safety and tolerability study of oral vismodegib in combination with pirfenidone in participants with idiopathic pulmonary fibrosis.Clinical Trials.gov. https://clinicaltrials.gov/ct2/show/NCT02648048?term=NCT02648048&rank=1 Published January 2016. Accessed April 2016.

14. National Insitutes of Health, National Library of Medicine. A phase 1 (PH1), single dose (SD), gsk961081 absorption, distribution, metabolism, and excretion (ADME) study in healthy subjects. Clinical Trials.gov website. https://clinicaltrials.gov/ct2/show/NCT02663089 Published January 2016. Accessed April 2016.

15. Ambery CL, Wielders P, Ludwig-Sengpiel A, Chan R, Riley JH. Population pharmacokinetics and pharmacodynamics of GSK961081(batefenterol). Drugs. 2015;15(3):281-291 .doi: https://dx.doi.org/10.1007/s40268-015-0104-x

16. National Institutes of Health, National Library of Medicine. Study to evaluate the safety, tolerability and pharmacokinetics of gsk2269557 administered via the Ellipta dry powder inhaler to healthy subjects. Clinical Trials. gov website. https://clinicaltrials.gov/ct2/show/NCT02691325?term=NCT02691325&rank=1 Published February 2016. Accessed April 2016.

17. Norman P. Evaluation of WO2013136076: two crystalline forms of the phosphatidylinositol 3-kinase-δ inhibitor RV-1729. Expert Opinion on Therapeutic Patents. 2014; 24(4):471-475.

18. Chen SK, Zhao P, Shao YX, et al. Moracin M from Morus alba L. is a natural phosphodiesterase-4 inhibitor.Bioorg Med Chen Lett. 2012; 22: 3261-3264.

19. Kälin N, Dörk T, Tumler B. A cystic fibrosis allele encoding missense mutations in both nucleotide binding folds of the cystic fibrosis transmembrane conductance regulator. Hum Mutat. 1992;1(3):204-210.

20. National Institutes of Health, National Library of Medicine. Study of GLPG1837 in subjects with cystic fibrosis (s1251n mutation) (saphira2). Clinical Trials.gov website. https://clinicaltrials.gov/ct2/show/NCT02690519 Published February 2016. Accessed April 2016.

21. National Institutes of Health, National Library of Medicine. Lipid formulation to increase the bioavailability of fatty acids in cystic fibrosis (CF) patients. Clinical Trials.gov website. https://clinicaltrials.gov/ct2/show/NCT02646995?term=NCT02646995&rank=1 Published December 2015. Accessed April 2016.

Posted in: The COPD Pipeline, Volume 3 | Issue 2

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