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Safety, Early Effectiveness of POL6014 Confirmed in Phase 1 Trial

Single dosing of orally inhaled POL6014, an experimental therapy to treat chronic lung inflammation, can effectively block the activity of a pro-inflammatory enzyme in the lungs of people with cystic fibrosis (CF), results from a Phase 1 clinical trial show.

Neutrophils, a type of immune cells, form part of the primary line of defense of the immune system in case of infection. These cells release an enzyme, called neutrophil elastase (NE), that normally digests damaged cells, and prevents the infection from spreading. However, neutrophils also are found in the inflamed lung tissue and sputum of CF patients. In CF lung, excessive release of NE causes additional tissue damage, leading to a progressive decline in lung function.

POL6014 is a potent, selective inhibitor of human NE that is being developed by Santhera Pharmaceuticals. Preclinical studies in animals demonstrated that the investigational NE inhibitor could reduce inflammatory markers and the number of neutrophils.

Next, researchers conducted a Phase 1 clinical trial (2015-001618-83 and 2016-000493-38) to determine the doses of POL6014 administrated using the eFlow nebulizer (marketed by PARI Pharma) that were best tolerated in healthy volunteers and to assess preliminary effects in CF patients.

Supported by the Cystic Fibrosis Foundation, the trial included 48 healthy male volunteers, ages 19 to 46, who had FEV1 (maximal amount of air forcefully exhaled in one second, a commonly used assessment method for lung function) greater than 80%. They were divided into six groups, each taking an increasing dose of POL6014 — 20, 60, 120, 240, 480, and 960 milligrams (mg) . Two participants in each group were selected randomly to take a matching dose placebo.

No serious adverse side effects were reported. At the highest dose the treatment triggered inhalation-related side effects including short transient decline in FEV1, cough, and respiratory tract irritation. At all lower doses, POL6014 was well-tolerated with no clinically significant adverse findings as measured by clinical laboratory tests, electrocardiogram, and blood pressure measurements.

After completion of this first part, researchers evaluated 24 CF patients, age 18 to 41 years, who had FEV1 greater than 60% of the predicted value. All CF patients had stable disease before being enrolled in the study, and they remained stable throughout. They also were allowed to continue their daily CF medications, like Pulmozyme (dornase alpha) and hypertonic saline, as long as they were taken more than 12 hours before POL6014 dosing.

CF participants were assigned randomly to take one of three doses of POL6014 — 80, 160, or 320 mg — previously selected based on healthy volunteers’ safety and tolerability data, and two in each group were selected to take a matching placebo.

All dose levels were deemed safe and were-well tolerated by CF patients.

Additional analysis showed that human NE activity was reduced in participant’s sputum shortly after inhalation at all dose levels. Researchers also found that three and 24 hours after inhalation the concentration of POL6014 was 1,000 times higher in the lungs compared to blood levels. This showed that systematic exposure to POL6014 throughout the body was small and was mainly restricted to the lungs, as anticipated.

“We are encouraged by these early data in healthy volunteers and patients with cystic fibrosis. POL6014 brings new promise to current CF treatment which, despite recent developments, is still lacking a solution to lung tissue inflammation, a cause of pulmonary exacerbations,” Kristina Sjöblom Nygren, MD, said in a company’s press release. Nygren is chief medical officer and head of development at Santhera. “In addition, inhalation of POL6014 shows a strong advantage over the oral route as it delivers the drug directly to the lung with a low systemic burden.”

The results of this trial provided the support Santhera needed to begin new Phase 1b/2a clinical trials (2016-005110-22 and 2018-002550-71) to further assess the safety, tolerability, and activity of multiple doses of POL6014 in CF patients. Lung function following treatment also will be evaluated by spirometry tests and blood oxygen levels.

The Phase 1 clinical trial was conducted by Polyphor, which, after the study was completed, transferred exclusive rights to Santhera Pharmaceuticals to develop and commercialize POL6014 to treat CF and other pulmonary diseases.

POL6014 also may be used to treat non-cystic fibrosis bronchiectasis (NCFB), alpha-1 antitrypsin deficiency (AATD) or primary ciliary dyskinesia, for which it was granted orphan drug status in the European Union.

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