Cystic Fibrosis and Current Treatment Options
Cystic fibrosis (CF) is a genetic disease affecting multiple organ systems. The respiratory system is affected by complications resulting from impaired mucociliary clearance in the airways and is the primary cause of disease manifestation. Impaired host defense against inhaled debris and microbes results in persistent lower airway bacterial infection, most commonly caused by Pseudomonas aeruginosa (PA) and Staphylococcus aureus. PA is linked to greater airway inflammation and is a major etiologic factor in disease progression and overall decline in health. Chronic PA infection results in a vicious cycle of infection and inflammation, which causes airway surface damage, airway plugging, which progressively leads to lung function decline and reduced survival. Strategies to administer anti-pseudomonal antibiotics to the airways have been a cornerstone of CF clinical care for many years. Although the overall prevalence of PA has gradually decreased in the last 25 years, it remains one of the most prevalent bacterial pathogens in CF, especially in adults > 25 years.
Infections will remain a major problem in CF post CFTR modulator era as patients live longer. PA infection is estimated to account for more than half of the chronic infections in Cystic Fibrosis. Data from the 2016 Cystic Fibrosis Foundation (CFF) Patient Registry indicate that 46.9% of CF patients in the US had at least one positive culture for PA, of which 29.1 percent were classified by as having chronic infection, and 17.8 percent as having intermittent infection. In approximately 18% of US patients with positive PA culture, the isolated strains were multi-drug resistant. Chronic PA infection is the leading cause of exacerbations, lung function decline and mortality in Cystic Fibrosis. Given infections remain to be a major problem in cystic fibrosis, the CFF has committed at least USD 100 million to the Infection Research Initiative in 2019.
The introduction of anti-pseudomonal antibiotics for the management of people with CF patients has played a major role in increasing their median survival. Inhaled antibiotics, which have been used in Europe since the 1980s and in the US since the late 1990s, are a key element of these antibiotic regimens. Despite the approval of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies that substantially improve the genetic malfunction of the CFTR protein, there is an increasing need for the use of inhaled antibiotics. Currently, the only commercially available formulations of inhaled broad spectrum antibiotics include tobramycin, aztreonam, colistimethate sodium, and levofloxacin, depending on the geographic location of the patient. Tobramycin and aztreonam are the most commonly used inhaled antibiotics for CF and were developed nearly 10-20 years ago for 2-3 times daily dosing and were initially typically administered every other month in cycles to reduce antibiotics resistance. In the US, only tobramycin and aztreonam are authorized for marketing and are now commonly used for through “continuous alternating therapy” to avoid off-months without inhaled antibiotic therapy. Still, large numbers of CF patients continue to experience acute pulmonary exacerbations and declining lung function. Treatment for acute exacerbation events in patients with PA infection often requires intravenous drug administration of antibiotics with associated health risks, such as hearing loss, renal impairment, and socioeconomic costs. The clinical decline that many patients continue to experience highlights a need to develop new therapies, which includes additional effective and safe inhaled antibiotics.
Spexis (through its subsidiary EnBiotix) has in-licensed ColiFin® from PARI Pharma GmbH, a global leader in nebulized therapies, for worldwide rights ex-Europe. ColiFin® represents a class of cyclic polypeptide antibiotics (polymyxins), with activity against gram-negative pathogens which acts via a different mechanism of action, compared to the other approved inhaled antibiotics and does not exhibit cross-resistance with these other classes. Chronic PA infection in people with CF requires lifelong antibiotic therapy; thus, the risk of developing resistance and the emergence of multi-drug resistant PA strains are a significant health concern. The significantly lower rate of resistance to colistimethate sodium (CMS) compared to other antipseudomonal antibiotics therefore renders CMS an invaluable treatment option.
CMS, the active substance in ColiFin®, has been developed as a nonactive prodrug of colistin to reduce the toxic side effects of active colistin. CMS undergoes hydrolysis to generate colistin, has shown not be less toxic following parenteral administration and is well tolerated after inhalation. ColiFin has been approved in Europe since 2010 at doses of 1 MIU (~80 mg CMS) and 2MIU (~160 mg CMS) administered two or three times daily with the PARI eRapid nebulizer system. ColiFin® has become a front-line therapy for chronic lung infections in CF with a proven safety and efficacy track record. We have received from the FDA a “Study may Proceed” letter to initiate a single Phase 3 trial (COPA) of inhaled ColiFin® in adult and adolescent subjects with cystic fibrosis and chronic PA lung infection to support a future US marketing authorization.
The clinical development of ColiFin® is supported by the FDA granting of Orphan Drug Designation for treatment of respiratory infection in patients with cystic fibrosis, Qualified Infectious Disease Product (QIDP) Designation for ColiFin® for the treatment of PA lung infections in CF patients, and Fast Track Designation.
ColiFin® Phase 3 Program Plan
We are currently finalizing details of the COPA protocol (“Study May Proceed” letter received in May 2020) in collaboration with the FDA. The Phase 3 trial is expected to start in mid 2022 and expected to be conducted in two parts: a 28-day randomized, ColiFin® vs placebo double-blind period (Part A) for efficacy assessment, after which study subjects will be switched to a 20-week open label period (Part B) for safety assessment of ColiFin® vs. usual care therapy with inhaled antibacterials. All subjects randomized to ColiFin® will receive a total of 24 weeks of continuous ColiFin® in Part A and Part B. Subjects randomized to placebo in PartA, will receive usual care therapy with inhaled antibiotcs during in Part B.
Colifin® is expected to be administered with an investigational PARI eFlow nebulizer system that is a modified, more efficient version of the eRapid system. The investigational eFlow nebulizer handset has a modified version of the medication reservoir and a larger nebulization chamber but is otherwise technically identical to the eRapid nebulizer. Labotaratory studies have shown that the modified device has a higher dose delivery and reduces the treatment time of ColiFin® per inhalation session while maintaining similar aerosolization characteristics. This allows us to reach the same dose delivered to the lung at a reduced Phase 3 dose of ColiFin® 1.25 MIU with the modified eFlow device.
Enrollment of the first COPA subject is expected in the third quarter of 2022 with trial completion projected for the second quarter 2024 and data read out 6-8 weeks thereafter.