Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis

ABSTRACT

Introduction: Non-cystic fibrosis bronchiectasis (NCFB) is an increasingly prevalent chronic respiratory disease, characterized by a cycle of infection and inflammation. It is progressive and associated with poor quality of life, increasing healthcare costs and mortality. Inhaled antibiotics offer the potential to decrease long-term bacterial burden and reduce or delay exacerbations which are a key driver of disease progression and healthcare costs. Currently however, no inhaled treatments are approved for the prevention of exacerbations in patients with NCFB.

Areas covered: We consider current evidence for inhaled treatment in NCFB and discuss ciprofloxacin dry powder for inhalation (DPI), a novel treatment using PulmoSphere™ technology, delivered via a pocket-sized, breath-actuated inhaler. We also detail the unique features of the ongoing Phase 3 RESPIRE trials for ciprofloxacin DPI.

Expert opinion: The simplicity of use and short administration time could make ciprofloxacin DPI an attractive treatment option with potential to reduce the number of exacerbations in patients with NCFB. The RESPIRE studies are the largest carried out in NCFB to date and will provide a benchmark for future trial design. If approved, following successful Phase 3 data, ciprofloxacin DPI has potential for significant use in NCFB due to its good tolerability and low treatment burden.

KEYWORDS:

• Bronchiectasis
• NCFB
• antibiotics
• inhaled antibiotics
• ciprofloxacin
• Ciprofloxacin dry powder for inhalation (DPI)

1. Introduction

Non-cystic fibrosis bronchiectasis (NCFB) is a chronic respiratory disease characterized by permanent and abnormal dilation of the bronchi leading to cough, purulent sputum and episodic infective exacerbations [1–3]. It is a progressive disease that results in thickening of the bronchial wall which worsens with time [2,3]. NCFB is associated with a poor quality of life and increased healthcare utilization and cost [4–6]. NCFB represents a heterogeneous respiratory pathology with multiple etiologies. Postinfectious disease is frequently reported [7], however, up to 53% of cases still have an idiopathic origin [2,7,8].

The pathophysiology of NCFB is modeled on the cycle hypothesis, Figure 1 [9]; the exacerbations and chronic respiratory infection that underlie the cycle are key drivers associated with disease progression, mortality, and poor quality of life [10–14]. Disrupting different aspects of the cycle has been the primary treatment approach to date [2,8,15]. Given that around 40% of NCFB patients suffer from three or more exacerbations per year, a large proportion of patients may benefit from strategies to reduce the frequency of exacerbations [16].

Figure 1. The vicious cycle of inflammation and infection and potential therapeutic interventions [9]. Reproduced with permission of the European Respiratory Society ©. Eur J Respir Dis Suppl. 1986; 147: 6–15.

Historically, NCFB prevalence has been poorly described [15] and the exact incidence remains unclear. However, some consistent themes can be observed in data from the US, Europe and Asia Pacific (Table 1); overall the prevalence of bronchiectasis is increasing and rates are particularly high in the elderly. Reports of prevalence have ranged from 4.2 per 100,000 in 18–34 year old people in the US [5], to as high as 135 per 10,811 in China [17] and recently, Quint et al. reported an overall point prevalence of 125.74 per 100,000 in UK primary care patients over the age of 70 [18]. Data from large registries are awaited to gain a greater knowledge of the prevalence of bronchiectasis. Data suggests wide variation in prevalence (Table 1, [5,17–20]).

Table 1. The exact prevalence of bronchiectasis is unclear and there are differing reports across the US, Europe and Asia Pacific.

Country	Year	Reported prevalence	Reference
USA	2005	4.2 per 100,000 (age 18–34)	[5]
		271.8 per 100,000 (age >75)
	2012	370 per 100,000 person years	[19]
		537 per 100,000 person years (women, age 80–84)
UK	2004	350.5 per 100,000 (women, age >18)	[18]
		301.2 per 100,000 (men, age >18)
	2013	566.1 per 100,000 (women, age >18)
		485.5 per 100,000 (men, age >18)
Germany	2015	67 per 100,000 person years	[20]
China	2013	135 in 10,811 (age >40)	[17]

2. Overview of the market

2.1. What are the current strategies being applied to tackle the unmet need?

Current treatment guidelines recommend a number of approaches to managing NCFB, including airway clearance, airway drug therapy (primarily bronchodilators) and long-term antibiotic use. Surgery may be indicated in highly selected cases with localized disease [2]. The rationale for using antibiotics to reduce or delay exacerbations is based on long-term reduction of bacterial burden and the subsequent reduction of inflammation. By lowering bacterial burden, there is a dampening of chronic inflammation and resultant tissue damage. Consequently, if the number of exacerbations is reduced, a concurrent improvement should occur in a patient’s symptoms [8,21]. Inhaled therapies that directly target the site of infection enable high drug doses to be delivered, while minimizing systemic exposure [22]. Unfortunately, there is a paucity of high-quality evidence for the use of inhaled therapies in NCFB and guidelines recommending the use of inhaled antibiotics are based on data graded as poor quality from small studies, or from larger Phase III clinical studies that did not meet their primary end point. Furthermore, as these studies have all used different end points, outcomes cannot be directly compared.

2.2. Which competitor compounds/classes of compounds are in the clinic/late development?

A small (n = 65) single-blinded, controlled study of nebulized gentamicin versus nebulized 0.9% saline, showed antibiotic therapy significantly reduces the density of sputum bacteria in patients with NCFB, as well as improving exercise capacity and reducing exacerbations. The authors concluded however, that therapy needed to be continuous to maintain efficacy [23]. Other recent trials of therapies aiming to reduce exacerbations, such as the non-antibiotic mucoactive inhaled mannitol [24,25], or nebulized antibiotics such as colistin [26], and aztreonam lysine [27] all failed to show significant benefits in their primary end points. This may reflect the choice of end point(s) or the prerequisite study population rather than a true lack of efficacy. Finally, a small Phase II study (n = 42) of dual-release ciprofloxacin delivered via nebulization indicated antipseudomonal activity and a delay in time to first exacerbation [28]; Phase III trials are ongoing [29,30]. Table 2 summarizes ongoing and recent clinical trials of inhaled antibiotics in NCFB.

Table 2. Ongoing and recent clinical trials of inhaled antibiotics in NCFB.

	RESPIRE 1 and 2 Ciprofloxacin DPI [31,32]	ORBIT 3 and 4 Dual release ciprofloxacin for inhalation [29,30]	AIR-BX 1 and 2 Aztreonam lysine for inhalation [33,34]	Colistin [35]
Geographic regions	Global	Global	Global	UK, Russia and Ukraine
Randomization ratio	2 : 1	2 : 1	1 : 1	1 : 1
Treatment	Ciprofloxacin DPI 32.5 mg (single inhalation) BID vs. placebo BID	Dual release ciprofloxacin for inhalation (150 mg of liposomal ciprofloxacin and 60 mg of free ciprofloxacin) QD vs. placebo QD	Aztreonam lysine for inhalation 75 mg TID vs. placebo TID	Colistin 1 million IU BID vs. placebo BID
Treatment regimen	12 cycles. 14 days on- and 14 days off-drug	6 cycles. 28 days on- and 28 days off-drug	2 cycles. 28 days on therapy followed by 28 days off therapy	Continuous therapy (not cyclical)
	6 cycles. 28 days on- and 28 days off-drug
Formulation	Dry powder (1 capsule)	Nebulized	Nebulied	Nebulized
Total duration of study	48 weeks + 4 weeks	48 weeks + 4 weeks	16 weeks (double-blind)	26 weeks
			28 weeks (total)
Stratification	Pseudomonas aeruginosa infection	Not stated	None	By center
	Macrolide use
	Geographic region
Primary outcome measures	Time to first exacerbation and frequency of exacerbation [Time frame: 48 weeks]	ORBIT 3 – Time to first exacerbation [Time frame: one year] ORBIT 4 – Time to first pulmonary exacerbation [Time frame: 48 weeks]	Change in QOL-B respiratory symptoms score at day 28 [Time frame: baseline to day 28]	The time (days) from baseline/visit 2 (first dose) for each individual patient, until he/she experiences an exacerbation

BID: twice daily dosing; QD: once daily dosing; TID: three times daily dosing; IU: international units.

It is clear that there is a significant unmet need for well-designed trials in appropriate patient populations to establish the efficacy and safety of inhaled antibiotic therapies, particularly in patients with moderate or severe disease.

3. Introduction to ciprofloxacin dry powder for inhalation (DPI) (Box 1)

Ciprofloxacin is a broad-spectrum fluoroquinolone antibiotic with proven bactericidal efficacy against a range of pathogens seen in NCFB, including P. aeruginosa [36]. It is currently indicated for the treatment of systemic infections including respiratory infections [36]. Since becoming available, approximately 522 million patients have been treated with oral or intravenous formulations of Cipro^® (Bayer; data on file, Bayer), the drug therefore has a well-established safety profile [37]. The activity of ciprofloxacin is concentration dependent: the higher the peak concentration, the higher the bactericidal activity. This makes it a particularly suitable candidate for an inhaled product, where high drug concentrations can be achieved in the lung.

Box 1. Drug summary

Drug Name	Ciprofloxacin dry powder for inhalation
Phase	III
Indication	NCFB
Mechanism of action	The bactericidal action of ciprofloxacin results from the inhibition of both type II topoisomerase (DNA-gyrase) and topoisomerase IV, required for bacterial DNA replication, transcription, repair and recombination.
Route of administration	Delivery is via an efficient, portable, breath-actuated dry powder inhaler.
Pivotal trial(s)	RESPIRE 1 and RESPIRE 2 [31,32]: largest trial program to be carried out in NCFB to date, with strict entry criteria to ensure enrolled patients represent those who are most likely to benefit from long-term treatment with ciprofloxacin DPI. Two treatment regimens are being studied and patients have been stratified for randomization according to (among other factors) positive culture for P. aeruginosa and/or macrolide use. It is hoped that these studies will provide novel insights into the effectiveness of ciprofloxacin DPI in NCFB patients.

Ciprofloxacin DPI is in development as a long-term intermittent therapy to reduce the frequency of acute exacerbations in NCFB patients with respiratory bacterial pathogens [38]. Patients inhale ciprofloxacin 32.5 mg inhalation powder from one capsule twice-daily using a pocket sized inhaler. To administer the drug patients insert a single capsule then inhale deeply, this breath is then held for an additional five seconds. The small delivery device is easily understood and is designed to be both user-friendly and portable as it does not require a power source or cleaning. Furthermore it has a short administration time, with the drug usually delivered in one breath. Together these qualities mean the drug/device combination avoids many of the problems associated with nebulizers such as time-consuming administration [39], complex cleaning, sterilization and maintenance, and a decrease in the efficiency of drug delivery over time [40]. The device is already approved for the delivery of tobramycin and used in some countries for the treatment of cystic fibrosis patients in the form of the TOBI^® Podhaler™ (Novartis) [41,42]

Ciprofloxacin DPI (Figure 2) is undergoing Phase III trials in patients with idiopathic or post-infectious NCFB, to assess its efficacy in reducing exacerbations in patients with evidence of respiratory pathogens who suffer from two or more exacerbations annually [31,32].

Figure 2. Ciprofloxacin DPI drug and device.

4. Chemistry

Ciprofloxacin DPI consists of aerosolized ciprofloxacin that has been spray dried using the PulmoSphere™ spray drying process [38]. The technology creates a dry phospholipid ‘shell’ around the ciprofloxacin core which is thought to disperse rapidly upon introduction to the lung thus exposing the ciprofloxacin crystals. This may improve the tolerability of the drug, potentially reducing bronchospasm or cough. The process also facilitates controllable and reproducible particle size, density, morphology, and surface composition, all of which are critical to ensuring efficient and reproducible dose delivery to the lungs [38]. The active ingredient in ciprofloxacin DPI is ciprofloxacin hydrated (sometimes referred to as betaine). This form has lower solubility than the HCl salt which is rapidly absorbed through lung tissue; the ciprofloxacin hydrated form allows for a longer residence time in the lungs [43].

A total of 50 mg of ciprofloxacin DPI (equivalent to 32.5 mg of ciprofloxacin) is delivered in each dose; the small particles (≤5 µm mass median aerodynamic diameter) are optimized for delivery into the bronchopulmonary system and the mode of administration ensures high concentrations of the drug reach the lungs [44].

5. Pharmacodynamics, pharmacokinetics and metabolism

Phase I studies assessing the pharmacodynamics (PD) and pharmacokinetics (PK) of ciprofloxacin DPI have been carried out in healthy volunteers, and patients with cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). These studies showed that ciprofloxacin DPI attains high pulmonary concentrations coupled with low systemic exposure [45–49]. Concentrations of the drug in induced sputum are considerably higher than plasma levels; in a study of patients with CF, ciprofloxacin DPI (single dose, 32.5 mg) achieved a C_max (mg/L) of 34.9 and 0.0790 and an AUC (mg•h/L) of 89.5 and 0.425 in sputum and plasma respectively [50]. Preclinical studies in vivo also show that ciprofloxacin DPI has a higher t_1/2 vs. the soluble ciprofloxacin hydrochloride (HCl) suggesting that it has prolonged residence in the lung [43]. Ciprofloxacin HCl has a serum half-life of approximately 4 h [36] while ciprofloxacin DPI terminal half-life in healthy volunteers was found to be 9.5 h in a Phase I study [44]. Further key pharmacokinetic properties are summarized in Table 3.

Table 3. Key pharmacokinetic/pharmacodynamics properties of ciprofloxacin DPI in plasma and sputum.

Reference	[46]	[45]	[47]	[48]	[49]		[44]	[50]
Patient population	Mild to moderate COPD	Moderate to severe COPD	Moderate to severe COPD	Moderate to severe COPD	CF		Healthy	CF
Dosing	32.5 mg single dose	32.5 mg twice daily	32.5 mg twice daily	32.5 mg single dose	32.5 mg once daily	65 mg once daily	32.5 mg single dose	32.5 mg single dose	65 mg single dose
Parameter
Plasma
AUC (mg•h/L)	0.715	0.49	0.650 ^a	0.600	0.386	1.38	0.354	0.425	0.995
Cmax (mg/L)	0.115	0.10	0.130 ^a	0.114	0.0896	0.300	0.0564	0.0790	0.182
t½ (h)	7.22	12.2	11.6 ^a	6.00	4.60	5.30	9.538	6.30	8.06
MRT (h)	–	–	–	–	–	–	10.68	6.48	7.27
Sputum
AUC (mg•h/L)	338	295	668	552	–	–	–	89.5	649
Cmax (mg/L)	187	151	310	409	–	–	–	34.9	376
t½ (h)	1.76	–	–	–	–	–	–	7.48	6.19
MRT (h)	–	–	–	–	–	–	–	2.32	3.16

^a There was a single dose on day 12 with BID dosing from day 2 to day 11.

AUC: area under the plasma/sputum concentration–time curve; C_max: maximum drug concentration in plasma/sputum after single dose administration; MRT: mean residence time; t_½: half-life associated with the terminal slope.

Lung deposition data are available for healthy volunteers and patients with NCFB, COPD and CF. Data from scintigraphic studies confirm that ciprofloxacin DPI is delivered in high and reproducible doses to the entire lung with minimal amounts of drug remaining in the device following administration [51]. Physiological modeling in healthy volunteers indicates that approximately 40% of the inhaled dose reaches the lower respiratory tract [44,51]. This is high in comparison to the drug deposition achieved by other DPI products currently on the market; for example Colobreathe^® Turbospin^® (Forest Laboratories) which delivered on average 11.9% and 11.6% to the whole lung with or without pretreatment with salbutamol respectively [52]. Ciprofloxacin DPI therefore has the potential to be one of the highest delivering systems to date, with good distribution to the airways and the distal airways/alveoli, which we will collectively refer to as ‘delivery to the lung’ for simplicity.

6. Clinical efficacy

6.1. Phase II studies

Phase II studies in patients with CF indicated that ciprofloxacin DPI reduced bacterial load but did not significantly improve FEV₁ [53]. This may have been due to several reasons including the advanced nature of disease in the study population [22,54].

In a Phase II randomized, placebo-controlled, double-blind study of ciprofloxacin DPI in NCFB, adult patients with post-infectious or idiopathic NCFB with positive culture for P. aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Enterobacteriaceae, Stenotrophomonas maltophilia or Achromobacter xylosoxidans were enrolled and received either ciprofloxacin DPI 32.5 mg (n = 60) or matching placebo (n = 64) dispensed from a T-326 inhaler for 28 days and were followed for a further 56 days after end of therapy [55].

The results of the Phase II study are the first in NCFB to demonstrate that ciprofloxacin DPI produces a statistically significant reduction in bacterial load. Ciprofloxacin DPI had a potent bactericidal action and led to a significantly greater mean reduction in colony forming unit (CFU) count vs placebo at the end of therapy, equal to a 3.62 log reduction in bacterial load. Bacterial eradication also occurred at significantly higher rates in the ciprofloxacin DPI arm vs. placebo at day 8 (20/42, 48% vs. 6/51, 12%; p < 0.001) and end of therapy (14/40, 35% vs. 4/49, 8% p = 0.001) (Figure 3) [55].

Figure 3. Phase II study results: significant reductions in bacterial load were seen for patients treated with ciprofloxacin DPI [55]. Mean bacterial load for the modified intent-to-treat population treated with ciprofloxacin DPI in the Phase II study. Shaded area indicates treatment period (days). Mean reductions in colony forming units at end of therapy were significantly higher ciprofloxacin DPI vs placebo: −3.62 log₁₀ CFU·g⁻¹, range −9.78–5.02 log₁₀ CFU·g⁻¹ vs −0.27 log₁₀ CFU·g⁻¹, range −7.96–5.25 log₁₀ CFU·g⁻¹ *** p = 0.001. Reproduced with permission of the European Respiratory Society ©: European Respiratory Journal May 2013, 41 (5) 1107‐1115; Doi: 10.1183/09031936.00071312.

Some increases in minimum inhibitory concentrations were seen in the ciprofloxacin DPI arm for P. aeruginosa (n = 4), S. maltophilia (n = 1) and H. influenzae (n = 1) but most were transient and decreased to susceptible levels by the end of the study. A trend toward improved quality of life was also seen at the end of treatment, with an adjusted mean difference in St Georges Respiratory Questionnaire (SGRQ) score for ciprofloxacin DPI compared with placebo of −3.56 (95% CI −7.3 to 0.1; p = 0.059). A concurrent improvement of four-points in the SGRQ (i.e. a clinically significant improvement) was also seen in 40% of patients receiving ciprofloxacin DPI vs. 32% in patients receiving placebo. Overall this study provided evidence that targeted delivery of ciprofloxacin DPI resulted in a clear reduction in bacterial load and was well tolerated, with potential to improve quality of life (QoL) outcomes. Following these positive results ciprofloxacin DPI moved into Phase III development.

6.2. Phase III studies

6.2.1. Study design

The fully enrolled, ongoing Phase III trials of ciprofloxacin DPI in NCFB – RESPIRE 1 and RESPIRE 2 – represent the largest program to be carried out in NCFB to date, with a planned study population of over 900 patients [31,32,56,57]. The two studies are of the same design: international prospective, parallel-group, randomized, double-blinded, multicenter, placebo-controlled trials scheduled to run for 48 weeks with an 8-week follow-up period after the last dose [56,57].

In both studies, patients follow a pattern of 28 days on- and 28 days off-drug, resulting in a total of six active cycles; or a pattern of 14 days on- and 14 days off-drug resulting in a total of 12 active cycles (Figure 4). These two patterns were chosen because, although a 28-day cycle is widely used in CF treatment, there is no evidence for the appropriate cycle duration in patients with NCFB; therefore the two treatment regimens are being studied with the aim of providing novel scientific insights into optimal treatment durations for NCFB. In both studies, patients with NCFB are scheduled to receive cyclical regimens of twice-daily ciprofloxacin DPI 32.5 mg or matching placebo.

Figure 4. RESPIRE 1 and 2 treatment regimens [56].

6.2.2. Inclusion and exclusion criteria

Taken in their entirety, the inclusion/exclusion criteria help ensure that the patients enrolled are representative of the population most likely to benefit from long-term, cyclical use of ciprofloxacin DPI.

The strict entry criteria for RESPIRE 1 and 2 aim to ensure that the study population only includes patients with either postinfectious or idiopathic disease, rather than a heterogeneous population as seen in previous studies (Table 4) [58]. Inclusion is also restricted to patients who have two or more exacerbations in the prior 12 months and are therefore most in need of a therapy that reduces exacerbation frequency. The program is designed to take into account the microbiological diversity found in patients with NCFB; respiratory pathogens infect the bronchial airways in a large number of those with the disease and recent data highlight the consequences of chronic bacterial infection on patient outcomes including increasing hospital admission and mortality rates [10,15,59]. Although P. aeruginosa is a known prognostic marker for poor outcomes, including a three-fold increase in mortality as well as increased risk of exacerbations [60], there is evidence that other common pathogens such as H. influenzae and S. aureus also have negative consequences [10,59,61]. P. aeruginosa isolation rates vary depending on the setting and may be subject to tertiary care center bias. In the US bronchiectasis registry, 37% Pseudomonas species isolation was reported [62] and recently EMBARC (European Multicentre Bronchiectasis Audit and Research Collaboration) reported that P. aeruginosa was isolated in 290 of 1283 patients [63]. A large proportion of patients are also colonized with pathogens other than P. aeruginosa and therefore RESPIRE was designed to enroll patients who have at least one of seven predefined pathogens – P. aeruginosa, H. influenzae, M. catarrhalis, S. aureus, S. pneumoniae, S. maltophilia and Burkholderia cepacia.

Table 4. Key inclusion and exclusion criteria for the RESPIRE clinical trial program.

Key inclusion criteria

Key exclusion criteria

Stable patients with primary diagnosis of NCFB Idiopathic or post infectious etiology FEV1 <90% and ≥30% predicted ≥2 exacerbations in the previous 12 months Positive culture from an adequate sputum at screening sample for P. aeruginosa, H. influenzae, M. catarrhalis, S. aureus, S. pneumoniae, S. maltophilia or B. cepacia Bronchodilators, anticholinergics, inhaled corticosteroids, or mucolytics, if used as chronic treatment for NCFB, at least for the past 4 weeks prior to screening Macrolides if used as chronic treatment for NCFB for at least 6 months prior to screening

Active allergic bronchopulmonary aspergillosis Active and actively treated nontuberculosis mycobacterial infection or tuberculosis Diagnosis of common variable immunodeficiency Recent significant hemoptysis (≥300 mL or requiring blood transfusion) in the preceding 4 weeks before screening (and during the screening period) Primary diagnosis of chronic obstructive pulmonary disease Systemic or inhaled antibiotic treatment for any indication within 4 weeks prior to the administration of study drug; except for chronic macrolide use Systemic corticosteroids at >10 mg/day prednisolone equivalent for >14 days within 4 weeks prior to the administration of study drug

NCFB: non-cystic fibrosis bronchiectasis; FEV₁: forced expiratory volume in one second.

6.2.3. End points

Two end points, developed in conjunction with the regulatory authorities, are being used in the RESPIRE studies (Table 5): time to first exacerbation and frequency of exacerbation during the 48-week study. Exacerbations are strictly defined as requiring systemic antibiotic use, and worsening of at least three signs or symptoms and fever or malaise/fatigue. This stringent definition aims to prevent symptoms that are caused by, for example respiratory viruses, from being mislabeled as bacterial exacerbations. Other end points include: frequency of exacerbations requiring systemic antibiotics and at least one sign or symptom; quality of life and microbiology end points, lung function and safety.

Table 5. Main end points in the RESPIRE clinical trial program.

Primary efficacy end points Frequency of exacerbations Time to first exacerbation

Secondary efficacy end points

Frequency of exacerbations over 48 weeks/time to first exacerbation within 48 weeks after start of treatment Frequency of pulmonary exacerbation as defined as events with systemic antibiotic use and worsening of at least one sign/symptom Apparent pathogen eradication present at baseline Changes from baseline in the disease-specific PRO score SGRQ (symptoms component score) Occurrence of new pathogens not present at baseline Changes from baseline in the disease-specific PRO score QoL-B respiratory symptom domain Changes from baseline in FEV1 (postbronchodilator spirometry)

PRO: patient-reported outcome; FEV₁: forced expiratory volume in one second; SGRQ: St Georges’ Respiratory Questionnaire; QoL-B: quality of life – bronchiectasis.

6.2.4. Analyses: patient stratification

Patients are stratified for 2 : 1 (ciprofloxacin DPI : placebo) randomization according to geographic region, positive culture for P. aeruginosa and chronic (≥6 months) macrolide use. As a number of NCFB patients in day-to-day clinical practice receive chronic macrolide therapy [16,64], the efficacy and safety of any new therapies that may be used in conjunction with this should be assessed, as in the RESPIRE cohorts. Furthermore given that patients chronically infected with P. aeruginosa have relatively high rates of persistent infection and hospitalization [59], and that ciprofloxacin has potent antipseudomonal properties it will be important to ascertain whether any benefits from the drug are dependent on the presence or absence of this pathogen.

7. Safety and tolerability

The safety profile of ciprofloxacin DPI has been assessed in several studies, and the drug has been shown to be generally well tolerated. Several Phase I and II trials indicate that ciprofloxacin DPI is generally well tolerated in patients with COPD, CF or NCFB and results from Phase III studies are awaited to confirm this [49–51,53,55]. Treatment emergent adverse events (AEs) in Phase II studies have been similar between ciprofloxacin DPI- and placebo-treated patients both in nature and frequency. Most commonly, ciprofloxacin DPI patients have reported abnormal product taste/dysgeusia which is characteristic of the drug [53,55]. The low occurrence of respiratory tract irritation in studies of ciprofloxacin DPI is particularly noteworthy as cough, bronchospasm and bronchial obstruction pose potential tolerability issues for current and future inhaled therapies. In a recent trial of aztreonam for inhalation solution, cough and bronchospasm were reported as serious AEs in 1/134 and 3/134 of aztreonam patients respectively [33] and cough reported amongst other AEs in 66/135 patients [34]. Of a total of 153 patients treated with ciprofloxacin DPI in two studies (one in NCFB and the other CF), bronchospasm was reported in only six patients overall [53,55]. Cough occurrence in ciprofloxacin DPI- and placebo-treated patients in the CF study was 3.2% and 10.8% respectively [53] and in the NCFB study this rate was 0% and 7.8% [55]. This compares favorably to other inhaled dry powder products such as the TOBI Podhaler where cough is perceived to be problematic [65].

8. Regulatory affairs

In April 2014, the US Food and Drug Administration’s (FDA) Office of Orphan Products Development granted Orphan Drug Designation (ODD) to ciprofloxacin DPI for the treatment of NCFB. In addition to ODD, in November 2014 the FDA also granted ciprofloxacin DPI Qualified Infectious Disease Product (QIDP) status. Antimicrobial drugs which are designed to treat serious and life-threatening infections and are designated as QIDP are eligible for fast-track designation, priority review by the FDA, and a five-year extension of market exclusivity.

9. Conclusions

NCFB is an increasingly prevalent respiratory pathology associated with significant morbidity and mortality. Inhaled antibiotic therapies that directly target the site of infection may provide effective treatment options to reduce and delay exacerbations and improve quality of life, however there are currently no such licensed products. Ciprofloxacin DPI is an inhaled formulation of an antibiotic with proven efficacy against a range of respiratory pathogens, and is currently in Phase III development. Lung tolerability data suggest that ciprofloxacin DPI has the potential to reduce adverse events, such as cough and bronchospasm, which are perceived to be common with other inhaled antibiotics in this patient population. The current clinical trial program is the largest interventional trial in NCFB with one of the most robust study designs including patients with a variety of common respiratory pathogens, including P. aeruginosa. The inclusion of patients infected with P. aeruginosa and non-P. aeruginosa bacteria aims to increase our understanding of the likely clinical impact of these pathogens. It is hoped that these studies will provide new treatment options for patients suffering from this debilitating disease.

10. Expert opinion

10.1. What, if any, improvement does the drug/therapy hold over other therapies?

Ciprofloxacin DPI is delivered directly to the lungs in as little as one breath without the need for nebulization. Unlike many nebulized formulations, the PulmoSphere technology that carries ciprofloxacin DPI is aerodynamic and optimized for delivery into the bronchopulmonary system thus ensuring high concentrations of the drug reach the distal lung. The dry powder form offers good tolerability with no significant cough or bronchospasm adverse events reported in Phase I and II trials. The simplicity and short administration time make ciprofloxacin DPI an attractive treatment option in comparison to nebulized delivery. Furthermore, by targeting the lung, high drug concentrations in the airways are obtained and these are coupled with low systemic exposure; this could decrease the risk of systemic adverse events and potentially reduce the development of resistance in some cases, though long-term data are needed to establish this.

10.2. In developing this drug, what are the key lessons for R&D scientists in the field? Could these lessons be applied to other rare diseases/niche indications?

The RESPIRE studies will provide a benchmark for clinical trial design in NCFB. The etiological entry criteria used greatly broadens the applicability of the study results. The assessment of a monthly and 2-weekly treatment schedule is distinct and unique to the RESPIRE studies and is the first time such a design has been used in trials for NCFB. Furthermore stratifying patients by P. aeruginosa presence or macrolide use may provide valuable insights into ‘responder populations’. As the studies have no restrictions on the baseline MICs of pathogens at the time of enrolment, the ability of the drug to treat patients with resistant pathogens will be elucidated.

10.3. What, if any, impact is this drug/therapy likely to have on current treatment strategies?

There is currently no approved inhaled antibiotic therapy for NCFB and the off-label use of inhaled antibiotics with no evidence base is common but likely unsustainable [16]. Robust efficacy data emerging from the RESPIRE trials is likely to improve clinical access. The simplicity of ciprofloxacin DPI use may increase the overall proportion of NCFB patients on inhalational antibiotics.

10.4. How likely are physicians to prescribe the drug?

Upon successful Phase III trials it is anticipated that there will be significant usage of this drug. The tolerability and low treatment burden coupled with the robust evidence expected make it an attractive option with advantages over current off-label NCFB treatments, to physicians, patients and payers alike. Ciprofloxacin DPI has potential to be used in both specialist and general respiratory secondary care clinics.

10.5. What data are still needed?

To be widely embraced, cost-effectiveness studies and better understanding of emergence and implications of ciprofloxacin resistance during prolonged treatment will be needed. Current studies are not powered to show mortality benefits and such data, perhaps in postmarketing observational studies, will be of great interest to clinicians. Furthermore, studies to determine ‘eradication’ of Pseudomonas in the long-term will be important.

Physicians will also wish to see ciprofloxacin DPI studies in more diverse phenotypes of bronchiectasis: current RESPIRE studies include around 40–60% of potential etiological causes of bronchiectasis [2,59]. Many patients also present with moderate to severe COPD and this bronchiectasis–COPD overlap [66] is associated with a poorer prognosis compared to idiopathic bronchiectasis [12]. It is estimated that bronchiectasis–COPD overlap syndrome (BCOS) may affect as many as 7 million patients in the EU alone [J Chalmers personal communication] and therefore studies of ciprofloxacin DPI in BCOS will be of great interest.

10.6. Where is this drug likely to be in 5 years’ time?

As ciprofloxacin DPI is still undergoing Phase III trials, it has not yet been approved and full efficacy and safety data are still required. If the drug reaches its primary end point in the RESPIRE studies, it is likely to be in widespread use in the future – possibly continuously or in milder cases covering the winter exacerbation period. It should be noted however that, as the drug is not currently approved, these uses may fall outside any future license.

Declaration of interest

Writing support was provided by highfield:communication, Oxford, UK and funded by Bayer Pharma AG. The manuscript was derived and completed independently of Bayer, but the final manuscript was assessed by Bayer for accuracy. A De Soyza has received speakers fees, travel/congress attendance support from AstraZeneca, Bayer, Chiesi, GlaxoSmithKline, Forrest and Novartis, and has received research grants from Bayer, Forrest and Novartis. T Aksamit has participated in trials sponsored by Bayer, Aradigm/Grifols, Insmed, and Gilead but has not received personal or research support. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.