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Introduction

Over the last several years the prevalence of respiratory diseases saw a strong increase, and there are now approximately 500 million patients today worldwide. Moreover the mortality doubled over the last 40 years in contrast to all other common causes for mortality such as cardiovascular disease, cancer, and infectious diseases. The most common types of respiratory diseases are asthma and Chronic Obstructive Lung Disease (COPD). The increased prevalence is attributed to increased exposure to risk factors and an ageing population. The majority of treatments today for these diseases are by inhalation therapy often in combinations. Advances in treatment are linked to better insights into the mechanisms of disease in particular the role of inflammation. These insights have also let to increase the possibilities for pheno- and endotyping. All clinical features determined by the combination of genotype and environment defines the phenotype, while the endotype means the subtypes defined by distinct physiological mechanisms.

The costs for developing the new drugs are, however, rising and the attrition rate is very high. Moreover the currently used pharmacodynamic techniques and surrogate outcome parameters lack sensitivity for testing new drugs, adding to the complexity of development.

The main primary outcome measurements that are used today in clinical trials are the dynamic lung volume after one second of forced expiration (FEV1), clinical exacerbations, and scales measuring impaired health and perceived wellbeing such as the Saint George Respiratory Questionnaire (SGRQ) used in the study of COPD. These metrics lack sensitivity and there is a poor correlation between them and with overall survival.

So there is a clear unmet need for more performant techniques, that can help to decrease the number of patients to include in studies and finally also to a more efficient early development, leading to lower attrition rate in confirmatory trials.

In this article we will discuss a number of alternative techniques, of which some are already used currently in clinical practice, but rarely in drug development and some are rather new.

Current Status of Respiratory Drug Development

At the end of 2014, there were 843 ongoing studies in respiratory drug development registered in clintrials.gov: 250 in oncology, 186 in asthma and 74 in COPD, the rest spread over infectious diseases, sleep apnea and interstitial lung diseases. During the last 5 years SGS performed over 50 trials mainly in the asthma and COPD area, some in other allergic diseases like rhinitis, and in cystic fibrosis and pulmonary arterial hypertension. Therefore we developed a wide range of respiratory techniques to use in respiratory trials. Some will be discussed here.

But first we describe a typical clinical trial in COPD, recently executed. It concerns a Phase 2, randomized, placebo-controlled, 5-way cross-over pharmacological study, with a classical inhalation combination of an anti-inflammatory corticoid (ICS) – beclomethasone- and a long-acting beta-agonist (LABA) – formoterol. The drug was administered as a Dry Powder Inhalator (DPI) to 50 moderate/severe stable COPD patients (GOLD guidelines 2013). Subjects received five different, one-day single-dose treatments, separated by a minimum 7-day washout period. The main objective of the study was to compare heart rate, effect on serum potassium, glucose, cardiovascular, safety and tolerability. The respiratory function parameter that was tested was FEV1.

Challenges for such a study are a correct dosing technique used in the right circumstances, as this a key factor for success in this type of studies and not an evidence and also the selection of the right patients in a short time frame. 106 patients need to be screened in order to include successfully 49 patients in less than 2 months.

Body Plethysmography

The Body Plethysmography, technique, also called “body box”, is increasingly used in clinical practice because of better-controlled circumstances and the possibility to measure a greater number of more sensitive dynamic lung volumes than only FEV1 or vital capacity, but also parameters as Residual Volume (RV), oscillometry, Diffusion Capacity for carbon monoxide (DLCO) and Airway Resistance. Also the use of the box for testing reversibility and eventual doing more repeatable bronchial challenge testing offers an advantage. Application of this technique in clinical studies adds to more sensitive measurements.

Challenge methods

In clinical development, respiratory challenge tests allow proof of concept (POC) studies even in healthy volunteers and in mild to moderately ill patients.

1. Bronchoprovocation testing

The best known test for many years is the inhalation of increasing concentrations of a histamine solution with measurement of airway responsiveness. It can be used for diagnosis and quantification of bronchial hyperreactivity. It is used in clinical practice for the diagnosis of asthma and it can replace/adjust reversibility testing, which has a lot of false negatives in well-controlled mild-to-moderate asthma. It can also be used in COPD and more precisely in the recently defines Asthma-COPD-Overlap Syndrome (ACOS). The use of bronchoprovocation testing in clinical trials of asthma and COPD can increase recruitment potential and decrease screen failure rate in studies. It is also included in some reimbursement criteria. The concentration of the challenge agent producing a 20% fall in FEV1 (PC20) is the measurement used in these studies. Histamine has however a number of adverse reactions like headache, tachycardia, bronchoconstriction (shortness of breath), making it difficult to use. Probably better and more specific alternatives, but less used are metacholine that exerts its action by direct stimulation of the bronchial smooth muscle cells, and adenosine (AMP) working rather indirect via mast cell degranulation releasing proinflammatory mediators. All three agents can be used as early POC for either bronchoprotection or bronchodilation trials, mainly in asthma.

For allergen testing circumstances have to be even more rigorously controlled. recently the use of a Mobile Chamber with nine places, build in a container with ideal environment, making testing independent from the allergy season, was presented at an allergy congres in Barcelona in 2015 (Mobile Chambers Experts GmbH).

2. LPS challenge

Inhaled lipopolysaccharide (LPS) or endotoxin is a Toll-like Receptor 4 (TLR4) agonist, which activates cytokine production. It invokes an acute inflammatory response in the lung, what is one of the important mechanisms in asthma and COPD. It can be used for the study of anti-inflammatory drugs for asthma and COPD. Endotoxin is administered as an inhaled agent via an ultrasonic nebulizer, up to 50 mcg LPS/mL isotonic saline or as an IV infusion LPS (4 ng/kg) over a 2-minute period in other indications like sepsis. SGS has experience with both type of administrations. Measurements of the effect are done in induced sputum (see further) by a response in the number of granulocytes or in the levels of various cytokines e.g. TNF-α, IL-1β, IL-6, IL-8, and IL-10.

This is illustrated in a case study of a Phase 1 SAD-MAD-POC study ( Single and Multiple Ascending Dose and Proof of Concept study) in asthma. LPS challenge was conducted on 1 cohort of healthy male subjects and 1 cohort of asthmatic patients. The endotoxin (50 µg/mL) was inhaled over a 2-minute period (5 deep breaths of the nebulized solution). Sputum induction was done at preset time points after the challenge using increasing concentrations of hypertonic saline (up to 5%).

3. Viral challenge testing

The Viral Challenge Model produces high quality proof of concept, safety and efficacy data mainly in upper respiratory tract infections and is used and appreciated by pharma and biotech companies in early phase development since a long time. It establishes clear correlates of protection (CoP) for vaccines and antivirals, informs Go/No Go decisions and facilitates the Up or Down selection of study arms. Its use in asthma is based on the new insights that asthma is an inflammatory disease, with exacerbations highly related to viral infections. It requires a dedicated isolation suite preferentially located within a clinical pharmacology unit (CPU) and with an experienced team like in SGS’s phase 1 unit.

In the case study that we describe with this methodology, SGS tested a monoclonal antibody (mAb) targeting human Toll-like receptor 3 (chemoattractant receptor-homologous molecule expressed on Th2 cells: CRTH2) for the prevention of asthma exacerbations. The trial was a Phase 1, randomized, double-blind, placebo-controlled study, in 12 healthy normal (part 1) and 60 asthmatic subjects (part 2) to which the study drug was intravenously administered prior to inoculation with human rhinovirus Type 16. The primary endpoint was safety and tolerability in part 1 and efficacy (pulmonary function testing and patient reported outcomes) in part 2. Secondary endpoints were Pharmacokinetics (PK), Pharmacodynamics (PD) by testing additional pulmonary function tests, Cold Symptom Assessment Score, and Fractional Excretion of Nitric Oxide (FENO) a parameter for inflammation, biomarkers in nasal lavage, immunogenicity and pharmacogenomics. Part 1 was successfully executed in 4 months but with major hurdles: getting regulatory approval for a drug with a new mechanism of action combined with viral challenge and a major recruitment challenge as we needed to test 160 healthy, consenting volunteers to enroll 12 individuals in the trial, mainly caused by the higher than expected positive antibody status. In part 2, the antibody status combined with additional very challenging in- and exclusion criteria led to a failure rate of 100 % after testing 80 asthmatic patients, so that we needed to stop the trial in our own asthma population.

Measuring lung disposition of inhaled drugs

1. Sputum induction

To study inhalation drugs we need to know the concentration of inhaled drugs and outcome biomarkers in the lower airways. These biomarkers are the inflammatory cytokines as previously mentioned. The technique of induction is relatively simple by inhalation of increasing concentrations of saline, and is non-invasive making it the preferred technique in drug development. However the reproducibility has been questioned for a long time and the preparation of the sputum samples for bio-analysis is quite elaborate, time-consuming and highly demanding for trained technicians. There are only a few methodological studies that have examined the influence of various technical factors on the repeatability of sputum induction and collection, so that there is no golden standard for this technique.

However, meeting all required conditions, SGS realized quite impressive results, compared with the literature. We had a success rate of 29 % (n=175) compared with 10 % in the literature in non-smoking healthy volunteers with and a success rate of 74 % (n = 35) compared with 70 % in the literature in asthma patients. There was also a very high success rate in smoking healthy volunteers, but in this series our numbers are until now to limited to make firm conclusions. So we are convinced that SGS can offer this as a reliable technique but with the restrictions mentioned previously.

2. Local bronchial pharmacokinetics

With this technique one can really determine the time-concentration profile of drugs and cytokines in bronchoalveolar lavage fluid (BALF) for prediction of therapeutic efficacy. It allows simultaneous assessment of the local and systemic pharmacokinetics of single and repeated doses of inhaled drugs. For executing this invasive technique a pulmonologist experienced in bronchoscopy is required, who can wedge the scope in different positions in the bronchial tree to infuse saline distant from the bronchoscope and collect BALF samples.

We present here a case study done in our phase 1 unit. A Phase 1, single center, open label study was done in male HV to evaluate local and systemic pharmacokinetics of a nanobody against Respiratory Syncytial Virus (RSV). The drug was administered to 41 healthy male volunteers, as an oral inhalation of single or multiple doses or an intravenous infusion of a single dose. The objective of the study was local (BALF) and systemic (blood) PK after single and repeated administration, urinary PK, safety, and immunogenicity. 44 healthy volunteers (3 drop-outs) were included after 74 screen failures. There were 4 moderate adverse events due to the BALF procedure (3 x fever, 1 x dyspnea). All recuperated completely after a short duration. The study was completed successfully and delivered robust data for the PK/PD modeling of the study drug.

Functional Respiratory Imaging

In Functional Respiratory Imaging (FRI), 3D segmented computer models are constructed of human organs scanned by different imaging techniques: High Resolution Computed Tomography (HRCT), Magnetic Resonance Imaging (MRI), and Ultrasound (US). The example in the respiratory field that we give is that of Fluidda, an FRI company, located close to SGS’s phase 1 unit with an established collaboration. Its technology combines High Resolution Computed Tomography with 2 advanced computational fluid dynamics tools of the aerospace industry: Computational Fluid Dynamics (CFD) and Finite Element Analysis (FEA). Currently the technique can support early phase clinical trials in asthma, COPD, idiopathic pulmonary fibrosis, cystic fibrosis, and sleep disorders. After constructing the models, the technique will measure airway resistance in different types of airways, changes in lobar hyperinflation and in lobar perfusion with the potential to measure local drug disposition. It is non-invasive technique, so it can potentially be used in the future for later phase trials as well.

These and other functional imaging techniques as mentioned higher eventually combined with Positron Emission Tomography (PET) and Inhaled Radiolabelled Drugs can further add to a growing number of efficient PD techniques.

Conclusion

We can conclude that the low performance of classical primary respiratory endpoints in exploratory and confirmatory studies, the increasing complexity of drug development and the new insights in the mechanisms of respiratory diseases, created a high need for more sensitive PD markers in respiratory research and development. An important number of new and existing techniques emerge to add or replace the currently used outcome parameters. Most proven value is demonstrated in early phase exploratory clinical trials, but some could become useful in later stages of development. We are convinced that offering these and upcoming techniques in the near future, are needed to support pharma and biotech companies in the development of new and better respiratory drugs.

Author

Robert Lins, MD, PhD
SGS Life Science Services, Senior Clinical Adviser - Clinical Research
www.sgs.com/cro

Sources

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