Our mission is to find effective non-antibiotic antimicrobial therapies for people with serious respiratory infections or chronic airway colonization, to extend or improve the quality of their lives.
About Cystic Fibrosis
Cystic Fibrosis (CF) is a rare hereditary disease affecting mostly Caucasians. Case finding studies resulted in incidence rates of ~1:2500 Caucasian children, with a carrier frequency of 1:25. Estimates from non-Caucasian populations from the US give incidence rates of 1:14,000 for black Americans and 1:11,500 for Hispanic births.
Since the discovery of the causative gene in 1989, pancreatic enzyme supplementation therapy and various antibiotics, mucolytics and other drugs have increased the life expectancy from <10 years to ~40 years in industrialized countries. Until today no causative therapy has been discovered for the large majority of patients and lung infection caused by a large variety of different bacterial and fungal pathogens is the major contributor of morbidity and mortality. Particularly, infections caused by the opportunistic pathogen Pseudomonas aeruginosa are virtually impossible to eradicate with antibiotics once the pathogen has established itself in the airways, resulting in a chronic vicious cycle of infection/inflammation which destroy and remodel airway tissues. Antibiotic therapy for CF lung infections has led to improvement in lung function in many studies (e.g., Ramsey et al., 1999). Chronic P. aeruginosa infections in CF necessitate many antibiotic therapy courses which carry the risk that resistance of the persisting pathogens towards a given drug increases more or less rapidly. Therefore, inhaled tobramycin is administered generally to CF patients in an intermittent regimen of one month on, one month off which leads to a decrease in lung function in the month off period if not adequately substituted with other antibiotics.
In addition to P. aeruginosa, many Burkholderia species are highly virulent pathogens in CF patients. These bacteria comprise a group of ten distinct but closely related species referred to as the Burkholderia cepacia complex (BCC). BCC strains can cause life-threatening lung infections in individuals with CF. B. cenocepacia and B. multivorans are the most common species in CF airways. In some cases, infection with B. cenocepacia results in a rapid deterioration in lung function, characterized by necrotizing pneumonia, bacteremia and sepsis, referred to as “cepacia syndrome”. BCC species are intrinsically resistant to many antibiotics and therefore nearly impossible to eradicate from CF lung infections.
Furthermore, the opportunistic pathogen Staphylococcus aureus is highly prevalent in CF patients. In 2011, S. aureus was isolated from respiratory tract secretions in nearly 80% of CF patients aged 11-17 in the USA. Its virulence is multifactorial and mediated by a variety of extracellular toxins and surface structures including biofilm formation in airways of CF patients. Moreover, the prevalence of methicillin-resistant S. aureus (MRSA) has increased. In 2001 MRSA was found to grow from respiratory tract secretions of only 7% of patients, compared with more than 30% in patients aged 18-24 in 2011. S. aureus is regarded as an important pathogen in patients with CF, for which treatment with antibiotics is only partially successful due to biofilm formation, sub-inhibitory concentrations in the airways, and the rapid development of antibiotic resistance.
The considerable difficulty to resolve bacterial infections associated with CF (and other infectious diseases) is thought to be mostly a reflection of the world wide increasing proportions of antibiotic resistant strains. To combat infections, various classes of potent anti-microbial drugs have been developed in the past 80 years, which have considerably improved the management of infectious diseases. This “golden age” of antibiotics engendered such optimism that it was commonly thought bacterial infections would be rapidly eliminated as a cause of mortality. Unfortunately, bacterial resistance to all classes of antibiotics soon appeared. Heavy antibiotic use and person-to-person spread of bacteria have greatly increased antibiotic resistance, and this problem is continually increasing in severity. As a result, multi drug-resistant bacteria are no longer limited to hospitals; they have arisen and spread in the community and represent today a global health risk. There is alarming evidence of increasing transmissible epidemic strains that prevail in major European centers with transmission occurring between unrelated CF patients. Even worse is the case of cross infection and significant morbidity of a healthy patient colonized by epidemic P. aeruginosa from chronically infected CF patients.
In addition to increasing resistance rates towards antibiotics worldwide, antibiotics may be less effective in CF airways due to sputum adsorption. CF sputum is mainly composed of negatively charged glycoproteins and DNA. Positively charged aminoglycosides such as tobramycin are thought to be bound to these compounds. Furthermore, the biofilm mode of growth of P. aeruginosa requires 100 to 1,000 times the concentration of a certain antibiotic to be effective compared to its non-mucoid variant. Taken together, several severe obstacles are present in infected CF patients, which compromise the use of antibiotics for combating respiratory tract infection. Thus, there is an urgent need to develop alternative treatment strategies.
The global increase in antimicrobial resistance of bacterial pathogens is a major threat for CF patients who routinely are visiting hospitals and are frequently treated with antibiotics. The speed of development of novel antibiotics by the pharmaceutical industry has been unfortunately slower than the emergence of resistance. To face the unmet medical need of lung infection in CF, the proposed gaseous Thiolanox® inhalation therapy has been developed.
About Multi-Drug Resistant Tuberculosis (MDR-TB)
There are approximately 2 billion people worldwide infected with Mycobacterium tuberculosis (MTB). MTB initially colonizes and then proliferates in lung macrophages, destroying the lung tissue. The key to MTB’s pathogenicity is its internal mechanisms that enable it to evade the body’s natural immune bactericidal response. The risk of developing MTB disease (“active TB”) after tuberculin infection is about 10%. In India, TB kills approximately 1,000 people every day.
The term “drug-resistant tuberculosis” refers to tuberculosis caused by an isolate of Mycobacterium tuberculosis that is resistant to one of the first-line anti-tuberculosis drugs (isoniazid, rifampin, pyrazinamide, ethambutol or streptomycin). Multidrug-resistant tuberculosis (MDR-TB) is caused by an isolate of M. tuberculosis that is resistant to at least isoniazid and rifampin, and possibly additional chemotherapeutic agents. The treatment of drug susceptible MTB requires 6-9 months of daily therapy and failure to adhere to the treatment is associated with the development of secondary multi-drug resistant strains (MDR TB). Primary drug resistant TB can occur in patients who have never received anti-tuberculosis therapy by exposure to others with MDR-TB.
For patients with confirmed MDR-TB, drug treatments include aminoglycosides which are known to be associated with nephrotoxicity and cranial nerve damage or fluoroquinolones which have been associated with cardiac toxicities. New agents are still needed to treat drug sensitive TB but there are critical needs, especially for multi-drug resistant TB (MDR-TB), Extensively drug resistant TB (XDR TB) for which there are only limited effective drugs and the latest identified strains of extensively drug resistant TB (XXDR-TB) for which there is no treatment. To understand the problem of drug resistant tuberculosis and the need for novel technologies, watch the Ted Talk by Dr. Zarir Udwadia in the following link: https://youtu.be/ziB_OwLda-g
For each person with active TB, they infect 10-15 other people and therefore infectivity is a major concern to contain the spread of drug resistant strains of TB. While short-term exposure to inhaled nitric oxide may not provide a curative treatment, there is a reasonable expectation that it can reduce the infectivity of patients by decontaminating their airways. A major goal of TB research is to identify methods to reduce infectivity of people with active TB.
Novoteris, is working with researchers from Canada and India in collaboration with the Indian Health Ministry and the Indian Council of Medical Research (ICMR) TB Consortium to conduct a clinical trial to evaluate inhaled gNO to convert sputum TB positive to TB negative for individuals with refractory MDRTB despite 6 months of Cat 5 antibiotic treatment regimens.
About Nitric Oxide
Nitric oxide (NO) is a naturally occurring endogenously produced nano-molecule shown to possess a wide variety of biochemical characteristics. These properties have been demonstrated to have a utility to treat infections. NO has also been recognized as a primary signaling molecule in biological systems. It has been shown that in low concentrations NO can promote the growth and activity of immune cells, while at higher concentrations, it nitrosylates microbial heme- or thiol-containing DNA, RNA, proteins and lipids, thereby inhibiting or killing target pathogens. NO is both a lipophilic and hydrophilic nitrosylating stable free radical gas, with a small Stokes radius that allows it to readily cross cell membranes and yet dissolves readily in water. NO is an efficient broad spectrum anti-infective agent. It has antimicrobial activity against Gram negative and Gram positive bacteria, yeast, fungi, and viruses both in vitro and in vivo studies. NO possesses simple pharmacokinetics and an extremely short half-life (seconds) without residual nitrites and methemoglobin. Inhaled NO will bind to hemoglobin and create methemoglobin within minutes. It is further reduced to nitrites and nitrates then excreted in the urine within hours.
NO is also a known mucolytic and vasodilator. It is a smooth-muscle relaxant and is therefore an effective short acting bronchodilator. As such, the bronchodilator effect of NO could contribute to the removal of secretions and maintain airway epithelial quiescence. NO has also been reported to modulate ciliary beat frequency in the airways. Furthermore, NO is a known nitrosylating agent and prevents cysteine bonding by binding to the sulfur moieties. Therefore, NO administered to the airways prior to or during pulmonary infections may reduce viral load and thus bacterial susceptibility, thin secretions, restore the mucociliary apparatus and augment removal of secretions.
During infection, NO may not only improve oxygenation but its direct vasodilatory effect may improve local blood flow to the entire respiratory tract. This increased blood flow could bring nutrients, white blood cells and increase local temperature; all of which are potentially beneficial for resolution of infection.
Novoteris product is Thiolanox® and its active ingredient is nitric oxide (NO), a gaseous molecule that is inhaled for its antimicrobial effects that may result in improved lung function.
About Nitric Oxide & Cystic Fibrosis
Thiolanox® is Novoteris’ inhaled antimicrobial gas and its active ingredient is a gaseous molecule called nitric oxide (NO). It is administered to spontaneously breathing patients for 30 minutes, 3-5 a day for multiple days and is delivered to patients at a dose of 160 ppm nitric oxide. The inhaled antimicrobial effect in patients with cystic fibrosis during pilot testing has resulted in improved lung function. Inhaled NO may potentially have other effects that might benefit the CF patient such as its potential anti-inflammatory, smooth-muscle relaxation and secretion thinning effects.
The pharmacology, toxicity, and safety data for inhaled NO in humans for other applications are well-established through both previously approved drugs by EMEA (Europe), TPD (Canada), FDA (USA) and many published studies. The synthetic NO gas produced for blending into Thiolanox® is an identical molecule to that naturally produced by the human body. There are no biochemical, pharmacokinetic or physical differences.
Thiolanox® was first shown to be safe and effective at reducing those bacteria frequently identified in patients with CF infections. This was demonstrated in both the laboratory and with pneumonia models in two other species prior to human use. A phase I clinical study in 10 healthy adult volunteers, under the auspices of government regulatory authorities, investigated the safety of delivery and the physiologic effects of inhaled 160 ppm Thiolanox® for 30 minutes, every four hours, five times a day for 5 consecutive days. The treatments were well tolerated without any significant adverse events.
In an open labeled non-randomized controlled study, 8 adult CF patients received 160ppm concentration of NO by inhalation for 30 min, three times daily, at a concentration of 160 ppm for two periods of 5 days each. The primary purpose of the study was to establish safety and this was confirmed without any finding of any serious drug-related adverse event. Secondary observations for the study included the effect on changes of bacterial and or fungal load after completion of the treatment from baseline and change in lung function (FEV1) from baseline. Specifically there was significant mean reduction of the colony forming units (cfu) of all bacteria (log10 cfu: pre: 7.4±2.7; post: 3.8±1.7; P=0.0008) and all fungi (log10 cfu: pre: 5.6±3.1; post: 2.6±2.4; P=0.0019). This also confirmed that NO treatment was effective against a wide variety of bacteria and fungi by several orders of magnitude including P. aeruginosa, S. maltophilia, S. aureus, including methicillin resistant S. aureus (MRSA), A. denitrificans, M. abscessus, C. albicans, A. fumigatus and A. flavus). Furthermore, it demonstrated complete eradication of extended broad spectrum β-lactamase (ESBL)-producing E. coli strain and two Aspergillus species.
Based on laboratory tests, in vivo models and healthy human data, the use of 160ppm inhaled NO is considered safe. Preliminary studies in adults with CF provides additional safety and efficacy evidence. Together, this provides strong rationale that Thiolanox® will be an effective therapy for individuals with CF and will result in increased lung function primarily by reduction in microbial loads.