Tuesday, 14 October 2014

Omalizumab: a New Treatment Option for Allergic Bronchopulmonary Aspergillosis (ABPA)

ABPA is an allergic infection of the airways. It is not yet clear why some people get ABPA while most of us do not as the infecting mould is inhaled by nearly all of us on a daily basis. For most of us this is not a problem as our lungs are lined with protective immune cells that destroy the mould before its can establish itself, but for those rare few with ABPA this did not happen and the mould (Aspergillus) persisted and grew to block airways and cause inflammation. It rarely invades anything but the air spaces, it does not invade our lung tissues but does cause a lot of irritation and breathing problems that cannot be cured. This is a long term seriously debilitating condition.

One population we know is particularly vulnerable to ABPA is those people with cystic fibrosis (CF). Figures vary but something like 10 - 25% of people with CF get ABPA. Perhaps that is not surprising as their lungs are prone to infections as they cannot properly rid themselves of infectious particles including mould spores. Someone with CF already has severe problems breathing without suffering from contributing infections and some figures suggest 50% of all people living with CF have some form of infection by Aspergillus - not all are thought to progress to ABPA.

Treatment for ABPA is to use steroids to control inflammation and often an antifungal drug which can allow the dose of the steroid medication to be minimised, thus helping to avoid some of the many unpleasant side effects of taking high dose corticosteroids. This doesn't work for everyone and alternatives are being actively sought.

Originally developed for severe asthmatics, Omalizumab (Xolair) directly targets the parts of our immune system that leads to excessive inflammation. In asthmatics this has been demonstrated to lessen symptoms and has benefited patients. Many CF patients and those with ABPA are also asthmatic. ABPA is known to cause chronic airway inflammation and so ABPA patients are a candidate for use of this drug.

Some of the toughest patients to treat are probably those with CF and ABPA and we now have the first reports of patients from those groups who are being treated with Omalizumab. The most recent paper by Lehman et. al. looks at a small number of patients (6) with wide age range (age 4 - 33) treated over 7 years and suggested that Omalizumab was beneficial especially in those who had less progressed disease with benefits of taking lass corticosteroid also apparent.

This result offers hope for alternative treatment to ABPA patients who do not have CF,

Wednesday, 1 October 2014

Detecting Fungus in the CF Patient Environment A Rising Concern

A recent paper released by the team here at the National Aspergillosis Centre has raised concern in the cystic fibrosis community that there may be many cases of Aspergillus infection amongst people living with CF that are going undetected.

This article, originally written by Maureen Newman discusses the implications:

In light of the news that almost 50% of cystic fibrosis patients are infected with Aspergillus mold,health leaders are reminding patients that it is important to limit exposure to agents that can cause infection for patients with cystic fibrosis. Certain services exist for patients interested in testing their environment for Aspergillus and other microorganisms.
“It is not healthy for anyone to be exposed to high levels of Aspergillus, but this new research sheds light on the need for those with cystic fibrosis to be especially vigilant,” said Jason Dobranic, PhD, Vice President of Microbiology and Life Sciences at LA Testing and EMSL Analytical, Inc., in a news release from the company. LA Testing, based in California, where a large percentage of the estimated 30,000 children with cystic fibrosis live, conducts indoor air quality testing for a number of chemicals and biologicals.
By detecting and limiting exposure to Aspergillus, an individual’s risk for developing aspergillosis is greatly decreased. Aspergillosis, which presents in many different forms, sometimes only causes symptoms and other times causes tissue damage. Allergic bronchopulmonary aspergillosis (ABPA) causes wheezing and coughing but does not invade or destroy tissue. Invasive aspergillosis causes damage to tissues–usually the lungs of patients with weakened immune symptoms.
For cystic fibrosis patients who have already been affected with ABPA, a new treatment option is being investigated at RWTH Aachen University’s University Hospital in Germany. A recent report, published online ahead of print in Therapeutic Advances in Respiratory Disease, entitled “Omalizumab: A New Treatment Option for Allergic Bronchopulmonary Aspergillosis in Patients with Cystic Fibrosis,” conducted a retrospective study of six patients with concurrent ABPA and cystic fibrosis who had been treated with omalizumab. The observation period was 7.5 years. During and after treatment, all patients showed clinical and laboratory stability of disease, with some patients showing improvements.
The researchers noted that “Early onset treatment may be beneficial and patients with early stage of lung disease seem to benefit more,” suggesting that early disease detection is vital. Patients who find their environments are enriched in Aspergillus through air quality testing may have a better chance of being diagnosed and treated sooner.

Tuesday, 30 September 2014

US IDSA Calls for Increased Emphasis on the Fight Against Antibiotic Resistance

As we have all become used to taking antibiotics for infections we tend to take them for granted. However awareness is growing that more and more antibiotics are being rendered useless by the rise of strains of fungi & bacteria that are resistant to one or more antibiotics.

Compounding the problem is the fact that few drug companies are voluntarily developing new antibiotics. One of the essential principles of the capitalist system is that you should only invest money in projects that will make money, and there seems to be little money in antibiotic development for the large private drug companies that must take major financial risks to develop any drug. Shareholders are generally interested in profits rather than philanthropy.

According to this timeline there were 20 antibiotics developed between 1990 and 1999 but only 6 entered use between 2000 and 2009.

It therefore falls to public funds to stimulate interest in antibiotics in the public interest. In the US the Infectious Diseases Society of America has joined in the fight to try to persuade the US government to promote the development of new antibiotics.


IDSA members enacted the 2012 Generating Antibiotic Incentives Now (GAIN) Act, which incentivizes antibiotic development by providing a 5-year extension of market exclusivity for new drugs that treat serious or life-threatening infections.
However, pharmaceutical companies are still facing significant economic, scientific and regulatory barriers, she said. Nowhere is this more evident than with carbapenem-resistant Enterobacteriaceae (CRE), which the CDC deemed the “nightmare bacteria” in 2013. With no safe or effective antibiotic treatments available, up to 50% of patients with CRE bloodstream infections die. Meanwhile, there are only a handful of novel antibiotics currently in development for CREs. All of these are unlikely to be approved by the FDA, given that they still face risk of failure in clinical trials.

Wednesday, 24 September 2014

Isavuconazole Causes Fewer Side Effects Compared With Voriconazole: ICAAC 2014

Important drug development work carried out by the University of Wurzburg and Johns Hopkins School of Medicine in the US was reported at the recent antimicrobial conference ICAAC 2014.

It had already been established that the new antifungal drug isavuconazole shows much promise for the treatment of aspergillosis. It is at least as good as existing antifungal drugs e.g. voriconazole when used to treat aspergillosis so it remained to be proven what the advantages of using this new drug might be.

This new report shows that patients given isavuconazole are less prone to side effects compared with voriconazole. This is an important issue as the rate of intolerance in patients who take antifungal drugs can be high and can lead to discontinuation of treatment.


Of those patients with uncontrolled cancer, 40% (70 subjects) who received isavuconazole experienced drug-related adverse events, compared with 60% (112 people) of those who received the already-licensed drug.
Of those with uncontrolled cancer who received voriconazole for their fungal infections, 24% (44 subjects) experienced problems related to the eye, compared with 15% (26 individuals) who were randomised to receive the experimental agent.
Of the 516 patients, 272 had uncontrolled malignancy, while others had cancer that was in remission, rheumatoid arthritis or HIV. Some had diabetes, a substantial number of whom had mucormycosis, Marr said.
For those subjects without an uncontrolled malignancy, 35% (25 individuals) of those on voriconazole had eye-related side effects, compared with 15% (13 patients) of those who received isavuconazole, the poster said.
The experimental drug was also associated with fewer cases of liver toxicity in patients without uncontrolled cancer. Four subjects (5%) without uncontrolled malignancy who received isavuconazole experienced liver problems compared with 14 subjects (19%) who were randomized to voriconazole.
We might conclude that there is a 40-60% reduction in severe side effects when using isavuconazole compared with voriconazole. This could be of great benefit to many patients.

In addition isavuconazole was shown to have 100% bio availability (compared with 82% bio availability of voriconazole). This means that there are likely to be fewer problems with managing drug dose when isavuconazole is taken orally - again this is an improvement likely to benefit some patients and may even make management of the drug cheaper in some cases!

Tuesday, 23 September 2014

US FDA Accepts New Drug Application Filing for Isavuconazole

Drug developer Astellas has applied for approval to bring its new antifungal medication to clinics in the United States (this antifungal drug approval application has already been accepted in Europe), A decision in the US is scheduled for March 8th 2015.


The US Food and Drug Administration (US FDA) has accepted for filing the New Drug Application (NDA) for Astellas' isavuconazole for the treatment of invasive aspergillosis and invasive mucormycosis (also known as zygomycosis), which are life-threatening fungal infections predominantly occurring in immuno compromised patients. In accordance with the FDA Prescription Drug User Fee Act (PDUFA), the FDA designated the date of March 8, 2015 for the completion of the review. 

The FDA designated isavuconazole as a Qualified Infectious Disease Product (QIDP) for both invasive aspergillosis and invasive mucormycosis. QIDP status provides priority review and a five-year extension of market exclusivity in the United States. QIDP incentives were granted under the 2012 US Generating Antibiotic Incentives Now (GAIN) Act as a part of the FDA Safety and Innovation Act. Also, in 2013, isavuconazole was granted Orphan Drug status for invasive aspergillosis and invasive mucormycosis which, if approved, will result in the product having seven years of market exclusivity in addition to that provided under the GAIN Act.

Original article 

Interestingly as isavuconazole was initially developed by a different company: Basilea, the FDA's acceptance of filing for New Drug Application will trigger a multi-million dollar payment to Basilea, presumably because it represents an agreed point when the drug may start to make money for the development companies.

NB Basilea still owns the rights to market isavuconazole outside of the US! Global drug development and marketing sometimes gets very complicated!

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