MICA: Efficacy of Saracatinib (AZD0530) in treatment of chronic otitis media in the pre-clinical mouse models Junbo and Jeff

Otitis media is an important medical condition affecting the middle ear. There are a number of distinct forms of the disease and all cause ill health and have considerable health care costs. 80% of children will suffer one or more episodes of earache before the age of three and this condition is one of the most common reasons for taking child to see their GP. In most cases these painful episodes of earache resolve spontaneously. However, about 10% of children go on to have persistent ear problems and one particularly common condition is known as 'glue ear'. Although the symptoms of pain and fever go away, the child may suffer significant hearing loss. Glue ear is the most common form of childhood hearing loss. It occurs as a result of fluid accumulation in the middle ear space behind the eardrum. The fluid occupies a space that is normally air-filled in the healthy ear and this interferes with sound transmission through the three small bones that link the eardrum to the inner ear. Hearing loss manifests itself in delays in the child's language development and can result in learning and behavioral problems. Currently the only effective treatment is surgery to place a grommet in the eardrum. Grommet surgery is the most common surgical procedure performed on children. The NHS performs 30,000 grommet surgeries per year. Grommet surgery is not always effective, but there are currently no alternative beneficial medical treatments.
In this work we will use an animal model of chronic otitis media to explore new medical treatments for glue ear. Previously we have has shown that a molecular pathway involved in the response to low oxygen conditions is important in the development of disease and similar process occurs in children.
Our plan is to use existing drugs that have been developed to target these pathways and look at their ability to moderate hearing loss in our animal model. The particular drug that will be used is Saracatinib that Astra Zeneca developed to treat cancer. Cancer is very different medical condition to glue ear but both diseases share an underlying disease process associated with blood vessel growth and fluid leakiness. In the ear we hypothesize the accumulation of glue and fluid is driven by the leakiness of the blood vessels that line the middle ear space.
The use of anti-cancer drugs in children is restricted to serious life-threatening disease because of the potential for significant side effects when given as a tablet. The aim of this project is to investigate the potential of medicating the ear directly so that the drug is delivered to where it is needed to prevent hearing loss. It will be necessary to develop a formulation of drug that will release drug over periods of up to one month. The response to the treatment will be measured in hearing tests and measuring the action of the drug on the blood vessels of the ear. We will also investigate whether drug levels in the blood are sufficiently low after medicating the ear to make them safe for use.
If our work is successful it will open up new avenues of research in medical treatment of ear disease. There is a major effort to find new ways of medicating the ear and if this is achieved there will be great interest from pharmaceutical companies to discover new uses for their existing drugs, as well as developing new drugs. This has the potential to revolutionize the treatment of chronic middle ear disease and shift treatment away from surgery to medical treatments such as eardrops that could be prescribed by a GP.

Middle ear effusion without the symptoms of acute infection is termed otitis media (OM) with effusion (OME). Chronic OME (COME) is the most common cause of hearing impairment in children potentially causing language delays, learning and behavioural problems [1,2]. About 2.2 million episodes of COME occur annually in the US with an annual cost estimate of $4.0 billion [3]. The prolonged ventilation of the middle ear with tympanostomy tubes, also known as grommets, remains the preferred treatment for COME [4]. Placement of tympanostomy tubes is the most common operation in the UK (30,000 procedures per annum) however children have to undergo general anesthesia and the benefits of surgery for hearing are temporary [4]. Therefore there is a clinical need to develop new medical treatments based on the molecular pathways of OM. Our work on the chronic OM mouse models Junbo and Jeff has identified chronic inflammatory hypoxia as a key mechanism of OM pathogenesis. VEGFR signaling inhibitors moderate hearing loss in the Junbo model [5]. Children with OME have elevated VEGF protein in their ear fluids implicating its clinical relevance [6]. Src signaling plays a key role in regulation of vascular endothelium permeability induced by VEGF [7]. We hypothesize that increased vascular permeability in blood vessels of the inflamed middle ear mucosa is a key pathophysiological mechanism that generates fluid and inflammatory cell accumulation. Our objective is to explore Src kinase as a novel target for treatment of chronic OM by testing AZD0530 in our mouse models.
1.Davidson J et al (1989) Int J Ped Otorhinolaryngol 17:239-266
2.Kubba H et al (2000) Clin Otolaryngol Allied Sci 25:181-194
3.Rosenfeld RM et al (2004) Otolaryngol Head Neck Surg 130:S95-S118
4.Lous J et al (2005) Cochrane Database Syst Rev CD001801
5.Cheeseman MT et al (2011) PLoS Genetics 7:e1002336.
6.Sekiyama K et al (2011) Auris Nasus Larynx. 3:319-24
7.Hu G et al (2008) Chem Biol Interact 171:177-189

Chronic forms of otitis media such as OM with effusion (COME), otherwise known as 'glue ear' are common and costly to treat. There are 2.2 million episodes of COME annually in the US with a per annum cost estimated at $4.0 billion. The standard treatment is grommet surgery and this surgery is the most common operation in the UK (30,000 procedures per annum). Surgery requires children having to undergo a general anesthetic and overall the benefits for hearing appear small, short lived and are accompanied by a risk of complications such as infection or persistent tympanic membrane perforation. There are no effective medical treatment options. Antibiotics, topical or systemic antihistamines, decongestants and topical or systematic steroids do not appear to be effective. For these reasons there is a clinical need for more effective medical treatments.
This work proposes to investigate a Src kinase inhibitor Saracatinib as a novel medical treatment using pre-clinical mouse models of chronic OM. An important aim is to establish proof of concept that the ear can be medicated directly by injection of slow release drug into the middle ear bulla. A major hurdle to using an anti-cancer drug such as a Src kinase to treat OM in children is to overcome their potential for systemic toxicity. There is considerable interest in medicating the middle ear non-invasively and this project would provide new targets for medical intervention when improved delivery systems for ototopical medication become available.
The potential impact on medical practice and patient benefits are as follows. If successful this would be a major breakthrough for the treatment of OME. Children would benefit because there would be an alternative to current surgical treatments and there are prospects of improving treatment success rates. There would be savings to health care systems. In the developed world, treating middle ear diseases with eardrops would shift the treatment of OME to the primary health care system. In the less developed world where surgery is not available the treatment of middle ear disease would become more widely available.
The discovery of new targets to treat middle ear disease would provide considerable commercial benefit for biotech and pharmaceutical companies. For instance if AZ0530 is efficacious with ototopical delivery there will be a significant market opportunity to use this existing drug in a new clinical indication. Success would encourage AZ and other pharmaceutical companies to consider new uses for their compound libraries. This approach makes more efficient use of clinical assets and finds new uses for drugs that fail in their primary clinical indication.
Health care systems and patients would ultimately benefit if there is commercial impetus to develop of non-invasive and more efficient methods for ototopical delivery to medicate the middle ear. Importantly the development of our pre-clinical mouse models of chronic OM for testing drugs for middle ear disease would accelerate the development of new medical treatments and an understanding the pharmacokinetics of treating the middle ear mucosa directly would underpin this future work.