Therapy Analysis - Hearing Loss & Tinnitus
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According to Pharmaprojects' data, there are currently only 18 drugs in development for hearing loss and tinnitus, which underlines the fact that these conditions represent a significant challengeAccording to Pharmaprojects' data, there are currently only 18 drugs in development for hearing loss and tinnitus, which underlines the fact that these conditions represent a significant challenge [Table 1]. Thomas Meyer, CEO of Auris Medical which specializes in hearing loss and tinnitus, believes that: "the lack of pharmacological treatments is certainly partly due to a lack of detailed understanding of the physiopathology of inner ear disorders, and the fact that the cochlea is a very tiny and complex organ". This, in addition to the lack of a pharmacological benchmark in the form of launched drugs, may discourage companies from exploring R&D in this neglected therapeutic area, even with the huge market that exists for effective treatments.
Currently, the molecular mechanisms involved in hearing loss and tinnitus are not fully understood, although there are a number of theories. Pharmacological evidence goes some way to supporting these theories, and it is has been suggested that oxidative stress plays a significant role in the death of the hair cell. The formation of damaging free radicals/reactive oxygen species (ROS), such as superoxide ions and hydroxyl anions, is usually dealt with by antioxidant mechanisms within the cell. In a reaction catalyzed by glutathione peroxidase, ROS are reduced to less reactive states, and monomeric glutathione is converted to glutathione disulphide. This process must then be reversed by glutathione reductase in order to maintain the stores of reduced glutathione available to detoxify ROS. In situations where excessive noise for prolonged periods continuously stimulates the hair cells, ROS are formed more quickly than the stores of glutathione can be replenished. The resulting oxidative stress on the cell can damage DNA, proteins, mitochondria and cell membranes, ultimately triggering apoptosis.
Many of the drugs in development target the process of apoptosis, or the oxidative stress thought to cause it. Under a licence from Xigen, Auris Medical is developing the cell permeable peptide AM-111, which selectively blocks JNK MAPK-mediated apoptosis of stress-injured hair cells and neurons in the cochlea. In a German Phase I/II trial, transtympanic injection of AM-111 was well tolerated and showed initial efficacy in reducing hearing loss following acute acoustic trauma. This peptide has European and US orphan drug status for acute sensorineural hearing loss, and Phase II efficacy trials are expected this year. Quark Biotech is targeting apoptosis at a different stage, using RNA interference to inhibit p53 expression. Its drug AHLi-11 is in preclinical studies for hearing loss caused by acoustic trauma or the use of ototoxic drugs.
An indirect method of preventing apoptosis is reducing the oxidative stress thought to cause it. The herbal remedy Ginkgo biloba is a free radical scavenger, and therefore may have potential in preventing oxidative stress-induced damage to hair cells of the cochlea. Based on this, Ipsen is developing Tanakan, a concentrated Ginkgo extract for cognitive disorders and vertigo, which has shown efficacy in Phase I trials for tinnitus. Another way of reducing oxidative stress within the cell is by promoting antioxidant mechanisms, exemplified by Sound Pharmaceuticals and its compound SPI-1005. This orally-active drug contains ebselen, which with its glutathione peroxidase-like activity, may boost the existing antioxidant capacity of the cell. It has recently completed a Phase I trial, and Phase IIb/III trials are planned.
In addition to acoustic damage to hearing, ototoxic drugs also pose a great threat. As previously mentioned, many drugs, including many chemotherapeutic cancer drugs, cause permanent damage to sensory hair cells. However, where the alternative to treatment is fatality, such drugs cannot be avoided. So whilst many companies are striving to find chemotherapeutics that lack this debilitating side-effect, others are developing otoprotectants for use in combination with ototoxic drugs. Adherex's formulation of sodium thiosulfate is intended to prevent hearing damage following platinum-based chemotherapy. It binds platinum complexes to protein, thus minimizing their toxicity and preventing their deposition in the cochlea. In a Phase II trial in children with high-frequency hearing loss, the need for hearing aids was reduced from 50% to 5%. A Phase III trial in children with liver cancer is expected early this year.
Despite the glimmers of hope shown by the drug candidates currently under development, it seems unlikely that any will reach the market for some time due to their early development statusWith the reduction in hair cells in the cochlea being the most common cause of sensorineural hearing loss, drugs targeting apoptosis could be used as preventative measures for noise- and drug-induced hearing loss, and potentially to slow the progression of presbyacusis. For those who have already lost significant numbers of hair cells however, therapies will need to target the replacement of these cells, either by transplantation or by the use of drugs that promote cell division and growth. With this in mind, Sound Pharmaceuticals is developing two small interfering RNAs (siRNAs) SPI-128 and SPI-129, which inhibit the expression of cyclin-dependent kinase inhibitor 1B and promote the transition of quiescent cells into the active, proliferative state. Delivered locally, these compounds may restore hearing, and in preclinical studies they were shown to promote cell proliferation in the organ of corti. Other drugs intended to promote cell proliferation in the cochlea are Merck & Co's siRNAs against retinoblastoma-1 protein, currently at the discovery stage, and GenVec's gene therapy that delivers the human atonal gene that induces the proliferation of sensory hair cells during embryonic development. The latter has shown proof-of-concept in mice.
Based on the theory that tinnitus following excitotoxicity may arise from dysregulation of cochlear NMDA receptors, Auris Medical is developing AM-101, an NMDA antagonist, which completely suppressed tinnitus in preclinical studies. It is now being assessed in a Phase I/II clinical trial.
Our data shows that there are currently no launched therapeutics for the treatment of hearing loss and tinnitus. Despite the glimmers of hope shown by the drug candidates currently under development, it seems unlikely that any will reach the market for some time due to their early development status [Graph 1]. The highest stage of development that drugs specifically intended for hearing loss or tinnitus have reached is Phase II clinical trials, and with current trends in pharmaceutical development suggesting around a 2 year timescale for Phase II development alone, and around a 29% Phase II attrition rate, hearing loss and tinnitus look set to remain unmet medical needs for the foreseeable future. In the absence of pharmacological treatments, those affected seek alternative therapies in the form of hearing aids and tinnitus masking devices, which emit a white noise to make tinnitus less noticeable. Some patients also undergo tinnitus retraining therapy, a process during which they train themselves to become used to their tinnitus, whilst others use antidepressants, anxiolytics and hypnotics drugs to treat the symptoms of the conditions.
The lack of serendipitous discoveries of effective treatments for hearing loss and tinnitus has severely limited insight into disease pathology, which is often gained by such chance pharmacological findings. It is the absence of a fully-determined mechanism for the conditions that makes research into this area potentially very high-risk, and the arena looks set to remain a niche market with little productivity in development. However, it is hoped that increase in stem cell research may offer hope for the future, and big pharma, although seemingly not willing to enter the market alone, appears to be willing to help - GlaxoSmithKline recently made a charitable donation of £126,000 to support Deafness Research UK in funding a new research programme using stem cells taken from umbilical cord blood or bone marrow.
There is still a long way to go, but with specialist companies such as Auris Medical and Sound Pharmaceuticals leading the field in therapeutics, and the potential of stem cells slowly becoming clearer, a therapy for deafness could one day become a reality.
Leanne Coyne
Pharmaprojects Analyst
Image courtesy of Mark Oxley
