Tinnitus Talk would like to thank Autifony for this Q&A session! Autifony Therapeutics — Updated FAQs Q. What is the QUIET-1 study? A. The QUIET-1 study is a clinical study to determine whether or not a new test drug, AUT00063, can reduce symptoms of tinnitus in comparison to a placebo (dummy drug) after 4 weeks of treatment. Q. What is AUT00063? A. This a synthetic small molecule which modulates specific voltage gated potassium ion channels present on certain nerve cells important for hearing; the safety and tolerability of “063” has been tested in a group of healthy volunteers but the QUIET-1 study is the first test in people with tinnitus. Q. Can I have some details of the drug itself, and how will it be administered during the trial? A. AUT00063 is an orally active preparation that will be taken as 4 capsules once daily with breakfast each day continuously for 28 days. This drug is presented in yellow capsules each of 200mg. Special tests and important questionnaires will compare tinnitus on day 28 with day 1 of taking “063”. Q. What are the side effects of AUT00063? A. AUT00063 has completed initial “Phase I” safety studies in healthy volunteers. The drug was very well tolerated in young and older healthy volunteers. No serious adverse effects were noted during the Phase I trial. Occasional events such as headache or fatigue were reported by some subjects. Q. How do I know whether or not I am eligible to take part in the QUIET-1 study? A. If you are ≥ 18 years old and have had continuous tinnitus for more than 6 months but less than 18 months, and are otherwise healthy, you may be eligible to take part. Screening will be required to make sure that you meet certain eligibility criteria and the final decision on study enrolment will be taken by the trial doctor. Further study particulars can be seen on Clinicaltrials.gov. Q. Who should I contact to find out more about enrolment in the QUIET-1 study? A. The QUIET-1 study will be conducted at a number of sites in the UK. More information on these sites can be found here, along with a contact telephone number for more details. This website will be updated periodically to list specific sites that are involved in the study. You can also telephone the Nottingham site (contact details found here) and talk to an advisor there who can go through a series of questions to help to assess your eligibility. However, the final evaluation can only take place when you have been seen at one of the hospital study sites. Q. What age restrictions apply to the study? A. Subjects entering the study must be adults aged ≥18 years; there is no upper age limit. Other entry and exclusion criteria can be seen on Clinicaltrials.gov. Q. Can I enter the study with normal hearing or do you have to have hearing loss to get a benefit from “063”? Are there plans to remove this requirement? A. The study requires subjects to have a small (>20dB) hearing loss at one or more frequencies from 0.5kHz up to 8kHz; this is a minimal loss and most tinnitus sufferers will have this. Q. Can a subject with hearing loss in only 1 ear still take part? A. This will depend upon how large is the difference from one ear to the other; this will be checked by the audiologist before entry into the study. Q. Will this drug adversely affect my hearing? A. AUT00063 has completed initial “Phase I” safety studies in healthy volunteers. No adverse effects of the drug on measures of hearing were observed in any of the subjects. Q. Can subjects with Chronic, i.e. longer term, tinnitus participate? A. In this first study, the duration of tinnitus must be from 6 to 18 months only; this is because of the heterogeneous nature of tinnitus and to help Autifony best evaluate the effects of “063” in the first instance. Q. How soon does the drug start to work? A. In models of tinnitus pre-clinically, a beneficial effect was seen quite rapidly, and we know that the effect of the drug on the nerve cells themselves is very quick. However, because the tinnitus will have been present for many months, it may take longer for the drug to have an effect, possibly days or even several weeks. It is for this reason that if somebody joins the study it is really important for them to stay right to the end. Q. Why are some sites doing EEG (ElectroEncephaloGraphy) and what is this for? A. EEG provides a measure of the electrical activity of the brain, and so can be useful to detect the effects of drugs like AUT00063. EEG will help to confirm that -‘063 is reaching the target area of the brain; we did this in our Phase I safety study and know this is a good indicator. Only two hospital sites will be doing EEG as it is really just a double check on a small number of subjects. No sites are set up to do this yet. Q. If I also suffer from hearing loss, can I expect to see an improvement in my audiogram, as I know AUT00063 is being tested also for Age Related Hearing Loss in the USA? A. No, we do not expect AUT00063 to improve the pure tone audiogram as the drug does not work on mechanisms in the cochlea itself. “063” is designed to improve auditory processing in the brain, and of course to reduce the central auditory activity that gives rise to tinnitus. A decline in central auditory processing is an important aspect of age related hearing loss, and gives rise to the difficulty people have understanding speech in challenging listening environments, such as in a background of noise. In preclinical models, AUT00063 has been shown to improve central auditory processing. Q. Are non-UK residents able to participate? A. Not this time. People who enrol in the QUIET-1 study must be resident here in the UK, have an NHS number, and be registered with a local GP, who will be kept informed of any patients who enrol. If this study were to show encouraging effects of AUT00063 [and we are a very considerable long way off showing anything at all at the moment, as it is only just starting] then other studies may follow across a broader range of people with tinnitus and across different countries. It is also important to know that the study participants will have to undertake a number of hospital visits over a period of 8-10 weeks and this will take considerable time and commitment. It is for the long-term benefit of people with tinnitus that the study generates high quality data; if you start on the study, we really need you to stick with it to the end! Q. When is a tinnitus study coming to the USA? A. With the benefit of advice from local experts in the USA, Autifony is exploring the possibility to conduct a US study; this may well have different, broader, entry criteria from the QUIET-1 study; any news on this would be posted first on the Autifony website; nothing has been decided yet. You may hear that Autifony has initiated another study in the US, the CLARITY-1 trial which is for people with Age Related Hearing Loss and who have difficulty with hearing speech in a noisy background. However, it is important to point out that the entry criteria into this study will be quite different, as will the dose and the study measurements. Q. If I cannot participate, will Autifony suggest possible treatment or therapy? A. Companies such as Autifony are not allowed to offer specific personal advice on healthcare to the general public; this is a matter for discussion with your GP or specialist. Q. If the study is successful then what would be the estimated arrival time to market? A. It is too early to estimate. The preclinical work looks very positive and exciting but, until we have done this first clinical study in people with tinnitus we have no idea of whether those models will be predictive of its activity in humans. So we shall have to wait until this study finishes before we know. Clinical research just takes a long time, certainly a number of years. However, an effective drug for tinnitus is critically needed and the regulatory authorities who approve medicines for marketing are aware of this and would take matters into account. Further information is also available at Clinicaltrials.gov. Q. Do you expect “063” to work for all types of tinnitus or is the focus on specific sub-types? A: Tinnitus can arise from many different causes. We have been studying tinnitus that often occurs after hearing loss; for example, after exposure to loud noise or as a result of ageing. AUT00063 is designed to work on the central auditory mechanisms that are affected following hearing loss, and which are thought to give rise to tinnitus. In preclinical models of noise exposure-related tinnitus, AUT00063 was effective at reducing signs of tinnitus in rodents. In the QUIET-1 study it is important that we first study the effects of AUT00063 in people whose tinnitus most likely arose due to noise or age-related hearing loss. Careful analysis of the data from the QUIET-1 study will tell us lots more about this. If the study is successful, we will broaden out the trials to test AUT00063 in people with other forms of tinnitus. Q. How similar is “063” to other potassium channel drugs (such as Retigabine)? A: AUT00063 is completely novel drug that affects Kv3 potassium channels, and so is very different to other known potassium channel drugs, such as Retigabine (Ezogabine). Q. Is the dosage fixed or do you expect to see benefits from increasing it in some cases? A. The dose is fixed. In the early stages of drug development it is important to fully explore the safety profile before considering the potential opportunity to increase the dose. Q. Is “063” to be taken for the 30 days only or is it something that will need to be taken indefinitely? A: The QUIET-1 study will evaluate the efficacy of AUT00063 given for 28 days. After we have completed this trial we will understand more about how quickly any effects of the drug are felt, and how quickly they might subside after treatment is stopped. In future trials we will be able to explore this further.