Title:  Cytokine antagonists for the treatment of sensorineural hearing loss

United States Patent:  6,423,321

Inventors:  Tobinick; Edward L. (100 UCLA Medical Plz., Suite 205, Los Angeles, CA 90024-6903)

Appl. No.:  749189

Filed:  December 27, 2000

Specific Cytokine Antagonists, including TNF antagonists and/or Interleukin-1 antagonists, are used as novel therapeutic agents for the treatment of hearing loss, including presbycusis and other forms of sensorineural hearing loss. The present invention provides a method for inhibiting the action of TNF and/or IL-1 antagonists for treating hearing loss in a human by administering a TNF antagonist and/or an IL-1 antagonist for reducing the inflammation affecting the auditory apparatus of said human, or for modulating the immune response affecting the auditory apparatus of said human, by administering a therapeutically effective dosage level to said human of a TNF antagonist and/or an IL-1 antagonist. Administration may be systemic, through the subcutaneous, intramuscular, oral, or intravenous routes; or by delivering an anatomically localized application in the region of the head. The TNF antagonist is selected from the group consisting of etanercept, infliximab, D2E7, CDP 571, or thalidomide; and the IL-1 antagonist is either IL-1 RA or IL-1R type II receptor. Antiviral agents may be added for treating certain patients.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Presbycusis, or age-related hearing loss, affects one-third of the U.S. population over age 75, and presents a significant hardship to these people, many of whom are faced with the burden of other age-related illnesses. At this time, it is difficult to determine the degree to which any individual patient will respond to treatment with the cytokine antagonists discussed herein. The advantages of using etanercept are its rapid onset of action, general lack of side effects, ease of administration, and relatively low cost per dose. For adult patients the dose will uniformly be 25 mg, administered subcutaneously in the same manner as with Rheumatoid Arthritis patients, i.e. into the abdominal area or the thigh. Some patients may have a better response from subcutaneous injection directly overlying the mastoid process. For these patients it is recommended that the side of the head be rotated with each dose, i.e. one dose on the right side of the head, and the next dose on the left side, etc. Some patients will respond to a lower dose, in the range of 5 mg to 15 mg, when etanercept is administered directly to the mastoid area. For all patients dosing is continued twice per week with the same dose. Etanercept administration is discontinued if the patient develops an infection at any site, and is not started in any patient that has an infection.

D2E7 is a fully human anti-TNF antibody. D2E7 is administered in exactly the same way as etanercept, with the same precautions. The only difference is the dose interval and the dosage. D2E7 for presbycusis will usually be administered at a starting dose of 20 mg subcutaneously given once every two weeks. The effective dose and interval may vary, according to individual response, from as little as 10 mg administered once per month to as much as 20 mg given weekly. As with etanercept, some patients may have a better response from subcutaneous injection directly overlying the mastoid process.

CDP-571 is a TNF antagonist in clinical development. It is a monoclonal antibody, and for purposes of this patent, it functions in a manner similar to infliximab. The intravenous route of administration is currently the preferred method for infliximab. Infliximab carries with it the advantage of reimbursement by additional third parties, and the advantage of a longer interval between doses than either etanercept or D2E7. The dosage regimen for infliximab recommended for initial use is the same as that recommended by the manufacturer for the treatment of arthritis, i.e. 3 mg/kg given as an intravenous infusion followed with additional 3 mg/kg doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. Because infliximab is a chimeric monoclonal antibody, with a mouse component, human anti-chimeric antibodies (HACA) may develop. Methotrexate has been shown to reduce the development of HACA. For this reason, methotrexate may need to be administered with infliximab.

Thalidomide is also beneficial for certain patients. The recommended starting dose is 50 mg orally taken once per day. Patients not responding can have their dose escalated monthly by a 50 mg increment, up to a maximum of 200 mg per day. A new aqueous formulation of thalidomide may allow the use of subcutaneous dosing. In this case, patients could be given a lower dosage, especially if injected subcutaneously in the area overlying the mastoid.

Certain patients may respond to the use of interleukin-1 antagonists, used instead of a TNF antagonist. The two medications in this class to be used here are IL-1 RA (anakira, A mgen) and IL-1 R type II (Immunex). The recommended dosage and dose interval are similar to the parameters recommended for their use for Rheumatoid Arthritis.

Some patients will receive additional therapeutic benefit from the use of a TNF antagonist administered with an interleukin-1 antagonist. The use of these medications in this manner has been demonstrated to be synergistic when used to treat an arthritis model in animals. The combination produces a more potent anti-inflammatory effect than when either agent is administered alone.

Patients with other forms of sensorineural hearing loss, and patients with central hearing loss are treated in the same manner as those with Presbycusis discussed above. The only difference will be the dosages, which in children will need to be adjusted appropriately for the patient's lean body mass.

Certain patients with selected forms of sensorineural and/or central hearing loss, including certain patients with presbycusis, will benefit from the addition of an antiviral agent in addition to a cytokine antagonist. This is because certain forms of hearing loss are due to focal infection of a locus of the auditory pathway by a neurotropic virus. Known neurotropic viruses include those in the herpes family, especially herpes simplex 1 and 2, human herpes virus 6, and varicella-zoster. These viruses can involve the neural components of the auditory pathway, such as the eighth cranial nerve, and thereby produce either sudden sensorineural hearing loss (in the case of acute infection) or chronic, progressive hearing loss (in the case of low-grade, chronic viral involvement). Certain patients will therefore require acute therapy, and others will require chronic therapy with antiviral agents, such as famciclovir, acyclovir, or valacyclovir. Antiviral therapy in combination with cytokine antagonists is the subject of a previous patent application by the inventor.

Idiopathic sudden sensorineural hearing loss is a known clinical entity. The only treatment with reported success is the use of corticosteroids. Some of these cases are thought to have viral causation. The use of a cytokine antagonist in combination with an antiviral medication may prove beneficial for these patients. No studies of this combination for this clinical condition have been published. The recommended regimen would be etanercept 25 mg subcutaneously twice a week in combination with valacyclovir 1 gram po BID for one month, with tapering as needed.

For children, there are additional considerations. Sensorineural hearing loss is an important cause of disability in children. Many of the causes are genetic, and these can lead to profound deafness. Those disorders with a known component of inflammation should give the best response to the antagonists disclosed herein. Etanercept has proven to be both safe and effective for chronic use for arthritis in children. The aforementioned caveats with regard to infection apply to children as well as to adults. D2E7 is also a therapy for use in children. For certain neurotropic viral infections of children, the combination of cytokine antagonists with antiviral medications will reduce or, even in some cases, prevent the development of hearing loss.

Claim 1 of 44 Claims

What is claimed is:

1. A method for inhibiting the action of TNF for treating sensorineural hearing loss in a human by administering etanercept for reducing the inflammation affecting the auditory apparatus of said human, or for modulating the immune response affecting the auditory apparatus of said human, comprising the step of:

a) administering a therapeutically effective dosage level to said human of said etanercept for reducing the inflammation affecting the auditory apparatus of said human, or for modulating the immune response affecting the auditory apparatus of said human.
 

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