Fosamprenavir for Laryngopharyngeal Upper Airway Tissue Treatment and Enzyme Reduction

Laryngopharyngeal reflux (LPR) causes chronic cough, throat clearing, hoarseness, and dysphagia and if left untreated can promote the development of laryngeal cancer. More than 20% of the United Stated population suffer from LPR, yet there is no effective medical therapy. Proton pump inhibitors (PPIs), which inhibit gastric acid production but do not prevent reflux events, continue to be prescribed for LPR despite their poor efficacy for this patient population, high cost ($26 billion/year), and associated risks. Pepsin, detected in the airway of these patients and now known to cause laryngeal inflammation and promote disease independent of gastric acid, is a key therapeutic target. We report preclinical studies of select HIV inhibitors that bind to and inhibit pepsin and thus hold promise for the treatment of LPR. In support, a very low incidence of LPR was found in patients taking these drugs compared to the general population. HIV inhibitors are ideal drugs to repurpose because they target a foreign virus. Thus, a repurposing approach can be used to safely perform proof of concept testing of the efficacy of a pepsin inhibitor for LPR.

The objective of this study is to evaluate the efficacy and safety of fosamprenavir (FOS), administered orally for improving symptoms of laryngopharyngeal reflux (LPR). The Specific Aim of this project is to perform a 12-week randomized, double-blind, placebo-controlled clinical trial to assess the efficacy of fosamprenavir pills for LPR. Fosamprenavir will be used at the FDA approved, manufacturers recommended dose for HIV for 12 weeks in medically refractory patients with clinically diagnosed moderate/severe LPR and combined multi-channel intraluminal impedance - pH (MII-pH) confirmed laryngeal reflux events. Routine clinical outcome measures for LPR (Reflux Symptom Index, Reflux Finding Score, Voice Handicap Index) will be documented pre- and post-treatment with Oral Fosamprenavir for LPR (n = 52) and placebo (n = 52). Additional research measures will include repeat administration of a newly created Daily Symptom Reflex Diary, as well as an intermittently distributed Patient Global Impression - Static & Change scales.

Participants for this study will be recruited from the Department of Otolaryngology (ENT) at Froedtert Hospital in Milwaukee, Wisconsin. Patients seen by Froedtert ENT laryngologists who receive a diagnosis of laryngopharyngeal reflux (LPR) during a standard-of-care visit will be informed about the study and offered additional information regarding participation. Individuals interested in participating will be invited to attend a separate screening and consent visit at the Adult Translational Research Unit (ATRU) on campus. The study consists of eight research visits, including the screening/consent visit, conducted over approximately 14 weeks. Up to two study visits may be completed remotely (Visit 2 and Visit 8).

Data will be collected from participant medical charts for the 3 standard-of-care clinic visits; Clinic visit 1 & 2 are for diagnosis of LPR, while clinic visit 3 is a follow-up that occurs 14 weeks after visit 1 & 2.

• Clinical diagnosis of LPR 2. Age ≥ 18 years 3. RSI > 13 4. RFS > 7 5. Documented LPR by MII-pH testing (> 1 proximal event) 6. Failed 3 month bid PPI therapy 7. Attending laryngology clinic with study providers, and having flexible laryngoscopy and MII-pH testing per routine clinical care with a minimum of three months between clinic visits (standard practice) 8. For continued participation after ATRU V1/V2:

• Hepatic Function Panel must be within normal limits
• Results from V1 safety labs must all be within normal limits
• Patient agrees not to make any changes to their usual diet and/or anti-reflux medications during the study.
• Patient is compliant with eDiary completion; that is, they have completed the eDiary questions on at least 5 days each week during the 14 calendar days before the start of the Treatment Period.
• Patient is compliant with continuing any current PPI (if using) during the 14 calendar days before the start of the Treatment Period. Patients are considered compliant if, as reported in the daily eDiary, they continued taking their current PPI (if using) on at least 5 days each week during the 14 calendar days before the start of the Treatment Period.

4.2 EXCLUSION CRITERIA 1. Age ≥ 65 years 2. Patient is not fluent and literate in English. 3. Pregnant (or plan to be) and nursing mothers 4. Women of child-bearing potential not willing to comply with contraceptive requirements during the study treatment and for 1 week following the last dose of study drug.

o Definition of women of child-bearing potential

Non-post-menopausal female, who has not had a bilateral oophorectomy or medically documented ovarian failure. A subject may be considered to be post-menopausal when there is either:

• twelve (12) months of spontaneous amenorrhea or;

• six (6) months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL or;

• six (6) weeks postsurgical bilateral oophorectomy with or without hysterectomy.

A female who has had a tubal ligation sterilization or hysterectomy would not be considered to be of reproductive potential unless participating in activities of reproductive potential other than heterosexual intercourse (e.g., egg donation, participation in in vitro fertilization).

• Contraceptive requirements Fosamprenavir may decrease the effectiveness of combined hormonal contraception through significant CYP3A4 induction of estrogen. If subjects' preferred choice of contraception is combined hormonal contraception, subjects must also agree to use a second method of contraception (condom + spermicide) during study drug treatment.

Other acceptable highly effective forms of contraception include:

• Medroxyprogesterone acetate injectable
• Intrauterine Device
• Female Sterilization
• Male Sterilization 4. Currently being treated with another investigational medical device and/or drug 5. A history of gastric or esophageal surgery 6. Gastrointestinal disease that might interfere symptom questionnaire, e.g. inflammatory bowel syndrome 7. A history of laryngeal or neck surgery including thyroidectomy and laryngomicroscopic surgery 8. Suspected esophageal cancer 9. Nasopharyngeal cancer 10. Previously undergone anti-reflux surgery 11. Polypharmacy (five or more concurrent medications due to comorbidities) 12. Any contraindications to FOS including the following:

a. Patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome) to any of the components of this product or to amprenavir.

b. Patients taking any drugs that are highly dependent on cytochrome P450 (CYP)3A4 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Specifically i. Alpha 1-adrenoreceptor antagonist: Alfuzosin ii. Antimycobacterial: Rifampin iii. Antipsychotic: pimozide iv. Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine v. GI motility agent: Cisapride vi. Herbal product: St. John's wort ( Hypericum perforatum) vii. Lipid modifying agents: Lomitapide, lovastatin, simvastatin viii. Non-nucleoside reverse transcriptase inhibitor: Delavirdine ix. PDE5 inhibitor: Sildenafil (Revatio) x. Sedative/hypnotics: Midazolam, triazolam 13. Patients not willing to avoid eating grapefruit and Seville oranges for five days prior to the first day of dosing study drug through the final study visit.

• Patients taking any of the prohibited medications or foods listed in Section 5.6.3 15. Anticipated poor understanding or compliance of the study protocol 16. History of hepatic impairment 17. Sulfa Allergy 18. Hemophilia 19. Active tuberculosis (TB) or history of active TB. 20. History of latent TB (e.g., positive QuantiFERON-TB test) without history of active TB unless the subject has completed a documented course of prophylactic treatment.

• History of human immunodeficiency virus (HIV) infection or positive for HIV 22. . Patients positive for hepatitis (Seropositive for hepatitis B surface antigen [HBsAg] or Hepatitis C virus [HCV] RNA positive) or taking HCV protease inhibitors such as boceprevir, simeprevir and paritaprevir 23. Not willing to refrain from taking biotin containing supplement for at least 12 hours before Visit 1.

• Patient has an acute or chronic condition that, in the Investigator's opinion, would limit the patient's ability to complete or participate in this clinical study.

• Additionally, subjects without the following will be excluded:

• Ownership of an electronic with access to internet websites and email required to conduct the DRSD, PGI-S, and PGI-C
• Internet access
• A valid email address for notifications