Theophylline Nasal Spray for PD-Related Hyposmia and Anosmia

The goal of this study is to learn if intranasal theophylline (CYR-064) improves sense of smell in participants with hyposmia or anosmia related to the onset of Parkinson's Disease. Fifteen adults, age 19-80, years will participate for about 32 weeks. They will use the study nasal spray for 24 weeks. The nasal spray is given as 2 sprays to each side of the nose twice per day. They will be seen every 2 weeks during the first month of treatment, followed by monthly in-person visits. Tests about memory, Parkinson's Disease symptoms, and ability to detect and identify smells will be completed. Participants are monitored for any side effects.

This is a single-arm study that will investigate the use of intranasal theophylline (CYR-064) for the treatment of hyposmia and anosmia related to the onset of Parkinson's disease. The study drug of CYR-064, self-administered for a 24-week Treatment Period, is intended to improve the sense of smell in participants with persistent hyposmia and anosmia related to the onset of Parkinson's Disease. The study population will include approximately 15 adult participants between the ages of 19 to 80 years with moderate to severe hyposmia or anosmia caused by the onset of Parkinson's Disease. Eligible participants who meet all study criteria and have consented to participation will receive the investigational new drug (CYR-064) with a dose strength of 1120ug/day administered for 24 weeks. During the 24-week Treatment Period, participants will be asked to complete a weekly paper Diary with two questions to monitor compliance to the study drug.

Participants will be prompted and instructed to provide responses to 11-point Numeric Rating Scale (NRS-11) smell and taste symptom assessments on a scale of 0-10 (10 indicating normal senses), starting with the baseline visit and then weekly throughout the duration of the study via paper diary. Participants will return to the clinic every 2 weeks for the first month of the Treatment Period, followed by monthly in-clinic visits thereafter for the assessment of safety and efficacy of CYR-064 at 8, 12, 16 and 24 weeks.

At baseline and week 24, patients will be given the Sniffin Sticks threshold, discrimination, and identification (TDI) test.

At baseline and week 24, patients will be given the global impression of smell loss severity (PGI-SLS), smell loss change (PGI-SLC), global impression of loss of ability to taste food (PGI-TS), and change in ability to taste food (PGI-TC) questions. (note: each of these constitutes one multiple choice question).

At baseline and week 24, patients will be given the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) parts I and III, the Craft Story Recall, the Benson Complex Figure Test, and the Hopkins Verbal Learning Test - Revised.

All participants will have intra-nasal examination and nasal endoscopy performed at baseline and at 24 weeks to ensure no structural or pathological issues are present leading to hyposmia and for assessment of safety. Adverse events (AE) will be assessed through clinical symptom presentation, intra-nasal examination, and endoscopy.

At each monthly in-clinic visit, participants will return the vials with the study drug (full or empty) and receive new vials for use during the following study period. Week 24/end of study (EOS) will serve as the last visit for all patients who complete the study, followed by a 30-day follow-up. Participants who discontinue treatment or study at any time will return to the clinic for the EOS visit. At Week 28 (± 7 days), a follow-up phone call to assess final safety and efficacy will conclude the participant's participation in the study.

Eligibility Criteria:
Inclusion Criteria:

* Able to provide written informed consent.
* 19-80 years of age.
* Subjective or clinically diagnosed hyposmia/anosmia \> 6 months with onset related to Parkinson's Disease. Note: participants may be rescreened at a later time if duration of hyposmia is determined to be \< 6 months.
* Hyposmia defined as ≤5 on the NRS-11 Smell-PRO smell scale (scale of 0-10; 10 indicating normal sense of smell, 0 indicating no sense of smell).
* Hoehn and Yahr scale is \<3.
* Montreal Cognitive Assessment (MOCA) score \>24.
* Endoscopy of the nasal cavity showing no structural or pathologic issues leading to hyposmia (nasal polyps, sinusitis, infection, etc.) that in the opinion of the Investigator, believes would hinder the delivery of study drug to the olfactory region of the nasal cavity.
* Willing and able to self-administer the study drug, follow the study drug administration instructions, comply with study procedures, and participate in the scheduled study visits specified in this protocol.
* Score Sniffin Sticks Olfactory Test Threshold, Discrimination and Identification (TDI) at baseline and EOS.

Exclusion Criteria:

* Hyposmia due to other causes (non-Parkinson's Disease related):

  * History of traumatic brain injury, viral related smell loss or any other condition in which hyposmia is not expected to improve in the opinion of the Investigator, such as history of congenital or idiopathic hyposmia or a surgical procedure that led to hyposmia.
  * History of systemic conditions or structural abnormalities known to impact the sinonasal cavity (e.g., granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, severe septal deviation, nasal polyposis, intranasal mass, or tumor) that would impact delivery of drug.
  * History of anosmia or hyposmia due to nasal polyps.
  * History of surgery that led to hyposmia.
* Participants whose primary complaint elated to olfactory dysfunction, in the opinion of the Investigator, is parosmia.
* Concomitant Medical Conditions:

  * Current symptoms or signs of acute respiratory viral illness at Screening or Baseline.
  * Any acute upper respiratory tract infection or allergy that has acutely changed the participant's sense of smell at Screening or Baseline.
  * Any nasal bleeding, crusting or other process that would impair ability to perform smell test.
  * Chronic viral infection or immunodeficiency condition (e.g., medical history of human immunodeficiency virus) based on medical records.
  * Any active malignancy.
  * Any concomitant medical condition that in the opinion of the Investigator, compromises patient safety or compliance with the study protocol or collected data.
* History of Substance Use Disorder of moderate or greater severity within the past 3 years as assessed by the Investigator.
* History of persistent chronic sinusitis without polyps or chronic sinusitis with polyps.
* Use or planned use of THC-containing products, tobacco, or nicotine-containing products, including smoking, smokeless tobacco, e-cigarettes, vapes, or nicotine replacement products within 3 months prior to Screening through end of study.
* Participants with visible signs of, and/or active symptoms of chronic sinusitis or respiratory infection at Screening or Day 1/Baseline.
* Severe allergic rhinitis requiring intranasal medications.
* Usage of Medications:

  * History of an allergic reaction to theophylline or other methylxanthines.
  * Unwilling or unable to discontinue current or planned use of over the counter (OTC) or prescription medication administered intranasally, including non-nasal indications such as bisphosphonates for osteoporosis, etc., with the exception of nasal saline.
  * Current, recent (within 30 days prior to Screening), or planned (from Screening through Follow-Up) use of theophylline for any reason other than the planned study drug.
  * Use or planned use of another investigational drug within 4 weeks prior to Screening through Follow-Up.
  * Receiving any concomitant medication/therapy that would, in the opinion of the Investigator, compromise participant safety or compliance with the study protocol or collected data.
* Concomitant procedures:

  * Planned nasal procedures within 90 days prior to screening and throughout study through follow-up.
  * Planned surgical procedure during study participation that would interfere with the participant's ability to perform study procedures.
  * Olfactory training must be discontinued 30 days prior to baseline through follow-up.
* General Exclusions:

  * Female who is pregnant, planning to become pregnant during the study, or who is lactating.
  * Any condition or abnormality (including clinical laboratory, physical examination, or vital sign abnormalities), current or past, that, in the opinion of the Investigator, would compromise the efficacy evaluation, safety of the patient, or would interfere with or complicate study procedures or assessments.