A Study of CNSA-001 in Women With Diabetic Gastroparesis

Nerves throughout the luminal gastrointestinal (GI) tract express neuronal nitric oxide synthase (nNOS), which generates nitric oxide (NO), a key neurotransmitter in the regulation of GI motility. Several co-factors are known to be important for nNOS activity, including nicotinamide adenine dinucleotide phosphate hydrogen (NADPH), calcium, and tetrahydrobiopterin (BH4). The homodimeric conformation of all 3 isoforms of nitric oxide synthase (NOS) is regulated by BH4. In the absence of BH4, uncoupling of NO production occurs and leads to super oxide production, resulting in further impaired nNOS bioactivity.

CNSA-001 is a new chemical entity that is an endogenous, naturally occurring precursor of BH4 via the pterin salvage pathway. Oral administration of CNSA-001 will result in increases in both intracellular and circulating BH4 concentrations. Increased BH4 concentration is hypothesized to improve nNOS function resulting in a positive effect on gastric accommodation and emptying.

Inclusion criteria

• Informed consent
• Diagnosis of diabetes mellitus
• Documentation of delayed gastric emptying on gastric emptying scintigraphy or gastric emptying breath test (GEBT) (within 2 year of enrollment)
• Symptoms of gastroparesis for at least 6 months with GCSI score >21 indicating moderate to severe symptoms
• Gastric accommodation, as measured by nutrient satiety testing, of ≤600 mL
• Negative upper endoscopy or upper GI series within 3 years of enrollment (no evidence of mechanical obstruction or peptic ulcer disease)
• Either postmenopausal for ≥1 year or surgically sterile (having undergone tubal ligation, hysterectomy, or bilateral oophorectomy) for at least 6 months or, if of childbearing potential and not abstinent, willing to use a highly effective method of contraception throughout the study such as 1 of the following:

• Hormonal contraception (stable dose for 3 months)
• Intrauterine device/Intrauterine Hormone-releasing System
• Barrier contraceptive method (diaphragm, cervical cap, contraceptive sponge, condom)

Participants who are abstinent will not be required to use a contraceptive method unless they become sexually active.

• If on analgesics (including narcotics), promotility agents (including metoclopramide), or neuromodulators (including tricyclic antidepressants, gabapentin, and pregabalin), doses are stable for >30 days before randomization and the participant is not expected to require dose changes during the study through the end of treatment (EOT)
• Have not used tobacco (for example, cigarettes, e-cigarettes, cigars, smokeless tobacco, nicotine replacement) for 2 weeks prior to Day 1 and willingness to abstain from these products during the study through the EOT

Exclusion criteria

• Male gender
• Normal gastric emptying
• Gastroparesis from postsurgical etiologies
• Another active disorder that could, in the opinion of the investigator, explain symptoms
• Weight >100 kg
• Alanine aminotransferase > 2× upper limit of normal (ULN)
• Pregnant, breastfeeding, or considering pregnancy
• Clinically significant cardiac arrhythmia at screening
• QT interval corrected for heart rate (QTc) ≥470 milliseconds (msec) using Fridericia's correction (based on triplicate measurements taken at screening)
• Resting heart rate ≤40 or ≥110 beats per minute (bpm) or resting blood pressure <90/40 millimeters of mercury (mmHg) or >150/90 mmHg at screening or prior to the first administration of study drug
• Recent clinically significant GI bleeding
• Taking levodopa or domperidone within 30 days before randomization or expected to require domperidone during the study through the EOT
• Taking erythromycin within 30 days before randomization or expected to require erythromycin within 30 days before randomization or expected to require erythromycin during the study; if a participant is taking erythromycin and is otherwise eligible to participate in the study, following informed consent, the participant may go through an erythromycin washout period of 30 days before randomization
• Taking any fundic-relaxing agents including, but not limited to, buspirone, clonidine, nitrates, phosphodiesterase inhibitors (that is, sildenafil citrate [Viagra®]) and triptan containing medications, within 30 days before randomization or expected to require any of these agents during the study through the EOT
• Taking any systemic antifolates, including, but not limited to, methotrexate, pemetrexed, and trimetrexate or expected to require any systemic antifolates during the study (topical antifolates [for example, cream, ointment, gel] or eye drops with antifolates are allowed)
• Pulmonary dysfunction (for example, chronic obstructive pulmonary disease)
• Surgery for placement of a gastric stimulator within the past 6 months (participants postoperative >6 months with persistent symptoms and delayed gastric emptying are eligible)
• Gastrointestinal disease (such as irritable bowel syndrome, inflammatory bowel disease, chronic gastritis, peptic ulcer disease, small bowel malabsorption) that could affect the absorption of study drug or contraindicate undergoing the GEBT
• History of gastric surgery, including Roux-en-Y gastric bypass surgery or an antrectomy with vagotomy, or gastrectomy
• History of allergies or adverse reactions to BH4 or related compounds, to any excipients in the study drug formulation, or to egg, wheat, or algae (Spirulina)
• Inability to tolerate oral medication
• Current participation in any other investigational drug study or use of any investigational agent, investigational device, or approved therapy for investigational use within 30 days or 5 half lives (whichever is longer) before screening
• Any clinically significant laboratory abnormality; in general, each laboratory value from screening and baseline chemistry and hematology panels should fall within the limits of the normal laboratory reference range unless deemed not clinically significant by the investigator
• Major surgery within the previous 90 days
• The participant, in the opinion of the investigator, is unwilling or unable to adhere to the requirements of the study
• History of alcohol or drug abuse within 6 months prior to screening or current evidence of substance dependence as determined by the investigator
• Episodes of ketoacidosis or hypoglycemia that are frequent as defined by the investigator
• History of phenylketonuria (PKU) or hyperphenylalaninemia
• Any other conditions, including diabetic comorbidities, that, in the opinion of the investigator or sponsor, would interfere with the participant's ability to participate in the study or increase the risk of participation for that participant