A Study of CNSA-001 in Women With Diabetic Gastroparesis

This is a Phase 2, randomized, double-blind, placebo-controlled pilot study of multiple doses
of CNSA-001 (sepiapterin) powder for suspension administered orally in women with moderate to
severe diabetic gastroparesis. Patients will be randomized in a ratio of 1:1 to receive
CNSA-001 20 mg/kg/day or placebo, each dosed twice a day (BID); each group will consist of 10
patients. All patients will receive the standard of care for 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 (sepiapterin) 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

- Females ≥18 and ≤65 years of age

- Diagnosis of diabetes mellitus

- Documentation of delayed gastric emptying on gastric emptying scintigraphy or gastric
emptying breath test (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 gastrointestinal (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) Patients 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 patient is not expected to
require dose changes during the study

- Have not used tobacco (e.g., 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

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) ≥480 msec (based on triplicate measurements
taken at Screening)

- Resting heart rate ≤40 or ≥110 bpm or resting blood pressure <90/40 mmHg or >150/90
mmHg at Screening or prior to the first administration of study drug.

- Recent clinically GI significant bleeding

- Taking levodopa or domperidone within 30 days before randomization or expected to
require domperidone during the study

- 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 patient is taking erythromycin and is otherwise eligible to
participate in the study, following informed consent, the patient 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 (i.e., sildenafil citrate [Viagra®]) and
triptan containing medications, within 30 days before randomization or expected to
require any of these agents during the study

- 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 [e.g., cream, ointment, gel] or eye drops with
antifolates are allowed)

- Pulmonary dysfunction (e.g., chronic obstructive pulmonary disease)

- Surgery for placement of a gastric stimulator within the past 6 months (patients
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 tetrahydrobiopterin 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 patient, 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 patient's ability to participate in
the study or increase the risk of participation for that patient