A Phase 2 Study of CX-8998 in Adolescents and Adults With Idiopathic Generalized Epilepsy With Absence Seizures

This is a Phase 2a, open-label study consisting of a screening period of up to 4 weeks and a
4-dose-titration treatment period to a dose of up to 10 mg twice daily (BID) of CX-8998,
followed by a 1-week safety follow-up period after the last dose of study medication.

Subjects will participate for a total of up to 9 weeks, including screening, the 4-week
treatment period and follow-up.

Inclusion Criteria:

1. Signed informed consent form (ICF) indicating that the subject has been informed of
the procedures to be followed, the experimental nature of the therapy, alternatives,
potential benefits, side effects, risks, and discomforts.

2. Men or non-pregnant, non-breastfeeding women 16 to 55 years-of-age who are able to
read and understand written and spoken local language.

3. Clinical diagnosis of IGE (including, but not limited to, CAE, JAE, juvenile myoclonic
epilepsy, or Jeavons syndrome) with absence seizures consistent with the International
League against Epilepsy Revised Classification of Seizures (2017).

4. Absence seizures persisting despite standard of care (SOC) treatment, defined as
treatment with at least 2 AEDs appropriate for the patient's epilepsy syndrome. SOC
failure, per investigator discretion, will be defined as insufficient clinical
response or intolerable side effects, which precludes use of the appropriate AED.

5. Observation of at least 3 instances of generalized discharges of approximately 2.5 - 4
Hz lasting ≥2 seconds via 24-hour ambulatory EEG (centrally reviewed), with
approximately 75% normal background based on age and medication use per the central
EEG reader's discretion. Intermittent focal spikes are allowed.

6. On stable doses of one or more antiepileptic medication(s) for at least 30 days. If a
subject is not on medication, adequate documentation justifying lack of therapy may be
acceptable for the subject after sponsor review. Ketogenic, modified Atkins diet
(MAD), or low glycemic diet with stable carbohydrate ratio for at least 30 days before
screening is an acceptable antiepileptic therapy. Vagal nerve stimulation at stable
settings (for at least 30 days before screening), without use of the magnet, is also
acceptable.

7. Body weight ≥ 45 kg at screening.

8. Subjects with reproductive capability including all males and women of child-bearing
potential (WOCBP) must agree to practice continuous abstinence or adequate
contraception methods (appropriate double barrier method or oral, patch, implant, or
injectable contraception) from as soon as feasible during screening period until at
least 30 days after the last dose (i.e., intermittent abstinence based on "rhythm",
temperature monitoring, or other means of timing is not acceptable). WOCBP include any
woman who has experienced menarche and who has not undergone successful surgical
sterilization (hysterectomy, bilateral tubal ligation, and/or bilateral oophorectomy)
or is not post-menopausal. Post-menopausal is defined as amenorrhea ≥ 12 consecutive
months without another cause, and a documented serum follicle stimulating hormone
(FSH) level ≥ 35 mIU/mL.

9. Male subjects with a partner of child-bearing potential must be surgically sterilized
or be willing to use condoms with spermicide from as soon as feasible during screening
period until at least 30 days after the last dose.

10. Able and willing to comply with scheduled visits, treatment plan, laboratory tests,
and other study procedures.

11. Approval by the sponsor medical personnel or delegate as to final eligibility for the
study.

Exclusion Criteria:

1. History of surgical intervention for treatment of epilepsy.

2. Additional seizure (clinical and electrographic) types, including, but not limited to,
epileptic spasms, generalized tonic seizures, atonic seizures, or focal seizures.
Subjects with GTCS or myoclonic seizures are eligible for the study.

3. Inadequately treated psychotic or mood disorder (e.g., schizophrenia, major
depression, bipolar disorder).

4. Presence of severe intellectual disability, severe autism spectrum disorder, or severe
developmental disorder such that the subject cannot sign the ICF or cannot cooperate
with the study procedures.

5. Presence of positive urine drug screen for drugs of abuse, except if this is explained
by use of an allowed prescription medicine.

6. Regular use of more than 2 standard drinks of alcohol per day (28 grams of pure
alcohol).

7. Hypersensitivity/allergic reaction to other T-type calcium agents, such as (but not
limited to) ethosuximide and zonisamide.

8. Use of strong CYP3A4 inhibitors, including prescription or non-prescription drugs or
other products (i.e. grapefruit juice), which cannot be discontinued at least 2 weeks
prior to Day 1 of dosing and throughout the study (Appendix C).

9. Concurrent illnesses that would be a contraindication to trial participation,
including, but not limited to:

1. Severe arterial thromboembolic events (myocardial infarction, unstable angina
pectoris, stroke) less than 6 months before screening

2. NYHA Class III or IV congestive heart failure, ventricular arrhythmias or
uncontrolled hypertension

3. Clinically significant ECG abnormality per the Investigator assessment or any of
the following: i) QTcF ≥450 msec (males) or ≥470 msec (females) ii) PR interval
≥250 msec iii) Atrioventricular block of second degree or higher, including
Mobitz I iv) Persistent sinus bradycardia ≤ 50 beats per minute; persistent means
the bradycardia is present on the first ECG and on one repeat ECG performed on
another day v) For other ECG findings (e.g., including, but not necessarily
limited to, tachycardia, bundle branch block, frequent ectopic beats, etc.) the
Investigator should send a scanned, identity-blinded copy of the ECG tracing to
the Study Safety Representative for review.

10. Positive result for HIV, Hepatitis B [indicating ongoing infection], or Hepatitis C at
screening or otherwise known ongoing infection with HIV, hepatitis B, or hepatitis C,
unless curative therapy completed; for hepatitis C curative therapy is defined as
negative PCR for HCV RNA.

11. Significant hepatic (AST/ALT or bilirubin ≥ 2X upper limit of normal) or renal disease
(creatinine clearance ≤39 mL/min) at screening.

12. History of alcohol or substance abuse within the last year.

13. A current C-SSRS score of 4 or 5 at screening or history of suicide attempt.

14. Psychological, social, familial, or geographical reasons that would hinder or prevent
compliance with the requirements of the protocol or compromise the informed consent
process.

15. Any other condition and/or situation that causes the Investigator or Study Safety
Representative to deem a subject unsuitable for the study (including, but not limited
to, expected study medication non-compliance, inability to medically tolerate the
study procedures, or a subject's unwillingness to comply with study-related
procedures).

16. Treatment with an investigational agent within 30 days prior to the first dose of
CX-8998 or planning to receive an investigational agent during the study.