An Open-Label, Multicenter, Extension Study of AG-348 in Adult Subjects with Pyruvate Kinase Deficiency Previously Enrolled in AG-348 Studies

Mitapivat sulfate is an orally available, potent, broad-spectrum activator of
PKR with demonstrated activity against both WT and mPKR enzymes in vitro.
Mitapivat sulfate acts by directly binding to the PKR tetramer and
allosterically enhancing its affinity for PEP. Pharmacology studies have
confirmed the potency of Mitapivat sulfate in activating wide-type (WT) PKR
enzyme activity and modulating ATP and 2,3 DPG levels in healthy adult
subjects. Mitapivat sulfate has also been shown to have acceptable absorption,
distribution, metabolism, and excretion (ADME) and toxicology profiles.
Treatment with Mitapivat sulfate has the potential to correct the underlying
pathology of PK deficiency by activating PKR and inducing metabolic changes,
leading to increased glycolytic pathway activity in RBCs and providing a
clinical benefit to patients with PK deficiency.
(See IB section 2.2)

Objectives:
Primary:
• To evaluate the long-term safety and tolerability of AG-348
Secondary:
• To evaluate the long-term efficacy of AG-348
• To evaluate the efficacy of AG-348 in increasing hemoglobin (Hb)
concentrations in subjects who previously received placebo in Study
AG348-C-006 (Cohort 1 only)
• To determine the effect of AG-348 on health-related quality of life (HRQoL)
using patient reported outcomes (PROs)
• To evaluate the pharmacokinetics of AG-348 after oral administration (Cohort
1 only)
• To evaluate the relationship between AG-348 pharmacokinetics and safety
parameters (Cohort 1 only)
Exploratory:
• To evaluate the effect of AG-348 on pharmacodynamics (PD) markers related to
pyruvate kinase deficiency (PK deficiency) (Cohort 1 only)
• To determine the effect of AG-348 on markers of iron metabolism and
indicators of iron overload
• To evaluate the relationship between AG-348 pharmacokinetics and indicators
of clinical activity (Cohort 1 only)

Overview:
This is a multicenter, open-label, extension study to evaluate the long-term
safety, tolerability, and efficacy of treatment with AG-348 in subjects who
were previously enrolled in Study AG348-C-006 or Study AG348C-007.

All subjects enrolled in this extension study, including those who received
placebo in Study AG348 C-006, will receive AG-348 during participation in this
extension study.
Subjects will be assigned to 1 of the following 3 cohorts, depending on the
antecedent study and the previous treatment received in the antecedent study:
• Cohort 1: Subjects who received placebo in Study AG348 C 006
• Cohort 2: Subjects who received AG-348 in Study AG348 C 006
• Cohort 3: Subjects who received AG-348 in Study AG348-C-007

Cohort 1:
Cohort 1 will consist of subjects who received placebo in Study AG348-C-006 and
meet the eligibility criteria of this extension study. The first visit of this
extension study should coincide with the last visit of Study AG348-C-006. After
completion of all scheduled assessments at the subject*s last visit of Study
AG348-C-006 and before the start of study drug in this extension study, the
subject, Investigator, and site personnel will be unblinded to the Study
AG348-C-006 treatment allocation of the subject, and the Investigator will
determine whether the subject meets all eligibility criteria of this extension
study.
The first visit of this extension study should consist of subject consent,
screening, confirmation of eligibility, and the start of study drug. If a
subject in Cohort 1 cannot start study drug on the first visit of this
extension study, discussion with and approval by the Medical Monitor, or
designee, will be required for participation in this extension study, and to
determine the timing and requirements for the start of study drug and
assessments to be performed.
Subjects in Cohort 1 will participate in a 12-week Dose Optimization Period
followed by a 12-week Fixed Dose Period. The goal of the Dose Optimization
Period is to maximize a subject*s increase in Hb while maintaining an
acceptable safety profile. Following the Dose Optimization Period, each subject
will remain on his/her individually optimized dose and enter the Fixed Dose
Period.
Following completion of the Fixed Dose Period, subjects who, in the opinion of
the Investigator, have demonstrated clinical benefit from AG-348 treatment will
continue AG-348 treatment in the Continued Treatment Period.

Cohort 2:
Cohort 2 will consist of subjects who received AG-348 in Study AG348-C-006 and
meet the eligibility criteria of this extension study. The first visit of this
extension study should coincide with the last visit of Study AG348-C-006. After
completion of all scheduled assessments at the subject*s last visit of Study
AG348-C-006 and before the start of study drug in this extension study, the
subject, Investigator, and site personnel will be unblinded to the Study
AG348-C-006 treatment allocation of the subject, and the Investigator will
determine whether the subject meets all eligibility criteria of this extension
study.
In Cohort 2, the first visit of this extension study will consist of subject
consent, screening, confirmation of eligibility, and the start of study drug on
this extension study. Importantly, there will be no planned dosing interruption
between the last dose of blinded AG-348 in Study AG348-C-006 and the first dose
of open-label AG-348 in this extension study due to the potential for
withdrawal hemolysis (an identified risk of AG-348). Specifically, the first
dose of open-label AG-348 in this extension study will be administered
approximately 12 hours (ie, 12 hours ± 2 hours) after the last dose in Study
AG348-C-006. Subjects will continue the AG-348 dose regimen they were receiving
at the last visit of Study AG348-C-006 (unless a dose modification is required
for reasons related to safety, the subject*s dose optimization, or other
reasons following discussion with and approval by the Medical Monitor or
designee).


Cohort 3:
Cohort 3 will consist of subjects who received AG-348 in Study AG348-C-007 and
meet the eligibility criteria of this extension study. The first visit of this
extension study should coincide with the last visit of Study AG348-C-007. After
completion of all scheduled assessments at the subject*s last visit of Study
AG348-C-007 and before the start of study drug in this extension study, the
Investigator will determine whether the subject meets all eligibility criteria
of this extension study.
In Cohort 3, the first visit of this extension study will consist of subject
consent, screening, confirmation of eligibility, and the start of study drug on
this extension study. Importantly, there will be no planned dosing interruption
between the last dose of AG-348 in Study AG348-C-007 and the first dose of
AG-348 in this extension study due to the potential for withdrawal hemolysis
(an identified risk of AG-348). Specifically, the first dose of AG-348 in this
extension study will be administered approximately 12 hours (ie, 12 hours ± 2
hours) after the last dose in Study AG348 C 007. Subjects will continue the
AG-348 dose regimen they were receiving at the last visit of Study AG348-C-007
(unless a dose modification is required for reasons related to safety, the
subject*s dose optimization, or other reasons following discussion with and
approval by the Medical Monitor or designee).

All Cohorts:
All subjects who interrupt or discontinue AG-348 at any time should undergo the
recommended dose taper, unless an emergency situation justifies discontinuing
or interrupting the study drug abruptly. Whether the dose taper is performed or
not, subjects discontinuing or interrupting AG-348 should be monitored for
signs of hemolysis and worsening of anemia. All subjects who permanently
discontinue AG-348 at any time will attend a Safety Follow-up Visit 28 days (±4
days) after the last dose of AG 348 (including the time required to dose taper).
Subjects with AEs will continue to be followed until resolution of the AE to
baseline (ie, baseline of the study during which AE onset occurred), the AE is
considered stable within the context of the study, the subject is lost to
follow up, or until 28 days after the last dose of AG-348. All SAEs will be
followed until final outcome of the SAE is known or the subject is lost to
follow-up.

AG-348 will be administered orally as tablets of different sizes for the 5, 20,
and 50 mg dose levels. Doses of AG-348 may be taken with or without food.
Tablets should be swallowed whole with water and not crushed, chewed, or
dissolved in water. The dose regimen will be 5, 20, or 50 mg twice daily (BID),
with each dose administered approximately 12 hours (ie, 12 hours ± 2 hours)
apart, unless a dose taper is required at any time during this extension study,
in which case the frequency of administration will be once daily (QD) or once
every other day (QOD) during different steps of the taper. At any time during
this extension study, the Investigator can reduce the subject*s dose or
interrupt dosing for reasons related to safety.
For subjects in Cohort 1, the initial dose will be 5 mg BID with the potential
for 2 sequential dose level increases (from 5 mg BID to 20 mg BID and from 20
mg BID to 50 mg BID), which may occur at the Week 4 and/or Week 8 Visits.
Subjects in Cohorts 2 and 3 will continue the dose regimen they were receiving
at their last visit of Study AG348-C-006 or AG348-C-007, respectively (unless
otherwise noted).

Mitapivat sulfate has been generally well tolerated in both healthy adult
subjects and adult subjects with PK deficiency, although aromatase inhibition
and transaminase increases have been observed in both subject populations. The
doses of Mitapivat sulfate planned for future clinical studies will not exceed
a 200 mg total daily dose, which is expected to reduce the risks associated
with aromatase inhibition and potential liver toxicity. Liver function tests
will be monitored in clinical studies of Mitapivat sulfate, and transaminase
elevations of more than 2.5× patient individual baseline or to Grade 2 will be
reported as an AE of special (AESI) interest. Moreover, data available at this
time also indicate that Mitapivat sulfate does not have a significant QT/QTc
prolongation effect. Based on currently available data, reported benefits of
treatment with Mitapivat sulfate outweigh the observed risks of treatment.
(see IB section 7).