A Dose-Finding Study of AG-348 in Sickle Cell Disease
Condition: Sickle Cell Disease
MeSH terms: Anemia, Sickle Cell
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Background:

      Sickle Cell Disease (SCD) is an inherited blood disorder. People with SCD have abnormal
      hemoglobin in their red blood cells. Researchers are investigating the safety and efficacy of
      an investigational medicine called AG-348 (mitapivat sulfate) to determine if it will help
      people with SCD.

      Objective:

      To test the tolerability and safety of AG-348 in people with SCD.

      Eligibility:

      People ages 18 and older with SCD.

      Design:

      Participants will have 8 visits over approximately 14 weeks. At the first visit participants
      will be screened with a medical history, a physical exam, blood and urine testing, and an
      EKG. During the following 5 visits, participants will stay at the clinic for 1 night each.
      Participants will take study drug in increasing doses up to visit 6, after which the drug
      will be tapered off. All visits will include physical exam, blood, and urine tests. The last
      visit will occur 4 weeks after stopping the drug. Participants will provide DNA from the
      blood samples they provide. The DNA will be tested for an inherited gene that can cause
      differences in response to the study drug. Researchers may also test other genes to see if
      they can find any genes that interact with SCD.
    

Detailed description: 
      Sickle cell disease (SCD) is a multisystem disorder associated with episodes of acute
      clinical events and progressive organ damage. Episodic pain, triggered by micro-vasoocclusion
      induced by sickled red blood cells, is the most common acute complication and the leading
      cause of hospitalization. Management strategies for SCD have evolved very slowly, and
      treatment of acute pain is still limited to supportive therapy with opioid medication. Until
      recently in 2017, the only approved therapy for SCD was hydroxyurea (HU), indicated to reduce
      frequency of acute painful crises but not universally effective. In addition to HU,
      transfusions with normal red blood cells are widely used to treat severe sickle crises, but
      this strategy has limitations (not uniformly accessible, accompanied by risks of
      alloimmunization, hemolytic transfusion reactions and transfusional iron overload). The only
      curative treatment is bone marrow transplantation, but this option carries significant risks
      and is limited by the availability of histocompatible donors.

      As the root cause of SCD is polymerization of deoxy-HbS, there is a strong rationale for
      exploring agents that could inhibit/ reduce the polymerization process itself. HbS
      polymerizes only when deoxygenated, its oxygenation is influenced by a few factors, one key
      factor being the 2,3- diphosphoglycerate (2,3-DPG) concentration in the red blood cell.
      2,3-DPG decreases oxygen binding by preferentially binding to the low oxygen-affinity T
      conformation of HbS and also stabilizes the T form of hemoglobin S and HbS fiber. In
      addition, increased 2,3- DPG concentration decreases intracellular red cell pH further
      promoting HbS polymerization. 2,3-DPG is an intermediate substrate in the glycolytic pathway,
      the only source of ATP production in red blood cells. Pyruvate kinase (PK) is a key enzyme in
      the final step of glycolysis; PK converts phosphoenolpyruvate to pyruvate, creating 50% of
      the total red cell ATP that is essential for maintaining integrity of the red cell membrane.
      Reduced PK activity leads to accumulation of the upstream enzyme substrates, including 2,3-
      DPG, that favors polymerization of deoxy-HbS. In humans with SCD, and even in sickle carriers
      who are generally asymptomatic, reduced oxygen affinity will favor deoxygenation of HbS and
      its polymerization, and thus sickling. Indeed, the combination of PK deficiency and sickle
      cell trait causing an acute sickling syndrome has been previously reported in two cases.

      Current approaches to reduce HbS polymerization include fetal hemoglobin induction via
      multiple strategies and drugs that targets HbS polymerization through increasing affinity of
      hemoglobin for oxygen (eg. Oxbryta (TM) / Voxelotor / GBT440).

      Increasing red cell PK (PK-R) activity, leading to a decrease in intracellular 2,3-DPG
      concentration, presents a potentially attractive therapeutic target for thwarting HbS
      polymerization and acute sickle pain. AG-348 / mitapivat is a novel, orally bioavailable,
      small molecule allosteric activator of PK-R, that is currently in Phase II/III clinical
      trials in humans with PK deficiency (NCT02476916, NCT03548220 / AG348-C-006; NCT03559699 /
      AG348-C-007). Overview of the preclinical AG-348 data and other data support dose-dependent
      changes in blood glycolytic intermediates consistent with glycolytic pathway activation at
      all multiple ascending doses tested, supporting the potential role of AG-348 in the treatment
      of sickle cell disease. The overall objective of the present study is to determine the
      clinical safety and tolerability of AG-348 in subjects with SCD.
    

Intervention name(s): AG-348
Intervention type(s): Drug
Intervention description(s): This is a nonrandomized, intra-patient dose escalating clinical study. AG-348 will be administered starting at 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Other intervention name(s): Mitapivat
Intervention MeSH terms: Mitapivat
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: HbS polymerization; pyruvate kinase; 2,3- diphosphoglycerate; ATP in red blood cells; acute sickle pain