Mitapivat inches its way towards becoming first approved therapy for PK deficiency
22 Dec 2021
byAudrey Abella
The investigational pyruvate kinase R (PKR) activator mitapivat continued to show benefit for individuals with PK deficiency (PKD) regardless of transfusion status, according to updated findings from the phase III ACTIVATE trials and the long-term extension (LTE) study.
“PKD is a rare hereditary disease resulting in chronic haemolytic anaemia, which is associated with serious complications,” said Dr Eduard Van Beers from the University Medical Center Utrecht, Netherlands, at ASH 2021. “There are no approved disease-modifying pharmacotherapies [for PKD, and] available supportive therapies are associated with short- and long-term complications.”
“Ineffective erythropoiesis is linked to iron overload in patients with haemolytic anaemias … [The current findings] show that PKR activation with mitapivat improves markers of ineffective erythropoiesis and iron metabolism in patients with PKD regardless of transfusion status, thereby decreasing iron overload,” said Van Beers.
ACTIVATE/LTE
Eighty adults confirmed to have mild-to-moderate PKD who were not regularly transfused were randomized 1:1 to receive mitapivat or placebo for 24 weeks*. The LTE phase ensued thereafter, wherein those on mitapivat went on with their regimen (M/M arm), while placebo recipients rolled over to mitapivat (P/M arm). [ASH 2021, abstract 757]
Mean baseline levels of erythropoietic activity markers were high in both the M/M and P/M arms, noted Van Beers. “Erythropoietin (EPO) was fairly high (73.9 and 74.1 IU/L, respectively). Looking at reticulocytes, baseline levels are very high (817.8 and 901.7 109/L, respectively), which are typical for PKD. We see the same patterns for erythroferrone (ERFE; 21,079.8 and 20,379.8 ng/L) and sTfR** (187.0 and 174.3 nmol/L).”
At week 24, the levels of these markers dropped in the M/M arm (–32.9 IU/L, –202.0 109/L, –9,834.9 ng/L, and –56.0 nmol/L for EPO, reticulocytes, ERFE, and sTfR, respectively), but not so much in the P/M arm (7.0 IU/L, –52.1 109/L, –2,132.9 ng/L, and –2.1 nmol/L, respectively).
The reductions became more evident after the placebo-to-mitapivat rollover, pointed out Van Beers, noting that the levels between the M/M and P/M arms began to “catch up”. By week 48, the levels of EPO, reticulocytes, ERFE, and sTfR in the M/M arm were –22.0 IU/L, –168.6 109/L, –11,341.8 ng/L, and –36.9 nmol/L, respectively. Corresponding levels in the P/M arm were –11.6 IU/L, –283.7 109/L, –9,246.1 ng/L, and –36.7 nmol/L, respectively.
“[Taken together], these suggest that there is good oxygen delivery with diminishing erythropoietic drive [with mitapivat],” explained Van Beers.
In terms of markers of iron metabolism and overload, there was nothing much happening in the P/M arm at week 24. By week 48 however, mean baseline levels of hepcidin, iron, TSAT***, ferritin, and LIC# improved, both in the M/M (from 25,920.0 to 2,642.1 ng/L, 24.1 to –1.4 µmol/L, 0.5 to –0.01 fraction of 1, 747.9 to 3.2 µg/L, and 7.6 to –1.6 mg Fe/g dw##, respectively) and the P/M arms (from 29,988.8 to 15,975.0 ng/L, 26.6 to –2.4 µmol/L, 0.5 to –0.06 fraction of 1, 688.0 to –17.8 µg/L, and 6.1 to –2.7 mg Fe/g dw, respectively).
ACTIVATE-T/LTE
In ACTIVATE-T, 27 adults with confirmed PKD who were regularly transfused received mitapivat for 40 weeks###. The cohort was too small to make sensible analyses, Van Beers said. Nonetheless, in a subgroup of transfusion-free responders (n=6), improvement were seen in markers of erythropoietic activity and iron overload.
Why evaluate these markers?
“This is an important [issue to address] because there are various drugs now that have comparable modes of action and increased oxygen affinity and/or erythropoiesis,” explained Van Beers. “We need to know what the drug is doing – does it increase erythropoiesis, does it improve red cell viability, or can it reproduce erythropoiesis?”
The current findings boost the initially reported improvements in haemoglobin, haemolysis, and transfusion burden. [EHA 2021 library, abstracts S270 & S271] “[Mitapivat may] improve iron haemostasis, thereby reducing iron overload … Through this mechanism … mitapivat has the potential to become the first approved therapy in patients with PKD,” concluded Van Beers.