Mitapivat shows potential for PK deficiency

Mitapivat, an investigational, first-in-class, oral, allosteric pyruvate kinase R (PKR) activator, had clinically meaningful benefit for individuals with PK deficiency regardless of transfusion status, according to the phase III ACTIVATE trials presented at EHA 2021.

 

A rare genetic disorder, PK deficiency leads to haemolytic anaemia, which is tied to serious comorbidities. Moreover, regular transfusions run the risk of chronic complications such as end-organ damage and iron overload. The lack of approved therapies for this condition underscores the unmet need for this patient setting.

 

This study comprised 80 adults with PK deficiency who were not receiving regular transfusions. Participants were randomized 1:1 (mean age 36.6 years, 40 percent male, mean baseline haemoglobin 8.5 g/dL) to receive mitapivat or placebo, initially for a 12-week dose-escalation phase (5, 20, 50 mg BID; part 1) followed by a 12-week fixed-dose phase (part 2). [EHA 2021, abstract S270]

 

The primary endpoint was met, with 16 mitapivat recipients achieving a sustained haemoglobin response* compared with none among placebo-treated patients (p<0.0001).

 

Secondary endpoints were also met, including changes from baseline haemoglobin concentration (least squares mean [LSM] difference, 1.8 g/dL), indirect bilirubin (LSM difference, –26.26 µmol/L), and reticulocyte percentage (LSM difference, –0.10; p<0.0001 for all). 

 

LSM differences were also notable for lactate dehydrogenase (–70.81 U/L; p=0.0027) and haptoglobin (0.158 g/L; p=0.0079), as well as for the disease-specific patient-reported outcomes of PKDD** (–3.11; p=0.0247) and PKDIA*** (–3.25; p=0.0421), all favouring mitapivat over placebo.

 

“The haemoglobin and haemolysis marker improvements in the mitapivat arm were rapid and maintained over time,” said the researchers.

 

There were more mitapivat vs placebo recipients reporting grade ≥3 treatment-emergent adverse events (TEAEs; n=10 vs 5), the most common being hypertriglyceridemia and hypertension. There were no discontinuations owing to TEAEs nor new safety signals reported.

 

“[These findings] indicate clinically meaningful benefit for patients treated with mitapivat,” said the researchers.

 

In this open-label trial, 27 regularly transfused^# participants (mean age 36.6 years, 26 percent male, mean baseline haemoglobin 9.2 g/dL) received mitapivat. Part 1 was a 16-week dose escalation period (5, 20, 50 mg BID); part 2 was a 24-week fixed-dose period. [EHA 2021, abstract S271]

 

Transfusion burden was significantly reduced^## in 10 participants (p_one-sided=0.0002). Mean number of annualized RBC units transfused was lower up to study end vs historically (11.38 vs 16.63), translating to a relative reduction of 39 percent. Six participants (22 percent) were transfusion-free during part 2.

 

Eight participants had grade ≥3 TEAEs. The most common any-grade TEAEs were increased alanine aminotransferase and headache. There were no TEAEs leading to treatment discontinuation.

 

“These results support that … through the novel mechanism of PKR activation, [mitapivat] provides meaningful benefit to regularly transfused patients with PK deficiency,” said the researchers.

 

Collectively, the findings of both studies demonstrate the potential of mitapivat to become the first disease-modifying drug therapy approved for PK deficiency.