Pyruvate kinase deficiency (PKD) is a rare autosomal recessive disorder leading to chronic haemolytic anaemia of variable severity, from fully-compensated to life-threatening, transfusion dependent anemia. Pyruvate kinase is a metabolic enzyme that catalyses the last step of glycolysis. PKLR gene encodes the red blood cell-specific (RPK) and liver-specific (LPK) isoforms. 240 mutations in PKLR have been identified responsible for red blood cell PKD. (www.lovd.nl/pklr).
Molecular characterization of the PKLR gene allows a precise diagnosis
However, about 10% of PKD patients fail to reveal causative mutations in one or both alleles in spite of decreased PK activity, strongly suggesting that PK structure and function is influenced by other yet unknown (regulatory) sequences. In addition, patients homozygous or compound heterozygous for PKLR shows a large range in clinical manifestation severity, as well as a different response to splenectomy, suggesting a variable genetic background for maintaining the needed equilibrium between haemolysis and erythropoieisis for avoiding blood transfusion requirement. In-depth biochemical and structural studies of native, mutant, and recombinant dysfunctional enzymes showed that little correlation exists between the molecular perturbation, residual enzymatic activity, and clinical phenotype. Hence, additional genes and proteins are likely involved in the expression of the PKD phenotype. Whole Exome Sequencing applied to patients with no abnormalities in PKLR gene will allow to search for new causative genes. Moreover, comparison among PKD patients carrying the same genotype with different phenotype will facilitate to identify modifier genes influencing the phenotype.
The only curative treatment is allogeneic stem cell transplantation
But this carries a considerable risk of mortality, especially from unrelated donors. Accordingly, contra-indications and adverse effects should be considered in each patient. Currently, other curative options as gene therapy or disease target drugs are under clinical trial phases.
However, as in other rare diseases, there are no patients' registries or exhaustive epidemiological studies hampering the development of collaborative research projects and/or clinical trials. Accordingly, in order to promote research on PKD physiopathological causes and on new treatment options, a European approach is required to set up a central registry of patients.
Different from haemoglobinopathy patients, more prevalent and concentrated by ethnical and/or geographical origin, patients affected by PKD are scarcer and highly distributed.
In addition, PKD diagnosis is commonly delay due to lack of adequate testing or misinterpretation and no specific drug is still available on the market. Accordingly, PKD patients could benefit for such European approach.
There is currently no treatment available that can actually cure PKD, apart from stem cell transplantation. Treatment for PKD patients generally consists of blood transfusions, splenectomy, and iron chelation therapy to prevent organ damage from iron overload. However, there are currently no approved medicines that treat the underlying cause of PKD.
Agios Pharmaceuticals is developing the investigational drug, AG-348 - an orally available, potent, small molecule activator of pyruvate kinase-R (PKR). Enrolment has been completed for the Phase II clinical trial "DRIVE PK" (NCT02476916). DRIVE PK is a multicenter study designed to evaluate the safety and efficacy of different dose levels of AG-348 in patients with PK deficiency. Trial locations are open at several sites across the USA, as well as in Canada, Italy, and the UK. To learn more about this study visit Agios' Drive PK Trial website at www.drivepktrial.com.
Agios has also begun two separate Phase III studies using AG-348. The ACTIVATE trial will enrol patients with PK deficiency who are not regularly transfused, while the ACTIVATE-T trial will enrol patients with PK deficiency who are regularly transfused. These trials will both begin enrolment in 2018.
Some pitfalls on PK diagnosis have been observed due to:
In addition, there is a number of cases misdiagnosed, the main causes are:
Accordingly, there is an urgent need to promote at European level best practices for PKD diagnosis and increase its awareness among medical community; GPs, paediatricians and even haematologists.
PKDeep will enable the pooling of information on PKD patients at the European level ensuring adequate diagnosis, reliable PK activity measurement and genotyping thus facilitating development of research projects and clinical trials.
The objective of PKDeep is to develop and implement the PKD arm of RADeep through the following activities: