PKDeep

What is PKDeep?

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.



Why PKDeep?

PKD Challenges

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.

PKD Treatments

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.

PKD Diagnosis Pitfalls

Some pitfalls on PK diagnosis have been observed due to:

  • No correlation between PK activities from non-experts and experts centres
  • RBC package is not separated properly driving to leucocytes presence in the sample and increased PK activity
  • PK/HK ratio is not performed in non expert labs leading to normal results in cases of high number of retyculocytes
  • Reference values for PK activity vary according to age and ethnical origin

In addition, there is a number of cases misdiagnosed, the main causes are:

  • Hereditary Spherocytosis, it is a more common cause of chronic hemolysis
  • Thalassaemia major, in cases of severe blood transfusion anemia
  • Liver abnormality, anaemia is considered secondary to the liver trastorn

European Approach

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.

PKDEEP speficic objectives

The objective of PK-DEEP is to develop and implement the PKD arm of RA-DEEP through the following activities:

  1. Creation of a research protocol for including PKD patients in RA-DEEP, including a list of baseline indicators for disease characteristics (proof of diagnosis, demographic, laboratory, clinical, therapeutic) in agreement with RADEEP’s legal frame for sharing and re-use of patients’ data based on EU policies for rare diseases.
  2. Implement database at EU level following pilot phase at specific sites (6-8) and/or member States.
  3. PK-DEEP website, leaflet and educational module
  4. Assessment of pan-EU PKD diagnoses: Mapping of diagnosis services offered by HCPs and % of PKD patients with adequate proof of diagnosis in currently existing registries initiatives.
  5. Promote best practices for PKD diagnosis through:
    1. Production of recommendations on PKD diagnosis and treatment
    2. Promote the establishment of an external quality assessment scheme for PK measurement in collaboration with UK-NEQAS
    3. Establish a referral system of samples for genetic diagnosis
    4. Improve disease state awareness/patient care through on-site courses or e-learning platform

Scientific Board

Scientific Board of PKDeep is formed by:

Name Institution Country
Wilma Barcellini Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico Italy
Paola Bianchi Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico Italy
Maria del Mar Mañú Pereira University Hospital Vall d'Hebron - Vall d'Hebron Research Institute Spain
Serge Pissard CHU Henri Mondor France
Eduard van Beers University Medical Center Utrecht Netherlands
Richard van Wijk University Medical Center Utrecht Netherlands
Tabita Magalhaes Maia Centro Hospitalar e Universitário de Coimbra Portugal
Celeste Bento Centro Hospitalar e Universitário de Coimbra Portugal