OXBRYTA (voxelotor) - Anémie hémolytique sévère

Key points

Favourable opinion for reimbursement only in the treatment of severe haemolytic anaemia due to sickle cell disease (SCD) in adults and paediatric patients 12 years of age and older as monotherapy or in combination with hydroxycarbamide.

Unfavourable opinion for reimbursement in the other populations of the MA (non-severe form of haemolytic anaemia).

What therapeutic improvement?

No clinical added value in the therapeutic strategy.

Role in the care pathway?

No medicinal products are currently specifically authorised in the treatment of haemolytic anaemia in patients with sickle cell disease. The medicinal products specifically authorised in the treatment of sickle cell disease are only for the prevention of vaso-occlusive crises (VOCs): hydroxycarbamide (SIKLOS and XROMI) and crizanlizumab (ADAKVEO).

The treatment of haemolytic anaemia is currently based on:

• Simple transfusions or exchange transfusions in the event of symptomatic or poorly tolerated chronic anaemia.
• Hydroxycarbamide (also known as hydroxyurea) off-label. According to the French national diagnostic and care protocols (PNDS) issued by the HAS in 2014, hydroxycarbamide can be offered in the event of anaemia:
  • in children and adolescents: in the event of severe anaemia (Hb < 6 g/dl or < 7 g/dl with poor clinical or functional tolerance)
  • in adults: in the event of severe chronic anaemia after having ruled out a curable cause for exacerbation and if the anaemia is symptomatic or combined with organ damage, in particular renal or cardiac.

It should be noted that in 2021, after the publication of the PNDS, the application for extension of the MA for SIKLOS (hydroxycarbamide) in the treatment of haemolytic anaemia was assessed by the CHMP. The latter concluded that the use of hydroxycarbamide could not be recommended in this indication, in view of the clinical data not enabling its benefit-risk balance to be adequately documented.

• Erythropoietin (EPO) off-label. EPO is not cited as a therapeutic option in the PNDS for children and adolescents. According to the PNDS for adults, EPOs are used following the opinion of reference and expert centres in certain off-label situations, in particular chronic anaemia, in combination with hydroxycarbamide.

The only curative treatment currently is a bone transplant. This is reserved for the most severe forms of the disease, particularly in children, and remains exceptional in adults.

Role of the medicinal product in the care pathway

OXBRYTA (voxelotor) is the first medicinal product to have a specific MA in the treatment of haemolytic anaemia in patients with sickle cell disease.

As knowledge currently stands, the Committee considers that the prescription of OXBRYTA (voxelotor) should be reserved for the treatment of severe haemolytic anaemia, in combination with hydroxycarbamide or as monotherapy. Since there is currently no consensus definition of severe haemolytic anaemia, prescriptions will depend on the assessment and experience of the specialist prescriber in the treatment of sickle cell disease, based on both clinical and laboratory criteria.

To date, only a benefit in terms of increase in haemoglobin and reduction in certain haemolysis markers in the short term (24 weeks) has been demonstrated versus placebo in the HOPE study, a study with a low level of evidence in a population predominantly treated with hydroxycarbamide at baseline and with a low rate of vaso-occlusive crises in the previous year.

The clinical impact of improving these laboratory parameters under voxelotor is not currently known. In fact, no benefit versus placebo was demonstrated in the HOPE study on clinical endpoints reflecting the severity of the disease or patient well-being (in particular the number of VOCs, disease symptoms, quality of life, need for blood transfusions and use of opioids).

Given its oral use, voxelotor could be useful in the care pathway of transfused patients if a benefit in terms of transfusion-sparing were to be demonstrated, although this is not yet the case.

The mechanism of action of voxelotor is a source of uncertainties in terms of the expected clinical benefits of increasing haemoglobin levels, and the potential risks of tissue hypoxia in the long term and of VOCs in the event of temporary interruption of treatment.

Voxelotor could lead to an excessive increase in haemoglobin levels in some patients, with a risk of blood hyperviscosity and associated complications that cannot be totally excluded, in view of the data from the HOPE study, during which 41.1% of patients treated at the dose of 1,500 mg/day achieved a haemoglobin level of > 10 g/dL at 24 weeks and in which a higher incidence of acute chest syndromes and priapism was observed in the voxelotor group than under placebo. Although a reduction in dose would appear to be justified in practice, no dosage reduction regimen has been validated in this situation and only the fixed dose of 1,500 mg/day is recommended in the SPC. The Committee highlights that, in sickle disease patients, it is not recommended to exceed an Hb level of 10 to 11 g/dL with the treatments currently used to correct haemoglobin5, since there is a risk of complications associated with blood hyperviscosity above this level. The Committee considers that the clinical data available is still inadequate to be able to conclude that this risk cannot be transposed to voxelotor.

Special attention must be paid to ensuring good compliance with treatment, particularly in adolescents and young adults and especially since there are questions concerning the existence of a risk of VOC, related to the mechanism of voxelotor, in the event of temporary interruption of treatment.

Special recommendations

The Committee regrets that no dosage reduction regimen has been evaluated during clinical trials in the event of an excessive increase in haemoglobin levels and that only the fixed dose of 1,500 mg/day is recommended in the SPC, given data in the HOPE study demonstrating a concentration > 10 g/dL after 24 weeks of treatment in over 40% of patients treated at this dosage.