Reason for request
Favourable opinion for reimbursement only for patients aged 18 years and over with acute hepatic porphyria (AHP) and with active disease (at least 2 porphyria attacks requiring hospitalisation, an urgent healthcare visit or treatment with IV hemin at home, in the past 6 months).
Unfavourable opinion for reimbursement in the other MA situations, i.e., in patients not meeting the ENVISION study inclusion criteria, in particular in patients with intermittent acute attacks (1 to 3 attacks per year), as well as in patients aged 12 to 18 years.
What therapeutic improvement?
Therapeutic improvement in management.
Role in the care pathway?
The treatment of acute neurological attacks should be initiated as soon as possible. It is first necessary to identify and eliminate all trigger factors, in particular porphyrinogenic drugs, and then to initiate symptomatic treatment, identical irrespective of the type of porphyria. This treatment is aimed at treating pain (opioids), gastrointestinal disorders, hypertension and arrhythmia, anxiety, insomnia or seizures, and correcting any hyponatraemia and inadequate calorie intake (carbohydrates). The intravenous administration of human hemin arginate (NORMOSANG), as an etiopathogenic treatment, is the treatment of choice for attacks in the event of signs of severity (neurological complications, hyponatraemia or persistent severe pain). The administration of exogenous haem suppresses ALAS1 and reduces ALA and PBG concentrations, resulting in the regression of symptoms within a few days. However, it should be noted that hemin arginate does not induce regression of existing neuropathy.
The prophylactic management of attacks is primarily based on the avoidance of trigger factors (alcohol, smoking, diets, etc.), as well as limitation of prescriptions to medicines that are authorised because they are non-porphyrinogenic. No treatment has an MA specifically in the prevention of attacks. In patients with recurrent (≥ 4 attacks per year) or intermittent attacks (1 to 3 attacks per year), off-label long-term prophylactic treatment (1 injection per month to 1 injection per week) with human hemin (NORMOSANG) is often considered in the absence of alternatives. However, this medicinal product is only indicated for the treatment of acute attacks and may cause damage to the superficial venous network, thrombosis and iron overload in the event of repeated administration. In very severe cases with major impairment of quality of life, particularly for recurrent acute intermittent porphyria (AIP), liver transplantation may be considered.
Finally, cutaneous involvement in variegate porphyria (VP) and hereditary coproporphyria (HCP) also require photoprotection (avoidance of sun, opaque creams, protective clothing, etc.).
Role of the medicinal product in the care pathway
- demonstration of the superiority of GIVLAARI (givosiran) compared to placebo in terms of the number of severe acute porphyria attacks (requiring hospitalisation, an urgent healthcare visit or treatment with IV hemin at home), the frequency of hemin administration for the curative treatment of attacks, and pain (ranked secondary outcome measures), and maintenance of this efficacy after 12 months,
- the absence of therapeutic alternatives to prevent acute porphyria attacks,
- demonstration of this efficacy only in patients with severe forms of AHP with repeated (≥ 2 porphyria attacks in the past 6 months) and severe attacks (requiring hospitalisation, an urgent healthcare visit or treatment with IV hemin at home)
- and the absence of data in patients aged 12 to 18 years,
the Committee considers that GIVLAARI (givosiran) is a treatment for acute hepatic porphyria (AHP) only for patients aged 18 years and over and with active disease, characterised by at least 2 porphyria attacks requiring hospitalisation, an urgent healthcare visit or treatment with IV hemin at home, in the past 6 months, in accordance with the inclusion criteria in the ENVISION study.
This corresponds to patients with recurrent attacks (≥ 4 attacks per year). For these patients, the long-term prophylactic treatment of attacks should no longer be based on the repeated administration of hemin, therefore.
The medicinal product has no role in the other clinical situations covered by the MA.
The Committee highlights the fact that:
- given the complexity of the diagnosis and management of these diseases, the decision to initiate treatment with GIVLAARI (givosiran) should be taken after a documented proposal resulting from a treatment review meeting with a reference centre with expertise in the treatment of porphyria,
- the implementation of careful monitoring of hepatic and renal function in accordance with the SPC recommendations (sections 4.2, 4.4 and 4.8 of the SPC) is essential,
- on an occasional basis, the use of givosiran may be considered as a prophylactic treatment in patients with a concomitant neoplastic or infectious disease or with a surgical indication liable to trigger a neurovisceral attack that could have a particularly significant impact in terms of morbidity and mortality or limitation of treatments (expert opinion),
- the data with givosiran are very limited or even non-existent in patients with VP, HCP and ALA dehydratase-deficient porphyria (ADP), but these types of porphyria were included in the inclusion criteria for the ENVISION study and the treatment efficacy appears to be extrapolable given the pathophysiology of the attacks and the mechanism of action of givosiran,
- its efficacy on chronic neuropathic pain has not been determined
- given the unmet medical need, it encourages the pharmaceutical company to continue development in patients with acute hepatic porphyria, potentially with a simplified dosing regimen in certain situations.
The Committee reiterates that therapy should be initiated under the supervision of a healthcare professional experienced in the management of porphyria.
It also draws attention to the need to perform liver function tests before and during treatment with givosiran (so that treatment interruption or discontinuation can be considered in the event of clinically relevant transaminase elevations) and to implement careful monitoring of renal function in patients with pre-existing renal disease in accordance with the SPC recommendations (sections 4.2, 4.4 and 4.8 of the SPC).
The clinical benefit of GIVLAARI (givosiran) is substantial only for patients aged 18 years and over, for the treatment of acute hepatic porphyria (AHP) and with active disease characterised by at least 2 porphyria attacks requiring hospitalisation, an urgent healthcare visit or treatment with IV hemin at home, in the past 6 months.
The clinical benefit of GIVLAARI (givosiran) is insufficient to justify its funding by the French national health insurance system in the other MA situations, i.e., in patients not meeting the ENVISION study inclusion criteria, in particular in patients with intermittent acute attacks (1 to 3 attacks per year), as well as in patients aged 12 to 18 years, in the absence of data.
Clinical Added Value
the Transparency Committee considers that GIVLAARI (givosiran) provides an important clinical added value (CAV II) in the therapeutic strategy for adult patients with acute hepatic porphyria (AHP).