Valoctocogen Roxaparvovec (1) – Roctavian®

• Clinical trials
  • The BMN 270-301 trial is an open-label, single-arm, multicentre Phase III trial designed to assess the efficacy and safety of valoctocogen roxaparvovec in adults with severe haemophilia A.
  • The open-label, single-arm Phase I/II dose-escalation trial BMN 270-201 investigated the safety, tolerability and efficacy of valoctocogen roxaparvovec in patients with severe haemophilia A.

Adults with severe haemophilia A (congenital factor VIII deficiency) with no history of factor VIII inhibitors and no detectable antibodies against adeno-associated virus serotype 5 (AAV5)

• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification
• The strength of the evidence is therefore classified as ‘hint’.
• mortality
  • One death occurred in the BMN 270-301 study.
• morbidity
  • Patients in the BMN 270-301 study record any bleeding events and their Factor VIII prophylaxis usage in a personal patient diary.
  • Approximately 31% of patients experienced no bleeding following administration of valoctocogen roxaparvovec; approximately 71% experienced no joint bleeding and 94% experienced no bleeding in the target joint.
  • 59% of patients experienced no treated bleeding throughout the entire course of the study.
  • The estimated annual bleeding rate (ABR) for ‘all bleeds’ is 1.45 and for ‘treated bleeds’ is 0.9.
  • Only 4.5% (n = 6) of patients resumed prophylactic therapy with factor VIII preparations at least 5 weeks after administration of valoctocogen roxaparvovec or started treatment with emicizumab.
  • In 44% (n = 59) of patients, factor VIII treatment was administered during the period from week 5 following administration of valoctocogen roxaparvovec or from 3 days after the end of factor VIII prophylaxis (whichever occurred last) until the last visit prior to the data cut-off.
  • During the same period, 56% (n = 75) of patients remained without any treatment with factor VIII preparations (neither as prophylaxis nor as on-demand treatment).
  • Long-term avoidance of regular prophylaxis or on-demand treatment with clotting factor preparations may be of clinical relevance to patients, provided that this does not adversely affect other endpoints (e.g. bleeding rate).
• Morbidity – Health status assessed using the EQ-5D-5L VAS
  • In the BMN 270-301 study, health status is assessed using the visual analogue scale (VAS) of the EQ-5D-5L.
  • The data show an increase in values for this endpoint from baseline to week 104.
  • As this before-and-after comparison is not recognised, no conclusions can be drawn regarding the extent of the additional benefit.
• Morbidity – Haemophilia Activities List (HAL)
  • The HAL is a patient-reported questionnaire that measures the impact of haemophilia on functional abilities in adults.
  • The HAL results show a change from baseline to week 104, suggesting a reduction in functional impairment.
  • As the present before-and-after comparison is not recognised, no conclusion can be drawn regarding the extent of the additional benefit.
• Morbidity – Factor VIII activity (presented as supplementary data)
  • The endpoint ‘Factor VIII activity’ is the primary endpoint of the BMN 270-301 study.
  • There is an increase in the mean value at week 104 compared with baseline.
  • The endpoint ‘Factor VIII activity’ is a parameter that is not, in itself, clinically relevant to patients, as it is a laboratory parameter.
  • It remains unclear how Factor VIII activity will develop in the long term beyond the observation period of the BMN 270-301 study.
• Quality of life – Haemophilia-specific Quality of Life Questionnaire for Adults (Haemo-QoL-A)
  • The Haemo-QoL-A is a patient-reported questionnaire used to measure quality of life in adults with haemophilia and is employed in the BMN 270-301 study.
  • The total score shows an increase from baseline to week 104.
  • The individual domain scores also show an increase from baseline to week 104.
  • As this before-and-after comparison is not recognised, no conclusions can be drawn regarding the extent of the additional benefit.
• Side effects
  • Adverse events occurred in all patients in the BMN 270-301 study.
  • Adverse events of CTCAE grade ≥ 3 were documented in approximately 31% of patients.
  • Serious adverse events were reported in approximately 18% of patients.
• Overall assessment
  • Data from the single-arm study BMN 270-301 on the endpoints of mortality, morbidity, quality of life and adverse events are available for valoctocogen roxaparvovec for the treatment of adults with severe haemophilia A (congenital factor VIII deficiency) with no history of factor VIII inhibitors and no detectable antibodies against adeno-associated virus serotype 5 (AAV5), data are available from the single-arm BMN 270-301 trial on the endpoints of mortality, morbidity, quality of life and side effects.
  • The before-and-after comparison is subject to major methodological limitations and is deemed insufficiently valid to be used for the benefit assessment.
  • Overall, there are no suitable data available for a comparative assessment. Consequently, it is not possible to quantify the extent of the additional benefit on the basis of the data presented.
  • Taking the available results as a whole, no conclusions can be drawn regarding the extent of the additional benefit. A quantitative assessment of the extent of the effect and a quantification of the additional benefit into one of the categories ‘minor’, ‘considerable’ or ‘major’ is not possible on the basis of the data provided.
  • Taking into account the severity of the condition, the written submissions and the oral hearing, the G-BA classifies the extent of the additional benefit of valoctocogen roxaparvovec for the treatment of severe haemophilia A in adults, on the basis of the criteria set out in Section 5(7) of the AM-NutzenV as ‘non-quantifiable’, because the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.