Isavuconazol (1) – Cresemba®

• Clinical trials
  • The G-BA’s assessment is based on the data from the Phase III SECURE trial (9766-CL-0104), which formed the basis for marketing authorisation, as submitted by the pharmaceutical manufacturer in the dossier demonstrating additional benefit. This multicentre, active-controlled, randomised non-inferiority trial included 516 patients (ITT population) with invasive aspergillosis.
  • The assessment is based on the VITAL registration trial (9766-CL-0103). This was a multicentre, single-arm, open-label Phase III trial that enrolled patients with invasive fungal infections caused by moulds, yeasts or dimorphic fungi.

a) Invasive aspergillosis

• In summary, the extent of the additional benefit of isavuconazole is assessed as follows: non-quantifiable
• Due to the methodological limitations of the study and the overall limited evidence base, the G-BA classifies the extent of the additional benefit of isavuconazole in the therapeutic indication of invasive aspergillosis, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease, as non-quantifiable.
• Consequently, 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 submitted. An additional benefit exists, but it is non-quantifiable because the scientific evidence does not permit this.
• mortality
  • The primary endpoint of the study was overall mortality up to day 42. Non-inferiority compared with voriconazole was demonstrated in both the myITT population and the ITT population: The upper limit of the 95% confidence interval for the treatment difference was below the non-inferiority margin of 10% in each case. Comparable results are evident in the additional endpoint ‘overall mortality up to day 84’. The results do not allow for a quantitative assessment of the extent of the additional benefit.
• morbidity
  • Among the endpoints in the morbidity category, ‘clinical response according to the DRC (Data Review Committee)’ can be considered to have greater statistical significance than ‘clinical response according to the investigator’ due to the more objective nature of the assessment. However, no significant difference between the two treatment arms was observed for either endpoint. The results do not allow for a quantitative assessment of the extent of the additional benefit.
• quality of life
  • No data on health-related quality of life were collected.
• Side effects
  • No significant differences were observed between the treatment arms in the myITT population for any of the endpoints ‘overall AEs’, ‘serious AEs’ and ‘AEs leading to permanent discontinuation of study medication’.
  • When considering the overall rate at SOC level in the myITT population, significantly fewer events were observed with isavuconazole in the SOC ‘eye diseases’; furthermore, when analysing the safety population, significantly fewer events were observed in the SOCs ‘Liver and gallbladder disorders’ and ‘skin and subcutaneous tissue disorders’.
  • Furthermore, in the safety population, there were significantly fewer AEs in the isavuconazole arm that led to permanent discontinuation of the study medication (14.4% vs. 22.8%). In the myITT population, there were also numerically fewer therapy discontinuations due to AEs, although these were not statistically significant.
  • However, these differences are difficult to interpret in light of the fact that the overall rates of AEs and serious AEs did not differ, and given the uncertain evidence regarding the dosage used, due to the lack of dose-finding studies conducted by the pharmaceutical manufacturer as part of the marketing authorisation process.
• Overall view
  • In summary, no quantifiable additional benefit of isavuconazole can be inferred from the mortality, morbidity and adverse reaction data. The uncertain evidence regarding the dosage used, due to the lack of dose-finding studies conducted by the pharmaceutical manufacturer as part of the marketing authorisation process, makes it difficult to interpret the data.

b) Mucormycosis in patients for whom treatment with amphotericin B is not appropriate

• In summary, the extent of the additional benefit of isavuconazole is assessed as follows: non-quantifiable
• Due to the methodological limitations of the study and the generally limited evidence base, the G-BA classifies the extent of the additional benefit of isavuconazole in the therapeutic indication of mucormycosis in patients for whom amphotericin B is not appropriate as ‘non-quantifiable’ on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the condition.
• Consequently, 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 submitted. An additional benefit exists, but it is non-quantifiable because the scientific evidence does not permit this.
• mortality
  • By day 84, 7 out of 16 (43.8%) patients in the mITT-Mucorales population who were refractory to or intolerant of prior treatment had died. As the pharmaceutical manufacturer has not provided a breakdown by prior therapy, it remains unclear which of these 7 patients had been pre-treated with amphotericin B.
  • The mortality rates for untreated patients with mucormycosis, identified on the basis of the pharmaceutical manufacturer’s literature search and used as a historical control for the endpoint of overall mortality up to day 42, cannot be assessed due to a lack of information on the comparability of the patient cohorts. According to the pharmaceutical manufacturer’s data, the weighted mortality rate for the historical control was 83.4%. Due to the lack of a comparison, no conclusion can be drawn regarding the extent of the additional benefit.
• morbidity
  • In the morbidity category, clinical response as assessed by a blinded committee was used as the patient-relevant individual component. By day 42, the endpoint had been reached by 5 (38.5%) of 13 symptomatic patients who were refractory to or intolerant of prior treatment. As the pharmaceutical manufacturer did not provide a breakdown by prior therapy, it remains unclear which of these 5 patients had been pre-treated with amphotericin B.
  • Due to the way the clinical response was defined, the severity of the symptoms, the nature of the improvement and the influence of the underlying condition on the symptoms remain unclear. Consequently, it is not possible to quantify the additional benefit for this endpoint.
• quality of life
  • No data on health-related quality of life were collected.
• Side effects
  • For the patients relevant to the assessment (n=13), no evaluable data on safety endpoints are available. A comparative assessment of the extent of the additional benefit is therefore not possible on this basis.
• Overall assessment
  • The assessment of the extent of the additional benefit of isavuconazole is based on evidence from a single-arm study with a very small sample size (13 patients relevant to the assessment). The evaluation of these study data is greatly complicated by this very small sample size, the open-label, single-arm study design, the marked heterogeneity of the patients in terms of baseline characteristics, and the lack of comparison with other antifungal active ingredients (INN). These factors result in a high potential for bias.

Courtesy translation only, please refer to the German original.