Velmanase alfa (1) – Lamzede®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer has submitted the randomised, double-blind, placebo-controlled Phase III registration trial rhLAMAN-05 and the single-arm trial rhLAMAN-10.

Patients with mild to moderate alpha-mannosidosis

• Velmanase alfa offers a non-quantifiable additional benefit for the treatment of non-neurological manifestations in patients with mild to moderate alpha-mannosidosis.
• An additional benefit exists in accordance with Section 35a(1), sentence 11, first clause of SGB V, but is non-quantifiable because the scientific evidence currently does not permit this.
• mortality
  • No deaths occurred.
• Morbidity – serum oligosaccharide levels
  • Serum oligosaccharide levels were recorded as the primary morbidity endpoint.
  • Systemic deposits of oligosaccharides are the cause of the clinical picture of alpha-mannosidosis.
  • However, serum oligosaccharide concentration does not yet represent an established standard for diagnosis or treatment monitoring, nor has the effect of a change in serum oligosaccharide concentration on patient-relevant endpoints been sufficiently clarified.
  • Furthermore, there are no reference values for serum oligosaccharide levels.
  • Consequently, neither the patient-relevance nor the therapeutic or clinical relevance of the serum oligosaccharide level can be adequately assessed.
  • The endpoint is therefore classified as not relevant for assessment.
  • For serum oligosaccharide levels, a statistically significant difference in favour of velmanase alfa compared with the control group was observed at week 52 during treatment with velmanase alfa (difference in absolute change [95% CI]: -3.50 [-4.37; -2.62]; p < 0.001).
• Morbidity – 3-minute stair-climbing test (3MSCT)
  • The 3MSCT measures the number of steps a person can climb within three minutes.
  • There is no established standard for conducting the test.
  • There is no statistically significant difference between the treatment groups.
• Morbidity – Forced Vital Capacity (FVC) and Forced Expiratory Volume in One Second (FEV1)
  • Respiratory function was measured using various parameters.
  • Forced vital capacity (FVC) measures the lung volume between maximum inhalation and exhalation, whilst forced expiratory volume in one second (FEV1) measures the volume exhaled within one second during forced exhalation.
  • Although lung function may be impaired in patients with alpha-mannosidosis, the patient-relevance and clinical relevance of the FVC and FEV1 endpoints remain unclear.
  • No statistically significant difference was observed between the treatment groups.
• Morbidity – 6-minute walk test (6MWT)
  • Walking ability was assessed using the 6MWT and conducted in accordance with the established standard of the American Thoracic Society (ATS).
  • The test measures the distance, in metres, that can be covered within six minutes on a hard, flat surface.
  • There was no statistically significant difference between the treatment groups.
• Morbidity – Bruininks-Oseretsky Test of Motor Proficiency (BOT-2)
  • The BOT-2 is a measure of gross and fine motor skills in children and adolescents aged 4 to 21 years.
  • No statistically significant difference was observed between the treatment groups.
• Morbidity – Hearing performance assessed by pure-tone audiometry
  • Pure-tone audiometry was carried out on all study participants to measure hearing ability.
  • There was no statistically significant difference between the treatment groups.
• Morbidity – Childhood Health Assessment Questionnaire (CHAQ)
  • The CHAQ is a tool for assessing disease-specific functional status in children and adolescents aged between one and 19 years with juvenile rheumatoid arthritis (JRA).
  • There was no statistically significant difference between the treatment groups.
• Overall assessment
  • The rhLAMAN-05 study provides findings on mortality, morbidity and side effects.
  • Treatment with velmanase alfa shows a statistically significant improvement in serum oligosaccharide levels compared with the control group.
  • However, as the impact of this change on patient-relevant endpoints or the clinical relevance of the endpoint cannot be adequately assessed, the result cannot be used to determine the extent of the additional benefit.
  • The results for patient-relevant endpoints show no significant differences between treatment with Velmanase alfa and placebo during the study duration (12 months).
  • The G-BA assesses the extent of the additional benefit of Velmanase alfa—to be assumed solely from a legal perspective under Section 35a(1), sentence 11, first clause, 1 SGB V, 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 the treatment of the disease, as a non-quantifiable additional benefit.
• Conclusion (summary)
  • The randomised, double-blind, placebo-controlled Phase III study rhLAMAN-05 is used for the benefit assessment.
  • As the data from the single-arm study rhLAMAN-10 do not provide any information beyond the results of the rhLAMAN-05 study (for example, regarding long-term outcomes) and are also subject to a high potential for bias, they are not taken into account for the benefit assessment.
  • Results on mortality, morbidity and side effects are available from the rhLAMAN-05 study.
  • The improvement in serum oligosaccharide levels achieved with velmanase alfa compared with the control group cannot be used to determine the extent of the additional benefit, due to the unclear patient-relevant or clinical relevance of this finding.
  • The results for patient-relevant endpoints show no significant differences between treatment with velmanase alfa and the control group at the end of the study duration (12 months).
  • The G-BA assesses the extent of the additional benefit of Velmanase alfa – to be assumed solely from a legal perspective under Section 35a(1), sentence 11, first half-clause, 1 of SGB V, 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 the treatment of the disease, as a non-quantifiable additional benefit.

Courtesy translation only, please refer to the German original.