Albiglutid (1) – Eperzan®

• Clinical trials
  • To demonstrate the additional benefit of albiglutide in combination with metformin compared with the appropriate comparator therapy – metformin in combination with a sulphonylurea (glimepiride) – the pharmaceutical manufacturer submitted the direct comparative trial GLP 112753 (HARMONY 3, hereinafter referred to as HARMONY 3).
  • This is a randomised, active- and placebo-controlled, double-blind, four-arm registration trial with a total treatment period of 156 weeks.

a) As monotherapy, when diet and exercise alone are insufficient to control blood glucose levels in patients for whom the use of metformin is considered unsuitable due to contraindications or intolerance

• For monotherapy with albiglutide, where diet and exercise alone do not adequately control blood glucose and the use of metformin is considered unsuitable due to intolerance, the additional benefit is not proven.
• No study has been submitted that would have been suitable for assessing the additional benefit of albiglutide monotherapy, in the above-mentioned therapeutic indication, compared with the appropriate comparator therapy (sulfonylurea: glibenclamide or glimepiride).

b1) In combination with another blood glucose-lowering medicinal product (other than insulin), if this does not sufficiently lower blood glucose levels in conjunction with diet and exercise – in dual combination with metformin

• For the treatment of adult patients with type 2 diabetes to improve glycaemic control, an overall assessment of the available data on mortality, Morbidity and side effects, there is an indication of additional benefit for albiglutide in combination with metformin compared with the appropriate comparator therapy of metformin in combination with a sulphonylurea (glimepiride or glibenclamide).
• The G-BA classifies the extent of the additional benefit of albiglutide (in combination with metformin) as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic goal in the treatment of the disease.
• The certainty of the finding (probability of additional benefit) is classified in the ‘indication’ category.
• mortality
  • In the HARMONY3 study, a total of 4 deaths occurred in the albiglutide + metformin group and 6 deaths in the glimepiride + metformin group over the period up to week 164. No statistically significant difference in overall mortality was observed between the treatment groups. An additional benefit of albiglutide + metformin compared with glimepiride + metformin for overall survival is not proven.
• Morbidity – strokes (all, adjudicated), strokes (non-fatal, adjudicated) and cardiac morbidity
  • No statistically significant differences were observed between the treatment arms for the endpoints of strokes (all, adjudicated, and non-fatal, adjudicated).
  • For the endpoint of cardiac morbidity, defined as the number of patients with a non-fatal, serious event in the MedDRA SOC for cardiovascular diseases, there was likewise no significant difference between the treatment arms.
• quality of life
  • Data on quality of life were not collected as part of the HARMONY3 study. Consequently, no usable data are available.
• Side effects – severe adverse events (SAEs) and discontinuation due to adverse events (AEs)
  • For the endpoints SAE and discontinuation due to AEs, the HARMONY 3 study showed no statistically significant differences between the treatment groups for the period up to week 164.
• Side effects – Severe hypoglycaemia
  • In the HARMONY 3 study, one case of severe hypoglycaemia (in the glimepiride + metformin group) occurred up to week 164; no cases of severe hypoglycaemia occurred in the albiglutide arm. The difference is not statistically significant. There is therefore no proof that albiglutide + metformin is either more or minorly harmful compared to glimepiride + metformin.
• Side effects – Non-severe hypoglycaemia
  • For the endpoint of symptomatic hypoglycaemia confirmed by a blood glucose reading of ≤ 54 mg/dl, a statistically significant advantage was observed for treatment with albiglutide in combination with metformin (3 (1.0%) vs. 24 (7.8%); RR = 0.13, 95% CI [0.04; 0.42], p < 0.001).
  • Over a period of up to 164 weeks, fewer symptomatic hypoglycaemic episodes, confirmed by a blood glucose reading of ≤ 70 mg/dl, occurred with albiglutide in combination with metformin than with glimepiride in combination with metformin (12 (4.0%) vs. 66 (21.5%); RR = 0.18, 95% CI [0.10; 0.33], p < 0.001)).
• Side effects – injection site reactions
  • With regard to the proportion of patients who had experienced at least one injection-site reaction by week 164, there was a statistically significant difference to the detriment of albiglutide plus metformin compared with glimepiride plus metformin (55 (18.2%) vs. 26 (8.5%); RR = 2.15, 95% CI [1.39; 3.33], p < 0.001).
• Overall assessment
  • An overall analysis of the results in the ‘side effects’ category reveals a minor additional benefit of albiglutide in combination with metformin compared with the appropriate comparator therapy (metformin + sulphonylurea). This is attributable to the prevention of non-severe, symptomatic hypoglycaemia.
  • In the overall analysis of the results on mortality, morbidity and side effects, one positive and one negative effect for albiglutide remain, each within the same endpoint category (non-severe/serious side effects). Weighing up the extent of the advantage of minor harm in terms of confirmed, symptomatic hypoglycaemia against the disadvantage of greater harm in terms of the occurrence of injection-site reactions, there is, overall, a minor additional benefit of albiglutide compared with glimepiride (both in combination with metformin), as a significant reduction in side effects is achieved compared with the appropriate comparator therapy (glimepiride in combination with metformin).
• Conclusion
  • Compared with the appropriate comparator therapy, this constitutes a relevant reduction in side effects (non-severe symptomatic hypoglycaemia) in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV. Classifying the extent of the additional benefit as ‘considerable’ is also not justified because, in particular, there are no long-term data on overall survival, cardiovascular safety or quality of life, which could be regarded as a significant improvement in treatment-related benefit over the appropriate comparator therapy that has not yet been achieved.

b2) In combination with another blood glucose-lowering medicinal product (other than insulin), if this does not sufficiently lower blood glucose in conjunction with diet and exercise – In dual combination with another blood glucose-lowering medicinal product other than metformin and insulin

• For combination therapy with albiglutide and another blood glucose-lowering medicinal product other than metformin and insulin, where diet and exercise alone do not adequately control blood glucose levels and the use of metformin is deemed unsuitable due to intolerance, the additional benefit is not proven.
• No study has been submitted that would have been suitable for assessing the additional benefit of treatment with albiglutide in combination with another blood glucose-lowering medicinal product other than metformin and insulin, in the above-mentioned therapeutic indication, compared with the appropriate comparator therapy (metformin + sulphonylurea).

c) In combination with at least two other blood glucose-lowering medicinal products, if these do not sufficiently lower blood glucose levels in conjunction with diet and exercise

• For the combination of albiglutide with at least two other blood glucose-lowering medicinal products, where these do not adequately control blood glucose levels in addition to diet and exercise, the additional benefit is not proven.
• No study was submitted that would have been suitable for assessing the additional benefit of treatment with albiglutide in combination with at least two other blood glucose-lowering medicinal products, in the above-mentioned therapeutic indication, compared with the appropriate comparator therapy (metformin + human insulin).

d) In combination with insulin (with or without oral antidiabetic agents)

• For the combination of albiglutide with insulin (with or without oral antidiabetic agents), the additional benefit is not proven.
• No study was submitted that would have been suitable for assessing the additional benefit of treatment with albiglutide in combination with insulin (with or without an oral antidiabetic agent) compared with the appropriate comparator therapy (metformin + human insulin).

Courtesy translation only, please refer to the German original.