How to Position Pasireotide LAR Treatment in Acromegaly

Eva C. Coopmans; Ammar Muhammad; Aart J. van der Lely; Joseph A. M. J. L. Janssen; Sebastian J. C. M. M. Neggers


J Clin Endocrinol Metab. 2019;104(6):1978-1988. 

In This Article

Primary Efficacy Endpoints

Preclinical and clinical phase II studies have shown promising data on the primary efficacy in normalizing GH and IGF-1 levels.[13–19] Two phase III studies [C2305 and C2404 study] reported the efficacy of pasireotide LAR therapy in patients with acromegaly.[20,21] These studies were performed in medically naive patients with acromegaly and those whose disease was inadequately controlled despite ≥6 months treatment on maximum dosages of first-generation SRLs.[20,21] Pasireotide LAR demonstrated in both studies superior efficacy over first-generation SRLs in achieving normal GH and IGF-1 levels. The efficacy of pasireotide LAR after maximum dose first-generation SRL is ≤20% higher than with continuation of first-generation SRLs.[21] The extension phase of both studies showed comparable response rates.[22,23] However, ~17% of patients with inadequate biochemical control after 12 months of therapy with octreotide LAR achieved biochemical control after switching to pasireotide LAR therapy.[24] Although the effects of pasireotide LAR and octreotide LAR therapy on the reduction of GH levels were comparable in the C2305 study, pasireotide LAR therapy was more effective in lowering IGF-1 levels.[20,25]

The Pasireotide LAR and Pegvisomant Study in Acromegaly (PAPE) was a prospective, open-label, single-center study aimed at assessing the efficacy and safety of pasireotide LAR, alone or in combination with PEGV therapy.[11,12] In this study we included 61 patients with well-controlled acromegaly [defined as IGF-1 levels ≤1.2 × upper limit of normal (ULN)] receiving combination therapy with maximum dosages of first-generation SRLs and weekly PEGV for >6 months. The primary endpoint was achieving IGF-1 normalization (≤1.2 × ULN) at 24 weeks. In the extension study we reported the secondary endpoints: efficacy and safety from 24 to 48 weeks.

At baseline of the PAPE study, the PEGV dosage was reduced by 50% in all patients. If IGF-1 was normal (≤ 1.2 × ULN) after 12 weeks' follow-up, patients were switched to pasireotide LAR 60 mg monotherapy. If IGF-1 levels were elevated (>1.2 × ULN) after 12 weeks' follow-up, patients were switched to pasireotide LAR 60 mg and continued with a 50% reduced dosage of PEGV. In patients whose disease was controlled with first-generation SRL and PEGV, switching to pasireotide LAR, either as monotherapy or in combination with PEGV, resulted in control of IGF-1 levels in 77% of patients.[12] Stratified by treatment group; 93% of patients on pasireotide LAR monotherapy achieved IGF-1 normalization after 24 weeks' follow-up, and this effect was sustained after 48 weeks' follow-up. Of patients on pasireotide LAR and PEGV combination therapy, 67% achieved IGF-1 normalization after 24 weeks' follow-up, which further increased to 72% after 48 weeks' follow-up.[11,12] In these studies, pasireotide LAR demonstrated after 48 weeks' follow-up a PEGV sparing effect of 52%, compared with combination therapy with first-generation SRLs, and as a consequence PEGV could be discontinued in 51% of patients.[12]