Promising new phase 3 data on pasireotide long-acting release (LAR) (Novartis) in patients with acromegaly who are poorly controlled on first-generation somatostatins have been reported.
The results of the PAOLA trial were presented in a poster by Monica Gadelha, MD, an endocrinologist from the Federal University of Rio de Janeiro, Brazil, at the European Congress of Endocrinology (ECE) 2014 last week.
The drug is currently approved in subcutaneous form for Cushing's disease by the US Food and Drug Administration and is marketed there as Signifor; it is awaiting approval for acromegaly in the United States and Europe, and the PAOLA trial is part of the approval submissions.
"These positive results, particularly regarding the composite end point of growth hormone and insulinlike growth factor-1 (IGF-1) control, demonstrate that pasireotide LAR is an alternative treatment option for those patients with uncontrolled acromegaly on standard somatostatin analog," Dr. Gadelha told Medscape Medical News.
But other clinicians at the meeting expressed concern over hyperglycemia, seen in a significant proportion of patients treated with the agent for Cushing's disease. This side effect was also seen more frequently in those treated with pasireotide LAR in the PAOLA study.
Sebastian Neggers, MD, consultant in clinical endocrinology at Erasmus University Medical Center, Rotterdam, the Netherlands, said he felt "the adverse-event profile would affect the use of pasireotide."
While the long-acting-release formulation seems to cause hyperglycemia less frequently than subcutaneous pasireotide, nevertheless "diabetes mellitus is an adverse event that one would rather withhold from an acromegaly patient. So…it is not the ideal first-line treatment."
But he said he still welcomes the results and the potential future option of an alternative medication for patients with acromegaly.
Better Biochemical Control and Normalization of IGF-1 With Pasireotide
Acromegaly is a disease that results from a growth hormone (GH)–secreting pituitary tumor, characterized by excessive skeletal growth, soft-tissue enlargement with disfigurement, and increased risk for cardiovascular death. The goals of treatment are the removal or reduction of the tumor mass via surgery and normalization of GH secretion.
Surgery is usually the first line of therapy, but cure rates remain low, because patients with these tumors usually present at an incurable stage. Therefore, medical therapy to control excess GH secretion plays a significant role in a large proportion of patients.
The PAOLA trial involved 198 patients with acromegaly who had previously received first-generation somatostatins, either octreotide LAR 30 mg (Sandostatin, Novartis) or lanreotide 120 mg (Somatuline Autogel, Ipsen) monotherapy, for 6 months or longer but remained uncontrolled.
They were randomized to either continue the first-generation agent (active control group, n=68) or to receive pasireotide LAR at a dose of 40 mg (n=65) or 60 mg (n=65) as a once-monthly injection.
The primary end point was the proportion of patients achieving biochemical control as measured by mean GH level of less than 2.5 µg/L as well as normalized IGF-1 at 24 weeks.
Significantly more patients on pasireotide LAR 40 mg and 60 mg, 15.4% and 20.0% respectively, achieved biochemical control, compared with 0% of the control group (P = .0006 and P < .0001, respectively).
Similarly, 24.6% and 26.2% of those on the 2 doses of pasireotide LAR achieved normalization of IGF-1, vs 0% in the control group (P < .001 for both).
Given that both doses of pasireotide were found to be efficacious, Dr. Gadelha said she envisaged starting treatment with pasireotide LAR 40 mg, "with the possibility of a dose increase to 60 mg after 3 injections, should biochemical control not be achieved."
But Hyperglycemia Still an Issue
Patients on pasireotide LAR showed a similar adverse-event profile to that of the active control group, except for the frequency and degree of hyperglycemia.
Hyperglycemia occurred in 33.3% and 30.6% of those taking pasireotide LAR 40 mg and 60 mg compared with 13.6% of patients in the control group. Diabetes mellitus was seen in 20.6%, 25.8%, and 7.6% of patients, respectively.
Dr. Gadelha explained that, in healthy volunteers, pasireotide has been shown to significantly reduce insulin and incretin secretion. However, she also noted that blood glucose and HbA1c "return to baseline levels upon discontinuation of pasireotide."
Despite his reservations about hyperglycemia, Dr. Neggers said, "there is certainly a place for pasireotide, and it seems to be more effective than the current somatostatin analogs, but its place is probably not as first line.
"Different types of medication are always welcome. Depending on their efficacy and safety profile, they will be included in the consensus statement of acromegaly, but to date, pasireotide is not in this statement."
In addition to the PAOLA trial, another phase 3 registration trial comparing pasireotide LAR vs octreotide LAR in a head-to-head study of medically naive acromegaly patients forms the basis of the United States and European Union approval applications; results of this trial were published in the Journal of Clinical Endocrinology and Metabolism in January (J Clin Endocrinol Metab. 2014;99:791–799).
Novartis said it was too early to speculate on if and when approvals for pasireotide in acromegaly might be granted.
Dr. Gadelha has declared that she is an advisory board member for Novartis and a principal investigator in clinical trials for Novartis and Ipsen and has research grants from Novartis and Pfizer. Dr. Neggers has declared that he has received grants for studies from Novartis, Ipsen, and Pfizer.
European Congress of Endocrinology 2014. May 5, 2014. Abstract P907.
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Cite this: Pasireotide LAR for Acromegaly but Hyperglycemia a Drawback - Medscape - May 15, 2014.