Octreotide Capsules Found Safe and Effective for Acromegaly in Phase 3 Study

Commentary by: Shlomo Melmed, MD

pituitary An investigational oral formulation of octreotide was found to be safe and effective in the treatment of acromegaly in a phase 3 open-label study published online ahead of print in the Journal of Clinical Endocrinology & Metabolism.

“Oral medication to suppress growth hormone and insulin-like growth factor-1 [IGF-1] to control symptoms in patients with acromegaly is safe and effective,” said lead author Shlomo Melmed, MD, Senior Vice President and Dean, Cedars-Sinai Medical Center, Los Angeles and global study principal investigator. “Furthermore, control achieved by the oral medication is sustained in the long-term for at least 13 months,” Dr. Melmed said.

Based on the result of this study, the drug’s developer Chiasma, Inc. plans to submit a New Drug Application to the U.S Food and Drug Administration (FDA) in 2015. Octreotide is currently only approved as an injectable formulation.

Phase 3, Open-Label Study
The study involved 155 people with acromegaly who were completely or partially controlled on injectable somatostatin receptor ligands at baseline. While 89% of these patients were considered well controlled on injectable medications, 81% of participants still had persistent acromegaly symptoms at baseline.

During the dose-titration phase of the study, patients initially received 40 mg/day (20 mg BID) of octreotide capsules, which could be increased if necessary up to 60 mg/day or 80 mg/day to maintain biochemical response. The dose-titration phase was followed by a fixed-dose phase for up to 7 months. A total of 86% of patients who completed the fixed-dose phase elected to participate in a voluntary 6-month extension phase.

At 13 Months, 62% of Patients Were Well Controlled on Oral Octreotide
At the end of the 7-month, fixed dose phase, 65% of patients maintained treatment response and achieved the primary endpoint (ie, IGF-1 levels <1.3 times the upper limit of normal and 2-hour integrated growth hormone concentrations <2.5 ng/mL). At the end of the 6-month extension phase, 62% of participants achieved the primary endpoint on oral octreotide.

In addition, 85% of the patients who were initially well controlled on oral octreotide at the end of the dose-titration phase maintained this response up to 13 months in the extension phase.

“That is a very important and reassuring message for patients,” Dr. Melmed said. “Once patients know that they are going to be controlled on the drug, the chances are pretty good that they will sustain control over the long term,” Dr. Melmed said.

Improved Severity, Frequency of Symptoms in Treatment Responders
Among treatment responders, the severity and frequency of acromegaly symptoms improved, compared to baseline. The reason for this added improvement over injectable somatostatin ligands is unknown, according to Dr. Melmed.

“We have to study the reason. A different route of drug application may affect symptoms differently, and there may be a unique symptom effect determined by route of administration,” Dr. Melmed said. “The actual octreotide molecule—the active drug that is present in the capsule—is identical to the molecule that is present in the injection. So it isn’t the molecule itself that is different, it is the mode of administration, which is different,” Dr. Melmed said.

Safety Profile Similar to Injectable Octreotide
The most common adverse events (AEs) reported were gastrointestinal (nausea, diarrhea and abdominal pain), neurological, and musculoskeletal, consistent with the known safety profile of octreotide and the disease burden of acromegaly. The incidence of AEs significantly decreased during the course of the study (median AE duration, 13 days).

“The safety profile which we observed was very reminiscent of the profile that we see in patients who receive the injectable, both in terms of the transient nature of the side effects as well as the absolute quality of the side effects” Dr. Melmed said. “There were no differences in expected or observed safety events with the oral medication,” he noted.

Overall, 89% of patients had an adverse event, the majority (92%) of which were mild to moderate in severity and typically resolved after a median of 13 days.

Consistent Dosing May Benefit Patients
Injectable somatostatin analogs (including octreotide) typically are given once a month. Towards the end of the cycle, some patients report a wearing-off effect and emergence of breakthrough symptoms, including severe headache, joint pain, tissue swelling, and coarsening of features.

“In my opinion, by having an option so that you can get consistent dosing every day, you won’t have those breakthrough symptoms any more,” said Jill Sisco, President of the Acromegaly Community. “I know people who are on the long-acting octreotide and, at the end of the monthly cycle, have to supplement it with short-acting octreotide injection 3 times a day,” she explained. “I know people who miss work because their [breakthrough] headaches are so bad,” she said.

“If there is an option that delivers medication at a consistent dose and that can improve symptoms even more than with injectable agents, I think that we as patients should have that option,” Ms. Sisco said.

March 2, 2015

 

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