Oral therapy shows promise as injection alternative for acromegaly
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Adults with acromegaly assigned an investigational oral form of the somatostatin analogue octreotide maintained a biochemical response at 36 weeks achieved with previous injection therapy with no serious adverse events, according to findings from the OPTIMAL study accepted for presentation at the Endocrine Society Annual Meeting.
Many adults with acromegaly prescribed long-acting somatostatin receptor ligand injections as first-line therapy report limitations, such as disease symptoms that worsen near the end of the injection cycle, as well as injection site pain, according to Susan Samson, MD, PhD, FRCPC, FACE, an Endocrine Today Editorial Board Member and associate professor in the department of endocrinology, diabetes and metabolism at Baylor College of Medicine in Houston.
“Oral octreotide capsules (Mycapssa, Chiasma) will provide us with a new option for appropriate patients with acromegaly, which we have not had before,” Samson told Healio. “It provides a novel treatment using the same principles of somatostatin analogues, which we already understand with respect to their efficacy as well as their side effects.”
In a randomized controlled trial, Samson and colleagues analyzed data from 56 adult patients with active acromegaly, defined as an insulin-like growth factor I level of at least 1.3 times the upper limit of normal at least 3 months after last pituitary surgery, and an average IGF-I level below one times the upper limit of normal while prescribed a stable dose somatostatin receptor ligand injections (octreotide or lanreotide [Somatuline Depot, Ipsen]).
Researchers randomly assigned participants to octreotide (n = 28) or placebo (n = 28) for 36 weeks, followed by an optional, open-label oral octreotide extension phase. Primary endpoint was the proportion of participants maintaining a biochemical response, defined as IGF-I level below one times the upper limit of normal (a two-value average at weeks 34 and 36); secondary endpoints were need for rescue with somatostatin receptor ligand injections, growth hormone level response and time to loss of IGF-I response.
At 36 weeks, 58% of participants assigned octreotide and 19% of participants assigned placebo maintained an IGF-I response (P = .008). Mean IGF-I levels were within the reference range at 36 weeks for participants in the octreotide group (mean, 0.97 times the upper limit of normal) vs. those assigned placebo (mean, 1.69 times the upper limit of normal).
Maintaining response
“We were all extremely curious about what would happen when you switch patients to placebo,” Samson said in an interview. “How many of those patients, even though they had proven, active disease prior to starting their previous somatostatin analogue therapy, could be in remission? For example, they receive placebo but remain controlled while off of their medication. That number was a little higher than we expected — it was close to 20% for maintaining an IGF-I response at week 36. However, when we dug down really deep into the data, all five of those patients still had fluctuations in their IGF-I during the trial that went above the normal range, and actually, three out of five that looked like responders in the placebo arms actually met loss of response criteria. Even more interesting was that the investigators, blinded to treatment arm, recommended that all five patients continue in the open-label extension because they felt the patients had active disease and would derive benefit from the treatment. At the end of the day, even when you use an IGF-I measure at the very end of a trial, a patient could look like they were controlled while assigned placebo, but when you analyze each IGF-I measurement throughout the trial, you see some occasional loss of control.”
Fewer participants in the octreotide group required rescue therapy during the study vs. placebo (25% vs. 68%). GH response (< 2.5 ng/mL) was maintained at week 36 among a larger proportion of participants assigned octreotide vs. placebo (78% vs. 30%; P = .001). The median time to loss of IGF-I response was not reached by the end of the study participants in the octreotide group, compared with a median time to loss of IGF-I response of 16 weeks among those assigned placebo (P < .0001). Five participants in the placebo group had IGF-I levels in the reference range at 36 weeks.
“Only two (7% of placebo group) did not meet loss of response criteria anytime throughout the study,” the researchers wrote in an abstract.
Most participants experienced at least one treatment-emergent adverse event; most were mild or moderate in intensity, according to researchers, and adverse events were consistent with previous experience with injectable somatostatin receptor ligands.
Added flexibility
In a press release, Chiasma reported that the FDA is considering its resubmitted new drug application for oral octreotide. If accepted, octreotide capsules would become the first oral somatostatin analogue for treatment of acromegaly in adults, according to Chiasma, which funded the OPTIMAL study.
“In my personal experience with my patients with acromegaly, getting those injections every month can mean missing work to come in,” Samson said. “I do my best to make sure my patients have nurse-home injections if possible, but it really is a time burden and it takes away from their independence as well. People want to travel and do things, but they often have to plan around their injections. The oral octreotide adds a flexibility that will really work for some patients.” – by Regina Schaffer
Reference:
Samson SL, et al. OR23-07. The Endocrine Society Annual Meeting; 2020 (conference canceled/virtual meeting).
Disclosures: Chiasma funded this study. Samson reports she has served as an advisory board member for Chiasma and Novartis, received grants from Novartis and served as a research investigator for Chiasma, Corcept, Novartis and OPKO. Please see the abstract for all other authors’ relevant financial disclosures.