HOUSTON — The safety of investigational oral octreotide, currently in clinical trials, appears to be on par with the currently available injectable formulation of the drug. This new delivery method may in the future provide relief for patients with acromegaly who struggle with injections, researchers said here.
Although acromegaly can be managed, the current delivery method of octreotide (Sandostatin, Novartis) is often painful and results in suboptimal quality of life for patients treated with the injection, Sam Teichman, MD, FACC, FACP, the Chief Medical Officer of Chiasma, a privately-held biopharmaceutical company told Endocrine Today.
“We’re talking about a big, large gauge, long, intramuscular needle that requires a lot of pressure to push the medication into the muscle,” Teichman said. “If the injection does not occur in exactly the right place, they have to repeat the process on the other side in that same setting. It is unpleasant. So, we think it is an advantage for some patients to switch to an oral agent.
“What we have done is take that same drug, octreotide, that has been safe and effective for 25 years and found a better way to deliver it. Patients can now avoid the painful injections and are now self-treated. They are no longer dependent upon the health care system. [Patients] have told us that that independence is very important to them,” Teichman said.
To date, investigational oral octreotide is in Phase 3 clinical trial and is not available for commercial distribution.
A novel formulation
Researchers at Chiasma Pharmaceuticals designed oral octreotide using a Transient Permeability Enhancer technology that enables the drug to permeate the gastrointestinal wall and safely reach the bloodstream in its active form.
Shmuel Tuvia, PhD, vice president of preclinical at Chiasma, and colleagues tested the exposure in animals and found that this formulation of the octreotide was safe and that the Transient Permeability Enhancer technology improved the intestinal absorption of octreotide.
When approved, Chiasma plans to market the oral formulation of octreotide under the name Octreolin.
Shlomo Melmed, MD, dean of Cedars-Sinai Medical Center and an Endocrine Today Editorial Board member, along with Teichman and other colleagues aimed to design an octreotide dose regimen for patients with acromegaly using pharmacokinetic results derived from healthy volunteers.
The researchers measured octreotide plasma concentrations after a single oral or subcutaneous dose of octreotide during a 12- to 24-hour period in 74 healthy participants. They also estimated time frames for octreotide therapeutic concentrations (≥0.5 ng/mL and ≥1 ng/mL).
Results indicated that plasma octreotide concentrations after 3 mg, 10 mg and 20 mg oral octreotide were proportional to dose. AUCinf were 2 h×ng/mL, 8 h×ng/mL and 15 h×ng/mL, respectively. Additionally, AUCinf and Cmax for oral octreotide 20 mg capsules were comparable to those for subcutaneous injection 0.1 mg. However, plasma octreotide concentrations rose more slowly after oral vs. subcutaneous octreotide (median Tmax of 2.7 hours vs. 0.6 hours). Results also showed that plasma octreotide concentrations remained above the two therapeutic thresholds for 7.7 hours and 5.9 hours after oral octreotide, respectively, and 6 hours and 3.9 hours, respectively, after injectable administration.
Bootstrap analysis showed that twice daily oral octreotide 20 mg should be comparable to subcutaneous octreotide 0.1 mg administered three times daily in regard to maintaining octreotide concentrations above the therapeutic threshold.
These findings led researchers to conclude that a regimen of oral octreotide 20 mg taken twice daily with an option for an increased dose could be advantageous for testing effects on growth hormone and insulin-like growth factor-I, which are elevated in patients with acromegaly.
“We think, based on clinical endocrinologists’ approach to patient care, physicians would always favor a more simplified effective oral treatment over a more complicated similarly effective treatment delivery,” Melmed told Endocrine Today.
As part of the phase 1 clinical studies, researchers assessed the pharmacodynamic effect of oral octreotide on basal and stimulated GH secretion. Teichman and colleagues enrolled 16 healthy men and women in a crossover design with and without octreotide doses.
Patients’ basal serum GH levels were measured 1 hour before and 2 hours after taking oral octreotide 20 mg. In addition, they administered GH releasing-hormone (RH)/arginine and GH levels were measured for an additional 2 hours.
The researchers found that GH response to GHRH/arginine was blunted in all participants receiving oral octreotide, noting a trend toward increased suppression with increased drug exposure. Oral octreotide also suppressed mean basal GH secretion by 44% from 1.3 ng/mL to 0.5 ng/mL (P<.05) and mean GHRH-stimulated GH secretion by 80% from 56.1 ng/mL to 12.2 ng/mL (P<.001).
“It is very significant to show that the drug is bioactive and exhibits clinical activity. In normal subjects, it blunts peak GH secretion and suppresses basal levels even further,” Melmed said.
Due to these positive findings and based on the nature of the drug, researchers said they are moving along in testing phases.
“Because this is a new way of giving an existing medication, we were able to expedite the movement of the drug through early clinical testing into late clinical testing,” Teichman said.
The researchers launched a phase 3 trial in March, and Teichman said there is potential for the first commercial introduction in US and Europe in just 2 years. Although it is premature to estimate the cost of the drug, Melmed said he hopes the cost will not exceed the cost of the monthly injectable. –by Samantha Costa
For more information:
Teichman SL. Abstract#OR49-4.
Tuvia S. Abstract#MON-688.
Tuvia S. Abstract#OR29-6.
All abstracts presented at: the Endocrine Society’s 94th Annual Meeting & Expo; June 23-26, 2012; Houston.