New Oral Acromegaly Treatment Has No Needles Required

Oral therapy for acromegaly solves logistical problems and is not associated with the discomfort of injectable drugs

With Lewis Blevins MD, Susan Samson MD PhD, and Anthony Heaney MD


An FDA Phase III clinical trial referred to as OPTIMAL is exploring the efficacy of an oral octreotide drug in acromegaly patients.

Acromegaly, which affects fewer than 15 people per 100,000, arises from excess production of growth hormone (GH). In more than 90% of cases, a pituitary tumor stimulates this overproduction. The excess GH disrupts glucose and lipid metabolism, which can lead to insulin resistance and diabetes.

In addition, high levels of circulating GH induce the release of Insulin-like growth factor-2 (IGF-1) from the liver. IGF-1 has powerful anti-apoptotic and pro-proliferative activities which could be the stimulus for much of the overgrowth seen in acromegaly as well as carpal tunnel syndrome, debilitating arthritis, and sleep apnea.

The cardiovascular effects of too much IGF-1 and GH include elevated plasma volume, renal sodium and water retention, and cardiac hypertrophypotentially resulting in or escalating already present hypertension and cardiac disease.

It has been suggested that acromegaly could be identified earlier if those that present with several of these concomitant disorders be tested for elevated IGF-1 and GH. The early detection of acromegaly may prevent or delay the rise of complications.

The clinical presentation of acromegaly, or jaw prognathism, brow bossing, acral overgrowth, and hyperhidrosis, can be readily apparent. These features of acromegaly tend to diminish the quality of life, but it is concomitant diseases such as high blood pressure and diabetes mellitus which can reduce life expectancy for these patients. Unfortunately, many often go years before being diagnosed. Once diagnosed, however, treatment is fairly effective at reducing the clinical features and normalizing the conditions that lead to these concomitant diseases.

Pituitary tumors in acromegaly

There are several pituitary tumor variants in acromegaly but the most common, nearly 80-90% of them, are somatotroph tumors of which there are two types, densely granulated (DG) and sparsely granulated (SG). DG tumors are more common and slow growing. Acromegaly in patients over 50 years of age often have this type of tumor. SG tumors grow more rapidly and are more common in younger patients. They are also associated with lower GH and IGF-1 release.

Pituitary tumors express high densities of somatostatin receptors (SST-R), the most common receptors being SST-R2 and SST-R5. SG tumors express lower levels of SST-R2, which may be the reason why some acromegaly patients seem less responsive to treatment.

Treating Acromegaly

Much about acromegaly is unconventional. Many disorders use surgery as a last resort, however the international acromegaly community suggests that surgery be the first line of defense. A transsphenoidal approach (that is through the nose and sphenoid sinus) can remove the tumor, decrease GH and IGF-1 levels, and improve symptoms. In patients with inoperable tumors or with residual hormone elevations, the second line of defense has been drug treatment.

The most common class of drug used in acromegaly are somatostatin analogs (SSA). Somatostatins are a class of inhibitory hormones. SSAs work in a similar manner by reducing the action of somatostatin receptors on GH release. SSAs are effective in about 30-80% of acromegaly patients. For tumors that are unresponsive to SSA treatment, patients can try dopamine agonists (bromocriptine) or growth hormone receptor antagonists (pegviscomant). All drugs have been shown to diminish tumor size and lower GH and IGF-1 levels. All have good safety profiles. Side effects usually involve gastrointestinal issues and irritation at the injection site.

The problem of injections

With the exception of bromocriptine, which is taken orally, all of these drugs are injected. When octreocide, the most prescribed SSA for acromegaly, was first introduced patients had to endure 2-4 times daily subcutaneous injections. Eventually, a long-acting version of octreocide (Oct-LAR) was introduced and patients were given one intramuscular injection every four weeks. To many, this was an improvement, but not a solution.

To find out why, EndocrineWeb reached out to Lewis Blevins, M.D., Medical Director of the California Center for Pituitary Disorders at UCSF Medical Center, San Francisco, CA. He told us:

“Most acromegaly patients have thickened skin as a consequence of their disorder. The injections are often difficult, and a fair number of them develop subcutaneous nodules that are painful as a consequence of injected somatostatin analogues. Some of these drugs require administration by a healthcare provider while others can be administered by patients themselves or a family member. Thus, injections are challenging.”

Oral octreotide

An FDA Phase III clinical trial referred to as OPTIMAL, is exploring the efficacy of an oral octreotide drug in acromegaly patients. This placebo-controlled, double-blind, randomized study was based on good results in earlier studies.

A previous clinical trial of oral octreotide, switched acromegaly patients from their injected SSA to an oral capsule. This was an open-label, dose-titration, baseline control study. Patients were given twice daily doses of octreocide. At 7 months, 65% of patients maintained their goal IGF-1 and GH levels, and 62% of patients kept these hormones low through another 6 months. Approximately 17% of patients were withdrawn for lack of response.

Early promising results of the OPTIMAL study were presented in an ENDO2020 abstract by Susan L. Samson, MD, PhD, Medical Director of the Pituitary Center at Baylor College of Medicine in Houston, Texas. This study is comparing oral octreotide capsules to placebo. In addition to the discomfort of frequent injections, Dr. Samson describes the reasoning why an oral treatment is preferred to injections:

“Patient survey data has been published which has revealed a dichotomy between physicians’ perceived treatment satisfaction with injectable SSAs and the patients’ perspective. There has been an emergence of data showing that patient‐reported acromegaly associated symptoms such as headache, sweating, joint pain, and tissue swelling can worsen or “breakthrough” nearing the end of the SSA injection period even in spite of a biochemically controlled IGF‐1. The need for timed injections can also lead to a feeling of loss of independence, with time lost at work to have the injections and a need to organize life events (e.g. vacations) around the injection date. The oral octreotide capsules have the potential to address these patient concerns because there are no painful injections, no appointments for injections, and, hopefully, the steady state levels of the oral drug also would prevent bothersome breakthrough acromegaly symptoms.”

Patients participating were previously treated with long-acting injected SSAs. For this study, they were assigned to either placebo or oral octreotide upon completion of their fourth week after their last injection. The primary outcome looked at IGF-1 levels at 36 weeks compared to baseline. Secondary outcomes included GH levels, time to loss of IGF-1 responsiveness, and time to emergency rescue injection (if needed).

In the oral octreotide treatment group, 58% of patients maintained IGF-1 levels at or less than the upper limit of normal (1xULN) throughout the 36-week period. Only 19% of placebo patients did, and 68% of placebo patients needed a rescue octreotide injection to lower hormone levels.

Experts respond to oral octreotide results

Anthony Heaney, MD, Director of the Pituitary Tumor and Neuroendocrine Program at the UCLA Gonda Diabetes Center in Los Angeles told EndocrineWeb, “It is extremely encouraging for patients with acromegaly that this safe and well-tolerated oral octreotide preparation maintained the IGF-1 ≤ 1.0 x ULN in almost 60% of patients in this multinational study of 56 patients with acromegaly. For many years, injectable somatostatin receptor ligands have been a key tool for acromegaly therapy and availability of oral versions of these agents is long awaited.”

Dr. Blevins agrees, telling us that “an oral therapy for acromegaly solves a lot of logistical problems and is not associated with the discomfort of injectable drugs. In many ways the advent of oral medicine is the new face of treatment for the disease and gives acromegaly patients hope for a better alternative to control their disease.”

Dr. Bjugstad reports no conflicts with regard to her involvement in conducting or discussing this study. Dr. Blevins and Dr. Heaney report no current conflicts with regard to discussing this study. Dr. Samson receives funding from Chiasma and serves as an advisor. 

Continue Reading:
Acromegaly: Know the Symptoms, Advocate for Necessary Screening
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