What are the current treatment options for acromegaly, including medications such as somatostatin receptor ligands (SRLs) like octreotide (Sandostatin) or lanreotide (Somatuline) and pegvisomant (Somavert)?

New Treatments in Acromegaly

Established Medical Therapies

Somatostatin receptor ligands (SRLs) remain the primary first-line medical therapy after unsuccessful surgery, with long-acting octreotide and lanreotide showing equivalent efficacy in normalizing GH and IGF-I levels in approximately 25-60% of patients. 1, 2

First-Generation SRLs (Octreotide and Lanreotide)

• Octreotide LAR and lanreotide Autogel are FDA-approved for acromegaly treatment in patients with inadequate surgical response or when surgery is not an option, with the goal of normalizing GH and IGF-I levels. 3, 4

• No evidence demonstrates a difference in efficacy between long-acting lanreotide and octreotide formulations. 1

• Standard dosing begins at 90 mg every 4 weeks for lanreotide, with adjustments to 60 mg or 120 mg based on GH/IGF-I response after 3 months. 3

• Dose escalation beyond standard doses can provide additional biochemical control in patients inadequately controlled with conventional starting doses. 5

• Extended dosing intervals (every 6-8 weeks) may be considered in well-controlled patients on 60-90 mg doses, using lanreotide 120 mg. 3

Pegvisomant (GH Receptor Antagonist)

• Pegvisomant is FDA-approved and should be used as second-line therapy in patients who do not respond to SRL therapy (minimal change in GH and IGF-I levels). 1, 6

• Pegvisomant has well-established efficacy in normalizing IGF-I levels with reassuring long-term safety data, requiring ongoing monitoring of liver function and tumor size. 2

• For partial responders to SRLs (reduction but not normalization of GH/IGF-I), combination therapy with pegvisomant plus SRL should be considered. 1

• Combined SRL-pegvisomant therapy can normalize IGF-I levels in virtually all patients when adequate pegvisomant dosing is used, with the advantage of maintaining tumor size control or shrinkage. 7

Cabergoline (Dopamine Agonist)

• Cabergoline may be considered as primary therapy in patients with mild disease (IGF-I <2 × upper limit of normal). 1

• A short-term trial (3-6 months) with dose escalation from 1.5 to 3.5 mg per week is appropriate if well tolerated. 1

• Combination therapy with SRL plus cabergoline or pegvisomant plus cabergoline can be considered in non-responders to monotherapy. 1

Novel and Emerging Therapies

Oral Octreotide

• Oral octreotide capsules (OOCs) represent the first oral SRL approved in the United States, using transient permeability enhancer technology to enable gut absorption. 1

• Clinical trials involving 238 patients demonstrated effective GH and IGF-I suppression with non-inferiority to injectable SRLs in maintaining biochemical response. 8

• OOCs are indicated for patients with acromegaly who previously responded to injectable SRLs, offering the benefit of avoiding injection-related side effects. 8

• The safety profile of oral octreotide is comparable to injectable SRLs, with most patients expressing preference for oral over injectable administration. 8

Pasireotide (Multi-Receptor SRL)

• Pasireotide is a new SRL with different somatostatin receptor binding profiles, having broader affinity for all somatostatin receptor subtypes compared to first-generation SRLs that preferentially bind sst2 receptors. 1, 9

• This agent is in advanced stages of clinical development for acromegaly treatment. 1

Investigational Therapies

• An antisense oligonucleotide that binds to GH receptor mRNA and inhibits translation of the receptor protein is in early clinical development. 1

• A targeted secretion inhibitor comprising a botulinum toxin-GHRH chimera molecule that binds to GHRH receptor-expressing cells and inhibits GH secretion is under investigation. 1

• Temozolomide, an alkylating agent, has been assessed for GH-secreting aggressive pituitary tumors resistant to conventional therapy, though further study results are required. 1

Treatment Algorithm for Medical Therapy

Post-Surgical First-Line Treatment

• Initiate long-acting SRL (octreotide LAR or lanreotide) at standard doses. 1, 2

• Reassess GH and IGF-I levels at 3 months to guide dose adjustments. 1

For SRL Non-Responders (Minimal GH/IGF-I Change)

• Switch to pegvisomant monotherapy. 1

For SRL Partial Responders (Reduction But Not Normalization)

• Add pegvisomant to continue SRL therapy (combination treatment). 1

• Alternatively, increase SRL dose beyond standard approved doses or decrease injection intervals. 1

For Mild Disease

• Consider cabergoline as primary therapy if IGF-I <2 × upper limit of normal. 1

For Well-Controlled Patients on SRLs

• Consider dose reduction to minimally effective dose or extended dosing intervals. 1

• Lifelong monitoring of IGF-I levels must be maintained even if drug withdrawal is attempted in rare cases of persistent control. 1

Critical Monitoring Considerations

• Medical treatment normalizing GH and IGF-I levels decreases mortality rates and improves left ventricular hypertrophy, hypertension, and obstructive sleep apnea. 2

• Pegvisomant increases GH levels while lowering IGF-I, requiring monitoring for potential pituitary adenoma enlargement. 10

• Liver function monitoring is essential with pegvisomant therapy. 2

• Main side effects of combination SRL-pegvisomant therapy include gastrointestinal symptoms, lipohypertrophy, and transient elevated liver transaminases. 7