New Therapies on the Horizon: Drugs in Clinical Trials
The role of SSTRs and DRs as molecular targets for the treatment of pituitary adenomas is well established. More recently, however, work on the expression of SSTR and DR subtypes, their coexpression, and their functional interface via dimerization has opened new perspectives for patients currently unresponsive to or intolerant of clinically available drugs. Research into an additional long-term delivery method (compared with the monthly injection of long-acting octreotide) as well as potential patient compliance and cost improvement is underway.
Multiligand SSA Pasireotide
A relatively high proportion of patients are resistant to octreotide and lanreotide, which could be explained in part by variable tumor expression and/or decreased density of SSTR-2. The multiligand SSA pasireotide (SOM 230) is a novel somatostatin analog (mimetic) with a unique structure. It has a very long plasma half-life, potent in vitro and in vivo inhibitory effects on GH and IGF-I release, a high binding affinity to SSTR-1, -2, -3, and -5, and up to a 40-fold greater affinity for SSTR-5 than octreotide. Therefore, it is a promising therapeutic candidate with several potential advantages over currently used SSAs. The high affinity of pasireotide for both SSTR-5 and SSTR-1 could be important in GH-secreting adenomas resistant to current therapy. Furthermore, binding and functional synergy between SSTR-2 and SSTR-5 could be beneficial even in responsive tumors.
Phase I and II trials on GH-secreting tumors have been encouraging with good biochemical control and "significant" tumor shrinkage, making SOM230 a promising candidate. There are, however, potential concerns related to glucose intolerance. The safety and efficacy of pasireotide LAR versus octreotide LAR in patients with active acromegaly is presently being studied in a large, Phase III, randomized, blind multinational study (www.clinicaltrials.gov).
A future role for pasireotide remains to be determined, but its use in the treatment of octreotide-resistant tumors, especially large ones, seems most likely.
Somatostatin-dopamine Chimeric Ligand
A functional interaction between D2R and SSTR-5 has been reported recently, with the subsequent development of a new chimeric compound containing structural elements of both somatostatin and dopamine, that is, dopastatin. The exact mechanism by which combined somatostatin-dopamine treatment has a synergistic effect on GH suppression is not completely clear, but Saveanu et al. suggested crosstalk of the G-coupled receptors or dimerization on the cell membrane/postmembrane level. Nonclinical pharmacological studies have shown that dopastatin is more potent and more effective than octreotide alone or octreotide in combination with cabergoline in suppressing GH secretion, and thus seems a promising approach for acromegaly treatment. Patients who express both SSRT-2 and D2R should be especially suitable for this treatment. As a note of caution, however, a discrepancy between the presence of a receptor profile SSTR/D2R and the limited efficacy of an agonist drug has been reported.
After encouraging in vitro results, a study to assess the efficacy and safety of the repeated administration of dopastatin (BIM-23A760) in patients with acromegaly is presently underway in a Phase II multinational clinical trial (www.clinicaltrials.gov).
Extended Delivery of Octreotide Including Octreotide Implants
Another exciting area of research involves changing the delivery system. A Hydron implant delivering octreotide for up to 6 months has been analyzed recently. Two Phase I/II clinical studies have evaluated the pharmacokinetics, efficacy, safety, and drug release characteristics of this octreotide implant in 45 patients with a full or partial response to octreotide. The implant maintained GH at < 5 ng/ml in 94% of patients and achieved normal IGF-I in 60% of patients as compared with octreotide LAR (83% and 51% of patients, respectively). There were no serious or severe adverse events, and all patients completed the study. These results suggest a possible improvement over currently used daily and monthly formulations of octreotide. The implant delivery system is being studied in Phase III multinational clinical trials (www.clinicaltrials.gov).
Overall, it remains to be determined where all of these new therapies will ultimately fit into the treatment paradigm.