Publications and Posters Related to Investigational Agent Veldoreotide

Publications and Posters

*Investigational product candidates. The safety and efficacy of levoketoconazole and veldoreotide have not been established.

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Posters and Publications – Related to Investigational Agent Veldoreotide*

*Please note veldoreotide was formerly referred to as somatoprim, COR-005, DG3173, and also PTR-3173.

Veldoreotide-specific — veldoreotide

  • Novel long-acting somatostatin analog with endocrine selectivity: potent suppression of growth hormone but not of insulin. M. Afargan, E. T. Janson. G. Gelerman, R. Rosenfeld, O. Ziv, O. Karpov, A. Wolf, M. Bracha, D. Shohat, G. Liapakis, C. Gilon, A. Hoffman, D. Stephensky, K. Oberg. Endocrinology. Volume 142. Number 1. Pages 477-86. 2001.
    • Abstract: Somatostatin, also known as somatotropin release-inhibiting factor (SRIF), is a natural cyclic peptide inhibitor of pituitary, pancreatic, and gastrointestinal secretion. Its long-acting analogs are in clinical use for treatment of various endocrine syndromes and gastrointestinal anomalies. These analogs are more potent inhibitors of the endocrine release of GH, glucagon, and insulin than the native SRIF; hence, they do not display considerable physiological selectivity. Our goal was to design effective and physiologically selective SRIF analogs with potential therapeutic value. We employed an integrated approach consisting of screening of backbone cyclic peptide libraries constructed on the basis of molecular modeling of known SRIF agonists and of high throughput receptor binding assays with each of the five cloned human SRIF receptors (hsst1-5). By using this approach, we identified a novel, high affinity, enzymatically stable, and long-acting SRIF analog, PTR-3173, which binds with nanomolar affinity to human SRIF receptors hsst2, hsst4, and hsst5. The hsst5 and the rat sst5 (rsst5) forms have the same nanomolar affinity for this analog. In the human carcinoid-derived cell line BON-1, PTR-3173 inhibits forskolin-stimulated cAMP accumulation as efficiently as the drug octreotide, indicating its agonistic effect in this human cell system. In hormone secretion studies with rats, we found that PTR-3173 is 1000-fold and more than 10,000-fold more potent in inhibiting GH release than glucagon and insulin release, respectively. These results suggest that PTR-3173 is the first highly selective somatostatinergic analog for the in vivo inhibition of GH secretion, with minimal or no effect on glucagon and insulin release, respectively... To read more, click here.
  • Human somatostatin receptor specificity of backbone-cyclic analogues containing novel sulfur building units. S. Gazal, G. Gelerman, O. Ziv, O. Karpov, P. Litman, M. Bracha, M. Afargan, C. Gilon. Journal of Medicinal Chemistry. Volume 45. Number 8. Pages 1665-71. 2002.
    • Abstract: Somatostatin-14 (somatostatin) and its clinically available analogues octreotide, lanreotide, and vapreotide are potent inhibitors of growth hormone, insulin, and glucagon release. Recently a novel backbone cyclic somatostatin analogue c(GABA-Phe-Trp-(D)Trp-Lys-Thr-Phe-GlyC3-Nh2) (analogue 1, PTR 3173) that possesses in vivo endocrine selectivity was described. This long-acting octapeptide exhibits high affinity to human recombinant somatostatin receptors (hsst) hsst2, hsst4, and hsst5. Its novel binding profile resulted in potent in vivo inhibition of growth hormone but not of insulin release. We report the synthesis, bioactivity, and structure−activity relationship studies of compounds related to 1. In these analogues, the lactam bridge of 1 was replaced by a backbone disulfide bridge. We present a novel approach for conformational constraint of peptides by utilizing sulfur-containing building units for on-resin backbone cyclization. These disulfide backbone cyclic analogues of 1 showed significant metabolic stability as tested in various enzyme mixtures. Receptor binding assays revealed different receptor selectivity profiles for these analogues in comparison to their prototype. It was found that analogues of 1, bearing a disulfide bridge, had increased selectivity to hsst2 and hsst5; however, they exhibited weaker affinity to hsst4 as compared to 1. These studies imply that ring chemistry, ring size, and ring position of the peptide template may affect the receptor binding selectivity... To read more, click here. (Subscription or purchase required.)
  • Research resource: real-time analysis of somatostatin and dopamine receptor signaling in pituitary cells using a fluorescence-based membrane potential assay. T. Gunther, M. Culler, S. Schulz. Molecular Endocrinology. Volume 30. Number 4. Pages 479-90. 2016.
    • Abstract: Stable somatostatin analogues and dopamine receptor agonists are the mainstay for the pharmacological treatment of functional pituitary adenomas; however, only a few cellular assay have been developed to detect receptor activation of novel compounds without disrupting cells to obtain the second messenger content. Here, we adapted a novel fluorescence-based membrane potential assay to characterize receptor signaling in a time-dependent manner. This minimally invasive technique provides a robust and reliable read-out for ligand-induced receptor activation in permanent and primary pituitary cells. The mouse corticotropic cell line AtT-20 endogenously expresses both the somatostatin receptors 2 (sst2) and 5 (sst5). Exposure of wild-type AtT-20 cells to the sst2- and sst5-selective agonists BIM-23120 and BIM-23268, respectively, promoted a pertussis toxin- and tertiapin-Q-sensitive reduction in fluorescent signal intensity, which is indicative of activation of G protein-coupled inwardly rectifying potassium (GIRK) channels. After heterologous expression, sst1, sst3, and sst4 receptors also coupled to GIRK channels in AtT-20 cells. Similar activation of GIRK channels by dopamine required overexpression of dopamine D2 receptors (D2Rs). Interestingly, the presence of D2Rs in AtT-20 cells strongly facilitated GIRK channel activation elicited by the sst2-D2 chimeric ligand BIM-23A760, suggesting a synergistic action of sst2 and D2Rs. Furthermore, stable somatostatin analogues produced strong responses in primary pituitary cultures from wild-type mice; however, in cultures from sst2 receptor-deficient mice, only pasireotide and somatoprim, but not octreotide, induced a reduction in fluorescent signal intensity, suggesting that octreotide mediates its pharmacological action primarily via the sst2 receptor... To read more, click here. (Subscription or purchase required.)
  • A transplantable phosphorylation probe for direct assessment of G protein-coupled receptor activation. A. Kliewer, A. Mann, A. Petrich, F. Pöll, S. Schulz. PLoS ONE. Volume 7. Number 6. Page e39458. 2012.
    • Abstract: The newly developed multireceptor somatostatin analogs pasireotide (SOM230), octreotide and somatoprim (DG3173) have primarily been characterized according to their binding profiles. However, their ability to activate individual somatostatin receptor subtypes (sst) has not been directly assessed so far. Here, we transplanted the carboxyl-terminal phosphorylation motif of the sst2 receptor to other somatostatin receptors and assessed receptor activation using a set of three phosphosite-specific antibodies. Our comparative analysis revealed unexpected efficacy profiles for pasireotide, octreotide and somatoprim. Pasireotide was able to activate sst3 and sst5 receptors but was only a partial agonist at the sst2 receptor. Octreotide exhibited potent agonistic properties at the sst2 receptor but produced very little sst5 receptor activation. Like octreotide, somatoprim was a full agonist at the sst2 receptor. Unlike octreotide, somatoprim was also a potent agonist at the sst5 receptor. Together, we propose the application of a phosphorylation probe for direct assessment of G protein-coupled receptor activation and demonstrate its utility in the pharmacological characterization of novel somatostatin analogs... To read more, click here.
  • A placebo-controlled study to assess the dose effect of COR-005, a novel somatostatin analogue, on plasma glucose regulation compared to octreotide in healthy male subjects (Poster). K. Kutz, M. Haschke, C. Beglinger, C. Dehning, F. Cohen. Strongbridge Biopharma plc. Poster presented at: European Society of Endocrinology's 18th European Congress of Endocrinology; May 28—31, 2016; Munich, Germany.
    • Abstract: Somatostatin analogues (SSAs) approved to treat acromegaly tend to suppress postprandial insulin/glucagon secretion and can worsen glucose tolerance. COR-005, a novel SSA, is under investigation for treatment of acromegaly. In rodents, COR-005 effectively inhibits GH secretion with 10,000-fold greater potency compared with insulin release suppression. We sought to determine for the first time the effects of COR-005 on postprandial glucose in humans.
      The pharmacodynamic effects of single subcutaneous doses of COR-005 300, 900, and 1800 μg, octreotide 300 μg and placebo on glucose, insulin and glucagon dynamics were investigated for 4 h after intake of a mixed meal in eight healthy male subjects using a randomized cross-over design.
      Following COR-005 300 and 900 μg, there were slight increases in maximum blood glucose concentrations (9.76±1.00 and 9.73±1.31 vs 7.56±0.93 mmol/l) and in the 4-h blood glucose AUECGlucose compared to placebo (26.13±2.18, 28.86±3.82 vs 23.02±1.83 mmolxh/l). A higher increase was observed after injection of COR-005 1800 μg and the highest after octreotide 300 μg (AUECGlucose: 33.56±4.71 and 38.69±5.79 mmolxh/l). Octreotide significantly suppressed plasma insulin and glucagon secretion compared to placebo (AUECInsulin 15.56±2.02 vs 44.29±10.65 μUxh/ml and AUECGlucagon 135.5±55.1 vs 363.2±40.9 pgxh/ml) whereas COR-005 caused only a dose-dependent delay in insulin and glucagon secretion but had no significant effect on AUECInsulin or AUECGlucagon.
      After intake of a mixed meal, COR-005 single doses up to 900 μg had no significant effect on total insulin and glucagon secretion compared to placebo and a marginal effect on blood glucose. COR-005 1800 μg less strongly inhibited postprandial insulin and glucagon compared to octreotide. COR-005 might offer a reduced risk of hyperglycemia relative to other SSAs currently used to treat acromegaly... To view poster, click here.
  • A placebo-controlled study of repeated subcutaneous doses of COR-005 alone or with octreotide on GHRH-stimulated GH and pharmacokinetics in healthy male subjects (Poster). K. Kutz, M. Haschke, C. Beglinger, J. Liska, C. Dehning, F. Cohen. Strongbridge Biopharma plc. Poster presented at: European Society of Endocrinology's 18th European Congress of Endocrinology; May 28—31, 2016; Munich, Germany.
    • Abstract: Octreotide is first-line medical therapy for patients with acromegaly. Up to 80% of patients are not satisfactorily controlled on octreotide alone and up to 20% have no response. COR-005 (previously DG3173) is a novel somatostatin analogue under investigation for treatment of acromegaly. COR-005 has high affinity for human somatostatin receptor subtypes 2, 4 and 5.
      The study was designed to assess pharmacokinetics of escalating doses COR-005 sc tid and compare the pharmacodynamics of COR-005 alone or in combination with octreotide 300 μg sc tid for 6.3 days versus octreotide 300 μg sc tid alone and placebo on GHRH-stimulated GH profiles.
      A total of 42 subjects (6 total per group) received placebo (P, N=1/gp), octreotide 300 μg tid (O, N=1/gp) or COR-005 alone (C, N=4/gp) as 100 μg, 300 μg, 900 μg, or 1800 μg C tid or as 100 μg or 300 μg or 900 μg C in combination with O. GHRH stimulation was performed before first and after four treatments.
      Maximal inhibition of GHRH-stimulated GH by COR-005 or octreotide alone was ranked as follows: P < (100 μg C or 300 μg C) < (900 μg C or O) <1800 μg C. GH inhibition with combinations of COR-005 and O were in the order of: O < (O+100 μg C and O+300 μg C) < O+900 μg C. COR-005 Tmax was ≤1 hour and t1/2 was ~2 h after first and last injections. Cmax and AUC0-8 increased dose-linearly. Co-administration of COR-005 with O did not affect C PK below 900 μg, greater variability in C AUC0-8 was noted at 900 μg.
      COR-005 inhibits dose-dependently GHRH-stimulated GH with less potency but similar maximal efficacy as maximally dosed octreotide... To view poster, click here.
  • A novel somatostatin analogue prevents early renal complications in the nonobese diabetic mouse. D. Landau, Y. Segev, M. Afargan, A. Silbergeld, L. Katchko, A. Podshyvalov, M. Phillip. Kidney International. Volume 60. Number 2. Pages 505-12. 2001.
    • Abstract: Background: PTR-3173 (S) is a novel somatostatin analogue that has been found to exert a prolonged inhibitory action on the growth hormone (GH)-insulin-like growth factor (IGF)-I axis, but not on insulin secretion. We investigated the potential effect of this agent on the development of markers of diabetic nephropathy in the nonobese diabetic (NOD) mouse model of insulin-dependent diabetes... To read more, click here.
  • DG3173 (somatoprim), a unique somatostatin receptor subtypes 2-, 4- and 5-selective analogue, effectively reduces GH secretion in human GH-secreting pituitary adenomas even in Octreotide non-responsive tumours. U. Plöckinger, U. Hoffman, M. Geese, A. Lupp, M. Buchfelder, J. Flitsch, P. Vajkoczy, W. Jakob, W. Saeger, S. Schulz, C. Dohrmann. European Journal of Endocrinology. Volume 166. Number 2. Pages 223-34. 2012.
    • Abstract: Objective: Somatostatin analogues (SSA) reduce autonomous GH secretion by activating somatostatin receptors (sst) 2 and 5 in 50-60% of acromegalic patients. However, by inhibiting insulin secretion these SSA reduce glucose tolerance. DG3173 is a novel SSA with additional binding to sst4 and low insulin-suppressing activity. We investigated the effect of DG3173, including its relation to specific tumour characteristics, on GH secretion in human somatotroph adenoma cell cultures (hSA) in comparison with Octreotide. Methods: Twenty-seven hSA were characterised immunohistochemically for their hormone- and sst-expression, granularity and pre-surgical therapy with SSA. GH was determined in supernatants of hSA treated with DG3173 or Octreotide in time- (n=6) and dose-response (n=21) experiments. A positive response was defined as GH suppression to below 80% of baseline. Results: In the dose-response experiments DG3173 suppressed GH secretion in more adenomas than Octreotide (10/21 vs 5/21), including 38% (6/16) of Octreotide non-responders. In responders the extent of GH suppression and IC(50) were comparable for both SSA. The response-rate of both SSA was higher in monohormonal vs bihormonal adenomas, yet GH declined similarly in both groups. Neither pre-surgical SSA (n=6) nor tumour morphology was related to the GH response. However, semi-quantitative analysis indicated a small but significant negative correlation between the GH response to Octreotide and the immunoreactivity scores of sst2 expression. Conclusions: DG3173 equalled Octreotide in suppressing GH secretion in hSA. Since DG3173 suppressed GH in some Octreotide-non-responsive adenomas, its clinical effectiveness will be worth testing. Moreover, its reduced insulin-suppressive potency would make it a valuable alternative to Octreotide... To read more, click here.
  • The novel somatostatin analogue PTR-3173 inhibits experimental diabetic retinopathy (Poster). K. Schreiter, Y. Feng, F. vom Hagen. Poster presented at: The Endocrine Society 2006 Annual Meeting (ENDO); June 24—27, 2006; Boston, MA.
    • Abstract: Diabetic retinopathy (DR) is by far the commonest microvascular damage in patients with both type 1 and type 2 diabetes. The state of the art therapy of proliferative diabetic retinopathy (PDR) is laser photocoagulation. However, photocoagulation is aggressive with severe side effects and variable success rates. Alternative strategies currently target growth factors involved in neovascularizations in the eye... To view poster, click here.
  • Comparison between somatostatin analogues and ACE inhibitor in the NOD mouse model of diabetic kidney disease. Y. Segev, R. Eshet, I. Rivkis, C. Hayat, L. Kachko, M. Phillip, D. Landau. Nephrology Dialysis Transplantation. Volume 19. Number 12. Pages 3021-8. 2004.
    • Abstract: Background: The growth hormone (GH)-insulin-like growth factor (IGF)-SST (SST) axis is involved in diabetic nephropathy (DN). We have recently shown a beneficial effect on diabetic kidney disease markers by the use of a novel somatostatin (SST) analogue (PTR-3173) (S). The purpose of this study is to compare the effects of S with a previously used SST analogue (octreotide) and an ACE inhibitor (ACEi), a standard of care in DN... To read more, click here.
  • PTR-3173 (SomatoprimTM), a novel somatostatin analog with affinity for somatostatin receptors 2, 4 and 5 is a potent inhibitor of human GH secretion. I. Shimon, T. Rubinek, M. Hadani, N. Alhadef. Journal of Endocrinological Investigation. Volume 27. Number 8. Pages 721-7. 2004.
    • Abstract: SS, a natural cyclic tetradecapeptide, is a potent suppressor of pituitary GH and TSH secretion. At least five distinct SS receptor (SSTR) subtypes have been cloned and termed SSTRs 1-5. Both SSTR2 and SSTR5 regulate human GH and TSH secretion. Recently, a novel enzymatically stable SS analog, PTR-3173 (SomatoprimTM), with affinity for human SSTR2, SSTR4 and SSTR5, has been identified. This cyclic heptapeptide analog suppressed rat GH in vivo with no effect on insulin and minimal effect on glucagon secretion. Using primary cultures of human fetal pituitaries (20-24-week gestation) and GH-secreting adenomas, we studied the in vitro inhibitory effects of PTR-3173 on human pituitary secretion. PTR-3173 suppressed GH release from both fetal pituitaries (maximal suppression of 54% with 10 nM) and cultures of GH-cell adenomas (35% suppression with 100 nM). Octreotide and PTR-3173 had comparable inhibitory effects on GH secretion from fetal human pituitaries. TSH was mildly suppressed by PTR-3173, whereas ACTH secretion was not affected in fetal pituitary cultures. In cultures of eight GH-secreting adenomas, octreotide was superior to PTR-3173 in suppressing GH from two adenomas, PTR-3173 was more potent in three other tumors, and three adenomas did not respond significantly to either analog. PTR-3173 suppressed PRL in several mixed GH-PRL adenomas. In conclusion, PTR-3173, a novel SS analog with a unique SSTRs binding combination, is a potent in vitro suppressor of human GH. Combining this inhibitory effect with the lack of effect on insulin secretion, it is suggested that PTR-3173 may be clinically useful for the treatment of acromegaly... To read more, click here. (Subscription or purchase required.)