Signifor (pasireotide)

At the pituitary level, pasireotide is an approved somatostatin receptor ligand, and compounds targeting cell cycle regulation, cell signalling and epigenetics are now under investigation. Levoketoconazole and osilodrostat are novel steroid inhibitors, and relacorilant overcomes the adverse effects of mifepristone. Adrenal ACTH receptor blockage and immunotherapy could also play a role.

Pasireotide long-acting release (PAS-LAR) is a second-generation somatostatin receptor ligand (SRL) approved for acromegaly treatment. These findings suggest that PAS-LAR is an effective option for acromegaly patients resistant to fgSRL, but careful monitoring of glucose levels is essential. The high heterogeneity observed across studies emphasizes the need for identifying PAS-LAR response biomarkers to set-up individualized treatment approaches for optimizing patient outcomes.

Pasireotide was therefore prescribed, and afterward cabergoline was added on. IGF-I concentrations decreased but did not normalize. We discovered a novel germline single nucleotide variant in the splicing donor region of intron 2 of the AIP gene (NM_003977.4:c.279+1 G>A), classified as likely pathogenic according to the American College of Medical Genetics and Genomics guidelines.

Here, we report four cryoelectron microscopy structures of Gi-coupled SSTR1 and SSTR3 activated by distinct agonists, including the FDA-approved panagonist pasireotide as well as their selective small molecule agonists L-797591 and L-796778...Together with mutagenesis analyses, our structures further reveal the dynamic feature of ligand binding pockets in SSTR1 and SSTR3 to accommodate divergent agonists, the key determinants of ligand selectivity lying across the orthosteric pocket of different SSTR subtypes, as well as the molecular mechanism underlying diversity and conservation of receptor activation. Our work provides a framework for rational design of subtype-selective SSTR ligands and may facilitate drug development efforts targeting SSTRs with improved therapeutic efficacy and reduced side effects.

We found that patients with SSTR1-low mCRPC tumors derived less benefit from subsequent ARSI therapy in a retrospective cohort. We showed that SSTR1 was antiproliferative in 22Rv1 cells and that the FDA-approved drug pasireotide suppressed 22Rv1 cell proliferation.CONCLUSIONOur findings expand the knowledge of ARSI resistance and point out actionable next steps, exemplified by potentially targeting SSTR1, to improve patient outcomes.FUNDINGNational Cancer Institute (NCI), NIH; Prostate Cancer Foundation; Conquer Cancer, American Society of Clinical Oncology Foundation; UCSF Benioff Initiative for Prostate Cancer Research; Netherlands Cancer Institute.

On the other hand, a number of somatostatin antagonists may prove useful in certain medical settings, based on their differential affinity for SSTRs. The aim of this review is to present in detail the principal characteristics of all five SSTRs and to provide an overview of the associated therapeutic potential in neoplasias.

P=N/A, N=100, Recruiting, IRCCS San Raffaele

Patients were divided into responders and non-responders based on their biochemical response to fgSRL and/or the newer agent, Pasireotide, or the GH-blocker, Pegvisomant. Our findings suggest that densely granulated tumors, with positive SSTR2 and E-Cadherin seem to be associated with favorable fgSRL responses. The strongest predictive value of the studied markers was found for E-Cadherin, which seems to surpass even SSTR2.

Somatostatin analogs, such as octreotide (OCT), lanreotide, and pasireotide, which function as somatostatin receptor ligands (SRLs), are the main drugs used for the treatment of acromegaly...The results revealed the residues that contribute to the ligand binding pocket and demonstrated that Trp8-Lys9 (the W-K motif) in somatostatin analogs is the key motif in stabilizing the bottom part of the binding pocket. In this review, we discuss the recent findings related to the structural analysis of SSTRs and SRLs, the relationships between the structural data and clinical findings, and the future development of novel structure-based therapies.

Interestingly, while octreotide did not modify H69 cell proliferation, a strong inhibition of proliferation was detected with the use of pasireotide. In view of these results, a clinical trial in NET G3 and NEC patients using pasireotide is necessary to determine the usefulness of this drug in improving patient treatment.

Two cyclic SST analog peptides (pasireotide and octreotide) both can activate SSTR5 and SSTR2...Moreover, we find that the Q2.63, N6.55, F7.35 and ECL2 of SSTR2 play a crucial role in octreotide biased binding of SSTR2. Our results will provide structural insights and offer new opportunities for the drug discovery of better selective pharmaceuticals targeting specific SSTR subtypes.

P2, N=28, Not yet recruiting, University Hospital Heidelberg

Current standards of care in PTCOEs include use of first-generation SRLs as the first medical option in about 50% of patients, as recommended by consensus guidelines. However, some patients are kept on this treatment despite inadequate control suggesting that cost-effectiveness, availability, patient preference, side effects, and therapeutic inertia may play a possible role also in PTCOE. Moreover, at odds with consensus guidelines, other monotherapies for acromegaly appear to have a marginal role as compared to combination therapies as extrapolated from PTCOE practice data. Presence of uncontrolled patients in each treatment category suggest that further optimization of medical therapy, as well as use of other therapeutic tools such as radiosurgery may be needed.

P4, N=413, Completed, RECORDATI GROUP | Active, not recruiting --> Completed

The experts agreed on a holistic management approach to acromegaly. It is therefore necessary to choose currently available highly effective second-line medical treatment (pegvisomant and pasireotide) based on the characteristics of the patients.

We treated cells derived from 23 NF-PitNETs with ITF2984, and a subset of them with octreotide, pasireotide (SRLs with high affinity for SSTR2 or 5, respectively), or cabergoline (DRD2 agonist) and we measured cell proliferation and apoptosis. In our model, SSTR3 expression levels did not correlate with ITF2984 antiproliferative nor proapoptotic effects. In conclusion, our data support a possible use of ITF2984 in the pharmacological treatment of NF-PitNET.

P=N/A, N=151, Completed, RECORDATI GROUP | Recruiting --> Completed | Trial completion date: May 2024 --> Jul 2023

Participants with acromegaly or CD initiated long-acting pasireotide 40 mg/28 days intramuscularly (acromegaly) or pasireotide 600 μg subcutaneously twice daily during pre-randomization (≤16 weeks). Those who did not need antihyperglycemic medication, were managed with metformin, or received insulin from baseline entered an observational arm ending at 16 weeks...Increasing age, HbA1c, and FPG and pre-diabetes/diabetes were associated with increased likelihood of requiring antihyperglycemic medication during pasireotide treatment. These risk factors may be used to identify those who need more vigilant monitoring to optimize outcomes during pasireotide treatment.

Pasireotide is effective and safe in the long-term. Hyperglycemia is a common event and is manageable even without insulin treatment.

P2, N=10, Recruiting, Memorial Sloan Kettering Cancer Center

Surgical resection of the associated tumour is curative in most NICTH cases. When the tumour is unresectable, moderate-dose glucocorticoids, low-dose glucocorticoids in combination with recombinant growth hormone, and pasireotide are medical therapies with promising results in controlling NICTH.

Tumor shrinkage was observed in 6 out of 7 evaluated responders, with no cases of size increase during the long-term follow-up. Pas-LAR is effective and safe and the early identification of responders is possible just after the first administration.

P2, N=6, Terminated, Gustave Roussy, Cancer Campus, Grand Paris | N=217 --> 6 | Trial completion date: Sep 2023 --> Feb 2024 | Suspended --> Terminated | Trial primary completion date: Jul 2023 --> Feb 2024; No more experimental drugs available

P2, N=72, Recruiting, RECORDATI GROUP | Not yet recruiting --> Recruiting | Initiation date: Oct 2023 --> Jan 2024

Medical treatment with dopamine agonists (DA), mainly cabergoline, is considered the primary therapy for these patients...Patients with aggressive and DA-resistant adenomas or with rare PRL-secreting carcinomas can be treated off-label with temozolomide (TMZ), a DNA alkylating agent...Other therapeutic options include aromatase inhibitors, the somatostatin receptor ligand pasireotide, peptide receptor radionuclide therapy (PRRT), immune-checkpoint inhibitors, tyrosine-kinase inhibitors, or everolimus, the mammalian target of rapamycin inhibitor. These experimental treatments were effective in some patients carrying refractory prolactinomas showing usually partial tumor control. However, the number of treated patients with any of these new therapeutic options is very limited and treatment results are inconsistent, thus additional experience with more patients is required.

Long-acting SSAs are an effective and safe initial therapy of patients with well differentiated NET, allowing tumor growth as well as symptoms control for long-time in selected patients.

Conformal or stereotactic radiotherapy may be discussed on a case-by-case basis, especially in case of drug inefficacy or poor tolerance. Acromegaly should be managed by a multidisciplinary team, preferably within an expert center such as a reference or skill center for rare pituitary diseases.

When first-generation somatostatin analogues (SSAs) fail to control hypoglycemia syndrome, second-generation SSAs and everolimus have to be considered for exploiting their hyperglycemic effect...PRRT seems to be an effective treatment when surgery and SSAs fail. The application of these therapeutic modalities has been shown to be efficacious in controlling the manifestations of the secretory syndrome and prolonging overall survival of patients suffering from these malignancies.

Most of the earlier studies used different definitions of POPF and other complications; included patients with varied pancreatic pathologies such as cancer, chronic pancreatitis, and benign lesions; surgical techniques such as pancreaticoduodenectomy, distal pancreatectomy, and other procedures; use of somatostatin and its analogs such as octreotide, lanreotide, pasireotide, and vapreotide; varied surgeon and institutional volume; and so on. Data indicate favorable role of newer somatostatin analogs, and further studies are urgently needed. The question about the efficacy of prophylactic octreotide to reduce POPF after pancreaticoduodenectomy remains open to debate.

In contrast, densely granulated somatotroph and corticotroph tumors express high levels of somatostatin receptors and are more responsive to somatostatin analogs. Since ACTH-producing PitNETs express SSTR5 without SSTR2, the second-generation somatostatin analog, pasireotide, is effective against ACTH-producing PitNETs.

Synthetic therapeutic agonists showing selectivity for SSTR2 (Octreotide) or for SSTR2 and SSTR5 (Pasireotide) have been approved for the treatment of patients with acromegaly and Cushing's syndrome, as their pituitary tumors highly express SSTR2 or SSTR2/SSTR5, respectively...Furthermore, ITF2984 displays antitumor activity that is dependent on SSTR3 expression levels in the MENX (homozygous mutant) NFPA rat model, which closely recapitulates human disease. Therefore, ITF2984 may represent a novel therapeutic option for patients affected by NFPA.

The most widely used are somatostatin analogues with three clinically approved drugs: lanreotide and octreotide (first-generation) and pasireotide (second-generation). Both everolimus and interferon used in combination with octreotide have shown significant reduction in urinary 5-hydroxyindoleacetic acid compared to octreotide alone. Telotristat ethyl has been increasingly utilised for patients with symptoms despite taking somatostatin analogues...There are therefore numerous different therapies. This paper describes the pathophysiology and therapy of carcinoid syndrome.

Low-dose (1 mg) dexamethasone suppression test reduced AM cortisol to 1.7 µg/dL and ACTH of 8 pg/mL...Some medications for CD impede pregnancy through their mechanism (eg, mifepristone)...Although her CD symptoms returned when pasireotide was discontinued, she delivered a healthy infant; limited pasireotide data in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. Our case underscores the potential for successful conception for women with CD when cortisol levels are normalized with treatment that avoids suppressing menstruation.

High-dose diazoxide, everolimus, dexamethasone, glucagon, pasireotide, or enteral feeding did not produce a response. No adverse effects have been observed. In summary, the anti-insulin receptor monoclonal antibody RZ358 effectively controlled hypoglycemia refractory to multiple other therapies, allowing restoration of normoglycemia and enabling additional successful cancer therapy.

Our results provide new insights into potential PRKCD contribution in Pasireotide mechanism of action and suggest that PRKCD might be a possible marker of therapeutic response in ACTH-secreting pituitary tumors.

P2, N=217, Suspended, Gustave Roussy, Cancer Campus, Grand Paris | Recruiting --> Suspended | Trial primary completion date: Feb 2023 --> Jul 2023

First line medical therapy consists of first-generation injectable somatostatin receptor ligands (SRL) (octreotide LAR, lanreotide autogel)...If IGF-1 levels do not normalize, pasireotide or pegvisomant can be tried...Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*

Patient is waiting for a second surgery via craniotomy and, given the SG finding on histology, pasireotide therapy will be offered...Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*

Key inclusion criteria included a biochemical and clinical diagnosis of acromegaly due to a pituitary adenoma with persistent or recurrent disease, treatment with a stable dose of octreotide long-acting release or lanreotide Autogel for at least 3 months as monotherapy, and controlled disease with IGF-1 =1 x upper limit of normal (ULN). Key exclusion criteria included GH =2.5 µg/L at screening, pituitary surgery within 6 months of screening, prior pituitary irradiation, and recent treatment with pasireotide, pegvisomant, or dopamine agonists...Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*

Due to elevated liver functiontests, the patient couldn't have started ketoconazole and relacorilant treatment.Because of non-controlled DM, pasireotide treatment was contraindicated in her case.She didn't agree either for metyrapone treatment or for adrenalectomy. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*

Outcomes were: demographic characteristics; treatment frequency by line of treatment (LOT) and changes between LOTs (Sankey plot); treatment persistence for first LOT (LOT 1) monotherapies (Kaplan-Meier estimator); and treatment up-/downtitration (=30% dose change, evaluated for octreotide long-acting release [OCT] and lanreotide depot [LAN])...Other LOT 1 classes were DAs (cabergoline; 34.5%) and GHRAs (pegvisomant; 10.5%). Only 7 patients received second-generation SRL pasireotide and no patients received oral octreotide in LOT 1...Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*

Depending on the route of administration in the parent study, pts received pasireotide long-acting release (LAR; n=303) or subcutaneous (sc; n=38) as monotherapy (n=36), or sc in combination with cabergoline (n=2). Hyperglycemia is an expected AE during pasireotide treatment, often occurring in the first 3 months of therapy. These data in pts with acromegaly, CD or other endocrine disorders support pasireotide as a well-tolerated long-term treatment and affirm that pts continue to receive long-term benefit, with a low discontinuation rate over 8 years.*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins.