Delving into the Latest Updates on PT-2385 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

PT 2385, PT2385

Target

HIF-2α

Mechanism

HIF-2α inhibitors(Endothelial PAS domain-containing protein 1 inhibitors)

Therapeutic Areas

NeoplasmsNervous System DiseasesCardiovascular Diseases+ [4]

Active Indication

Renal Cell CarcinomaVon Hippel-Lindau DiseaseLocally Advanced Clear Cell Renal Cell Carcinoma

Inactive Indication

Recurrent Glioblastoma

Originator Organization

Peloton Therapeutics, Inc.

Active Organization

Peloton Therapeutics, Inc.

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

Structure

Molecular FormulaC17H12F3NO4S

InChIKeyONBSHRSJOPSEGS-INIZCTEOSA-N

CAS Registry1672665-49-4

This is an exploratory study to assess [18F]PT2385 Positron Emission Tomography/Computed Tomography (PET/CT) in patients with renal cell carcinoma (RCC). This is an open-label, nontherapeutic trial. The main objective is to correlate hypoxia-inducible factor-2alpha (HIF2α) levels as determined by an investigational [18F]PT2385 PET/CT scan with the levels on subsequently obtained tissue by HIF2α immunohistochemistry (IHC). There will be three cohorts. The first pre-surgical cohort will have [18F]PT2385 PET/CT prior to nephrectomy. The uptake and retention on Positron Emission Tomography (PET), quantified as standardized uptake value (SUV) max and mean, abbreviated SUV henceforth will be correlated with HIF2α levels by IHC on the primary tumor. The second cohort will comprise patients with metastatic clear cell renal carcinoma (ccRCC). SUV will be correlated with HIF2α levels measured by IHC on a biopsy sample from a metastasis. Both low- and high-avidity sites will be biopsied and tracer uptake correlated with HIF2α IHC. A third cohort will include patients with Von Hippel-Lindau (VHL) syndrome and any of the following disease manifestations - RCC, central nervous system (CNS) hemangioblastoma, and/or pancreatic neuroendocrine tumor(s). Investigational imaging will evaluate HIF2α expression within a tumor type and across different tumor types. A biopsy is encouraged but not mandatory for this cohort.

Start Date18 Aug 2021

Sponsor / Collaborator-

NCT03108066 / CompletedPhase 2

An Open Label Phase 2 Study to Evaluate PT2385 for the Treatment of Von Hippel-Lindau Disease-Associated Clear Cell Renal Cell Carcinoma

The primary objective of this study is to assess the overall response rate (ORR) of von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC) tumors in VHL patients treated with PT2385.

Start Date24 Apr 2017

Sponsor / Collaborator

Peloton Therapeutics, Inc.

[+1]

NCT02553356 / CompletedPhase 1

A Single-Dose, Open-Label, Randomized, Food Effect Study in Healthy Volunteers With PT2385 Tablets

This Phase 1, single-dose study will be conducted in adult female subjects (N = 16) who are in general good health and selected for participation in the study according to the selection criteria. This study will assess the effect of food on the pharmacokinetics of PT2385 Tablets. The study will consist of two periods and will be conducted in a crossover fashion.

Start Date01 Sep 2015

Sponsor / Collaborator

Peloton Therapeutics, Inc.

100 Clinical Results associated with PT-2385

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100 Translational Medicine associated with PT-2385

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100 Patents (Medical) associated with PT-2385

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40

Literatures (Medical) associated with PT-2385

01 Oct 2023·Journal of neuro-oncology

Activity of a first-in-class oral HIF2-alpha inhibitor, PT2385, in patients with first recurrence of glioblastoma

Article

Author: Strowd, Roy ; Desai, Arati ; Grossman, Stuart ; Clarke, Jennifer L ; Ye, Xiaobu ; Ahluwalia, Manmeet ; Raymond, Catalina ; Nabors, L Burt ; Desideri, Serena ; Piotrowski, Anna ; Wen, Patrick Y ; Lieberman, Frank S ; Yao, Jingwen ; Ellingson, Benjamin

INTRODUCTION:

Hypoxia inducible factor 2-alpha (HIF2α) mediates cellular responses to hypoxia and is over-expressed in glioblastoma (GBM). PT2385 is an oral HIF2α inhibitor with in vivo activity against GBM.

METHODS:

A two-stage single-arm open-label phase II study of adults with GBM at first recurrence following chemoradiation with measurable disease was conducted through the Adult Brain Tumor Consortium. PT2385 was administered at the phase II dose (800 mg b.i.d.). The primary outcome was objective radiographic response (ORR = complete response + partial response, CR + PR); secondary outcomes were safety, overall survival (OS), and progression free survival (PFS). Exploratory objectives included pharmacokinetics (day 15 C_min), pharmacodynamics (erythropoietin, vascular endothelial growth factor), and pH-weighted amine- chemical exchange saturation transfer (CEST) MRI to quantify tumor acidity at baseline and explore associations with drug response. Stage 1 enrolled 24 patients with early stoppage for ≤ 1 ORR.

RESULTS:

Of the 24 enrolled patients, median age was 62.1 (38.7-76.7) years, median KPS 80, MGMT promoter was methylated in 46% of tumors. PT2385 was well tolerated. Grade ≥ 3 drug-related adverse events were hypoxia (n = 2), hyponatremia (2), lymphopenia (1), anemia (1), and hyperglycemia (1). No objective radiographic responses were observed; median PFS was 1.8 months (95% CI 1.6-2.5) and OS was 7.7 months (95% CI 4.9-12.6). Drug exposure varied widely and did not differ by corticosteroid use (p = 0.12), antiepileptics (p = 0.09), or sex (p = 0.37). Patients with high systemic exposure had significantly longer PFS (6.7 vs 1.8 months, p = 0.009). Baseline acidity by pH-weighted CEST MRI correlated significantly with treatment duration (R² = 0.49, p = 0.017). Non-enhancing infiltrative disease with high acidity gave rise to recurrence.

CONCLUSIONS:

PT2385 monotherapy had limited activity in first recurrent GBM. Drug exposure was variable. Signals of activity were observed in GBM patients with high systemic exposure and acidic lesions on CEST imaging. A second-generation HIF2α inhibitor is being studied.

01 May 2023·Hypertension (Dallas, Tex. : 1979)

Specific HIF-2α (Hypoxia-Inducible Factor-2) Inhibitor PT2385 Mitigates Placental Dysfunction In Vitro and in a Rat Model of Preeclampsia (RUPP)

Article

Author: Baldin, Pamela ; Leducq, Camille ; Peers de Nieuwburgh, Maureen ; Gatto, Laurent ; Sonveaux, Pierre ; Depoix, Christophe Louis ; Bedin, Marie ; Lambert, Isaline ; Colson, Arthur ; De Beukelaer, Michèle ; Loriot, Axelle ; Hubinont, Corinne ; Debiève, Frédéric ; Bouhna, Khadija

Background::

Preeclampsia is one of the leading causes of maternal mortality worldwide and is strongly associated with long-term morbidity in mothers and newborns. Referred to as one of the deep placentation disorders, insufficient remodeling of the spiral arteries during the first trimester remains a major cause of placental dysfunction. Persisting pulsatile uterine blood flow causes abnormal ischemia/reoxygenation phenomenon in the placenta and stabilizes the HIF-2α (hypoxia-inducible factor-2α) in the cytotrophoblasts. HIF-2α signaling impairs trophoblast differentiation and increases sFLT-1 (soluble fms-like tyrosine kinase-1) secretion, which reduces fetal growth and causes maternal symptoms. This study aims to evaluate the benefits of using PT2385—an oral specific HIF-2α inhibitor—to treat severe placental dysfunction.

Methods::

To evaluate its therapeutic potential, PT2385 was first studied in primary human cytotrophoblasts isolated from term placenta and exposed to 2.5% O 2 to stabilize HIF-2α. Viability and luciferase assays, RNA sequencing, and immunostaining were used to analyze differentiation and angiogenic factor balance. The ability of PT2385 to mitigate maternal manifestations of preeclampsia was studied in the selective reduced uterine perfusion pressure model performed in Sprague-Dawley rats.

Results::

In vitro, RNA sequencing analysis and conventional techniques showed that treated cytotrophoblast displayed an enhanced differentiation into syncytiotrophoblasts and normalized angiogenic factor secretion compared with vehicle-treated cells. In the selective reduced uterine perfusion pressure model, PT2385 efficiently decreased sFLT-1 production, thus preventing the onset of hypertension and proteinuria in pregnant dams.

Conclusions::

These results highlight HIF-2α as a new player in our understanding of placental dysfunction and support the use of PT2385 to treat severe preeclampsia in humans.

01 Oct 2022·Drug testing and analysis

Metabolic study of hypoxia‐inducible factor stabilizers BAY 87‐2243, MK‐8617, and PT‐2385 in equine liver microsomes for doping control

Article

Author: Karatt, Tajudheen K. ; Mathew, Binoy ; Karakka Kal, Abdul Khader ; Subhahar, Michael Benedict ; Perwad, Zubair ; Philip, Moses

Abstract:

A number of erythropoiesis stimulants are entering the final stage of clinical trials due to recent scientific progress in hypoxia‐regulated erythropoiesis. Considering how erythropoiesis‐stimulating compounds enhance the capacity of the organism to transport oxygen, they pose a great risk of being misused as performance enhancers. In this paper, we report the metabolic fate of three popular hypoxia‐inducible factor‐prolyl hydroxylase Inhibitors (HIF‐PHI) compounds, namely, BAY 87‐2243, MK‐8617, and PT‐2385 in equine liver microsomes using Q‐Exactive high‐resolution mass spectrometry. This study found 22 metabolites for BAY 87‐2243 (19 phase I and three phase II), three metabolites for MK‐8617 (all phase I), and five metabolites for PT‐2385 (two phase I and three phase II). The major findings of the present study are as follows: (1) all three potential HIF‐PHI drug candidates, namely, BAY 87‐2243, MK‐8617, and PT‐2385 are susceptible to oxidation, producing their corresponding hydroxylated metabolites; (2) the ring dissociated metabolites were detected for BAY 87‐2243 and PT‐2385; (3) in the case of BAY 87‐2243 and PT‐2385, glucuronic acid conjugated metabolites were detected; and (4) none of the drugs produced sulfonic acid conjugated metabolites.

100 Deals associated with PT-2385

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16055

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Recurrent Glioblastoma	Phase 2	US	Peloton Therapeutics, Inc.	14 Sep 2017
Renal Cell Carcinoma	Phase 2	US	Peloton Therapeutics, Inc.	24 Apr 2017
Von Hippel-Lindau Disease	Phase 2	US	Peloton Therapeutics, Inc.	24 Apr 2017
Locally Advanced Clear Cell Renal Cell Carcinoma	Phase 1	US	Peloton Therapeutics, Inc.	25 Nov 2014

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03216499 (ASCO2019) Manual	Phase 2	Glioblastoma	24	PT-2385	lyqzehsise(alywkgmrbl) = No objective radiographic responses were observed cqkovvuacx (vtxcowelpr ) View more	Positive	02 Jun 2019
NCT03216499 (ASCO2019) Manual	Phase 2	Glioblastoma	24	PT-2385 (Cmin< 300 on Day 15)		Positive	02 Jun 2019
NCT02293980 (3795-001 \| MK-3795-001, ASCO_GU2019) Manual	Phase 1	Renal Cell Carcinoma	50	PT2385+nivolumab	djefdxfzau(anhxdxisjg) = swmmftxsoe ezokmsnoay (caxlyzmokk ) View more	Positive	16 Feb 2019
NCT02293980 (3795-001 \| MK-3795-001, Pubmed \| J Urol) Manual	Phase 1	Locally Advanced Clear Cell Renal Cell Carcinoma Second line	51	PT2385	ucxaothuhz(memqkxxktk) = lncxlykdbw vejwwbxeqe (kucgbcuqbz ) View more	Positive	20 Mar 2018
NCT02293980 (3795-001 \| MK-3795-001, ASCO2016)	Phase 1	Locally Advanced Clear Cell Renal Cell Carcinoma	43	PT2385	emauqfvqch(ninuyzplla) = 14 dwsyugwbjd (zskpqmbpto ) View more	Positive	20 May 2016