pruxelutamide (GT0918) / Kintor Pharma - LARVOL DELTA

Investigation of absorption, metabolism, and excretion of [14C]pruxelutamide (GT0918), an androgen receptor antagonist in humans. (PubMed, Br J Clin Pharmacol) - "Overall, all the dosed subjects completed the study, and GT0918 was found to be safe, with no grade II or above adverse events reported. A total dose of 82.81% was quantified in the urine (29.47%) and faeces (53.34%) of healthy adult male subjects after a single oral administration of 200 mg (80 μCi) GT0918 ([14C]GT0918). The metabolism of GT0918 is catalysed predominantly by CYP3A4, and an uncommon pathway of oxazole ring-opening to an aldehyde intermediate has also been proposed."

Journal • Infectious Disease • Novel Coronavirus Disease • CYP3A4

Small-molecule antivirals treatment for COVID-19: A systematic review and network meta-analysis. (PubMed, Int J Antimicrob Agents) - "A thorough evaluation of effectiveness, applicable to both mild-to-moderate and unstratified populations, highlights the specific advantages of proxalutamide, nirmatrelvir/ritonavir, triazavirin, azvudine, molnupiravir, and VV116 in combating COVID-19. Additional clinical data are required to confirm the efficacy and safety of simnotrelvir/ritonavir and leritrelvir. The safety profiles of these antivirals were deemed acceptable."

Journal • Retrospective data • Review • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

The Safety and Tolerability of GT0918 in Subjects With mHSPC and mCRPC (clinicaltrials.gov) - P2 | N=61 | Completed | Sponsor: Suzhou Kintor Pharmaceutical Inc, | Recruiting ➔ Completed

Trial completion • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

Proxalutamide plus Endocrine Therapies in Women with HR+/HER2-/AR+ Metastatic Breast Cancer: A Phase Ic Study (SABCS 2023) - " Patients in part 1 regimen-finding phase received proxalutamide plus specific ETs (letrozole [cohort A], exemestane [cohort B], or fulvestrant [cohort C]) and were assessed for dose-limiting toxicity (DLT), PK, PD, and anti-tumor activity. These findings suggested favorable clinical outcomes and safety profiles of the combination of proxalutamide and fulvestrant in AR+/HR+/HER2- mBC patients who have progressed on the first-line therapy, and maybe with better efficacy in patients with lower AR/ER ratio. Trial registration: NCT20191063"

Clinical • Metastases • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • AR • HER-2

Proxalutamide plus endocrine therapy as a combination therapy in women with HR+/HER2-/AR+ metastatic breast cancer: A phase I study (ESMO 2023) - "Monotherapies were initiated including letrozole (2.5 mg/day on days 1-14) for cohort A, exemestane (25 mg/day on days 1-14) for cohort B, and fulvestrant (intramuscularly 500 mg once on days 1, 15 and 28) for cohort C, followed by proxalutamide 200 mg QD and ETs for in a 28-day cycle. Conclusions This study suggested a good antitumor activity and safety profile of the combination therapy of proxalutamide and fulvestrant for HR+/HER2-/AR+ mBC patients in the ≥2nd-line settings. Moreover, it may provide survival benefits for these patients, warranting further investigation in a larger population."

Clinical • Combination therapy • Metastases • P1 data • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • AR • HER-2

Kintor Pharmaceutical : Pharma Announces 2023 Interim Results and Recent Business Highlights (Market Screener) - "Pruxelutamide's Phase I clinical trial for the treatment of metastatic breast cancer(mBC) in China will be presented at ESMO 2023."

P1 data • Breast Cancer • Oncology • Solid Tumor

A Study to Evaluate the Efficacy and Safety of Proxalutamide (GT0918) in Hospitalized COVID-19 Subjects (clinicaltrials.gov) - P3 | N=139 | Terminated | Sponsor: Suzhou Kintor Pharmaceutical Inc, | N=762 ➔ 139 | Trial completion date: Jan 2023 ➔ Jul 2023 | Recruiting ➔ Terminated; Sponsor's decision

Enrollment change • Trial completion date • Trial termination • Infectious Disease • Novel Coronavirus Disease

A Phase 3 Randomized, Double-Blind Placebo Controlled, Multi-regional Trial to Evaluate the Efficacy and Safety of GT0918 for the Treatment of Mild to Moderate COVID-19 Male Patients (clinicaltrials.gov) - P3 | N=380 | Terminated | Sponsor: Suzhou Kintor Pharmaceutical Inc, | N=724 ➔ 380 | Trial completion date: May 2022 ➔ Aug 2023 | Recruiting ➔ Terminated | Trial primary completion date: Feb 2022 ➔ Sep 2022; This decision is made on changing the development strategy of GT0918 to adapt ever-changing COVID-19 pandemic management globally.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Infectious Disease • Novel Coronavirus Disease

Proxalutamide reduces SARS-CoV-2 infection and associated inflammatory response. (PubMed, Proc Natl Acad Sci U S A) - "Proxalutamide exerted similar effects as enzalutamide, an AR antagonist prescribed for advanced prostate cancer, in decreasing AR signaling and expression of TMPRSS2 and angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor...Importantly, proxalutamide inhibited infection by multiple SARS-CoV-2 variants and synergized with remdesivir...Mechanistically, we found that proxalutamide increased levels of NRF2, an essential transcription factor that mediates antioxidant responses, and decreased lung inflammation. These data provide compelling evidence that proxalutamide can prevent SARS-CoV-2 infection and cytokine-induced lung damage, suggesting that promising clinical data may emerge from ongoing phase 3 trials."

Journal • Genito-urinary Cancer • Infectious Disease • Inflammation • Novel Coronavirus Disease • Oncology • Pneumonia • Prostate Cancer • Respiratory Diseases • Solid Tumor • IFNG • TMPRSS2 • TNFA

Efficacy and safety of proxalutamide (GT0918) in severe or critically ill patients with COVID-19: study protocol for a prospective, open-label, single-arm, single-center exploratory trial. (PubMed, BMC Pharmacol Toxicol) - "The trial is the first to investigate the efficacy and safety of proxalutamide in severe or critically ill patients with COVID-19. The findings of this study might lead to the development of better treatment for COVID-19 and provide convincing evidence regarding the efficacy and safety of proxalutamide."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Proxalutamide for the treatment of COVID-19 rebound following Paxlovid treatment: Report of four cases and review of the literature. (PubMed, J Clin Lab Anal) - "Our cases suggested that proxalutamide might be an effective remedial treatment option for patients experiencing a COVID-19 rebound after Paxlovid treatment."

Clinical • Journal • Retrospective data • Review • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Antiandrogens for the treatment of COVID-19 patients: A meta-analysis of randomized controlled trials. (PubMed, J Med Virol) - "However, on subgroup analysis, only proxalutamide/enzalutamide and sabizabulin were found to significantly reduce mortality (RR 0.22, 95% CI: 0.16-0.30 and RR 0.42, 95% CI: 0.26-0.68, respectively), while aldosterone receptor antagonists and antigonadotropins did not show any benefit...Antiandrogens also reduced hospitalizations and the duration of hospital stay, and improved recovery rates. Proxalutamide and sabizabulin may be effective against COVID-19, however, further large-scale trials are needed to confirm these findings."

Journal • Retrospective data • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

A phase I/II study of proxalutamide (GT0918), a potent androgen receptor blocker, in patients with mCRPC progressed after both hormonal therapy and chemotherapy. (ASCO-GU 2019) - P1/2; "All pts progressed on multiple lines of therapies including but limited to bicalutamide, abiraterone, enzalutamide, docetaxel, cabazitaxel, radium 223, sipuleucel T and pembrolizumab. GT0918 administrated orally once a day is well tolerated and resulted in SD in late-stage pts. No DLT has occurred to date (at 500 mg) and dose escalation is planned to 600 mg or higher. Extended/Ph II trial will further evaluate safety and efficacy of GT0918 in mCRPC pts."

Clinical • P1/2 data • Genito-urinary Cancer • Oncology

A partially open conformation of an androgen receptor ligand-binding domain with drug-resistance mutations. (PubMed, Acta Crystallogr F Struct Biol Commun) - "Commonly found mutations include L702H, W742C, H875Y, F877L and T878A, while the F877L mutation can convert second-generation antagonists such as enzalutamide and apalutamide into agonists. However, pruxelutamide, another second-generation AR antagonist, has no agonist activity with the F877L and F877L/T878A mutants and instead maintains its inhibitory activity against them...Additional structural studies suggest that both the L702H and F877L mutations are important for conformational changes. This structural variability in the AR LBD could affect ligand binding as well as the resistance to antagonists."

Journal • Genito-urinary Cancer • Infectious Disease • Novel Coronavirus Disease • Oncology • Prostate Cancer • Solid Tumor • AR

Proxalutamide in metastatic castration-resistant prostate cancer: primary analysis of a multicenter, randomized, open-label, phase 2 trial. (PubMed, Int J Cancer) - "These findings preliminarily showed the promising antitumor activity of proxalutamide in patients with mCRPC with a manageable safety profile. The proxalutamide dose of 200 mg daily is recommended for future phase 3 trial."

Journal • Metastases • P2 data • Fatigue • Genito-urinary Cancer • Hematological Disorders • Oncology • Prostate Cancer • Solid Tumor

Circulating tumor DNA and RNA as an exploratory biomarker to evaluate GT0918 in a Phase 1/II clinical trial in mCRPC patients (ESMO 2018) - P1/2; "We explored ctDNA & ctRNA-based biomarkers from patient blood to assess their associations with clinical response of GT0918, a potent AR antagonist, in a Phase 1/2 clincal study in mCRPC who progressed after abiraterone or enzalutamide and docetaxol, or cannot tolerate either or both therapies. This is a preliminary study to explore genomic alterations in mCRPC in response to GT0918 treatment. As a non-invasive assay, the ctDNA & ctRNA-based assay was highly sensitive and provided useful molecular insights for monitoring treatment effect and deciphering drug sensitivity & resistance mechanisms."

Biomarker • BRCA Biomarker • Clinical • P1/2 data • Prostate Cancer

Biomarker analysis (CTC and ctDNA/RNA) of GT0918 (Proxalutamide) new AR blocker in phase I mCRPC patients with dose escalation. (ASCO-GU 2020) - P1/2; " Pts with histologically confirmed mCRPC who progressed on enza, abi, docetaxel, etc were enrolled and treated with GT0918 continuously until PD, intolerable toxicity or withdraw...More patients will be tested in phase II study GT0918 in mCRPC progressed on either abiraterone or enzalutamide. This is a preliminary study to explore genomic alterations and the CTC enumeration in late stage of mCRPC pts in response to GT0918 treatment with dose increase. As non-invasive assays, both CTC and ctDNA/RNA assays provided valuable molecular insights for monitoring treatment effects besides PSA and imaging scan. Early detection of possible drug sensitivity/resistance mechanisms will facilitate clinical development programs."

Biomarker • Clinical • New P1 trial • P1 data

Plasma-based exploratory biomarker analysis to evaluate GT0918 in a phase I/II study in mCRPC patients. (ASCO-GU 2019) - P1/2; "This is a preliminary analysis to explore potential predictive or pharmacodynamic biomarkers in mCRPC in response to GT0918 treatment. As an non-invasive assay, PredicinePLUS assay was able to detect genomic alterations in blood with a high sensitivity and provided useful molecular insights for treatment monitoring and drug sensitivity & resistance mechanisms."

Biomarker • Clinical • P1/2 data

[VIRTUAL] Repurposing 2nd generation androgen receptor antagonist Proxalutamide to treat COVID-19 (AACR 2021) - P=N/A | "These results support the role of androgen-AR signaling in the disease progression and mortality in male patients with COVID-19. We are currently conducting clinical study in COVID-19 patients with Proxalutamide in Brazil (NCT04446429)."

Genito-urinary Cancer • Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • TMPRSS2 • TNFA

Retraction of Clinical Trials about the SARS-CoV-2 Infection: An Unaddressed Problem and Its Possible Impact on Coronavirus Disease (COVID)-19 Treatment. (PubMed, Int J Environ Res Public Health) - "Eight drugs were tested (Ivermectin, Vitamin D, Proxalutamide, Hydroxychloroquine, Remdesevir, Favipiravir, and Sofosbuvir + Daclatasvir) in the studies...The different Altmetric indexes show that possibly people who read those retracted articles are not reading their retraction notes and are unaware of the erroneous information they share. COVID-19- related clinical trials were ~two-time times more retracted than the other clinical trials performed during the same time."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Proxalutamide in patients with AR-positive metastatic breast cancer: Results from an open-label multicentre phase Ib study and biomarker analysis. (PubMed, Eur J Cancer) - P1 | "Proxalutamide showed promising anti-tumour activity with good tolerability in patients with heavily pretreated AR mBC, supporting further investigation."

Biomarker • Journal • P1 data • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AR • PIK3CA

Kintor Pharma Announces Publication of Phase Ib Data from Pruxelutamide for AR+ mBC in EJC (PRNewswire) - P1 | N=63 | NCT04103853 | Sponsor: Suzhou Kintor Pharmaceutical Inc | "Highlights: Pruxelutamide showed promising activity in heavily pretreated AR+ mBC patients. Pruxelutamide showed an acceptable safety profile in heavily pretreated AR+ mBC. Recommended phase II dose of pruxelutamide was defined as 200mg orally once daily. AR expression, cell-free DNA yield, CNV might be associated with response. Patients with PIK3CA pathogenic mutation showed longer progression-free survival....Among 39 evaluable patients, DCR at 8 and 16 weeks was 25.6% (95% confidence interval [CI], 11.9–39.4%), with 26.9% in cohort A and 23.1% in cohort B. The 6-month progression-free survival (PFS) rate was 19.6% (95% CI, 10.2–37.5%). In the triple-negative subgroup, DCR at 8 weeks was 38.5%, with median PFS of 9.1 months (95% CI, 7.8–NA) in those who achieved response at 8 weeks (n = 5)."

P1 data • Breast Cancer • Oncology • Solid Tumor

the Safety and Tolerability of Proxalutamide (GT0918) in Subjects With Metastatic Castrate Resistant Prostate Cancer (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: Suzhou Kintor Pharmaceutical Inc, | Trial completion date: Jun 2022 ➔ Oct 2022

Trial completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CTCs

[VIRTUAL] A phase II, multicenter, randomized, open-label study to evaluate the safety and tolerability of proxalutamide (GT0918) in subjects with metastatic castrate-resistant prostate cancer (mCRPC). (ASCO-GU 2021) - " Patients with historically confirmed mCRPC who progressed after/intolerant to/reluctant to receive Docetaxel and previously treated with abiraterone or enzalutamide were excluded. GT0918 showed a manageable safety profile. This study provided preliminary anti-tumor activity in patients with mCRPC. 200mg/day is recommended dose for Ph III trial."

Clinical • P2 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

"What is needed is a head to head: Proxalutamide vs Fluvoxamine vs PAXLOVID as 3 options on the same trial. No placebo. I bet PAXLOVID would lose. So, has to be an independent group." (@WambierMD)

Clinical • Head-to-Head