Endoxifen for Bipolar Disorder
Recruiting in Palo Alto (17 mi)
+11 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Waitlist Available
Sponsor: Jina Pharmaceuticals Inc.
Must not be taking: Antidepressants, Benzodiazepines, Estrogens, others
Disqualifiers: Seizure disorder, OCD, Personality disorder, others
Pivotal Trial (Near Approval)
Prior Safety Data
Approved in 1 Jurisdiction
Trial Summary
What is the purpose of this trial?
Bipolar disorder (BPD) is a chronic debilitating illness characterized by drastic swings in mood, energy and functional ability that affects the adult population. Endoxifen is an active metabolite of the marketed drug Tamoxifen and the present study aims to evaluate the efficacy and safety of 8 mg endoxifen in the Bipolar I disorder patient population compared to a placebo arm. Endoxifen will be compared to a placebo to demonstrate that the test product is active and to establish that the study is sufficiently sensitive to detect differences between the investigational products. Thus, Endoxifen will be compared to placebo to demonstrate that the test product is safe and active.
Do I need to stop my current medications to join the trial?
Yes, you will need to stop taking your current medications for bipolar disorder 2-7 days before joining the trial, depending on the specific medication. Additionally, certain other medications are not allowed during the study period.
What data supports the effectiveness of the drug Endoxifen for treating bipolar disorder?
Research shows that Endoxifen, a drug related to tamoxifen, has antimanic properties and significantly improved mania symptoms in patients with bipolar I disorder during a 21-day study. Additionally, tamoxifen, a similar drug, has shown effectiveness in reducing manic symptoms in women with bipolar disorder.12345
Is endoxifen safe for use in humans?
Endoxifen has been studied in clinical trials for various conditions, including breast cancer and bipolar disorder, and has shown promising safety results. In these studies, it demonstrated good oral bioavailability and did not show significant harmful effects on the endometrium (lining of the uterus) compared to similar drugs.12367
How is the drug endoxifen different from other treatments for bipolar disorder?
Endoxifen is unique because it targets the protein kinase C (PKC) signaling system, which plays a role in mood disorders, making it a novel option for treating mania in bipolar disorder. Unlike traditional treatments, endoxifen is an active metabolite of tamoxifen and is administered orally, showing significant improvement in manic symptoms within a few days.12389
Eligibility Criteria
This trial is for adults with Bipolar I Disorder, a condition causing extreme mood swings. Participants must meet specific health criteria to join but details are not provided here.Inclusion Criteria
Patients and/or LAR must agree to comply with all study requirements
I have been diagnosed with bipolar I disorder and am currently experiencing a manic episode.
Patients must have at least one first-degree relative or legally acceptable representative (LAR) to participate
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Exclusion Criteria
I have been newly diagnosed with bipolar disorder and haven't received treatment yet.
Patients with personality disorders interfering with study conduct
My mood disorder symptoms have improved recently.
See 9 more
Treatment Details
Interventions
- Endoxifen (Selective Estrogen Receptor Modulator)
Trial OverviewThe study tests the effectiveness and safety of an 8 mg endoxifen tablet against a placebo in managing symptoms of Bipolar I Disorder. Endoxifen is derived from Tamoxifen, which is already on the market.
Participant Groups
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Endoxifen ArmExperimental Treatment1 Intervention
Endoxifen enteric-coated tablet (8 mg). Patients will continue treatment with their initial randomized medication for 3 weeks
Group II: Placebo ArmPlacebo Group1 Intervention
Placebo tablets. Patients will continue administration with their initial randomized medication for 3 weeks
Endoxifen is already approved in India for the following indications:
🇮🇳 Approved in India as Endoxifen for:
- Bipolar I disorder
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
SynexusCerritos, CA
NRC Research InstituteLos Angeles,, CA
Innovative Clinical Research, Inc.Miami Lakes, FL
NRC Research InstituteOrange, CA
More Trial Locations
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Who Is Running the Clinical Trial?
Jina Pharmaceuticals Inc.Lead Sponsor
Novum Pharmaceutical Research ServicesIndustry Sponsor
References
Endoxifen, an Estrogen Receptor Targeted Therapy: From Bench to Bedside. [2022]The selective estrogen receptor (ER) modulator, tamoxifen, is the only endocrine agent with approvals for both the prevention and treatment of premenopausal and postmenopausal estrogen-receptor positive breast cancer as well as for the treatment of male breast cancer. Endoxifen, a secondary metabolite resulting from CYP2D6-dependent biotransformation of the primary tamoxifen metabolite, N-desmethyltamoxifen (NDT), is a more potent antiestrogen than either NDT or the parent drug, tamoxifen. However, endoxifen's antitumor effects may be related to additional molecular mechanisms of action, apart from its effects on ER. In phase 1/2 clinical studies, the efficacy of Z-endoxifen, the active isomer of endoxifen, was evaluated in patients with endocrine-refractory metastatic breast cancer as well as in patients with gynecologic, desmoid, and hormone-receptor positive solid tumors, and demonstrated substantial oral bioavailability and promising antitumor activity. Apart from its potent anticancer effects, Z-endoxifen appears to result in similar or even greater bone agonistic effects while resulting in little or no endometrial proliferative effects compared with tamoxifen. In this review, we summarize the preclinical and clinical studies evaluating endoxifen in the context of breast and other solid tumors, the potential benefits of endoxifen in bone, as well as its emerging role as an antimanic agent in bipolar disorder. In total, the summarized body of literature provides compelling arguments for the ongoing development of Z-endoxifen as a novel drug for multiple indications.
Endoxifen, a New Treatment Option for Mania: A Double-Blind, Active-Controlled Trial Demonstrates the Antimanic Efficacy of Endoxifen. [2019]The protein kinase C (PKC) signaling system plays a role in mood disorders and PKC inhibitors such as endoxifen may be an innovative medicine for bipolar disorder (BP) patients. In this study we show for the first time the antimanic properties of endoxifen in patients with bipolar I disorder (BPD I) with current manic or mixed episode. In a double-blind, active-controlled study, 84 subjects with BPD I were randomly assigned to receive endoxifen (4 mg/day or 8 mg/day) or divalproex in a 2:1 ratio. Patients orally administered 4 mg/day or 8 mg/day endoxifen showed significant improvement in mania assessed by the Young Mania Rating Scale as early as 4 days. The effect remained significant throughout the 21-day period. At study end point, response rates were 44.44% and 64.29% at 4 mg/day and 8 mg/day of endoxifen treatment, respectively. Thus, endoxifen has been shown as a promising novel antimanic or mood stabilizing agent.
A pilot study of hormone modulation as a new treatment for mania in women with bipolar affective disorder. [2022]We tested and compared the use of two adjunctive hormonal agents, tamoxifen and medroxyprogesterone acetate (MPA), for the treatment of acute mania or hypomania. A total of 13 women with acute Bipolar Affective Disorder in the manic or hypomanic phase were recruited from a clinical population to participate in this 28-day, three-arm, double blind, placebo-controlled study. The women who received tamoxifen exhibited significant improvement in symptoms of mania from baseline to final assessment compared with the placebo group. The MPA group improved more than the placebo group. Further exploration of tamoxifen as a useful adjunct in the treatment of acute manic symptoms in women with Bipolar Affective Disorder is warranted.
Suicidality and Illness Course Worsening in a Male Patient with Bipolar Disorder during Tamoxifen Treatment for ER+/HER2+ Breast Cancer. [2022]Tamoxifen is a selective estrogenic receptor modulator (SERM) drug. In addition to its common use in breast cancer ER+, Tamoxifen has been object of growing interest in psychiatry as antimanic drug. At the same time, clinical concerns about Tamoxifen's depressogenic effect have been repeatedly raised even without reaching univocal conclusions. We discuss the case of a 45-year-old-male with a diagnosis of Bipolar Disorder type II, treated with Tamoxifen as relapse prevention treatment after surgery for a ER+/HER2+ breast cancer. The patient required two psychiatric admissions in a few-month time span since he showed a progressive worsening of both depressive and anxiety symptoms, with the onset of delusional ideas of hopelessness and failure up to suicidal thoughts. The clinical picture showed poor response to treatment trials based on various associations of mood-stabilising, antidepressants, and antipsychotic drugs. During the second hospitalization, after a multidisciplinary evaluation, the oncologists agreed on Tamoxifen discontinuation upon the severity of the psychiatric condition. The patient underwent a close oncological and psychiatric follow-up during the following 12 months.
Fast and Adequate Liquid Chromatography-Tandem Mass Spectrometric Determination of Z-endoxifen Serum Levels for Therapeutic Drug Monitoring. [2017]Z-endoxifen (further referred to as endoxifen, unless stated otherwise) is proposed as the most important metabolite of tamoxifen. Patients receiving adjuvant tamoxifen treatment with endoxifen levels below the threshold of 5.9 ng/mL may have an increased risk of breast cancer recurrence. Several factors, such as genetic polymorphisms, drug interactions, and (non)adherence, lead to large interpatient variability in endoxifen exposure, resulting in a substantial number of patients showing subtherapeutic levels. As genotyping and phenotyping are not able to adequately predict endoxifen exposure, therapeutic drug monitoring (TDM) seems to be the best approach for tailored tamoxifen therapy.
Endoxifen: A new, protein kinase C inhibitor to treat acute and mixed mania associated with bipolar I disorder. [2022]Endoxifen is a protein kinase C inhibitor. The objective of the present phase III study was to demonstrate the safety and efficacy of endoxifen in treating bipolar I disorder (BPD I) patients.
Tamoxifen for bipolar disorder: Systematic review and meta-analysis. [2020]Tamoxifen is an oral medication that has been proposed as a potential treatment for bipolar disorder. Tamoxifen acts to inhibit the intracellular action of protein kinase C, which is also an action of well-established treatments such as lithium and valproate. Here we aimed to identify randomised controlled trials (RCTs) of tamoxifen in the treatment of bipolar disorder and synthesise their results using meta-analysis.
Characterization of the isomeric configuration and impurities of (Z)-endoxifen by 2D NMR, high resolution LC⬜MS, and quantitative HPLC analysis. [2021](Z)-Endoxifen (4-hydroxy-N-desmethyltamoxifen), an active metabolite generated via actions of CYP3A4/5 and CYP2D6, is a more potent selective estrogen receptor modulator (SERM) than tamoxifen. In the MCF-7 human mammary tumor xenograft model with female athymic mice, (Z)-endoxifen, at an oral dose of 4⬜8 mg/kg, significantly inhibits tumor growth. (Z)-Endoxifen's potential as an alternative therapeutic agent independent of CYP2D6 activities, which can vary widely in ER+ breast cancer patients, is being actively evaluated. This paper describes confirmation of the configuration of the active (Z)-isomer through 2D NMR experiments, including NOE (ROESY) to establish spatial proton⬜proton correlations, and identification of the major impurity as the (E)-isomer in endoxifen drug substance by HPLC/HRMS (HPLC/MS-TOF). Stability of NMR solutions was confirmed by HPLC/UV analysis. For pre-clinical studies, a reverse-phase HPLC⬜UV method, with methanol/water mobile phases containing 10 mM ammonium formate at pH 4.3, was developed and validated for the accurate quantitation and impurity profiling of drug substance and drug product. Validation included demonstration of linearity, method precision, accuracy, and specificity in the presence of impurities, excipients (for the drug product), and degradation products. Ruggedness and reproducibility of the method were confirmed by collaborative studies between two independent laboratories. The method is being applied for quality control of the API and oral drug product. Kinetic parameters of Z- to E-isomerization were also delineated in drug substance and in aqueous formulation, showing conversion at temperatures above 25 °C.
Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen. [2019]Introduction: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30-100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride has been successfully evaluated. Areas covered: the principal pharmacogenetic and non-genetic differences in the pharmacology of tamoxifen and endoxifen are evaluated. To this end, references from PubMed, Embase or Web of Science, among others, were reviewed As non-genetic factors, important differences and similarities such age, or adherence to tamoxifen therapy are comprehensively illustrated. Additionally, since CYP2D6 genotypes are considered the main limitation of tamoxifen, many studies have investigated the association between the worsened clinical outcomes in patients with non-functional CYP2D6 genotypes. In this review, an overview of the research on this field is presented. Also, a summary describing the literature about individualizing tamoxifen therapy with endoxifen concentrations and its limitations is listed. Expert opinion: z-endoxifen hydrochloride is only investigated in the metastatic setting, still more research is required before its place in therapeutics is known. Similarly, monitoring tamoxifen efficacy based on endoxifen concentrations might not be overall recommended due to the limited evidence available.