Proellex (telapristone) / AbbVie - LARVOL DELTA

Selective progesterone receptor modulators for the treatment of dysmenorrhea: an update. (PubMed, Expert Opin Pharmacother) - "The present review examines the development of the clinical trials and observational studies done with the different SPRMs for the treatment of dysmenorrhea in patients with uterine diseases. Mifepristone, telapristone acetate and vilaprisan have antagonistic activity on PRs, while ulipristal acetate and asoprisnil have both potent antagonist and partial agonist effects.While no studies have been done on primary dysmenorrhea, the different SPRMs have been studied in the treatment of endometriosis, adenomyosis and uterine fibroid-related dysmenorrhea."

Journal • Review • Endometriosis • Gynecology • Pain • Solid Tumor • Uterine Leiomyoma • Women's Health

Development and Validation of the Diagnostic Model of 7 Gene in Endometriosis. (PubMed, Curr Med Chem) - "These results may facilitate the in-depth understanding of the development of endometriosis, and guide early diagnostic as well as clinical treatments for patients with endometriosis."

Journal • Endometriosis • Gynecology • Inflammation • Women's Health • CDH2 • CTSK • EPCAM • FN1 • NCAM1 • RUNX2

Baseline characteristics associated with Ki67 drop after neoadjuvant endocrine therapy in patients with HR+/HER2- early breast cancer: a systematic review (ESMO-BC 2023) - "Conversely, one study using telapristone acetate showed Ki67d only in premenopausal pts. Higher body mass index (BMI) was reported to be associated with Ki67d, in one of the studies together with metformin...Higher Ki67d was reported when pictilisib or enzalutamide were added to NET in luminal B or luminal A tumors, respectively...The effect of this mutation was reverted in these studies by the addition of targeted therapy to NET (pictilisib, everolimus, or lapatinib). Conclusions We summarize baseline characteristics associated with Ki67d after NET in pts with eBC. These characteristics are important to inform clinical trial design and pts selection in clinical practice."

Clinical • Review • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PGR • PIK3CA

Progesterone receptor (PR) antagonism by telapristone acetate (TPA): A randomized, placebo-controlled phase IIB pre-surgical window trial in women with stage 0-II breast cancer (SABCS 2018) - P2; "An anti-proliferative (Ki67) signal of TPA was observed in early stage breast cancer patients, but interpretation was limited by placebo group changes. The TPA group demonstrated differential suppression of proliferation-related genes among Ki67 responders, but the placebo group did not. Ongoing analysis will examine signatures related to stemness, metastasis, and immune suppression (potentially better endpoints in trials targeting P signaling)."

Clinical • P2b data • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

Local transdermal therapy (LTT): Drug permeation and distribution of telapristone acetate (TPA) in a pre-surgical window study of women undergoing mastectomy (SABCS 2018) - P2b; "The gel formulation of TPA did not permeate the skin well. However, the drug delivered to the breast was distributed throughout the breast, similar to the oral delivery route, with the highest concentration in the deep central location. These drug distribution data are novel; drug distribution at multiple locations throughout the breast has not previously been shown."

Clinical • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor

Transdermal or Oral Telapristone Acetate in Treating Patients Undergoing Mastectomy (clinicaltrials.gov) - P2 | N=67 | Completed | Sponsor: Northwestern University | Unknown status ➔ Completed

Trial completion • Breast Cancer • Oncology • Solid Tumor • BRCA • ER

The selective progesterone receptor modulator, telapristone acetate, is a mixed antagonist/agonist in the human and mouse endometrium and inhibits pregnancy in mice. (PubMed, F S Sci) - "CDB-4124 exerts mixed P4 antagonistic/agonistic effects in the human and mouse endometrium, which result in failed embryo implantation because of the absence of stromal decidualization."

Journal • Preclinical • Transplantation

Validating alternative splicing events between bulk and scRNA sequencing data: A bioinformatic approach (SABCS 2021) - "Methods : Bulk fastq’s were utilized to identify AS events in luminal progenitor (LP) and mouse mammary stem cell (MSC) lineages in ovariectomized FVB mice that had been randomized into three treatment groups (SHAM [C], estradiol + progesterone [EP], EP + the selective progesterone receptor inhibitor telapristone acetate, TPA [EPT])...We hypothesize that as scRNA-seq becomes more developed and quantification errors caused by short-read lengths fixed by full length scRNA seq methods currently in development, comparing data between single-cell and bulk may be made easier. However, we have shown that, when orthogonal methods for validation may not be feasible, events as specific as alternative splices can be validated using publicly available data and in-silico methods."

Breast Cancer • Oncology • BRD4 • CDH1 • KRT18 • KRT5

[VIRTUAL] Mipra, a window of opportunity study evaluating mifepristone treatment for postmenopausal breast cancer patients with higher levels of progesterone receptor isoform a than b (SABCS 2020) - P=N/A | "Mifepristone (MFP), as well as onapristone and telapristone acetate, showedpartial responses in breast cancer clinical trials. The median (range) Ki67 value of biopsies was 11.87% (2.70- 34.56) and for surgicalspecimens was 6.45% (0.48-23.77). A 45.67% of decrease in the median % Ki67 (41.63%comparing the arithmetic mean values and 50.83% comparing the geometric mean values) wasregistered in all surgical specimens compared to baseline (p= 0.003). Using the pre-specifiedresponse parameter (30% relative reduction in Ki67), we identified 15/20 (75%) responders."

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

Progesterone receptor antagonists reverse stem cell expansion and the paracrine effectors of progesterone action in the mouse mammary gland. (PubMed, Breast Cancer Res) - "PR inhibition reverses known tumorigenic pathways in the mammary gland and suppresses a previously unknown effect of progesterone on RNA splicing events. In total, our results strengthen the case for reconsideration of PR inhibitors for breast cancer prevention."

Journal • Preclinical • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • BRD4 • CDH1 • CDH3 • GLI3 • MMP7 • PGR • ZEB1

Selective progesterone receptor blockade prevents BRCA1-associated mouse mammary tumors through modulation of epithelial and stromal genes. (PubMed, Cancer Lett) - "We examined chemopreventive efficacy of telapristone acetate (TPA), ulipristal acetate (UPA) and mifepristone (MFP) in mice with a conditional knockout of the Brca1 C-terminal domain. The anti-glucocorticoid effects of MFP appeared not to be tumor-protective, while altering estrogen receptor signaling and NF-kB activation. Our study points to an important role of epithelial PR and its paracrine action on the microenvironment in BRCA1-deficient mammary tumorigenesis, and prevention."

Journal • Preclinical • Breast Cancer • Hormone Receptor Breast Cancer • Immunology • Inflammation • Oncology • Solid Tumor • BRCA1 • ER • PGR • PTGS2 • TGFB2

[VIRTUAL] Alternative splicing events from progesterone exposure differ based on BRCA1 mutation status (SABCS 2020) - "One group was treated was estradiol and progesterone (EP) while the other was treated with EP and the PR antagonist telapristone acetate (TPA) to identify PR-mediated effects...CD44 , associated with cellular proliferation and migration, NCOR2 associated with tamoxifen resistance, and AKR1C2 associated with progesterone metabolism all showed significant skipped exon (SE) events...We hypothesize that the skipping of Exon 4 of AKR1C2 in BRCA1 mut results in a structural alteration that decreases protein activity, leading to increased concentrations of P4 and 5α-pregnane-3,20-dione. This may explain the previously reported high median luteal phase serum P levels (p=0.00034) in BRCA1 mut /BRCA2 mut (PMID: 24140203)."

Breast Cancer • Hormone Receptor Breast Cancer • Oncology • BRCA1 • BRCA2 • CD44 • PGR

Mechanism of telapristone acetate (CDB4124) on progesterone receptor action in breast cancer cells (AACR 2018) - "This is the first study showing TRPS1 complexes with PR and regulates its activity. Ongoing studies are focused on the potential role of TRPS1 as a predictive biomarker of SPRM response in breast cancer."

IO Biomarker • Hormone Receptor Breast Cancer

Local transdermal delivery of telapristone acetate through breast skin, compared to oral treatment: a randomized double-blind, placebo-controlled Phase II trial. (PubMed, Clin Pharmacol Ther) - "Despite poor dermal permeation, within-breast drug distribution pattern was identical in both groups (R =0.88, p=0.006), demonstrating that transdermally and orally delivered drug is distributed similarly through the breast, and is strongly influenced by tissue adiposity (p<0.0001). Other skin-penetrant drugs should be tested for breast cancer prevention."

Clinical • Journal • P2 data • Breast Cancer • Hormone Receptor Breast Cancer • Obesity • Oncology • Oral Cancer • Solid Tumor

Selective progesterone receptor modulators in early stage breast cancer: a randomized, placebo-controlled Phase II window of opportunity trial using telapristone acetate. (PubMed, Clin Cancer Res) - "TPA-treated patients whose Ki67 decreased by ≥30% demonstrated a selective anti-proliferative signal, with a potentially important effect on HER2 amplicon genes. Evaluation of SPRMs in a neoadjuvant trial is merited, with attention to predictors of response to SPRM therapy, and inclusion of pre and postmenopausal women."

Clinical • Journal • P2 data • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

Jefferies Global Healthcare Conference (Repros) - Anticipated FDA review for endometriosis pain in Q3 2012

Anticipated FDA event • Endometriosis

"$RPRX Announces Proellex Development Program Will Remain on Partial Clinical Hold by the FDA https://t.co/JcM0ID1KIe" (@BioStocks)

Biosimilar

Oral CDB-4124 vs. Placebo in Stage I-II Primary Breast Cancer (clinicaltrials.gov) - P2b; N=50; Active, not recruiting; Sponsor: Northwestern University; Trial primary completion date: Feb 2018 ➔ Feb 2019

Trial primary completion date • Biosimilar • Breast Cancer • Oncology • Solid Tumor

The evaluation of safety and efficacy of Proellex in the treatment of pre-menopausal women with confirmed, symptomatic endometriosis (clinicaltrials.gov) - P2, N=90; Sponsor: Repros Therapeutics; Recruiting; Primary Completion Date: Dec 2013 -> Dec 2014.

Trial primary completion • Endometriosis

A Multi-Center, Parallel Design, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of 6 and 12 mg Proellex® (Telapristone Acetate) Administered Orally in the Treatment of Premenopausal Women With Confirmed Symptomatic Uterine Fibroids (clinicaltrials.gov) - P2; N=43; Completed; Sponsor: Repros Therapeutics Inc.; Active, not recruiting ➔ Completed; Trial primary completion date: Dec 2016 ➔ Jun 2017

Trial completion • Trial primary completion date • Biosimilar • Oncology • Solid Tumor • Uterine Leiomyoma • Women's Health

The evaluation of safety and efficacy of proellex in the treatment of pre-menopausal women with confirmed, symptomatic endometriosis (clinicaltrials.gov) - P2, N=90; Recruiting; Completion Date: Sep 2013 -> Dec 2013.

Trial completion date • Endometriosis

BRCA1 mutation influences progesterone response in human benign mammary organoids. (PubMed, Breast Cancer Res) - "These data show that BRCA1 mutation influences hormone response and in particular PR activity which differs from that of non-carrier organoids. Our organoid model system revealed important insights into the role of PR in BRCA1-mutated benign breast cells and the critical paracrine actions that modify hormone receptor (HR)-negative cells. Further analysis of the molecular mechanism of BRCA1 and PR crosstalk is warranted using this model system."

Journal

Repros updates Proellex program (Repros Press Release) - "Repros Therapeutics...today announced that it believes that topline results from all three of its ongoing Proellex® studies can be reported by the end of third quarter of 2016. Based on results from an interim analysis of the data, women treated with placebo exhibited pain scores at the end of treatment that were 83% of baseline but showed no reduction in analgesic usage (100% of baseline). Based on this assessment the Company has decided to end enrollment of the endometriosis study, as it believes the study will provide sufficient data to design a Phase 3 study based on the 40-45 subjects expected to be randomized. The Company plans to request meetings with the FDA at the appropriate time to determine the Phase 3 programs that will be required for NDAs for these two indications."

Anticipated enrollment status • Anticipated P2 data • P2 data • Endometriosis • Uterine Leiomyoma

FDA provides recommendations for phase 2 protocol for low dose oral Proellex in the treatment of endometriosis (Repros) - FDA has provided the guidance for a phase 2 study of low dose oral Proellex in the treatment of endometriosis; Repros could commence the P2 (N=90) trial in the Q4 2012

Anticipated new P2 trial • Anticipated target enrollment • FDA event • Endometriosis

Repros reports positive clinical data for oral Proellex in women with severe menstrual bleeding due to uterine fibroids (Repros Press Release) - P2b, N=43; NCT02301897; Sponsor: Repros Therapeutics; "Repros Therapeutics...today reported that oral administration of Proellex® at doses of both 6 and 12 mg achieved significant reduction in excessive menstrual bleeding, the key symptom of uterine fibroids.... In this Phase 2b study, 12, 17 and 14 women with confirmed uterine fibroids were enrolled in the 6mg, 12mg and Placebo arms, respectively. One subject dosed at 6mg and one Placebo-treated subject were discontinued as they did not meet entry criteria, and thus were not eligible for efficacy analysis. At baseline, the mean amount of blood lost for one menstrual cycle was 177 mL, 251 mL and 260 mL for each arm, respectively....The results of the second course of treatment should be reported within the next 5 months."

Anticipated P2b data • P2b data • Uterine Leiomyoma