An Analytical Report on the Investigational Drug: Telapristone Acetate (DB05253)

Executive Summary

Telapristone acetate, also known by its developmental code name CDB-4124 and proposed brand names Proellex and Progenta, is a synthetic, steroidal small molecule classified as a Selective Progesterone Receptor Modulator (SPRM).[1] Originally developed by the National Institutes of Health (NIH) and later advanced by Repros Therapeutics, it was investigated for the treatment of hormone-dependent gynecological conditions, primarily uterine fibroids and endometriosis, with additional exploration into its potential as an antineoplastic agent in early-stage breast cancer.[1]

The drug demonstrated significant clinical promise, driven by a potent antiprogestogenic mechanism of action. Unlike simple receptor antagonists, Telapristone acetate was found to function through a novel molecular pathway, globally reducing the binding of the progesterone receptor (PR) to chromatin and uniquely recruiting the transcriptional corepressor TRPS1 to mediate gene silencing.[4] This potent activity translated into compelling efficacy in clinical trials, particularly for uterine fibroids, where it produced substantial reductions in tumor volume, controlled heavy menstrual bleeding, and improved patient quality of life.[6]

However, the promising therapeutic profile of Telapristone acetate was ultimately overshadowed by a critical and insurmountable safety flaw: dose-dependent hepatotoxicity. During late-stage clinical development, serious adverse events involving elevated liver enzymes were observed, including cases that met the criteria for Hy's Law, a strong predictor of a drug's potential to cause fatal liver injury.[8] This safety signal led the U.S. Food and Drug Administration (FDA) to impose a full clinical hold on the oral formulation in August 2009, an order that was later downgraded to a partial hold but never fully lifted.[8]

Despite attempts by Repros Therapeutics to mitigate this risk through a "low-dose" strategy and the development of a novel vaginally administered formulation designed to reduce systemic exposure, the company was unable to satisfy the FDA's stringent safety requirements.[8] The regulatory impasse, compounded by the significant financial and logistical burden of generating the large safety database required to definitively rule out the risk of rare but severe liver injury, led to the eventual discontinuation of the entire development program.[10] Telapristone acetate thus stands as a significant case study in pharmaceutical development, illustrating the critical tension between compelling efficacy and an unacceptable safety profile. Its journey provides valuable insights into the molecular pharmacology of SPRMs, the challenges of dose-finding for potent hormonal agents, and the primacy of safety in the regulatory evaluation of therapies for non-life-threatening conditions.

Pharmacological and Chemical Profile

Classification and Structure

Telapristone acetate is a synthetic, steroidal compound classified as a small molecule drug.[10] Its primary pharmacological classification is as a Selective Progesterone Receptor Modulator (SPRM), a class of agents designed to interact with the progesterone receptor (PR) and exert tissue-specific agonist, antagonist, or mixed agonist/antagonist effects.[1] It is structurally related to mifepristone, the prototypical SPRM, and was developed as a "next-generation" agent with the goal of improving selectivity for the PR while minimizing activity at other steroid receptors, such as the glucocorticoid receptor (GR).[1]

The chemical structure of Telapristone acetate is complex, featuring the characteristic multi-ring steroidal backbone of its class. Its formal International Union of Pure and Applied Chemistry (IUPAC) name is-17-(2-methoxyacetyl)-13-methyl-3-oxo-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-17-yl] acetate.[1] This structure is responsible for its specific binding affinity and modulatory action at the progesterone receptor.[15]

Physicochemical Properties and Identifiers

The molecular formula for Telapristone acetate is C31​H39​NO5​.[1] It has an average molecular weight of 505.655 g·mol⁻¹ and a monoisotopic mass of 505.282823 g/mol.[1]

Throughout its development, the compound has been referred to by several names and codes, a common practice that reflects its progression from a laboratory compound to a clinical candidate. These include the primary research code designation CDB-4124, which is frequently used in preclinical and clinical study literature, as well as the proposed commercial brand names Proellex and Progenta.[1] Other less common identifiers include HRP 2000 and RU 44675.[3] The formal generic name, Telapristone acetate, is its United States Adopted Name (USAN).[15] This multiplicity of identifiers maps the drug's history, originating as a compound from the National Institutes of Health (CDB-4124) before being licensed to Repros Therapeutics, which pursued its clinical development and planned for commercialization (Proellex) prior to the program's termination.[1]

For precise identification and cross-referencing across scientific and regulatory databases, a comprehensive set of identifiers has been established for Telapristone acetate, as summarized in Table 1.

Table 1: Chemical and Physical Identifiers for Telapristone Acetate

Identifier Type	Value	Source(s)
DrugBank ID	DB05253	1
CAS Number	198414-31-2	1
UNII	1K9EYK92PQ	1
PubChem CID	9806190	1
ChEMBL ID	CHEMBL2105694	1
IUPAC Name	-17-(2-methoxyacetyl)-13-methyl-3-oxo-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-17-yl] acetate	1
InChIKey	JVBGZFRPTRKSBB-MJBQOYBXSA-N	1
SMILES	CC(=O)O[C@@]1(CC[C@@H]2[C@@]1(CC@@HC5=CC=C(C=C5)N(C)C)C)C(=O)COC
CompTox Dashboard	DTXSID60173587
NCI Thesaurus Code	C104055

Molecular Mechanism of Action

Core Function as a Selective Progesterone Receptor Modulator (SPRM)

The primary pharmacological activity of Telapristone acetate stems from its function as a Selective Progesterone Receptor Modulator (SPRM). It exerts its effects by competitively binding to the progesterone receptor (PR), the specific nuclear receptor that mediates the biological actions of the steroid hormone progesterone. As an SPRM, its activity is nuanced; these molecules are designed to exhibit a mixed profile of agonist (pro-progestational) and antagonist (anti-progestational) effects that can vary depending on the specific target tissue.

In the context of its intended therapeutic applications—such as the endometrium in uterine fibroids and endometriosis, and breast tissue in breast cancer—Telapristone acetate demonstrates potent antiprogestin activity. This antagonist profile is central to its therapeutic rationale. A key design objective for next-generation SPRMs like Telapristone acetate was to enhance selectivity for the PR, thereby minimizing the off-target effects that limited earlier compounds. A primary concern was the cross-reactivity with the glucocorticoid receptor (GR), which contributed to the side-effect profile of mifepristone. While Telapristone acetate largely achieved this goal of enhanced selectivity, it does retain some minor antiglucocorticoid activity.

Novel Transcriptional Regulation via Corepressor Recruitment

The antagonist action of Telapristone acetate extends beyond simple competitive blockade of the progesterone receptor. Its mechanism involves a sophisticated modulation of the receptor's function at the level of gene transcription, fundamentally altering how the PR interacts with DNA and its associated regulatory proteins.

Seminal research utilizing the T47D breast cancer cell line elucidated this unique mechanism. When the PR is activated by a progestin agonist (e.g., R5020), it is robustly recruited to its specific binding sites on chromatin, known as progesterone response elements (PREs), where it initiates gene transcription. In contrast, treatment with Telapristone acetate leads to a

global reduction in the recruitment of the PR to these chromatin binding sites.

Most critically, the binding of Telapristone acetate induces a conformational change in the PR that alters its surface topology, causing it to preferentially interact with a different set of transcriptional coregulator proteins than it would when bound to an agonist. Specifically, Telapristone acetate binding promotes the recruitment of the transcriptional corepressor

TRPS1 to the PR complex. This recruitment is a pivotal step in its antagonist function. Experimental validation through the silencing of TRPS1 using small interfering RNA (siRNA) demonstrated that the absence of this corepressor significantly attenuated the inhibitory effects of Telapristone acetate on both gene expression and cell proliferation. This confirmed that TRPS1 is not a passive bystander but an active and essential mediator of Telapristone acetate's antiprogestogenic action.

This mechanism, reliant on the active recruitment of a corepressor, represents a significant advance in the understanding of SPRM pharmacology. It also presents a plausible pathway for the development of therapeutic resistance. If cancer cells under selective pressure from Telapristone acetate were to downregulate the expression of TRPS1 or acquire mutations in the PR that disrupt its interaction with TRPS1, they could potentially evade the drug's antiproliferative effects. Such a mechanism would leave the PR bound by the drug but would sever the downstream signaling required for transcriptional repression, highlighting a testable hypothesis for future investigations into SPRM resistance.

Antineoplastic Activities and Cellular Effects

The molecular actions of Telapristone acetate translate into distinct and therapeutically relevant cellular effects. By interfering with progesterone signaling in the reproductive system, it can effectively suppress ovulation and inhibit the hormone-driven proliferation of endometrial tissue. This forms the biological basis for its investigation as a treatment for endometriosis and for controlling the heavy menstrual bleeding associated with uterine fibroids.

In the context of oncology, particularly in estrogen receptor (ER) and progesterone receptor (PR) positive breast cancer cells, Telapristone acetate exhibits direct antineoplastic properties. Its mechanism in these cells is multifaceted, leading to cell cycle arrest at the G1/S transition and the induction of apoptosis (programmed cell death). This is accomplished through several coordinated actions: a reduction in progesterone levels, the downregulation of ER expression, and the suppression of key cell cycle regulators, specifically cyclin-dependent kinases 2 and 4 (CDK2 and CDK4).

A significant advantage of Telapristone acetate, contributing to its favorable specificity, is its lack of discernible estrogenic, androgenic, anti-estrogenic, or anti-androgenic activities. This "clean" hormonal profile ensures that its effects are narrowly targeted to the progesterone receptor pathway, avoiding the complex and often undesirable systemic effects associated with less selective hormonal agents.

Pharmacokinetics, Metabolism, and Potential Drug Interactions

Absorption, Distribution, Metabolism, and Excretion (ADME) Profile

The pharmacokinetic profile of Telapristone acetate has been characterized through clinical studies, revealing its behavior within the human body following administration.

Absorption: Telapristone acetate is formulated for oral availability and is rapidly absorbed from the gastrointestinal tract. Following oral administration, it reaches peak plasma concentrations (Tmax​) within a short window of 0.5 to 2 hours. The absorption process is characterized by a first-order absorption rate constant (

Ka​) of 1.26 h−1.

Distribution: The drug demonstrates extensive distribution into tissues throughout the body, which is reflected in its large apparent volume of distribution. Pharmacokinetic modeling estimates the volume of the central compartment (V2​/F) to be 37.4 L and the volume of the peripheral compartment (V4​/F) to be 120 L. This wide distribution is consistent with a lipophilic, steroidal molecule capable of penetrating cellular membranes.

Metabolism: Telapristone acetate undergoes primary metabolism in the liver. The principal metabolic pathways are N-demethylation of the dimethylamino group and hydroxylation of the steroid core. These biotransformation reactions are predominantly catalyzed by the cytochrome P450 isoenzymes

CYP3A4 and CYP3A5. This hepatic metabolism results in the formation of several metabolites, including an active monodemethylated metabolite (CDB-4453), a didemethylated metabolite, and a hydroxylated metabolite.

Excretion: The available documentation does not provide explicit details on the final routes of excretion (e.g., the specific percentages eliminated via feces versus urine) for Telapristone acetate and its metabolites. However, based on the profiles of other structurally similar SPRMs like mifepristone and ulipristal acetate, which are predominantly eliminated through the biliary-fecal route, it is reasonable to presume that Telapristone acetate follows a similar pattern. This remains an extrapolation, as direct evidence is not present in the provided sources.

Active Metabolite: CDB-4453

A key aspect of Telapristone acetate's metabolism is the formation of the pharmacologically active monodemethylated metabolite, CDB-4453.

In vitro studies have shown that CDB-4453 is equipotent to the parent drug, Telapristone acetate, in its antiprogestogenic activity. Importantly, this metabolite exhibits less antiglucocorticoid activity than the parent compound. The formation of this active metabolite likely contributes significantly to the overall

in vivo therapeutic efficacy and may enhance the drug's selectivity profile by maintaining potent anti-progesterone effects while further reducing off-target glucocorticoid receptor activity.

Polymorphic Clearance and Clinical Implications

Population pharmacokinetic modeling of Telapristone acetate revealed a critical finding with profound clinical implications: the drug's clearance from the body is not uniform across the patient population. The data were best described by a mixture model that identified two distinct subpopulations with significantly different clearance rates.

• Low-Clearance Population: Comprising approximately 75% of subjects, this group exhibited an apparent oral clearance (CL/F) of 3.34 L/h.
• High-Clearance Population: Comprising the remaining 25% of subjects, this group exhibited a much faster apparent oral clearance (CL/F) of 11.6 L/h, more than three times that of the low-clearance group.

This observed polymorphism in drug metabolism is hypothesized to be a direct consequence of genetic variations in the CYP3A5 enzyme. CYP3A5 is known to have common genetic variants (polymorphisms) that result in some individuals expressing a highly active form of the enzyme while others express a non-functional version. This genetic variability provides a compelling explanation for the bimodal distribution of clearance rates observed in the clinical trial population.

This pharmacogenetic difference has critical implications for the drug's safety profile. The dose-dependent hepatotoxicity that ultimately led to the termination of the development program may be mechanistically linked to this polymorphic clearance. A standard fixed dose of Telapristone acetate administered to an individual in the "low-clearance" group (i.e., a CYP3A5 poor metabolizer) would result in significantly higher and more sustained plasma concentrations of the drug and its metabolites compared to the same dose in a "high-clearance" individual. This elevated drug exposure could surpass a critical toxicity threshold in the liver, leading to the type of severe, idiosyncratic adverse events observed in the trials. This hypothesis aligns with the developer's own assessment that the liver toxicity likely resulted from the formation of reactive "adducts favored at high concentrations" of the drug. Therefore, the observed "dose-dependent" toxicity may be more accurately described as an "exposure-dependent" toxicity, unmasked in a genetically susceptible sub-population of poor metabolizers. This suggests that a prospective pharmacogenetic screening strategy for CYP3A5 status could have potentially been a viable approach to de-risk the drug's development by allowing for dose adjustments or patient exclusion, a path that was either not pursued or deemed unfeasible at the time.

Table 2: Summary of Population Pharmacokinetic Parameters for Telapristone Acetate

Parameter	Value	Source(s)
Absorption Rate Constant (Ka​)	1.26 h−1
Oral Clearance (CL/F) - Low-Clearance Population	3.34 L/h
Oral Clearance (CL/F) - High-Clearance Population	11.6 L/h
Apparent Central Volume of Distribution (V2​/F)	37.4 L
Apparent Peripheral Volume of Distribution (V4​/F)	120 L
Apparent Inter-compartmental Clearance (Q/F)	21.9 L/h
Apparent Metabolite Clearance (CLM​/F)	2.43 L/h

Predicted Drug-Drug Interactions

As Telapristone acetate is a substrate for both CYP3A4 and CYP3A5, two of the most important enzymes in drug metabolism, the potential for clinically significant drug-drug interactions is high. While no specific interaction studies are documented in the provided materials, predictions can be made based on its established metabolic pathway.

CYP3A4/5 Inhibitors: Co-administration of Telapristone acetate with potent inhibitors of CYP3A4 would be expected to decrease its metabolism, leading to increased plasma concentrations and overall drug exposure (AUC). This would significantly elevate the risk of concentration-dependent toxicities, most notably hepatotoxicity. Examples of such inhibitors include azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin), and certain protease inhibitors (ritonavir).

CYP3A4/5 Inducers: Conversely, co-administration with potent inducers of CYP3A4 would be expected to accelerate the metabolism of Telapristone acetate, leading to lower plasma concentrations and reduced drug exposure. This could result in a partial or complete loss of therapeutic efficacy. Examples of potent inducers include certain anticonvulsants (carbamazepine, phenytoin), rifamycins (rifampin), and the herbal supplement St. John's Wort.

Given the narrow therapeutic window suggested by the hepatotoxicity findings, any co-medication that significantly alters the drug's pharmacokinetics would pose a substantial clinical risk. A summary of these predicted interactions is provided in Table 3.

Table 3: Potential Clinically Significant Drug-Drug Interactions with Telapristone Acetate

Interacting Drug Class	Example Drugs	Predicted Effect on Telapristone	Clinical Recommendation	Rationale Source(s)
Potent CYP3A4/5 Inhibitors	Ketoconazole, Itraconazole, Ritonavir, Clarithromycin	Increased plasma concentration and AUC	Avoid co-administration due to significantly increased risk of hepatotoxicity.
Potent CYP3A4/5 Inducers	Rifampin, Carbamazepine, Phenytoin, St. John's Wort	Decreased plasma concentration and AUC	Avoid co-administration due to potential loss of therapeutic efficacy.
Moderate CYP3A4/5 Inhibitors/Inducers	Diltiazem, Verapamil, Efavirenz	Moderate increase/decrease in plasma concentration	Use with caution and monitor for signs of toxicity or lack of effect.

Clinical Development Program: Efficacy Across Indications

The clinical development program for Telapristone acetate was ambitious, exploring its therapeutic potential across several hormone-sensitive conditions. The most advanced investigations were in uterine fibroids, followed by endometriosis and early-stage breast cancer.

Indication: Uterine Fibroids (Leiomyomas)

Uterine fibroids represented the lead indication for Telapristone acetate, with the development program reaching at least Phase 3 before its ultimate discontinuation. The drug demonstrated robust and consistent efficacy in treating the primary symptoms and underlying pathology of this condition.

Clinical Efficacy: Multiple clinical trials confirmed that Telapristone acetate effectively alleviated the key symptoms associated with uterine fibroids. Patients treated with the drug experienced statistically significant reductions in heavy menstrual bleeding, as measured objectively using the Pictorial Blood Loss Assessment Chart (PBAC), and a corresponding decrease in pelvic pain. These symptomatic improvements translated into meaningful gains in patient-reported quality of life, assessed using the validated Uterine Fibroid Symptom Quality of Life (UFSQOL) questionnaire.

Fibroid Volume Reduction: Beyond symptom control, Telapristone acetate induced a marked reduction in the size of the fibroids themselves. Studies of the oral formulation showed a clear dose-response relationship; a 25 mg daily dose resulted in a mean fibroid volume reduction of nearly 50%, while a 50 mg daily dose achieved a reduction of approximately 75% from baseline. A separate study investigating vaginal administration found that a 12 mg daily dose led to a 28% reduction in fibroid volume. Another report noted an overall tumor size reduction of about 20%.

Induction of Amenorrhea: A primary therapeutic goal in the management of symptomatic fibroids is the cessation of menstruation (amenorrhea) to control bleeding. Telapristone acetate was highly effective in this regard. In a study of the vaginal formulation, 58% of women receiving the 12 mg dose achieved amenorrhea, compared to only 18% in the lower-dose groups.

Development of an Alternative Delivery Route: In direct response to the emerging safety concerns of systemic hepatotoxicity with the oral formulation, Repros Therapeutics made a strategic pivot to develop a vaginal suppository formulation, named Proellex-V. The scientific rationale for this approach was to achieve high, therapeutic concentrations of the drug locally in the target uterine tissues while minimizing systemic absorption and circulating blood levels. This was intended to preserve efficacy while significantly reducing the risk of liver injury. Preclinical animal models supported this strategy, suggesting that vaginal delivery could produce more potent anti-proliferative effects in the uterus with substantially lower systemic exposure compared to an equivalent oral dose.

Indication: Endometriosis

Telapristone acetate was also investigated as a treatment for endometriosis, a condition characterized by the growth of endometrial-like tissue outside the uterus, causing chronic pain and infertility. The development program for this indication reached Phase 2.

A key clinical trial, NCT01728454, was a Phase 2 study designed to evaluate the safety and efficacy of oral Telapristone acetate in pre-menopausal women with confirmed, symptomatic endometriosis. This trial is officially listed as "Completed." However, a notable aspect of the available documentation is the absence of any detailed, published results or conclusions from this study. While its completion is noted, the lack of disseminated data is conspicuous. This could suggest several possibilities: the results may have been inconclusive or failed to demonstrate a compelling therapeutic benefit, or the findings were simply overshadowed by the escalating safety concerns and the company's strategic decision to focus resources on the uterine fibroid program before the data could be formally published.

Indication: Early-Stage Breast Cancer

Leveraging its potent antiprogestogenic and antineoplastic mechanism of action, Telapristone acetate was explored as a potential agent for the prevention and treatment of PR-positive breast cancer.

The primary investigation was a randomized, double-blind, placebo-controlled Phase 2 "window-of-opportunity" trial (identified by identifiers NCT01800422 and NCT02314156). In this study design, patients with newly diagnosed, early-stage, operable breast cancer were treated with either Telapristone acetate (12 mg daily) or a placebo for a short period (2 to 10 weeks) between their initial diagnosis and scheduled surgery. This allows for the direct assessment of the drug's biological effects on tumor tissue.

Antiproliferative Efficacy: The primary endpoint of the trial was the change in the cellular proliferation marker Ki67, a standard measure of tumor cell growth. The results showed that treatment with Telapristone acetate led to a statistically significant mean decline in Ki67 of 5.5% (p=0.003), indicating a clear antiproliferative effect on the tumors. This effect was particularly significant in the subgroup of premenopausal women.

Novel Gene Expression Findings: Analysis of gene expression in the tumor tissues pre- and post-treatment yielded a particularly intriguing finding. In the subset of tumors that showed a strong biological response to the drug (defined as a ≥30% reduction in Ki67), gene set enrichment analysis revealed a significant downregulation of genes involved in cell-cycle progression. More unexpectedly, it also showed downregulation of genes located within the HER2 amplicon. This suggests a potential molecular crosstalk between the progesterone receptor pathway modulated by Telapristone acetate and the HER2 signaling pathway, a key driver in a subset of breast cancers. This finding points to a novel area of biological activity that could merit further investigation in the context of PR and HER2 co-expressing tumors.

A comprehensive summary of the key clinical trials conducted during the Telapristone acetate development program is provided in Table 4.

Table 4: Comprehensive Summary of Telapristone Acetate Clinical Trials

Indication	Trial Identifier	Phase	Title/Objective	Status	Key Finding/Comment	Source(s)
Uterine Fibroids	NCT02301897	2	Safety and Efficacy of 6 and 12 mg Oral Proellex® for Symptomatic Uterine Fibroids	Completed	Evaluated lower oral doses to find a safer therapeutic window.
Uterine Fibroids	NCT01739621	2	Safety, PK, and Efficacy of Vaginal Proellex® in Women Who Completed ZPV-200	Completed	Extension study for vaginal delivery, assessing long-term safety and efficacy.
Uterine Fibroids	NCT02323646	2	Safety and Efficacy of Vaginal Proellex® for Treatment of Uterine Fibroids	Completed	Part of the strategic pivot to a non-systemic delivery route.
Uterine Fibroids	NCT00735553	3	Evaluating Safety and Efficacy of Proellex® (25mg and 50mg)	Terminated	Terminated by sponsor for safety; subsequently placed on clinical hold by FDA.
Uterine Fibroids	NCT00874302	3	Safety and Efficacy of 25mg and 50mg Doses of Proellex®	Withdrawn	Study withdrawn prior to enrollment due to safety concerns and FDA clinical hold.
Uterine Fibroids	NCT02811159	2	Open-Label Extension Study of 12 mg Oral Proellex®	Terminated	Extension study for low-dose oral formulation, terminated due to ongoing clinical hold.
Endometriosis	NCT01728454	2	Safety and Efficacy of Telapristone Acetate (Proellex®) in Symptomatic Endometriosis	Completed	Key Phase 2 trial for this indication; detailed results are not publicly available.
Early-Stage Breast Cancer	NCT01800422 / NCT02314156	2	Oral CDB-4124 vs. Placebo in Stage I-II Primary Breast Cancer	Completed	Window-of-opportunity trial demonstrating significant reduction in Ki67 proliferation marker.

Safety and Tolerability Profile

The safety and tolerability profile of Telapristone acetate was the ultimate determinant of its developmental fate. While it exhibited some predictable class-related effects, a severe and dose-dependent organ toxicity emerged as the program-ending issue.

Hepatotoxicity: The Program-Ending Adverse Event

The most significant and clinically consequential safety finding for Telapristone acetate was dose-dependent liver toxicity (hepatotoxicity). This adverse event proved to be the insurmountable barrier that halted its development.

In August 2009, emerging data from ongoing clinical trials revealed "findings of serious adverse events associated with liver toxicity," prompting the sponsor, Repros Therapeutics, to suspend the studies. This was immediately followed by the FDA's imposition of a full clinical hold on the program. The liver injuries observed were not minor; they included significant elevations in liver enzymes (transaminases). Critically, at least two cases met the laboratory criteria for "Hy's Law," which is defined as drug-induced hepatocellular injury (elevated ALT or AST) coupled with jaundice (elevated bilirubin) in the absence of biliary obstruction. Hy's Law is a strong predictive marker for a drug's potential to cause severe or fatal drug-induced liver injury, making it a red flag of the highest order in drug development.

The hepatotoxicity demonstrated a clear relationship with the administered dose. The most severe events, including the Hy's Law cases, were observed in patients receiving the 50 mg daily dose. In contrast, lower doses of 12.5 mg and 25 mg were associated with a substantially lower incidence of liver-related adverse events. This dose-dependency formed the basis of the company's subsequent strategy to try and salvage the program by focusing on a "low dose" oral regimen and the alternative vaginal delivery route. The company's internal hypothesis for the mechanism of toxicity was the formation of reactive metabolite "adducts" that were favored at the high drug concentrations achieved with the 50 mg dose.

The experience with Telapristone acetate can be viewed in a broader context. The later emergence of rare but severe cases of liver injury associated with another SPRM, ulipristal acetate, which led to a formal review by the European Medicines Agency (EMA) and restrictions on its use, suggests that hepatotoxicity may be a potential class-wide safety concern for SPRMs. The EMA's review explicitly referenced the effects seen with high-dose Telapristone as part of its rationale for investigating a potential class effect. In this light, the failure of Telapristone was not merely an isolated incident of idiosyncratic toxicity but rather a critical early warning signal for the entire therapeutic class, highlighting a potential risk that must be carefully monitored for all current and future SPRMs.

SPRM Class Effects and Other Adverse Events

As a member of the SPRM class, Telapristone acetate was associated with predictable effects on the endometrium. The most notable of these is a phenomenon known as Progesterone Receptor Modulator-Associated Endometrial Changes (PAECs). These are benign, non-hyperplastic, and non-cancerous histological changes that occur in the endometrium as a result of the potent, unopposed antiprogestogenic effect on the tissue. While these changes can appear unusual on biopsy, they are considered a benign and reversible consequence of the drug's mechanism of action.

Other, more general side effects have been reported in overviews of the drug, though detailed incidence data from the specific trials are not available in the provided sources. These common adverse events include nausea, headache, abdominal pain, and menstrual irregularities such as spotting or amenorrhea, which are consistent with the effects of potent hormonal modulation.

Regulatory History and Discontinuation

The regulatory history of Telapristone acetate is defined by its interaction with the U.S. Food and Drug Administration (FDA) concerning the critical issue of hepatotoxicity. The agency's actions and the resulting regulatory impasse were the direct cause of the drug's discontinuation.

The FDA Clinical Hold

A clinical hold is an order issued by the FDA to a sponsor to delay or suspend a clinical investigation, and it represents one of the most serious regulatory actions during drug development. The timeline of the clinical hold on Telapristone acetate was as follows:

• August 3, 2009: In response to emerging data on liver toxicity, Repros Therapeutics made the proactive decision to unilaterally suspend its ongoing clinical studies of Proellex®.
• August 4, 2009: The FDA formalized this suspension by placing the entire Proellex® Investigational New Drug (IND) application on full clinical hold. This order was based on the reports of serious adverse events related to hepatotoxicity. A full clinical hold is the most restrictive type, prohibiting the enrollment of new subjects and requiring that all current subjects be taken off the investigational drug.
• Circa Mid-2010: After reviewing follow-up safety data showing that the liver enzyme elevations in affected patients had resolved, the FDA downgraded the status from a full hold to a partial clinical hold. This less restrictive status allowed the company to conduct a limited clinical study, specifically a low-dose escalating trial (ZP-203), to investigate whether a safe therapeutic window could be established.
• Ongoing Partial Hold (2010-2017): Despite the successful completion of the low-dose study, which did not reveal new liver toxicity signals, the FDA declined to lift the partial clinical hold on the oral formulation. The agency's position was that, given the severity of the initial safety signal, a very "large safety database" would be required to adequately characterize the risk and rule out the possibility of rare but severe liver injury before further broad-scale development could proceed.

Developmental Pivot and Eventual Discontinuation

The FDA's persistent partial clinical hold on the oral formulation created a significant and ultimately insurmountable obstacle for Repros Therapeutics. The requirement for a large safety database represented a massive investment of time and capital with an uncertain outcome. This regulatory challenge was not merely a scientific hurdle but also a strategic and economic one. For a smaller pharmaceutical company, the cost of conducting clinical trials on the scale necessary to satisfy the FDA's safety requirements for a drug with a known, serious liability can be prohibitive. The tolerance for risk is low for therapies intended for non-life-threatening conditions like uterine fibroids, making the bar for demonstrating safety exceptionally high.

In response to this regulatory impasse, Repros executed a strategic pivot, shifting its primary development focus to the vaginally administered formulation, Proellex-V. This formulation had a separate IND application that was not under clinical hold, providing a potential path forward. The scientific rationale was sound—local delivery could potentially uncouple uterine efficacy from systemic toxicity.

Despite continued clinical work with both low-dose oral and vaginal formulations for several more years, with patents being issued as late as 2017 , the company was ultimately unable to resolve the regulatory overhang from the oral drug's toxicity. The program was eventually halted entirely. Current pharmaceutical databases now list the development status of Telapristone acetate as "Discontinued," and the records for several of its key clinical trials are marked as "Terminated" or "Withdrawn," with the explicit reason cited as "Repros stopped the study for safety and FDA put the study on hold for safety". The drug's failure was thus a result of a regulatory and economic reality where the cost and risk of proving safety became greater than the potential commercial reward.

Expert Analysis and Concluding Remarks

Synthesis of Telapristone Acetate's Profile

Telapristone acetate represents a compelling yet cautionary chapter in the development of hormonal therapies. The comprehensive analysis of its profile reveals a molecule of high potency and mechanistic novelty that demonstrated unequivocal clinical efficacy for common and debilitating gynecological conditions. Its ability to significantly reduce uterine fibroid volume and alleviate associated bleeding and pain positioned it as a potentially transformative non-surgical treatment option for millions of women. Furthermore, its unique mechanism of action, involving the recruitment of the corepressor TRPS1, provided a deeper understanding of progesterone receptor pharmacology and opened new avenues for research.

The Promise and Peril of Potency

The central theme in the story of Telapristone acetate is the double-edged sword of its biological potency. The very strength of its antiprogestogenic activity was the source of both its therapeutic promise and its ultimate downfall. The severe hepatotoxicity observed at higher doses suggests that its potent biological activity, particularly at the elevated and sustained exposures likely experienced by individuals with polymorphic CYP3A5-mediated slow metabolism, may have overwhelmed hepatic detoxification pathways or led to off-target effects resulting in cellular injury. The drug's development journey is a stark reminder that for hormonal modulators, achieving a sufficiently wide therapeutic index—the window between the effective dose and the toxic dose—is the paramount challenge.

Legacy and Contribution to the Field

Despite its failure to reach the market, the Telapristone acetate program made several invaluable contributions to pharmaceutical science and clinical medicine.

1. Advancement of Molecular Pharmacology: The research into its mechanism of action, particularly the discovery of the role of TRPS1 recruitment, significantly advanced the molecular understanding of how SPRMs function, moving beyond a simple agonist/antagonist model.
2. Innovation in Drug Delivery: The strategic pivot to a vaginal delivery system was a pioneering effort to improve the therapeutic index of a potent hormonal agent by maximizing local tissue concentration while minimizing systemic risk. This approach continues to be a relevant strategy for other drugs in gynecology.
3. A Critical Safety Signal for the SPRM Class: The hepatotoxicity observed with Telapristone served as a crucial early warning for the entire SPRM class. It highlighted a potential, albeit rare, safety liability that has since informed the clinical development, regulatory review, and post-marketing surveillance of all subsequent drugs in this category, including ulipristal acetate.

Final Conclusion

In conclusion, Telapristone acetate is a quintessential example of a highly promising drug candidate that failed in late-stage development due to an unacceptable safety profile. Its history underscores the non-negotiable primacy of patient safety in drug regulation, especially for non-life-threatening conditions. The program's termination was the result of a confluence of factors: a potent but narrow therapeutic window, the pharmacogenetic variability that likely predisposed a subset of patients to severe toxicity, and the immense regulatory and economic burden of definitively proving safety after a serious adverse signal had been detected. While it never became a medicine, the story of Telapristone acetate remains a rich source of scientific learning and a crucial cautionary tale for the fields of pharmacology, clinical development, and regulatory science.

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