GTx, Inc. (Public, NASDAQ:GTXI)

[Michael Scally MD]

GTx-758, ERa Agonist, Reduces Both Serum Free Testosterone(T) and Serum PSA in Men With Advanced and Castrate Resistant Prostate Cancer
http://edrv.endojournals.org/cgi/content/meeting_abstract/34/03_MeetingAbstracts/SAT-319 (GTx-758, ERa Agonist, Reduces Both Serum Free Testosterone(T) and Serum PSA in Men With Advanced and Castrate Resistant Prostate Cancer -- Coss et al. 34 (3): SAT-319 -- Endocrine Reviews)

Introduction: Androgen deprivation therapy (ADT) improves disease-free survival in men with advanced prostate cancer. Primary ADT with LHRH analogs lowers serum total testosterone (T) by reducing testicular androgen production, thereby lowering serum total and serum free T. Estrogen-based ADT induces sex hormone binding globulin (SHBG) expression resulting in proportionally greater reductions in serum free T. Primary ADT patients achieving lower serum T levels, and men with CRPC undergoing secondary hormonal therapy to further reduce T, experience better prostate cancer outcomes.

Objectives: Herein we compare the effects GTx-758 (an oral, selective estrogen receptor alpha (ER?) agonist) versus leuprolide on total T, free (unbound) serum T, SHBG and PSA levels in men with advanced prostate cancer.

Methods: In Phase II studies, men with advanced prostate cancer (n=164) received 1000 mg or 2000 mg GTx-758 daily or Lupron Depot® (4 month), while men with CRPC (n=7) received 2000 mg GTx-758 daily while on ADT. Serum concentrations of total T, free T, PSA and SHBG were determined at baseline and during treatment.

Results: The ADT naïve ITT population receiving GTx-758 demonstrated a mean reduction in serum total T from baseline of 54±52 and 72±43% for the 1000 and 2000 mg doses, respectively, compared to 93±2.8% reduction in the Lupron treated arm at Day 21. However, mean PSA reductions from baseline at Day 21 were 55±47 and 60±32% for the 1000 and 2000 mg doses of GTx-758, respectively, compared to 38±24% in Lupron treated patients. GTx-758 treatment resulted in 55 and 51% greater reduction in serum free T per unit reduction in serum total T relative to Lupron in the 1000 mg and 2000 mg arms, respectively, at Day 21. Reductions in serum free T coincided with mean increases in SHBG of 399±186 and 439±165% for 1000 mg and 2000 mg GTx-758 groups, respectively, compared to 5±14% in Lupron treated patients at Day 28. SHBG inductions were highly correlated with reductions in %Free T([free T/total T]X100) in both ADT naïve and CRPC prostate cancer patients (p<0.001).

Conclusions: Although GTx-758 and LHRH ADT, both reduce total serum T and PSA levels in ADT naïve advanced prostate cancer patients, SHBG induction rapidly reduced %free T to a greater degree in only the GTx-758 treated patients. GTx-758 therapy also demonstrated efficacy in men with CRPC, with similar reductions in %free T and PSA observed. The ability of GTx-758 to reduce free T demonstrates a unique and effective mechanism to treat men with advanced prostate cancer and CRPC.

 

[Michael Scally MD]

Dalton JT, Taylor RP, Mohler ML, Steiner MS. Selective androgen receptor modulators for the prevention and treatment of muscle wasting associated with cancer. Curr Opin Support Palliat Care 2013;7(4):345-51. Selective androgen receptor modulators for the prevention an... : Current Opinion in Supportive and Palliative Care

PURPOSE OF REVIEW: This review highlights selective androgen receptor modulators (SARMs) as emerging agents in late-stage clinical development for the prevention and treatment of muscle wasting associated with cancer.

RECENT FINDINGS: Muscle wasting, including a loss of skeletal muscle, is a cancer-related symptom that begins early in the progression of cancer and affects a patient's quality of life, ability to tolerate chemotherapy, and survival. SARMs increase muscle mass and improve physical function in healthy and diseased individuals, and potentially may provide a new therapy for muscle wasting and cancer cachexia. SARMs modulate the same anabolic pathways targeted with classical steroidal androgens, but within the dose range in which expected effects on muscle mass and function are seen androgenic side-effects on prostate, skin, and hair have not been observed. Unlike testosterone, SARMs are orally active, nonaromatizable, nonvirilizing, and tissue-selective anabolic agents.

SUMMARY: Recent clinical efficacy data for LGD-4033, MK-0773, MK-3984, and enobosarm (GTx-024, ostarine, and S-22) are reviewed. Enobosarm, a nonsteroidal SARM, is the most well characterized clinically, and has consistently demonstrated increases in lean body mass and better physical function across several populations along with a lower hazard ratio for survival in cancer patients. Completed in May 2013, results for the Phase III clinical trials entitled Prevention and treatment Of muscle Wasting in patiEnts with Cancer1 (POWER1) and POWER2 evaluating enobosarm for the prevention and treatment of muscle wasting in patients with nonsmall cell lung cancer will be available soon, and will potentially establish a SARM, enobosarm, as the first drug for the prevention and treatment of muscle wasting in cancer patients.

 

[Michael Scally MD]

Good-Bye SARM!!! As I have written here, SARMs are DEAD. IMO, the chance [Fat, Slim. None] for FDA approval for a SARM have now become more evident than ever. GTx as a company is essentially no more.

On April 14, 2014, James T. Dalton, Ph.D., Vice President, Chief Scientific Officer of GTx, Inc. notified the Company of his decision to resign from his employment with GTx, effective August 31, 2014. http://phx.corporate-ir.net/phoenix.zhtml?c=148196&p=irol-sec

And, this comes on top of the recent resignation of Mitchell S. Steiner, its vice chairman and chief executive officer (CEO) and a co-founder of the company. Dr. Steiner has stepped down from his roles as CEO and vice chairman of the Board of Directors at the company effective Thursday April 3, 2014. http://phx.corporate-ir.net/phoenix.zhtml?c=148196&p=irol-newsArticle&ID=1915833&highlight=

 

[Michael Scally MD]

GTx Provides Clinical Update [SARM] Enobosarm (GTx-024) [LMAO]
http://phx.corporate-ir.net/phoenix.zhtml?c=148196&p=irol-newsArticle&ID=1928642&highlight=

Enobosarm (GTx-024) 3mg, an oral selective androgen receptor modulator, being developed for the prevention and treatment of muscle wasting in patients with advanced non-small cell lung cancer: Following GTx’s announcement in August 2013 that the POWER1 (platinum plus taxane) and POWER2 (platinum plus non-taxane) Phase 3 clinical trials evaluating enobosarm 3mg for the prevention and treatment of muscle wasting in patients with advanced non-small cell lung cancer (NSCLC) failed to achieve the statistical significance, as agreed upon with the Food and Drug Administration (FDA), GTx has met with regulators in both the US and Europe to better understand the prospects for commercializing its enobosarm product candidate as a treatment for muscle wasting in NSCLC patients.

Since enobosarm 3mg demonstrated a statistically significant effect versus placebo on physical function at three months in the POWER1 Phase 3 clinical trial, assessed by continuous variable analysis as pre-specified in the statistical analysis plan for the European Medicines Agency (EMA), the Company believes data from the POWER trials may be sufficient to support the filing of a marketing authorization application (MAA) in the European Union (EU) for enobosarm 3mg for the prevention and treatment of muscle wasting in patients with advanced NSCLC treated with platinum plus taxane chemotherapy. The Company has retained experts in both the US and EU to work with its internal team to explore the option of submitting a MAA.

In a meeting with FDA earlier this year, the FDA confirmed that the current data from the POWER trials are insufficient to support the filing of a new drug application (NDA), as the POWER trials did not meet the pre-specified statistical criterion for the co-primary endpoints of lean body mass and stair climb power, using responder analyses, as agreed upon with FDA. The Company is evaluating options for further development of enobosarm 3 mg.


And, in further desperation ...

Enobosarm 9mg, being studied for the targeted treatment of androgen receptor and estrogen receptor positive metastatic breast cancer: GTx is conducting a Phase 2, open label clinical study evaluating an oral daily dose of 9mg enobosarm for the treatment of androgen receptor (AR) positive and estrogen receptor (ER) positive metastatic breast cancer in women who have previously responded to hormonal therapy for the treatment of their advanced breast cancer.

 

[BBC3]

Now there's a POS I would have liked to been a little LONG on PUT'n it down. Or is it perhaps SHORT on selling the CALL. Potato - POTAATO... I was sitting here thinking to myself how is it some yocal jackass actually getz drugs like Faraston to market. Then I saw my post above as a minor INFARKSHEUN.... Hope you didn't buy too many tickets on that L-TRAIN... I just fuckin wish I had known who was running the bastard and what a small little turdlett it was. POISE... SNAP.. POIZE>.... LOL That was a BITCH built to BLO or BUST... Hang tough...!

 

[Michael Scally MD]

Dubois V, Simitsidellis I, Laurent MlR, Jardi F, Saunders PTK, et al. Enobosarm (GTx-024) modulates adult skeletal muscle mass independently of the androgen receptor in the satellite cell lineage. Endocrinology. http://press.endocrine.org/doi/abs/10.1210/en.2015-1479

Androgens increase skeletal muscle mass, but their clinical use is hampered by lack of tissue selectivity and subsequent side-effects.

Selective androgen receptor modulators (SARMs) elicit muscle-anabolic effects while only sparingly affecting reproductive tissues. The SARM GTx-024 (enobosarm) is being investigated for cancer cachexia, sarcopenia, and muscle wasting diseases.

Here, we investigate the role of muscle androgen receptor (AR) in the anabolic effect of GTx-024. In mice lacking AR in the satellite cell lineage (satARKO), the weight of the androgen-sensitive levator ani muscle was lower, but decreased further upon orchidectomy.

GTx-024 was as effective as dihydrotestosterone (DHT) in restoring levator ani weights to sham levels. Expression of the muscle-specific androgen-responsive genes S-adenosylmethionine decarboxylase and myostatin was decreased by orchidectomy and restored by GTx-024 and DHT in control mice, while expression was low and unaffected by androgen status in satARKO.

In contrast, insulin-like growth factor IEa expression was not different between satARKO and control muscle, decreased upon castration, and was restored by DHT and GTx-024 in both genotypes. These data indicate that GTx-024 does not selectively modulate AR in the satellite cell lineage and that cells outside this lineage remain androgen-responsive in satARKO muscle.

Indeed, residual AR positive cells were present in satARKO muscle, coexpressing the fibroblast-lineage marker vimentin. AR positive, muscle-resident fibroblasts could therefore be involved in the indirect effects of androgens on muscle.

In conclusion, both DHT and GTx-024 target AR pathways in the satellite cell lineage, but cells outside this lineage also contribute to the anabolic effects of androgens.

 

[Michael Scally MD]

GTx Receives FDA Clearance to Initiate Clinical Trial [SARM] in Stress Urinary Incontinence [LMAO]
http://phx.corporate-ir.net/phoenix.zhtml?c=148196&p=irol-newsArticle&ID=2096372

• Trial to evaluate an orally administered SARM in postmenopausal women with stress urinary incontinence --
• Preclinical data demonstrates a SARM can increase pelvic floor muscle mass and potentially improve outcomes in women with SUI --

MEMPHIS, Tenn.--(BUSINESS WIRE)--Oct. 13, 2015-- GTx, Inc. (Nasdaq:GTXI) today announced that the U.S. Food and Drug Administration (FDA) has accepted the Company’s investigational new drug (IND) application for a Phase 2 clinical trial to treat postmenopausal women with stress urinary incontinence (SUI).

The IND enables GTx to initiate a Phase 2 proof-of-concept trial of enobosarm that will be the first clinical trial to evaluate a selective androgen receptor modulator (SARM) for SUI. The Company plans to initiate the trial by the first quarter of 2016 and anticipates top-line data later in 2016.

The rationale for evaluating enobosarm (GTx-024) as a treatment for SUI in the proof-of-concept trial is supported by preclinical in vivo data demonstrating increases in pelvic floor muscle mass following treatment with GTx’s SARM compounds, including enobosarm, as well as human safety and efficacy data from enobosarm clinical trials involving more than 1,500 subjects. Enobosarm has been found to be generally safe and well tolerated.

Following results from the proof-of-concept trial, the company will determine which GTx SARM compound, including enobosarm, may be further developed for this indication.

 

[Michael Scally MD]

GTx Announces Initiation of Phase 2 Clinical Trial of Enobosarm in Stress Urinary Incontinence
-- Trial will evaluate orally administered SARM in postmenopausal women with stress urinary incontinence
-- Objective to determine whether a SARM may increase pelvic floor muscle mass and potentially improve outcomes in women with SUI
http://phx.corporate-ir.net/phoenix.zhtml?c=148196&p=irol-newsArticle&ID=2128822

 

[Michael Scally MD]

[Open Access] [FAILED] Study Design and Rationale for the Phase 3 Clinical Development Program of Enobosarm, a Selective Androgen Receptor Modulator, for the Prevention and Treatment of Muscle Wasting in Cancer Patients (POWER Trials)

Muscle wasting in cancer is a common and often occult condition that can occur prior to overt signs of weight loss and before a clinical diagnosis of cachexia can be made. Muscle wasting in cancer is an important and independent predictor of progressive functional impairment, decreased quality of life, and increased mortality.

Although several therapeutic agents are currently in development for the treatment of muscle wasting or cachexia in cancer, the majority of these agents do not directly inhibit muscle loss. Selective androgen receptor modulators (SARMs) have the potential to increase lean body mass (LBM) and hence muscle mass, without the untoward side effects seen with traditional anabolic agents.

Enobosarm, a nonsteroidal SARM, is an agent in clinical development for prevention and treatment of muscle wasting in patients with cancer (POWER 1 and 2 trials). The POWER trials are two identically designed randomized, double-blind, placebo-controlled, multicenter, and multinational phase 3 trials to assess the efficacy of enobosarm for the prevention and treatment of muscle wasting in subjects initiating first-line chemotherapy for non-small-cell lung cancer (NSCLC).

To assess enobosarm's effect on both prevention and treatment of muscle wasting, no minimum weight loss is required. These pivotal trials have pioneered the methodological and regulatory fields exploring a therapeutic agent for cancer-associated muscle wasting, a process hereby described.

In each POWER trial, subjects will receive placebo (n = 150) or enobosarm 3 mg (n = 150) orally once daily for 147 days. Physical function, assessed as stair climb power (SCP), and LBM, assessed by dual-energy X-ray absorptiometry (DXA), are the co-primary efficacy endpoints in both trials assessed at day 84.

Based on extensive feedback from the US Food and Drug Administration (FDA), the co-primary endpoints will be analyzed as a responder analysis. To be considered a physical function responder, a subject must have >/=10 % improvement in physical function compared to baseline. To meet the definition of response on LBM, a subject must have demonstrated no loss of LBM compared with baseline.

Secondary endpoints include durability of response assessed at day 147 in those responding at day 84. A combined overall survival analysis for both studies is considered a key secondary safety endpoint.

The POWER trials design was established with extensive clinical input and collaboration with regulatory agencies. The efficacy endpoints are a result of this feedback and discussion of the threshold for clinical benefit in patients at risk for muscle wasting. Full results from these studies will soon be published and will further guide the development of future anabolic trials.

Crawford J, Prado CM, Johnston MA, et al. Study Design and Rationale for the Phase 3 Clinical Development Program of Enobosarm, a Selective Androgen Receptor Modulator, for the Prevention and Treatment of Muscle Wasting in Cancer Patients (POWER Trials). Curr Oncol Rep 2016;18(6):37. Study Design and Rationale for the Phase 3 Clinical Development Program of Enobosarm, a Selective Androgen Receptor Modulator, for the Prevention and Treatment of Muscle Wasting in Cancer Patients (POWER Trials) | SpringerLink