Clinical Trials

Date: 2018-03-19

Type of information: Results

phase: 2b

Announcement: results

Company: Mereo Biopharma (UK)

Product: BGS-649 (leflutrozole)

Action mechanism:

• aromatase inhibitor. BGS-649 (leflutrozole) is a novel once weekly oral aromatase inhibitor being developed as a first-line therapy for the treatment of obese men with hypogonadotropic hypogonadism (HH). This syndrome results from inadequate levels of testosterone, and can cause increased obesity, cardiovascular disease, hypertension, insulin resistance, type 2 diabetes, depression, osteoporosis, and infertility. In the obese, the decrease in testosterone is driven by high levels of the aromatase enzyme in the fat tissue. The aim is to use BGS-649 to normalise testosterone levels and improve the related conditions.
• About BGS-649 BGS-649 is a once a week oral treatment for HH in obese men, that restores a patient’s own testosterone. It is a novel aromatase inhibitor that inhibits conversion of the patients’ own testosterone to oestradiol, thereby increasing testosterone levels. BGS-649 is designed to be more convenient compared with current therapies and due to its mechanism of action restores normal testosterone production without the risk of supra-physiological levels or suppression of LH and FSH, thereby treating the symptoms of HH whilst maintaining or improving testicular function.

Disease: hypogonadotropic hypogonadism (HH)

Therapeutic area: Endocrine diseases - Hormonal diseases - Metabolic diseases

Country: Italy, Spain, UK, USA

Trial details:

• The purpose of this study is to evaluate the safety and efficacy of BGS649 in male obese subjects with hypogonadotropic hypogonadism. All subjects will be treated for a maximum of 24 weeks. Some subjects who complete 24 weeks of treatment will be invited to participate in a 6-month blinded safety extension study (Protocol MBGS206). The study is planned to enroll 268 subjects.
• The primary endpoint of this study is to demonstrate the efficacy of BGS-649 to normalise total testosterone levels in over 75% of subjects after 24 weeks of treatment. Secondary endpoints are based on the impact of BGS-649 on luteinising hormone (LH), follicle stimulating hormone (FSH) and semen parameters. In addition the company is exploring patient recorded outcomes including sexual function and fatigue. (NCT02730169)
• About the Phase 2b Study The Phase 2b dose-confirmation study, which commenced in 2016, was a randomized, double-blind, placebo-controlled clinical trial assessing three different dosing regimens of BGS-649 in 271 obese men with HH. Following baseline assessment, patients were randomized to receive one of three weekly doses of BGS-649 or placebo for 24 weeks. The primary endpoint was normalization of total testosterone levels in greater than 75% of subjects after 24 weeks of treatment. Secondary measures included determining the impact of BGS-649 on the levels of testosterone LH and FSH, as well as normalization of total testosterone in greater than 90% of the subjects after 24 weeks of treatment. Exploratory end points included semen parameters and patient reported outcomes (PROs). At the end of the initial 24-week treatment period, patients had the option to enrol into a six-month safety extension study in which they will receive the same dose or in the case of placebo patients, they will be randomized to one of the three doses. Patients will continue to be monitored for LH and (FSH) levels and bone mineral density. The Phase 2b safety extension study has fully enrolled 143 patients and results are expected in Q4 2018.

Latest news:

•  • On March 19, 2018, Mereo BioPharma announced positive top-line results from a Phase 2b dose-ranging study with BGS-649 for the treatment of hypogonadotropic hypogonadism (HH) in men with a body mass index of over 30. The study met its primary endpoint, normalizing total testosterone levels in over 75% of subjects after 24 weeks of treatment (p<0.001 versus placebo for each of the three doses tested), and its secondary endpoint of normalizing testosterone in at least 90% of patients after 24 weeks, which occurred at the two highest doses. All three doses met all the other secondary endpoints, including the improvement of testosterone luteinising hormone (LH) and follicle stimulating hormone (FSH) levels. The study demonstrated a clear dose response in both the primary and secondary endpoints. The exploratory endpoint of improvement in total motile sperm count was also met. A positive trend of treatment effect was also observed on reduction of fatigue in the exploratory patient reported outcomes (PROs) of the PROMIS short fatigue score.
• Primary Endpoint
• -All three doses normalized testosterone in 75% of subjects at 24 weeks (p<0.001 for each dose versus placebo).
• -Normalization of testosterone observed at first time point after initial dosing of day 8 in >80% of subjects at all three doses (p<0.001 for each dose versus placebo).
• -Dose response observed with respect to absolute testosterone levels and response time.
• Secondary Endpoints
• - No subjects on BGS-649 with testosterone levels >1500 ng/dl at any time during the study.
• -Statistically significant increase in LH at all three doses at week 24 (p<0.001 for each dose versus placebo) with a clear dose response. Increase observed at first time point after initial dosing of day 8.
• -Statistically significant increase in FSH at all three doses at week 24 (<0.001 for each dose versus placebo) with a clear dose response. Increase observed at first time point after initial dosing of day 8.
• - The two highest doses normalized testosterone in 90% of subjects at 24 weeks with the lowest dose normalising testosterone in 88% of subjects at 24 weeks.
• Exploratory Endpoints
• - Improvement in total motile sperm count across all three doses versus placebo (mean changes at 20 weeks of 70 million, 14 million, and 58 million for high, medium and low doses, respectively, compared with a decrease of 23 million for placebo) with statistical significance attained with the high dose although the trial was not powered to detect statistical significance for this endpoint (p=0.03). -A positive trend of treatment effect was observed on reduction of fatigue in the exploratory patient reported outcomes (PROs) of the PROMIS short fatigue score at 8-12 weeks treatment. The trial was not powered to detect statistical significance for this endpoint.
• Safety
• -BGS-649 was reported to be safe and well tolerated during the study. -An increased incidence of elevated haematocrit levels was noted in the treatment arms of the study, which is consistent with increasing testosterone levels
• • On September 9, 2017, Mereo BioPharma announced that it has successfully completed patient enrolment in a Phase 2b dose-confirmation study for the treatment of hypogonadotropic hypogonadism in men with a body mass index of over 30. A total of 270 patients have been enrolled into a randomised placebo controlled Phase 2b dose-confirmation study assessing three different dosing regimens. This follows a positive outcome, announced in March 2017, of a blinded interim review of the safety and efficacy of all the three doses based on 93 patients who had received at least one month’s treatment (see below). Top-line data are expected in the first quarter of 2018. Additionally, a six-month extension study in up to 120 patients to confirm the safety of long term treatment with BGS-649 is well underway. Top line results of the trial are expected to be announced during the first half of 2018.
• • On March  7, 2017, Mereo BioPharma announced that the Independent Data Monitoring Committee (IDMC) has recommended the continuation of all three different dose arms of the Phase 2b BGS-649 study following a prospectively defined interim analysis of safety and efficacy. The company remains completely blinded to the data from this analysis.BGS-649 is currently being investigated in a Phase 2b clinical study in 268 HH patients with a body mass index (BMI) of more than 30. This study compares three doses of BGS-649 with placebo.
• The interim analysis was performed once the first 93 patients had completed at least one month’s treatment. In addition to safety, the efficacy analysis assessed if each dose was likely to normalise testosterone in at least 75% of patients, the primary endpoint, over the six months course of treatment.
• Based on the review of the data, the IDMC has recommended that all three arms should continue versus placebo until patients have received the full six months of treatment. At the end of the initial treatment period, patients have the option to enrol into a six month safety extension study in which they will receive the same dose or in the case of placebo patients they will be randomised to one of the three doses.
• To date there have been no trends that raise safety concerns including all patients enrolled into the initial six month study. The primary objective of this Phase 2b study is to demonstrate the efficacy of BGS-649 to normalise total testosterone levels in greater than 75% of subjects after 24 weeks of treatment. Mereo is also assessing patient recorded outcomes and determining the impact of BGS-649 on the levels of LH and FSH and on semen parameters. The company has also initiated a six-month Phase 2b extension study for BGS-649 to confirm the safety of long-term treatment. This study aims to enrol up to 120 patients from the initial six month BGS-649 study and will include monitoring of testosterone levels and any changes in bone parameters.
• In previous clinical studies with Novartis, BGS-649 was shown to normalise testosterone levels, increase LH and FSH and was safe and well tolerated in men with HH with an average body mass index (BMI) of 34. These data will be presented as a late breaker poster at the Endo 2017 meeting on 2 April in Orlando.

Is general: Yes