Abstract
Objectives
Many patients with rheumatoid arthritis (RA) are not able to achieve long-term disease remission. This phase 2a study (NCT02884635) evaluated the efficacy, safety, pharmacokinetics, and pharmacodynamics of the novel, oral, gonadotropin-releasing hormone antagonist, ASP1707, in combination with methotrexate (MTX) for treatment of RA.
Methods
Postmenopausal women with RA who had been receiving MTX for ≥90 days were randomized to ASP1707 30 mg twice daily or placebo for 12 weeks. The primary endpoint was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. Secondary endpoints included: ACR20, ACR50, and ACR70 response rates; disease activity score (DAS)28-CRP; DAS28-ESR; Tender or Swollen Joint Counts; and remission rates.
Results
Of 105 patients screened, 72 were randomized to ASP1707 30 mg twice daily (n = 37) or placebo (n = 35). ASP1707 did not improve ACR20, ACR50, or ACR70 response rates at any time point and did not improve any secondary efficacy endpoint. Plasma luteinizing hormone (LH) concentration decreased >90% in >90% of patients receiving ASP1707, with a rapid decrease to <1 IU/L at week 1 that remained stable throughout the treatment.
Conclusion
In the current study, ASP1707 did not demonstrate a clinical benefit.
Introduction
Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by persistent inflammation of the joint synovium that causes pain and swelling leading to structural damage, loss of function, and impaired quality of life [Citation1,Citation2]. In 2010, the global prevalence of RA was reported to be 0.24% and was approximately two times higher in females (0.35%) than in males (0.13%) [Citation3].
Currently, there is no curative treatment for RA, and the available pharmacologic therapies aim to control inflammation, reduce symptoms, and maintain a low disease activity state [Citation2]. In the last decade, treatment goals have shifted toward the achievement of persistent remission, or at the very least, low disease activity, with improved physical function and inhibition of structural damage [Citation1,Citation4]. Treatment with the conventional synthetic disease-modifying antirheumatic drug (DMARD), methotrexate (MTX), administered alone or in combination with short-term glucocorticoids (GC) or other DMARDs, has demonstrated efficacy and remains the standard therapy for RA [Citation2,Citation5]. More recently, biological DMARDs including tumor necrosis factor (TNF)-inhibitors, anti-CD20 and interleukin (IL)−6 receptor antibodies, Janus kinase (JAK) inhibitors, and small molecule DMARDs have demonstrated clinical efficacy in treating RA [Citation2]. However, despite the improvement of patient outcomes associated with these new therapies, many patients do not achieve long-term disease remission. Because current RA treatments target immune cells or cytokines, infections are difficult to avoid as on-target adverse effects and are common with these therapies [Citation2]. In order to address this challenge, there is a need for drugs that employ alternative mechanisms.
An association between RA and hormones has been supported by evidence that RA is more prevalent among women than men and that the hormonal changes occurring in the hypothalamic – pituitary – gonadal axis during pregnancy or menopause impact the severity of RA symptoms [Citation6]. Evidence also suggests that gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) may contribute to the regulation of the immune response [Citation7–9], and inhibition of GnRH has demonstrated anti-inflammatory effects in animal studies [Citation10]. A recent study reported that 5-day treatment with the GnRH inhibitor, cetrorelix, in patients with RA had a significant anti-inflammatory effect and was effective in improving RA symptoms [Citation11].
ASP1707 is an oral GnRH antagonist that suppresses the release of LH and FSH from the pituitary gland by blocking the GnRH receptor. This phase 2a study evaluated the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ASP1707 in combination with MTX in postmenopausal women with RA.
Methods
Study design
This was a phase 2a, randomized, placebo-controlled, double-blind, parallel group study conducted at 27 centers in Japan (Supplementary Table S1; ClinicalTrials.gov, NCT02884635) from September 2016 to October 2017. Patients were enrolled into the trial between September 2016 and July 2017. The treatment and follow-up period were from October 2016 to October 2017. Before study initiation, the Clinical Trial Notification, including the study protocol, was submitted to the Pharmaceuticals and Medical Devices Agency (PMDA) in accordance with the Pharmaceuticals and Medical Devices (PMD) Act. The study consisted of a ≤ 4-week screening period, a 12-week treatment period, and a 1-week follow-up period. After screening, patients were randomized (1:1 without stratification factors) to oral ASP1707 30 mg twice daily (BID) or placebo; treatment with MTX was continued throughout the study. Randomization numbers were randomly allocated to patients in a blinded manner using Interactive Response Technology, which was managed by a third party. Patients, investigators, the sponsor, and clinical staff were blind to treatment. The regimen of ASP1707 30 mg BID was chosen based on a previous study that showed 5-day treatment with the GnRH inhibitor, cetrorelix, reduced the mean concentration of serum LH by 90% and improved RA symptoms [Citation11]. Modeling simulations using data from a phase 1 study suggested that ASP1707 30 mg BID would reduce LH serum concentration by ≥94% in ≥90% of patients (data on file). This study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use guidelines. An Institutional Review Board at each study site reviewed and approved the study protocol and all patients provided informed consent.
Study population
Patients were postmenopausal women who had their last regular menstrual cycle ≥24 months before enrollment. Because estrogen is produced via GnRH in the ovaries of premenopausal women, the risk of influence on the skeletal system associated with decreased estrogen due to the pharmacological effects of ASP1707 may be reduced by recruiting exclusively postmenopausal women. Inclusion criteria included FSH levels of ≥30 mIU/mL at screening (for patients <60 years of age); a diagnosis of RA according to the 1987 American College of Rheumatology (ACR) criteria or the 2010 ACR/European League Against Rheumatism (EULAR) criteria ≥6 months before screening; ≥6 tender/painful joints; ≥6 swollen joints; and C-reactive protein (CRP) levels of >0.3 mg/dL or an erythrocyte sedimentation rate (ESR) of >28 mm/h at screening. Patients must have been receiving MTX for ≥90 days before screening, been on a stable MTX dose for ≥28 days before screening, and been able to continue stable MTX through the end of the follow-up period. Patients could not have received the following drugs (or must have received them at a stable dosage for ≥28 days before baseline): NSAIDs, oral morphine (≤30 mg/day) or equivalent opioid analgesics, acetaminophen, and oral corticosteroids (≤5 mg/day in prednisolone equivalent). Patients were excluded if they had other inflammatory diseases beyond RA; met any of the following laboratory values: white blood cell count <4000/µL, platelet count <100,000/µL, alanine aminotransferase or aspartate aminotransferase ≥2 times the upper limit of normal (ULN), total bilirubin ≥1.5 times the ULN; had a positive T-SPOT or QuantiFERON Gold test within 90 days before screening; history of or concurrent pituitary adenoma or malignant tumor; high risk of fracture; had been diagnosed with osteoporosis that was untreated; and were positive for the hepatitis B surface antigen, hepatitis B virus (DNA quantitation), or hepatitis C virus antibody.
Study drug
ASP1707 (30 mg BID) was provided as 10-mg tablets; placebo was provided as matching tablets. Patients self-administered study drug BID in the morning and in the evening. During days when visits were scheduled, patients took the study drug in the morning at the study site after completion of all assessments. At week 4, patients took the study drug 2 hours before their scheduled visit.
Endpoints
The primary endpoint was the American College of Rheumatology 20% improvement criteria (ACR20) [Citation12] response rate at week 12. Secondary endpoints included ACR20 response rate at weeks 1, 2, 4, and 8; the following endpoints at weeks 1, 2, 4, 8, and 12: ACR 50% improvement criteria (ACR50) and ACR 70% improvement criteria (ACR70) response rates; change from baseline in disease activity score (DAS) 28-joint count C-reactive protein (DAS28-CRP) or DAS28 erythrocyte sedimentation rate (DAS28-ESR) score [Citation13]; proportion of patients achieving DAS28-ESR score for remission (<2.6) or low disease activity (≤3.2); change from baseline in Tender Joint Count (TJC), Swollen Joint Count (SJC), and CRP; proportion of patients achieving ‘good’ or ‘moderate’ response according to EULAR criteria; proportion of patients achieving an ACR/EULAR score for remission (defined as achieving TJC ≤1, SJC ≤1, CRP ≤1.0 mg/dL, subject’s global assessment of arthritis [SGA] ≤ 10 mm); proportion of patients achieving a simplified disease activity index (SDAI) score for remission (≤3.3); change from baseline in SDAI and clinical disease activity index (CDAI) score; and change from baseline in Health Assessment Questionnaire – Disability Index (HAQ-DI) [Citation14].
Assessments
Study visits were conducted at screening (between day −28 and day −1), at baseline (day 1), during the treatment period at weeks 1, 2, 4, 8, and 12, and during the follow-up period, 7 days after the end of treatment or drug discontinuation. Blood was collected at each visit for CRP and ESR measurements. CRP was measured by the central laboratory and ESR was measured at the study site. The TJC and SJC were assessed during each visit. Subject assessment of pain, SGA, physician’s global assessment of arthritis (PGA), and HAQ-DI was conducted during each visit starting from the baseline visit.
An ACR20 responder met the following criteria: ≥20% decrease from baseline for TJC and SJC and ≥20% improvement from baseline in ≥3 of the following parameters: subject assessment of pain, SGA, PGA, HAQ-DI, and CRP. ACR50 or ACR70 responders had percentage changes of 50% or 70%. DAS28 scores were calculated at each postscreening visit based on TJC, SJC, CRP or ESR, and SGA values. The EULAR response criteria [Citation15] were applied to determine whether patients had achieved “no response,” “moderate response,” or “good response” based on the difference in DAS28 score before and after treatment. The SDAI score was calculated as the sum of TJC, SJC, SGA, PGA, and CRP.
Blood samples for PK/PD assessments were collected on weeks 1, 2, 8, and 12 before taking the morning dose and on week 4 approximately 2 hours post-dose. Plasma concentrations of ASP1707 and AS1948006, the S-enantiomer of ASP1707, were measured (central laboratory) using validated liquid chromatography-tandem mass spectrometry. Pharmacodynamic assessments were measured by a central laboratory and included serum estradiol (E2), FSH, LH, TNF-α, matrix metalloproteinase 3 (MMP3), and IL-6. Safety was assessed at each postbaseline visit by monitoring adverse events (AEs), laboratory parameters, vital signs, and 12-lead electrocardiograms.
Statistical analysis
Based on previous RA studies, each treatment group planned to enroll 35 patients. Assuming ACR20 response rates at week 12 of 30% and 60% in the placebo and ASP1707 groups, respectively, a sample size of 33 patients per group would provide 80% power to detect differences between the groups at a two-sided significance level of 0.10. The ACR20 response rates of 30% and 60% were based on results of studies of Japanese patients with RA and an inadequate response to MTX. Results of these studies showed ACR20 response rates after 12–14 weeks of treatment that ranged from 20.8 to 31% for placebo and 59.6 to 77% for the active drugs [Citation16–19]. Increasing the sample size to 35 patients per group allowed for exclusion of ∼5% of patients. Efficacy analyses were conducted on the full analysis set (FAS), including all patients receiving ≥1 dose of study drug with ≥1 efficacy measurement. The safety analysis set (SAF) included all patients receiving ≥1 dose of study drug and was used to summarize demographics and baseline characteristics and all safety analyses. The PK analysis set (PKAS) included all patients receiving ≥1 dose of study drug who provided ≥1 PK analysis sample. The PD analysis set (PDAS) included all patients receiving ≥1 dose of study drug who provided ≥1 PD analysis sample. Chi-square tests with a two-sided significance level of 0.10 compared the ASP1707 and placebo groups for ACR20 and all binary variables of the secondary endpoints. For ACR20, non-responder imputation (NRI) was implemented for any patient withdrawn before Week 12 or for any patient who had missing data as a non-responder. Analysis of covariance (ANCOVA) with treatment group as the factor and baseline score as the covariate compared the change from baseline of continuous variables between treatment groups. Summary statistics were calculated for the PK analysis.
Results
Patient disposition
Of 105 patients providing informed consent, 72 were randomized to ASP1707 30 mg BID (n = 37) or placebo (n = 35); 65/72 patients (ASP1707, n = 32; placebo, n = 33) completed the study (). Seven of the 72 patients (ASP1707, n = 5; placebo, n = 2) discontinued the study due to lack of efficacy (placebo, n = 1), progressive disease (ASP1707, n = 2; placebo, n = 1), withdrawal by patient (ASP1707, n = 2), and failure to meet randomization criteria (ASP1707, n = 1). All 72 patients were included in the SAF, FAS, PKAS, and PDAS. Demographics and baseline characteristics were similar between the treatment groups in the SAF ().
Figure 1. Patient disposition.
Table 1. Demographics and baseline characteristics (SAF).
The mean (SD) duration of study drug exposure in the ASP1707 and placebo groups was 76.0 (18.8) and 81.3 (11.6) days, respectively. Most patients received study drug for ≥57 days (32/37 [86.5%] for ASP1707 and 33/35 [94.3%] for placebo).
Efficacy of ASP1707
At week 12, the difference between ACR20-CRP response rates for the ASP1707 (12/37; 32.4%) and placebo (13/35; 37.1%) groups was not clinically beneficial or statistically significant (−4.7%; p = .675). Similarly, there were no clinical benefits or significant differences between ASP1707 and placebo in ACR20 response rates at weeks 1, 2, 4, and 8 (). In a subgroup analysis, no apparent differences were observed between groups when stratified by baseline factors (i.e. age group, MTX dose, prior DMARD use, duration of RA, data not shown).
Figure 2. ACR20 response rates at weeks 1, 2, 4, 8, and 12 (FAS). ACR20: American College of Rheumatology 20% improvement criteria; FAS: full analysis set.
No clinical benefits or statistically significant differences in ACR50 or ACR70 were observed between the ASP1707 and placebo groups during the study ( and Supplementary Tables S2, S3 and S4).
Table 2. Response rates at week 12 (FAS, NRI).
No clinical benefits or statistically significant differences in DAS28-CRP, DAS28-ESR, SDAI, or CDAI scores from baseline were observed between the treatment groups (). At week 12, the proportion of patients achieving a DAS28-ESR score for remission (<2.6) was similar between the ASP1707 (n = 4/32; 12.5%) and placebo (n = 3/33; 9.1%) groups (p = .658).
Figure 3. Mean (SD) change from baseline in DAS28-CRP (A), DAS28-ESR (B), SDAI (C), and CDAI (D) (FAS). CDAI: clinical disease activity index; CRP: C-reactive protein; DAS: disease activity score; ESR: erythrocyte sedimentation rate; FAS: full analysis set; SD: standard deviation; SDAI: simplified disease activity index.
No clinical benefits or statistically significant differences in CRP change from baseline were observed between the ASP1707 and placebo groups (Supplementary Table S5, Figure S1). Similarly, there were no clinical benefits or statistically significant differences between ASP1707 and placebo for any secondary endpoint, including change from baseline in TJC 68 or SJC 66 (Supplementary Table S6); proportion of patients achieving 1) DAS28-CRP or DAS28-ESR score for low disease activity (≤3.2) (Supplementary Table S7), 2) good response/good or moderate response according to EULAR response criteria, ACR/EULAR score for remission, and SDAI score for remission (≤3.3) (Supplementary Table S8); and 3) change from baseline in HAQ-DI score (Supplementary Figure S2).
The mean plasma concentrations of ASP1707 and AS1948006 were 8.17 ng/mL and 50.0 ng/mL at week 1 and remained stable throughout the study. In the ASP1707 group, plasma LH decreased >90% in >90% of patients; concentration decreased rapidly to <1 IU/L at week 1 and remained stable throughout the treatment period, whereas mean (SD) FSH decreased to 4.683 (2.416) IU/L at week 2 and remained stable at approximately 3 IU/L until the end of treatment. Luteinizing hormone and FSH concentrations did not change in the placebo group. The E2 concentration did not change in any treatment group during the study (). No significant changes in levels of TNF-α, MMP3, or IL-6 occurred throughout the study (Supplementary Figure S3).
Figure 4. Mean (SD) percent change from baseline in plasma concentrations of LH (A), FSH (B), and estradiol (C) (PDAS). FSH: follicle-stimulating hormone; LH: luteinizing hormone; PDAS: pharmacodynamics analysis set; SD: standard deviation.
Safety
The incidence of treatment-emergent AEs (TEAEs) was similar between the ASP1707 (n = 23/37; 62.2%) and placebo (n = 19/35; 54.3%) groups, whereas drug-related TEAEs were higher in the ASP1707 (n = 9/37; 24.3%) group versus placebo (n = 5/35; 14.3%). The only serious AE observed during the study (cholelithiasis) occurred with placebo and was considered unrelated to study drug. The incidence of TEAEs leading to discontinuation was (n = 2/37; 5.4%) and (n = 1/35; 2.9%) in the ASP1707 and placebo groups, respectively. No deaths were reported. The most common TEAEs were nasopharyngitis and rheumatoid arthritis with a higher incidence of nasopharyngitis with ASP1707 compared with placebo ().
Table 3. Overview of TEAEs (SAF).
Discussion
This study evaluated the efficacy, safety, PK, and PD of ASP1707 30 mg BID administered in combination with MTX for 12 weeks in postmenopausal women with RA. As expected, ASP1707 resulted in reduced LH and FSH levels, but this did not translate into an improved ACR20 response rate compared with placebo. In addition, there were no clinically beneficial changes between groups for any secondary endpoints during the study; therefore, ASP1707 did not demonstrate a clinical benefit in postmenopausal women with RA.
Mean plasma concentrations of ASP1707 and AS1948006 did not change significantly throughout the study. In the ASP1707 group, LH and FSH decreased rapidly and remained stable at 0.6 IU/L and 3 IU/L, respectively, throughout the treatment period; no significant changes in the levels of E2, TNF-α, MMP3, or IL-6 occurred. The results of this study contrast with those of the proof-of-concept Antagonist to Gonadotropin-Releasing Hormone in RA (AGRA) study of the GnRH antagonist, cetrorelix, which showed a significant reduction of TNF-α in the cetrorelix group, compared with the placebo group (p = .023) [Citation11]. Although the primary endpoint (DAS28-CRP) of AGRA was not met, improvements were observed in key secondary endpoints (i.e. ACR20 response, DAS28-CRP <2.6) and TNF-α was reduced, suggesting an anti-inflammatory effect associated with antagonizing GnRH in patients with RA. In our study, we observed a similar reduction of LH and FSH, suggesting the dose used was appropriate to assess a GnRH antagonist for treatment of RA. In contrast to the AGRA study, we did not observe a decrease in TNF-α levels.
While the mechanism of intervention was similar between the current study and AGRA, differences in study design may partially account for the conflicting results. Perhaps the greatest difference between studies was the patient population. The AGRA study enrolled slightly younger patients (mean age of ∼55 years vs. ∼65 years in the current study) and included male and female patients, whereas the current study exclusively enrolled postmenopausal women. Hormonal differences in the patient populations may have influenced the current findings. However, as gonadotropin levels increase after menopause [Citation20,Citation21], one might expect our study to align closer to the AGRA study, in which a subgroup analysis found that cetrorelix demonstrated better efficacy in patients with higher gonadotropin levels [Citation22]. In addition, the AGRA study was conducted at a single center in Oslo, Norway, compared with 27 Japanese centers in the current study; cultural and regional differences in treatment patterns may contribute to differences in findings. Lastly, patients in the current study were on stable treatment with MTX, while 33% of patients in AGRA were taking MTX, ∼50% were taking conventional synthetic DMARDS, including MTX, and ∼50% were taking prednisolone.
Overall, ASP1707 had a favorable safety profile and was well tolerated when administered in combination with MTX. The PD data confirm that ASP1707 significantly reduces LH concentrations in postmenopausal women with RA; however, the efficacy of ASP1707 in reducing RA symptoms is not supported by the efficacy outcomes that were assessed. The conflicted findings observed in the literature warrant further investigation of this mechanism for the treatment of RA symptoms. These negative results will contribute to the understanding of RA and the mechanisms of effective treatments.
Ethical approval
An Institutional Review Board at each study site reviewed and approved the study protocol and have therefore been performed in accordance with the ethical standards laid down in the WMA Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subject.
Supplemental Material
Download MS Word (174.5 KB)Acknowledgements
The authors thank the investigators and staff at all study sites. All authors had access to study results, and the lead author vouches for the accuracy and completeness of the data reported. Medical writing and editorial support was provided by Mike Zbreski, PhD, Elizabeth Hermans, PhD, and Patrick Tucker, PhD of OPEN Health Medical Communications (Chicago, IL) and funded by the study sponsor.
Data sharing
Researchers may request access to anonymized participant level data, trial level data and protocols from Astellas sponsored clinical trials at www.clinicalstudydatarequest.com.
For the Astellas criteria on data sharing see: https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Astellas.aspx
Conflict of interest
CH, MI, KK, RA, CL: Employees of Astellas Pharma, Inc.
TT: Grants from Astellas Pharma, Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., AbbVie GK, Asahikasei Pharma Corp., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Eisai Co., Ltd., AYUMI Pharmaceutical Corporation, Nipponkayaku Co., Ltd., Novartis Pharma K.K. Speaking fees from AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Astellas Pharma, Inc., Diaichi Sankyo Co., Ltd., Eisai Co., Ltd., Sanofi K.K., Teijin Pharma Ltd., Takeda Pharmaceutical Co., Ltd., Novartis Pharma K.K. Consulting fees from Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Abbivie GK, Nipponkayaku Co., Ltd., Janssen Pharmaceutical K.K., Astellas Pharma, Inc., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., UCB Japan Co., Ltd.
YT: Speaking fees and/or honoraria from Daiichi-Sankyo, Astellas, Eli Lilly, Chugai, Sanofi, Abbvie, YL Biologics, Bristol-Myers, Glaxo-Smithkline, UCB, Mitsubishi-Tanabe, Novartis, Eisai, Takeda, Janssen, Asahi-kasei. Grants from Mitsubishi-Tanabe, Bristol-Myers, Eisai, Chugai, Takeda, Abbvie, Astellas, Daiichi-Sankyo, Ono, MSD, Taisho-Toyama.
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