Lynkuet

Pharmacotherapeutic group: other gynaecologicals, other gynaecologicals, ATC code: G02CX07 Mechanism of action Elinzanetant is a non-hormonal, selective neurokinin 1 (NK 1 ) and 3 (NK 3 ) receptors antagonist.​​​‍​​‍​​​​‍​​‍‍ It blocks NK 1 and NK 3 receptor signalling on kisspeptin/neurokinin B/dynorphin (KNDy) neurons to modulate neuronal activity involved in thermo- and sleep regulation. KNDy neurons in the hypothalamus are hyperactivated due to oestrogen decline in menopause. Elinzanetant has high affinity for human NK 1 receptors (pK i values of 8.7 to 10.2) and NK 3 receptors (pK i values of 8.0 to 8.8), but not for human NK 2 receptors (as shown by a low pK i of 6.0). Elinzanetant is more than 100‑fold selective for the human NK 3 receptor and more than 300‑fold for the human NK 1 receptor versus multiple other non‑NK receptors and off‑targets. Pharmacodynamic effects No clinically relevant prolongation of the QTc interval was observed after single oral administration of elinzanetant at doses up to five times the maximum recommended dose. Clinical efficacy and safety The efficacy and safety of elinzanetant were investigated in two similar randomised, double-blind, placebo-controlled, multicentre phase III studies (OASIS 1 and 2). A total of 796 postmenopausal women were randomised 1:1 to receive elinzanetant 120 mg or placebo once daily at bedtime for 12 weeks, followed by elinzanetant for 14 weeks, for a total treatment of up to 26 weeks. Women who had at least 50 moderate to severe hot flushes (HF), including nighttime HF, per week were enrolled in OASIS 1 and 2. In OASIS 1 and 2 studies, the following patient demographics were balanced between treatment groups. The mean age of women was 54.6 years (range 40-65). Most women were White (80.4%), 17.1% were Black or African American, 0.5% Asian, and 8.5% with Hispanic or Latino ethnicity. The study population also included women with prior hysterectomy (38.8%), prior uni-/bilateral oophorectomy (20.6%), or prior Hormone Replacement Therapy (HRT) use (31.4%). The primary efficacy endpoints in OASIS 1 and 2 were the mean change in frequency of moderate to severe HF from baseline to weeks 4 and 12, including day and night HF, measured using a Hot Flush Daily Diary (HFDD). The key secondary endpoints were the mean change in severity of moderate to severe HF from baseline to weeks 4 and 12, and the mean change in frequency of moderate to severe HF from baseline to week 1 using HFDD, the mean change in the Patient‑Reported Outcome (PRO) instruments Patient‑Reported Outcome Measurement Information System Sleep Disturbance Short Form 8b (PROMIS SD SF 8b) to assess sleep disturbances total T‑score, and Menopause‑specific Quality of Life (MENQOL) total score to evaluate menopause‑related quality of life from baseline to week 12. In OASIS 1 and 2 elinzanetant treatment groups showed statistically significant and clinically meaningful reduction in frequency of moderate to severe HF from baseline to weeks 4 and 12 compared to placebo. In OASIS 1 and 2 elinzanetant treatment groups showed a statistically significant reduction in severity of moderate to severe HF from baseline to weeks 4 and 12 compared to placebo. Results of the change in mean frequency and severity of moderate to severe HF over 24 hours from OASIS 1 and 2 are shown in Table 2. Table 2: Mean change in frequency and severity of moderate to severe HF from baseline to Weeks 4 and 12 (OASIS 1 and 2) OASIS 1 OASIS 2 Parameter Elinzanetant 120 mg (N=199) Placebo (N=197) Difference elinzanetant – placebo 95% CI p‑value a Elinzanetant 120 mg (N=200) Placebo (N=200) Difference elinzanetant – placebo 95% CI p‑value a Frequency at baseline Mean (SD) 13.38 (6.57) 14.26 (13.94) 14.66 (11.08) 16.16 (11.15) Change from baseline to week 4 LS‑Means (SE) ‑7.60 (0.43) ‑4.31 (0.43) ‑3.29 (0.61) ‑4.47, ‑2.10 <0.0001 ‑8.58 (0.49) ‑5.54 (0.49) ‑3.04 (0.69) ‑4.40, ‑1.68 <0.0001 Change from baseline to week 12 LS‑Means (SE) ‑8.66 (0.58) ‑5.44 (0.59) ‑3.22 (0.81) ‑4.81, ‑1.63 <0.0001 ‑9.72 (0.50) ‑6.48 (0.49) ‑3.24 (0.69) ‑4.60, ‑1.88 <0.0001 Severity at baseline Mean (SD) 2.56 (0.22) 2.53 (0.23) 2.53 (0.24) 2.54 (0.24) Change from baseline to week 4 LS‑Means (SE) ‑0.73 (0.04) ‑0.40 (0.04) ‑0.33 (0.06) ‑0.44, ‑0.23 <0.0001 ‑0.75 (0.04) ‑0.53 (0.04) ‑0.22 (0.06) ‑0.34, ‑0.09 0.0003 Change from baseline to week 12 LS‑Means (SE) ‑0.92 (0.05) ‑0.52 (0.05) ‑0.40 (0.07) ‑0.54, ‑0.25 <0.0001 ‑0.91 (0.06) ‑0.62 (0.05) ‑0.29 (0.08) ‑0.44, ‑0.14 <0.0001 CI = Confidence Interval, LS-Means = Least Squares Means, SD = Standard Deviation, SE = Standard Error a one‑sided p‑value b key secondary endpoint The results in reduction of frequency and severity of moderate to severe HF were consistent across various patient subgroups such as race, ethnicity, BMI and smoking status. For the key secondary endpoints assessed in the OASIS 1 and 2 trials, women treated with elinzanetant vs placebo showed statistically significant improvement in sleep disturbances from baseline to week 12 as assessed by the PROMIS SD SF 8b total T score (difference in LS Means (SE) for OASIS 1: -5.58 (0.82) [95% CI, -7.18 to -3.98], P < 0.0001; OASIS 2: -4.32 (0.74) [95% CI, -5.77 to -2.86], P < 0.0001). Women treated with elinzanetant showed statistically significant improvement in the menopause related quality of life vs placebo from baseline to week 12 as assessed by the MENQOL total score (difference in LS means (SE) for OASIS 1: -0.42 (0.11) [95% CI, -0.64 to -0.20], P < 0.0001; OASIS 2: -0.30 (0.12) [95% CI, -0.53 to -0.07], P = 0.0059). A statistically significant reduction in frequency of moderate to severe HF was observed with elinzanetant vs placebo from baseline to week 1 (difference in LS Means (SE) for OASIS 1: -2.45 (0.46) [95% CI, -3.36 to -1.55], P < 0.0001; OASIS 2: -1.66 (0.55) [95% CI, -2.73 to -0.58], P = 0.0013). The OASIS 3 study was a randomised, double‑blind, placebo‑controlled, multi-centre phase III study with a primary efficacy endpoint of mean change in frequency of moderate to severe HF from baseline to week 12 and a long‑term safety evaluation up to 52 weeks in 628 postmenopausal women (randomised 1:1 to elinzanetant or placebo). Elinzanetant showed a statistically significant outcome on the primary endpoint with a stable effect as evaluated up to week 50. Endometrial safety The endometrial safety of elinzanetant was assessed in the clinical studies OASIS 1, 2 (6 months duration) and OASIS 3 (12 months duration) by transvaginal ultrasound and endometrial biopsies. The 12 month placebo-controlled study investigated a total of 628 women of whom 313 women received elinzanetant. Transvaginal ultrasound testing showed no increase in endometrial thickness. There were no cases of endometrial hyperplasia or malignancy identified in the endometrial biopsies. Bone safety Bone safety of elinzanetant was assessed in 343/628 women in the OASIS 3 study by bone mineral density (BMD) measurements. After 52 weeks of treatment, the observed mean percentage changes from baseline in BMD with elinzanetant was comparable to that with placebo and was within the expected age‑related changes per year. Driving ability Driving performance was assessed at 9 hours after bedtime administration of elinzanetant 120 mg and 240 mg (two times the recommended dose) in a randomised, double-blind, placebo- and active-controlled, four-period crossover study in 64 healthy women (mean age 52.1 years) using a computer-based driving simulation. The primary outcome measure was the difference from placebo in the Standard Deviation of Lateral Position (SDLP). Driving performance was evaluated using a validated threshold established in a population with blood alcohol concentration of 0.05%. The mean SDLP did not reach the threshold for driving impairment after administration of elinzanetant 120 or 240 mg. Compared to placebo minor differences in mean SDLP, not exceeding the predefined threshold for driving impairment, were seen with both doses after one day but not after five consecutive days of elinzanetant administration.