Regulatory Decision Summary for Lynkuet

The purpose of this New Drug Submission, filed by Bayer Inc., was to obtain market authorization under section C.08.004 of the Food and Drugs Regulations for Lynkuet (elinzanetant). The submission sought approval for Lynkuet 60 mg capsules, administered orally, for the treatment of moderate to severe vasomotor symptoms associated with menopause. The sponsor proposed a recommended dose of 120 mg taken orally once daily.

After reviewing the data package submitted, Health Canada authorized Lynkuet for the proposed indication. The decision was based on the assessment of the quality, non-clinical and clinical information provided in the submission.

This submission was reviewed as part of the international work‑sharing model within the Access Consortium. Health Canada assessed the Quality information (Module 3: Chemistry and Manufacturing). The Therapeutic Goods Administration (Australia) assessed the Non‑Clinical information (Module 4). Swissmedic (Switzerland) assessed the Clinical information (Module 5). The Medicines and Healthcare products Regulatory Agency (United Kingdom) participated as a peer reviewer for all modules.

Menopause is defined by the permanent cessation of ovarian function following 12 consecutive months of amenorrhea. It is commonly associated with vasomotor symptoms (VMS), including hot flashes and night sweats, which affect up to 80% of women.

The efficacy of Lynkuet is supported by two identically designed, randomized, double-blind, placebo-controlled, multicentre pivotal phase 3 trials. Studies 21651 and 21652 enrolled a total of 399 postmenopausal women randomized to Lynkuet 120 milligrams (mg) (n = 199 and n = 200 patients, respectively) and 397 randomized to placebo (n = 197 and n = 200 patients, respectively). The co-primary efficacy endpoints in both studies were the mean change from baseline in the frequency of moderate to severe hot flashes at Week 4 and then at Week 12, assessed using the Hot Flash Daily Diary (HFDD). The two key secondary efficacy endpoints were the mean change from baseline in severity of moderate to severe hot flashes at Week 4 and then at Week 12. Lynkuet demonstrated statistically significant reductions compared with placebo across all four VMS endpoints in both studies at Week 4 and Week 12. In Study 21651, Lynkuet treatment reduced mean daily VMS frequency by 7.60 episodes at Week 4 and 8.66 at Week 12, versus 4.31 and 5.44 for those treated with placebo, respectively. In Study 21652, corresponding reductions were 8.58 and 9.72 with Lynkuet treatment, versus 5.54 and 6.48 for patients treated with placebo. The treatment effect exceeded 2 episodes per day at both time points, and thus suggested a clinically meaningful benefit. Between-group differences in change in episode frequency at Week 4 were 3.29 episodes in Study 21651 (p = <0.0001) and 3.04 in Study 21652 (p = <0.0001), remaining stable through Week 12 (3.22 and 3.24 episodes, respectively; p = <0.0001 for both studies).

In Study 21651, Lynkuet reduced mean VMS severity scores by 0.73 and 0.92 points at Weeks 4 and 12, respectively, compared to 0.40 and 0.52 points with placebo, resulting in treatment differences of 0.33 (p <0.001) and 0.40 points (p <0.001). In Study 21652, reductions with Lynkuet were 0.75 and 0.91, versus 0.53 and 0.62 with placebo, corresponding to treatment differences of 0.22 (p = 0.0003) and 0.29 points (p <0.001), respectively.

The primary safety data were derived from the pooled pivotal trials during the 12-week placebo-controlled period (n = 793 [n = 400 Lynkuet-treated patients and 393 placebo-treated patients]) and the 52-week, placebo-controlled Study 21810 (n = 627 [n = 313 Lynkuet-treated patients and 314 placebo-treated patients]). During the 12-week placebo-controlled periods of Studies 21651 and 21652, the most common adverse drug reactions (ADRs) reported with Lynkuet 120 mg daily at ≥2% frequency and greater than placebo, included headache (8.5% vs 2.5%), fatigue (6.5% vs 1.8%), gastroesophageal reflux disease (3.0% vs 0.5%), dizziness (2.8% vs 1.0%), somnolence (2.5% vs 0.5%), and abdominal pain (2.0% vs 0.5%).

In Study 21810, ADRs reported at ≥2% frequency and greater than placebo included headache (9.6% vs 7.0%), fatigue (7.3% vs 2.9%), somnolence (5.1% vs 1.3%), abdominal pain (4.5% vs 2.5%), diarrhea (3.8% vs 1.0%), dizziness (3.8% vs 1.6%), muscle spasms (3.2% vs 0.6%), and rash (3.2% vs 1.3%).

Serious adverse events were infrequent and predominantly deemed unrelated to treatment. Thromboembolic and cardiovascular events were reported (n = 4), including two cases of pulmonary embolism, one transient ischemic attack, and one myocardial infarction. Causality has not been established; however, these events support the need for continued monitoring. Discontinuations due to adverse events were more common in the Lynkuet group compared to the placebo group (7.8% vs 3.6%, respectively). They were due to fatigue (2.0%), headache (1.8%) and diarrhea (0.8%) during the 12-week placebo-controlled period of the pivotal studies. In Study 21810, discontinuation was due to fatigue (1.6%), abdominal pain (1.6%) and headache (1.3%). Elevations in hepatic enzymes were more frequent with Lynkuet but were generally mild, transient, and asymptomatic; no cases met Hy’s Law criteria. . Endometrial safety was supported by biopsy findings showing no cases of hyperplasia or malignancy, although the upper bound of the 95% confidence interval for hyperplasia slightly exceeded internationally accepted guidelines, warranting further long-term evaluation. Palpitations occurred more frequently in patients treated with Lynkuet compared to patients treated with placebo. These events were generally mild and may relate to underlying vasomotor symptomatology, but the consistent imbalance supported its inclusion in the safety section of the Product Monograph. There is a lack of clinical safety data in patients with pharmacologically induced menopause, including those with estrogen-dependent malignancies. This exclusion is highlighted in the Product Monograph and is being mitigated by ongoing follow-up studies.

Concomitant use of elinzanetant with CYP3A4 inducers or inhibitors can change elinzanetant exposure to varying degrees. Patients receiving moderate to strong CYP3A inducers could experience a reduction in efficacy; however, no dosage adjustment is recommended. A strong CYP3A4 inhibitor can increase the exposure of elinzanetant up to 6.3-fold; the concomitant use of elinzanetant with strong CYP3A4 inhibitors is contraindicated. For patients taking moderate CYP3A4 inhibitors, the recommended daily dose of Lynkuet is reduced to 60 mg/day. Elinzanetant and weak CYP3A4 inhibitors can be administered concomitantly without any dose adjustment. Elinzanetant itself is a weak inhibitor of CYP3A4. Caution is required when co-administering Lynkuet with sensitive CYP3A4 substrates with a narrow therapeutic window.

Lynkuet can be taken with or without food.

In rats, elinzanetant was found to be phototoxic, to bind melanin, and to significantly absorb light within the range of natural sunlight. The observed long half-life of 14C-elinzanetant-derived radioactivity in rat skin indicated prolonged retention of elinzanetant in the skin and thus could potentially lead to accumulation in this tissue. Clinical relevance is unknown. In human patients, phototoxicity was rare and mostly mild in severity.

Elinzanetant caused embryo-fetal toxicity in rats, was found to cross the placenta, and was excreted in milk of lactating rats. Therefore, elinzanetant is contraindicated in pregnancy and is not recommended in breastfeeding patients.

Risks have been communicated in the approved Product Monograph and will continue to be monitored post-market as outlined in the approved Risk Management Plan by the Marketed Health Product Directorate.

The chemistry and manufacturing information submitted for Lynkuet has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. The final labelling and Product Monograph were considered acceptable.

In summary, the benefit-risk profile of Lynkuet (elinzanetant) 60 mg capsules (with a recommended dose of 120 mg oral daily) was favourable for the authorized indication when used under the conditions of use recommended in the approved Product Monograph. Most adverse events were mild and transient, and key safety uncertainties are considered manageable through appropriate risk mitigation measures and post-marketing surveillance. Therefore, a Notice of Compliance was recommended.

For further details about Lynkuet, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.