ABCL635 Phase 1/2 VMS Signal Impresses, But Phase 3 Replication and 12-Week Gap Define the Real Bet

AbCellera's ABCL635 Sets New Efficacy Bar for Hot Flashes

AbCellera Biologics' investigational antibody ABCL635 demonstrated significant efficacy in a Phase 1/2 study for post-menopausal women experiencing hot flashes. At week four, ABCL635 reduced the daily number of moderate and severe hot flash episodes by an average of 8.8, compared to a 3.5 decrease in the placebo group, a statistically significant difference. The drug also eased hot flash severity by 58% versus 12% for placebo. ABCL635 was well-tolerated over four weeks, with no serious toxicities or trial discontinuations. BMO Capital Markets noted these results could establish a new efficacy bar, projecting unadjusted worldwide peak sales of $2.3 billion.

• Differentiated Efficacy Against Competitors: ABCL635's observed efficacy, including an 8.8 mean daily reduction in hot flashes compared to 3.5 for placebo and a 58% reduction in severity versus 12% for placebo, positions it as potentially best-in-class. BMO Capital Markets highlighted that these numbers appear differentiated from currently commercial oral drugs for hot flashes, such as Astellas’ Veozah and Bayer’s Lynkuet.
• Favorable Safety and Tolerability Profile: The investigational antibody was well-tolerated over the four-week study period, with no serious or severe toxicities reported and no patients discontinuing the trial due to side effects. This clean safety profile is a crucial differentiator, as previous hot flash treatments have been limited by off-target activity and liver toxicities, which often necessitated dose selection below optimal efficacy levels.
• Significant Market Potential and Regulatory Pathway: BMO Capital Markets views the positive readout as "transformational" for AbCellera's business, forecasting unadjusted worldwide peak sales of $2.3 billion for ABCL635. AbCellera plans to engage with the FDA to discuss the late-stage development of the asset, with further 12-week follow-up data from the ongoing Phase 2 trial anticipated in the coming months to inform optimal dosing strategies.

AbCellera's ABCL635 Delivers Strong Phase 1/2 Results

The OASIS program evaluated elinzanetant, a dual neurokinin NK-1 and NK-3 receptor antagonist, across multiple trials in postmenopausal women with vasomotor symptoms (VMS). The OASIS-1 and OASIS-2 trials demonstrated reductions in both the frequency and intensity of moderate-to-severe VMS, with a potentially independent benefit on sleep disturbances and a favorable safety profile. The OASIS-3 trial extended these findings in a longer-duration assessment of elinzanetant 120 mg once daily: at week 12, the mean change from baseline in daily moderate-to-severe VMS frequency was −5.4 (95% CI, −6.3 to −4.5) for elinzanetant versus −3.5 (95% CI, −4.1 to −2.9) for placebo, yielding a least-squares mean difference of −1.6 (95% CI, −2.0 to −1.1; P < .001). Numerical advantages over placebo were sustained across 50 weeks for VMS frequency and severity, with additional improvements in sleep disturbances and menopause-related quality of life over 52 weeks.

From a safety perspective, elinzanetant in the OASIS-3 trial was not associated with hepatotoxic effects, endometrial hyperplasia, or meaningful changes in bone density or bone turnover markers — reassuring findings given regulatory scrutiny of these endpoints in this therapeutic class. Treatment-related adverse events were more common with elinzanetant than placebo (30.4% vs. 14.6%), with somnolence, fatigue, and headache emerging as the most frequently reported.

The SKYLIGHT 1, SKYLIGHT 2, and SKYLIGHT 4 trials evaluated fezolinetant, a selective neurokinin 3 (NK3) receptor antagonist, at doses of 30 mg and 45 mg once daily. Fezolinetant demonstrated efficacy in reducing VMS, though without a clear independent effect on sleep disturbances beyond VMS improvement. In a pooled safety analysis, treatment-emergent adverse events (TEAEs) occurred in 55.3% of placebo recipients versus 62.9% and 65.4% in the fezolinetant 45 mg and 30 mg groups, respectively. Commonly reported TEAEs included upper respiratory tract infection, headache, COVID-19, back pain, arthralgia, diarrhea, urinary tract infection, and insomnia. Liver transaminase elevations were observed in 1.5–2.3% of fezolinetant-treated participants, but were typically asymptomatic and transient, resolving on continued treatment or discontinuation, with no evidence of severe drug-induced liver injury meeting Hy's law criteria. Endometrial safety results fell well within FDA criteria, and no increased risk of benign or non-benign neoplasms versus placebo was identified.

ABCL635: Differentiating in the Hot Flash Treatment Landscape

The vasomotor symptom (VMS) treatment landscape spans hormonal and non-hormonal modalities with meaningful differences in efficacy, safety, and patient eligibility. While menopausal hormone therapy (MHT) remains the most effective intervention, safety concerns have driven development of non-hormonal alternatives — including a new class of neurokinin receptor antagonists — that offer compelling efficacy profiles without the hormonal risk burden.

Overcoming Current Limitations in Hot Flash Treatment

Current treatment approaches for hot flashes in postmenopausal women face a complex risk-benefit landscape that limits their universal applicability. While menopausal hormone therapy (MHT) remains the gold standard for vasomotor symptom control, safety concerns have driven demand for nonhormonal alternatives — yet these alternatives carry their own efficacy constraints.

• Breast cancer risk with MHT: The risk of breast cancer is generally increased with MHT, particularly in lean women with no prior MHT exposure who initiate estrogen-progestin therapy close to menopause onset and continue for several years — posing a significant barrier to long-term use in eligible candidates.

• Cardiovascular and thromboembolic risk with MHT: Oral estrogen-based MHT, combined with or without progestin, increases the risk of venous thromboembolism (VTE) by approximately 70%, rendering it contraindicated in women with VTE risk factors. Risks of stroke and coronary heart disease are further modulated by age at initiation, dose, and route of administration, with MHT contraindicated in women over 60 or more than 10 years post-menopause due to heightened thromboembolic risk and the absence of cardiovascular benefit — or potential harm — in those with established or subclinical atherosclerosis.

• Limited efficacy of nonhormonal options: The nonhormonal treatment landscape is narrow in both scope and effectiveness. SSRIs such as fluoxetine and sertraline are considered second-line options due to inferior efficacy relative to MHT, and patient response is highly variable — if one agent fails to provide adequate relief, a sequential trial-and-error approach across a 1–2 week drug trial period is required before switching.