Why ABCL635 Has a Strong Chance of Positive Phase 2 Efficacy Results (Q3 2026)
Menopausal hot flashes are driven by overactive KNDy neurons in the hypothalamus. When estrogen drops, these neurons go into overdrive and disrupt the brain’s temperature regulation center (the MnPO), triggering hot flashes. Small-molecule drugs like fezolinetant work by blocking the NK3R receptor. Because they are small, they easily cross the blood-brain barrier and can hit both the KNDy neurons (upstream) and the MnPO directly (downstream). This dual action has been proven to reduce hot flashes effectively. AbCellera’s ABCL635 is a monoclonal antibody. Antibodies are much larger, so they have limited ability to cross into certain parts of the brain. This means ABCL635 primarily blocks NK3R on the KNDy neurons upstream, with much less direct effect on the MnPO.
Why This Can Still Work Well
A landmark study (Mittelman-Smith et al., PNAS 2012) tested exactly this idea. In ovariectomized rats (a menopause model), researchers used a targeted toxin to completely ablate (destroy) the KNDy neurons, an upstream-only intervention. The result was a clear reduction in hot flash-like symptoms (reduced tail skin vasodilation) and lower MnPO activation. This experiment is crucial: it shows that strongly suppressing KNDy neuron activity upstream alone is sufficient to calm the downstream pathway and reduce hot flashes — even without direct pharmacological action on the MnPO.
Phase 1 Data Strengthens the Case
AbCellera’s Phase 1 study showed that a single dose of ABCL635 produced strong and sustained suppression of testosterone, LH, and FSH for several weeks (far longer than the transient daily effect of small molecules). This is a validated biomarker confirming robust target engagement on KNDy neurons. In other words:
- The animal study (Panel C) proves upstream KNDy suppression works
- Panel C also proves that with the absence of the KNDy neurons, MnPO is activated, reducing hot flashes. This ultimately shows that engagement on KNDy neurons have strong activation on MnPO downstream and that having direct activation on MnPO is not necessary to get reduction in hot flashes
- Phase 1 proves ABCL635 is achieving strong, long-lasting upstream KNDy suppression in humans
TLDR
When you combine the strong mechanistic evidence from the ablation study with the impressive Phase 1 biomarker data, the probability that ABCL635 will show meaningful efficacy in Phase 2 looks reasonably high (I’d estimate 75-80%+). The antibody’s sustained pharmacology could even offer an advantage over daily pills. Of course, clinical results are never guaranteed, and Phase 2 (expected Q3 2026) will be the real test. But the science lines up well for this program.
