If you’ve been in biotech long enough, you remember Cortexyme.
The San Francisco shop that bet a whole company on the theory that Porphyromonas gingivalis, the gum disease bacterium, drives Alzheimer’s pathology through a special family of bacterial proteases called gingipains.
Their lead asset, atuzaginstat, was a Kgp inhibitor.
The Phase 2/3 GAIN trial read out in 2021. It missed its primary endpoint.
The company eventually pivoted, rebranded as Quince Therapeutics, and the entire “gingipain hypothesis” got filed under “interesting, didn’t pan out.”
Apparently, the biology disagreed.
Lighthouse Pharmaceuticals, a clinical-stage shop also out of San Francisco, closed a $12 million Series A led by Double Point Ventures, stacked on top of a $49.2 million grant from the National Institute on Aging.
Their lead drug, LHP588, is also a brain-penetrant lysine-gingipain inhibitor.
Yep, tat’s right – the exact same target class as the molecule that flamed out four years ago.
The argument for trying again is sharper than the original hypothesis one, though.
Lighthouse is enrolling 300 patients with mild-to-moderate Alzheimer’s who also have confirmed P. gingivalis infection. The Phase 2 SPRING trial kicked off in February at the Northwest Clinical Research Center in Bellevue.
The patient selection is the meaningful tweak.
Where Cortexyme didn’t biologically stratify their patient selection rigorously; Lighthouse is treating the bacterium-positive subset as the only patients who could plausibly benefit.
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Also, is it just me or is the “dilutive-to-non-dilutive ratio” here striking?
$12M Series A on top of $49.2M from the National Institute on Aging means the federal government is funding roughly 80% of the runway.
I am guessing this changes how Double Point Ventures and the syndicate get to think about valuation, dilution, and timing.
It also says something about how aggressive NIH is willing to be on Alzheimer’s bets right now, especially ones that offer an alternative path to the worn out “amyloid-only orthodoxy”.
One other thing worth saying…
Now that anti amyloid drugs like Leqembi and Kisunla are actually on the market and doing… something (but, honestly, not a ton and they’re SUPER super expensive), there’s real appetite from patients and honestly the whole field for anything disease modifying that isn’t just more anti amyloid.
A pathogen-driven hypothesis fits that opening.
When that sweet, sweet clinical data comes, it will either retire the gingipain story permanently (clinical failure) or restart it.
No pressure!
The future of an entire therapeutic class is riding on you!!
It is hard to think of many other Phase 2 readouts that carry that much weight for an entire mechanism class.
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