It is a bold claim to make, but the recently listed German group Probiodrug reckons it might have cracked the problem that has seen anti-beta amyloid agents like solanezumab and aducanumab underwhelm in Alzheimer’s disease studies.
That said, Probiodrug is fundamentally underpinned by the same beta amyloid hypothesis, in which “you're either a believer or you're not”, the group’s chief executive, Konrad Glund, tells EP Vantage. And investors taking a bet on this binary outcome do not have to wait long: Lilly should soon report data from LY3002813, providing a vital clue to Probiodrug’s lead assets.
The key lies in Probiodrug’s identification of pyroglutamate beta amyloid (pGlu-Abeta) as being crucial to the formation of soluble, toxic “pre-plaques” that it says lie behind Alzheimer’s progression. And, while the competition has focused on targeting beta amyloid in general, Probiodrug has specifically focused on the pGlu-Abeta form.
This is where LY3002813 comes in: the Lilly project is an antibody specifically against pGlu-Abeta, in a phase I study in 100 mild to moderate Alzheimer’s patients. When the data are reported – perhaps at October’s Society for Neuroscience meeting – they could validate Probiodrug’s approach.
Few binary outcomes have as important a readacross. If the data are positive Probiodrug will put its own anti-pGlu-Abeta MAb, PBD-C06, into phase I, says Mr Glund. “We think our antibody would then also be of interest to many others, and we think we can finance [phase I] on the spot.”
Ace up its sleeve
But the German group also has a more advanced ace up its sleeve: PQ912, a small-molecule inhibitor of glutaminyl cyclase, or QC – the precise enzyme that Probiodrug has identified as catalysing the conversion of beta amyloid into the toxic pGlu-Abeta form.
PQ912 is in Saphir, a phase II early Alzheimer’s trial reading out in mid-2016. The Lilly data should provide investors with clues to the outcome of Saphir too, though PQ912’s ability to cross the blood/brain barrier is an important difference.
“The conversion to pGlu-Abeta takes place in the brain, and PQ912 has brain exposure – we’ve shown that in an extensive phase I study,” says Mr Glund. “We pushed the dose really high and didn’t really reach the maximum tolerated dose.”
Of special interest will be Saphir’s exploratory efficacy metrics looking at cognition, measures of brain connectivity and molecular biomarkers in the cerebrospinal fluid (CSF). “We have safe doses that have shown >90% QC inhibition in the CSF in phase I,” says the chief executive.
The company raised €23m ($25m) in its Euronext IPO last October, enough to reach the Saphir readout as well as putting PBD-C06 into the clinic. “The Saphir data would then be the basis to discuss partnering with pharma,” says Mr Glund, adding that on a strongly positive result PQ912 would be ready for phase III.
Less convincing data – Saphir is testing acute treatment over three months – might necessitate a one-year phase II confirmatory trial to show disease modification. Another possibility is combining the small molecule with the MAb.
“The solution probably lies in a combination,” says Mr Glund. Lilly has already looked preclinically at combining LY3002813 with a BACE inhibitor, and might well throw solanezumab into the mix.
As with any Alzheimer’s project there are risks, though Mr Glund is sure that thanks to broad characterisation and focus on molecular signatures Probiodrug is recruiting patients at the right stage of early disease.
He also highlights the work his group has done to show that PQ912 actually engages with its target, QC, in the CSF. “Look at solanezumab: can Lilly measure target engagement? They cannot.”
And while Lilly and Biogen have only generated hints of supporting evidence, Mr Glund remains a firm believer in the beta amyloid hypothesis, saying soluble beta amyloid is what carries toxicity (Glimmers of support, but no Alzheimer’s breakthrough, July 23, 2015). “We’re just focusing on a minor fraction of beta amyloid, and think we’re much more efficacious.”
It might come as a surprise that Probiodrug has not yet made a push into the US, though Mr Glund says he is preparing a pre-IND meeting with the FDA this year.
Considering the recent Nasdaq flotations of Axovant ($315m) and vTv Therapeutics ($117m) – both on the strength of failed Alzheimer’s projects – there are no prizes for guessing where Probiodrug might have the best chance of raising more money.
|Duelling Alzheimer's approaches focused on pGlu-Abeta|
|LY3002813||Lilly||Phase I safety trial in 100 early to moderate Alzheimer's||NCT01837641|
|PQ912||Probiodrug||Saphir, phase II safety trial in 110 early patients||NCT02389413|