For some, the amyloid beta (Aβ) theory is dead since the Solanezumab trials failed in late 2016. “Not so fast”, says Probiodrug, a small Germany biotech, which aims to tell a different story about Aβ. The company recently released top line data from an Phase IIa study and as it seems, they might be up to something.
Probiodrug’s theory is based on the idea that neither Aβ monomers nor oligomers are responsible for the damage done to the brain but that a toxic form of Aβ, called pGlu‐Aβ is the main culprit. They also stress that normal Aβ has a physiological function and targeting it is therefore useless if not counterproductive.
According to Probiodrug’s hypothesis, a protein called Glutaminyl Cyclase (QC) turns normal Aβ into toxic pGlu‐Aβ which then goes on and quickly forms these well known oligomers found in Alzheimer patient’s brains. So inhibiting QC is the way to go for Probiodrug.
Even before the phase IIa trial read out, this hypothesis in fact predicted that Solanezumab would likely fail, while Aducanumab might have a chance to succeed.
In contrast to Aducanumab, which mainly binds Aβ oligomers, Solanezumab was specifically designed to target monomers. Now while it probably does this at a good rate, there are always still enough monomers left to be turned into pGlu‐Aβ and start the toxic cascade.
Aducanumab on the other hand is known to target multimers and therefore indirectly also its catalyst – pGlu‐Aβ. And since a few weeks we also know now first hand that the pGlu‐Aβ theory warrants further research. Probiodrugs study called SAPHIR, a 3 months, double-blind, placebo controlled randomised study showed quite encouraging results, given the short time frame. From the press release:
There was a strong trend for reduction in the level of neurogranin, a marker of synaptic dysfunction in the ITT population in the treatment arm compared to placebo (p=0.1), which became significant if 3 patients starting prohibited concomitant medication during the study were excluded (p=0.046, a 5% absolute reduction of baseline in neurogranin observed in the treatment arm). There was also a strong trend in the mean reduction of YKL 40, a biomarker of inflammation, in the PQ912 arm compared to placebo (p= 0.07, 5% absolute reduction of baseline–level in the treatment arm).
EEG: The analysis of the EEG power spectra showed a significant reduction of theta power in the PQ912 arm compared to placebo (p=0.002). Slow wave theta activity is reported to increase with the onset and progression of AD. Further analysis of functional connectivity and EEG network parameters is pending.
Neuropsychological test battery (NTB): Patients in the placebo arm showed overall a stable performance with no or marginal change between baseline and week 12. Performance on the ‘One Card Back Test’, an assessment of working memory showed a statistically significant effect in favour of PQ912 (p=0.05, Cohen’s d = 0.24) while the ‘Detection Test’ an assessment of attention, also showed a meaningful improvement under PQ912 (Cohen’s d=0.20) although not sufficient to reach statistical significance. Performance on the five other cognitive assessments, as well as on their aggregate scores, were not influenced by treatment with PQ912 for 12 weeks (Cohen`s d < 0.2).
Not too exciting one might say. The catch with any Alzheimer study however is that you don’t want to show that the drug cures the disease but that it stops progression while the placebo arm keeps worsening. Neither the Solanezumab nor the Aducanumab studies showed meaningful differences between the drug arm and the placebo arm at the 12 week cutoff. So seeing a signal in the neuropsychological tests after only 12 weeks is quite encouraging, even if it’s just a weak one.
On a negative note, the trial revealed some side effects issues not seen in previous studies. But while this is a negative for the drug, it does not change the validity of the pGlu‐Aβ hypothesis.
The treatment of Alzheimer will most probably require a multidimensional approach but an anchor for such a treatment is still missing. It should not be ruled out that inhibition of QC will be a core pillar of an Alzheimer treatment.