BIogen AD Drug v. PBT2

Biogen PRIME Study
PRIME is an ongoing Phase 1b randomized, double-blind, placebo-controlled, multiple-dose study evaluating the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of aducanumab in patients with prodromal or mild AD. The company has stated that they are moving to a Phase 3 trial based on these results.
This interim analysis of PRIME reflects data for 166 patients, up to week 54 in the placebo (n=40), 1 mg/kg (n=31), 3 mg/kg (n=33) and 10 mg/kg (n=32) dose arms, and up to week 30 data for the 6 mg/kg (n=30) dose arm.
Here's a key point as it relates to Prana’s trial "In the placebo arm, the SUVR was virtually unchanged at 26 and 54 weeks." As we have said here many times this is how the PBT2 placebo should have responded during the IMAGINE study. Statistically significant responses in amyloid reduction at week 54 were only seen at doses greater than 3 mg/kg and the 6 mg/kg data are not yet. No MMSE or CDR-SB statistical significance were seen in 1mg/kg dose and the values for amyloid and cognition are dose dependent. The values for the 3 and 10 mg/kg dosing for MMSE were also dose dependent and achieved a p-value of 0.05 which is on the borderline of statistically significant. For CDR-SB only the 10 mg/kg dose level showed significance with a p-value of 0.05 (on the border).

So it appears that Biogen will have to focus on possibly the 6 mg/kg (not all the data are in for this level curiously)or the 10 mg/kg dose level to show improvement or stat signficance.

Victor Villemagne's abstract tells us what we know but in black and white from the company. In the SUVR greater than 2.5 group there was a statistically significant reduction in amyloid burden. In the less than 2.5 SUVR group there was not. If the placebo arm of the IMAGINE study wasn't confounded and acted as it should have as displayed by the Biogen trial the top line results would have been reported as statistically significant. This Biogen trial supports the conclusion that the IMAGINE trial placebo group was confounded. PBT2 also showed a signal toward HA reduction (which we knew). No HA reduction was reported in the BIogen trial results.

The problem comes for Biogen in the safety issues at the dose levels that showed stat significance and was highest in ApoE4 carriers which IMPORTANTLY comprise as we know about 65-75% of the AD population. Based upon MRI scans, ARIA-E (edema or swelling of the brain) was identified and was dose- and apolipoprotein E4-(ApoE4) status-dependent. ARIA-E was detected in was 55 percent pf the ApoE4 carriers in the 10 mg/kg arm. In ApoE4 non-carriers, the incidence of ARIA-E was 11 percent and 17 percent in the 6 mg/kg and 10 mg/kg aducanumab arms, respectively. In ApoE4 carriers, the incidence of patients who developed ARIA-E and discontinued treatment was 10 percent in the 6 mg/kg arm and 35 percent in the 10 mg/kg arm. There were no discontinuations in the 3 mg/kg arm. In ApoE4 non-carriers, the incidence of patients who developed ARIA-E and discontinued treatment was 11 percent in the 6 mg/kg arm and 8 percent in the 10 mg/kg arm.
These safety issues are significant and so far Prana has not reported any safety issues with PBT2 in the IMAGINE trial. I would be very surprised if Biogen did not have a clinical hold put on their Phase 3 based on these safety issues or told to do a Phase 2. AD is not an orphan indication so their drug won’t be able to get that classification. They will be able to apply for some sort of expedited process likely but compare this to the partial clinical hold that Prana received for the HD indication and I doubt they will be able to speed through the FDA process with these safety issues.

IMO, the safety issues are significant and no better than the PFE drug that was pulled from development.