Things I noted from the following DD. (Never hurts to see others progress and timelines)
1. A dose that was declared safe in a small trial of ~70 people proved unsafe in a larger ~ 400 person trial.
2. Who would have guessed the FDA would grant “fast track” as results didn’t seem particularly impressive. Perhaps a good sign for A2-73’s chances.
3. Notice how long the trial is taking even with Fast Track? Three years! And that’s for strictly a Phase 3 not a combined 2/3. They actually received fast track in 2013 so it’s been closer to 5 years to design and complete the Phase 3.
4. Perhaps “rates of hippocampal shrinking or CSF biomarker measures. “ are indicators that Anavex should be measuring?
5. Looks like this soon to be completed trial is not targeting A-beta either, maybe it can help lower that 99.6 rate?
“This compound was discovered by TransTech Pharma as TTP488 and licensed to Pfizer as PF-04494700. In 2005, Pfizer ran a 10-week Phase 2 trial in 67 people with mild to moderate AD. This trial compared two doses—15 mg for six days followed by daily dosing of 5 mg, and 60 mg for six days followed by daily dosing of 20 mg—against placebo for safety and tolerability. Both doses were reported to be safe and well-tolerated, with more people in the treatment groups completing the trial than people in the placebo group (Sabbagh et al., 2011). In 2007, Pfizer and the National Institute on Aging jointly funded a larger, 18-month Phase 2 trial run via the Alzheimer's Disease Cooperative Study (ADCS). This trial recruited 399 people with mild to moderate AD and evaluated the same doses for safety and efficacy as measured by the ADAS-cog. The higher dose was dropped after a six-month interim analysis flagged both safety signals and faster deterioration. The low dose was halted before its intended conclusion following a futility analysis that indicated no benefit; however, follow-up examination conducted after treatment was suspended did suggest a possible belated clinical benefit for the low dose (see Nov 2011 conference news story).
Pfizer terminated its work with this compound in 2011. Pfizer had previously been developing PF-04494700 for diabetic neuropathy but discontinued this program as well. In March 2013, TransTech Pharma announced in a press release that it had received fast-track designation from the Food and Drug Administration for this compound in Alzheimer's disease, and in July it announced that it had met with the FDA and was planning a pivotal trial in patients with mild to moderate AD.
In April 2015, a Phase 3 trial of azeliragon began at three sites in the United States and in Toronto. This study will compare an 18-month course of the 5 mg daily dose to placebo in 800 people who have a clinical diagnosis of mild probable Alzheimer's disease and an MRI consistent with this diagnosis. The trial does not use CSF or amyloid PET to ascertain that Alzheimer's underlies the clinical symptoms. The twin primary outcomes are the ADAS-cog and CDR-sum of boxes. The trial is set to run until 2018.
“Galasko’s presentation offered a glimmer of hope when he described results of a follow-up examination, conducted after treatment was suspended. That analysis hinted at a possible belated clinical benefit for a low dose of the study drug; however, that only became evident after most patients had already been taken off the treatment. Although far from conclusive, the findings may serve as a cautionary tale for adaptive-style trials that rely on interim analyses, said Galasko.”
“When Galasko and colleagues analyzed the complete dataset including all 18-month measurements, things got interesting (or confusing, depending on one’s point of view). They found that the rate of cognitive decline in the high-dose group had slowed down, and their ADAS-cog scores were now similar to those of the placebo group, at least for those patients who continued to return for follow-up visits. Galasko could not explain the faster cognitive worsening in this group or their subsequent stabilization of cognitive symptoms. “We don’t know the mechanism of toxicity. We did not find any evidence of vasogenic edema or any other abnormality on MRI,” he said. When the researchers analyzed the results of the 69 patients in the lower-dose group who completed the 18-month analysis, they found post-hoc evidence of improvement in their ADAS-cog scores compared to the 68 patients in the placebo group. There were, however, no differences in other clinical outcome measures or in the rates of hippocampal shrinking or CSF biomarker measures. This improvement in ADAS-cog scores was not detected at the 12-month timepoint, and it disappeared if the researchers only analyzed test scores obtained from patients while they were receiving the study drug.
Although the clinical trial did not provide evidence to support continued development of PF-04494700, Galasko said ending the trial early may have prevented the scientists from seeing any positive effects that required more than 12 months to become apparent. “We need to be careful about adaptive designs and stopping rules if we want to get the maximum amount of information about a drug,” he said. Other researchers at the meeting pointed out that the findings are difficult to interpret, given that the trial was stopped early and so many patients dropped out. “
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