One Small Biomarker Step for Bapineuzumab

Our boss wouldn't sign off on a business trip to Hawaii, even to cover the International Conference on Alzheimer's Disease in Honolulu. Something about not letting us leave our brains on the beach.

Instead we've been neural surfing from the IVB HQ this week. We spent time on the phone with a couple clinical execs to discuss Johnson & Johnson and Pfizer's release of biomarker data Tuesday, which the firms say is evidence the drug bapineuzumab is having an effect on the underlying processes of Alzheimer's.

The news is not the answer to the $64 million (or several-billion-dollar?) question whether the drug is slowing or reversing cognitive decline through disease modification. No drug has shown that yet, and until one does the frustration that's come with several Phase III setbacks will continue. (We'll have to wait until at least 2012 to know the answer about bapineuzumab.)

But the new bapi data underscores the importance developers are placing on biomarkers to help understand disease progression and guide clinical trial practice in the Alzheimer's field. The Phase III bapi trials are underway and can't be modified, but the data could affect future studies. (We'll examine the effects of biomarker development and the clinical setbacks on Alzheimer's-focused startups in the upcoming issue of START-UP.)

Pfizer and J&J were quick to caution that the data are also preliminary. Taken from Phase II trials that ended in 2008, they need to be confirmed in the global Phase III program that Pfizer and J&J's Janssen Alzheimer Immunotherapy division are running. Company officials said Tuesday that bapi seems to lower the amount of a variant of the protein tau in spinal fluid (CSF) that has been linked to neurodegeneration. (Data are at the end of this post.)

Bapineuzumab itself does not target tau. The CSF measurements are a "downstream" biomarker rather than direct effect, Ron Black, Pfizer's assistant vice president of clinical R&D, told the IN VIVO Blog.

A humanized monoclonal antibody, bapineuzumab is designed to prevent the beta-amyloid plaques that accumulate in patients' brains. But the tau biomarker study, which measured "phospho" tau, or P-tau, shows bapi is also having some effect on a second Alzheimer's pathology. "Recent scientific data suggests both [Aβ and tau] processes might be important," Janssen Alzheimer Immunotherapy's head of clinical development Eric Yuen told IN VIVO Blog. "The initial step may be overproduction or underclearance of toxic Aβ...that aggregate and become more toxic. The increase in P-tau subsequently produces more toxicity to neurons. It's a long process."

Another study released Tuesday showed the predecessor to bapineuzumab, AN1792, also made statistically significant reductions in tau (as well as Aβ). Development of AN1792 was halted after Phase II trials in 2002 when patients were struck with brain inflammation. Researchers continued to follow the patients, however. "The findings give us more basic information about the interaction between beta amyloid and tau in Alzheimer's and may clarify how the disease progresses in the brain," researcher Delphine Boche of the University of Southampton's School of Medicine said in a statement.

When neurons die, the tau from the microtubules inside the neurons is released into the spinal fluid. With less P-tau in the spinal fluid, it's more evidence to suggest bapineuzumab is preventing neuronal death. (The statistically significant data came from 46 patients in two Phase II studies; 27 got bapineuzumab, 19 received placebo.)

But that's a long way from showing positive clinical outcomes. The main Phase II tests for bapineuzumab, run by J&J and Pfizer's predecessors Elan and Wyeth, showed that only patients who did not carry the ApoE4 allele had statistically significant cognitive and functional improvement. That's crucial, because in Alzheimer's trials only such "real-world" measurements, can lead to a drug's approval. It's one reason why the so-called amyloid hypothesis, which holds that to cure Alzheimer's you have to curtail Aβ, is in question these days: There's little evidence so far that fighting Aβ leads to a functional difference to patients.

That's another reason to study biomarkers: the more data researchers gather about the underlying molecular biology of Alzheimer's, the more chance to correlate changes in the biology to improved cognition and function if and when those improvements carry the day in a late-stage trial.

Elan's rights went to J&J in a far-reaching deal last year, and Pfizer got partial rights when it bought Wyeth. Janssen's data are due main trial is expected to end in 2012 and Pfizer's in 2014.

The top-line data from the Phase II CSF tau study pooled two patient populations. They showed a statistically significant decrease (p=0.0270) in P-tau in bapineuzumab treated patients (9.49±2.74 pg/mL) compared with placebo-treated patients (-0.51±3.26 pg/mL). Although not statistically significant, the analysis also showed a trend (p=0.0856) for a decrease in T-tau in bapineuzumab-treated patients (-73.31±32.73 pg/mL) compared to placebo (+9.79±38.95 pg/mL) in the change from baseline to month 12 values.

Image courtesy of flickr users Eva and Rodney Harris.