Drug maker Biogen Idec is one step closer to a breakthrough in the Alzheimer’s disease field. For the first time, an experimental treatment seems to both clear out the telltale clumps of protein called beta amyloid from the brains of Alzheimer’s patients and—more important—slow down those patients’ cognitive decline.
At a medical conference in Nice, France, Biogen (NASDAQ: BIIB) today is reporting Phase 1b data promising enough on both fronts that the company will move its treatment, a monoclonal antibody called aducanumab, into a Phase 3 study, making good on plans executives have telegraphed since at least December, and which R&D chief Doug Williams reiterated to Xconomy in early January.
“It will probably be a pair of Phase 3 studies, that’s traditional,” Williams said at the time. “The aim for us would be to try to replicate what we saw in Phase 1b and stay as faithful as possible to that design.”
Williams stressed at that time the company had not settled on the final design, however. There were no details about the Phase 3 plans in this morning’s announcement except that the company was on track to start those tests later this year.
It’s no breakthrough yet. Big, late stage trials have a history of knocking flat what once seemed like promising Alzheimer’s treatments. But one veteran neuroscientist not affiliated with Biogen, who has been deeply involved in the clinical development of numerous Alzheimer’s compounds, reviewed the interim data and said Biogen had reason to be bullish. “This is really something to be excited about,” the scientist said, speaking on condition of anonymity.
The data out today are from a 166-patient Phase 1b study, dubbed PRIME, which tested four different doses of aducanumab, ranging from 1 mg/kg to 10 mg/kg, against patients taking a placebo.
On both measures—slowing down cognitive decline and clearing out amyloid plaque—the effects grew stronger as the doses increased and as time went on. “Directionally these signals are all highly consistent,” said the neuroscientist. “That’s a very important result and you don’t always see it.”
There are important questions about the drug’s safety. One major side effect was edema—swelling caused by leaky blood vessels—which in Alzheimer’s is measured with imaging technology. This in itself was not surprising. As with other antibodies that have targeted amyloid, edema was present in a large number of patients. (It’s thought, but not proven, that removing amyloid causes vessels to leak.) In one PRIME subset—patients in the highest-dose group who also had a genetic mutation that puts them at extremely high risk for Alzheimer’s—had a 55 percent incidence in edema, and 35 percent of them discontinued treatment.
However, Biogen stated that most cases were asymptomatic—they showed up in brain scans but not as outward medical problems—or if they did show up, the symptoms were “mild” and “transient.”
In stating forthrightly that aducanumab will move into Phase 3, Biogen is obviously confident the high edema rates in certain patient sets are not showstoppers. But it’s also worth noting that bapineuzumab, the antibody brought into Phase 3 by Pfizer (NYSE: PFE) and Johnson & Johnson (NYSE: JNJ), showed edema side effects early in clinical testing. That prompted its developers to use a lower dose. It’s possible that the lower dose resulted in its lack of effect, which ultimately made the Phase 3 trial a failure.
But bapi, as it was known, and solanezumab (another plaque-clearing antibody, developed by Eli Lilly (NYSE: LLY)) were also tested in patients whose Alzheimer’s was too far along. (Imagine trying to stop a war by clearing away the rubble of the destroyed buildings.)
The field has shifted since then, with many experts believing that to alter the course of the disease, you have to attack it much earlier. That’s what Biogen is doing with aducanumab, testing patients with the earliest signs of the disease. “This is the only stage of the disease in which intervention is possible,” said Elli Kaplan, CEO of Neurotrack, a San Francisco Bay Area startup with eye-tracking technology to help researchers and clinicians diagnose early-stage Alzheimer’s patients.
The PRIME data, which we’ll lay out in a moment, were highly anticipated. R&D chief Williams began the rollout of the results at an investment conference in December, prompting a run-up that has added 41 percent to Biogen’s share price and nearly $30 billion—not a typo—to its market capitalization.
Analysts earlier this week wrote to clients that they expected good results. “With management’s bullish commentary going into the meeting, we remain optimistic in our estimates of a ‘game-changing’ effect size of BIIB037 on cognitive benefit,” wrote Leerink Partners analyst Joseph Schwartz on Monday.
Here’s what the data show:
After 26 weeks of treatment, patients receiving all four doses showed reductions in amyloid plaque that increased with the dose size. After 54 weeks, the amount of plaque reduction in the 1mg, 3mg and 10mg patients was even greater. (Data from the 6mg cohort were not yet available.) Reductions in the smallest dose group were not statistically significant.
Clearing plaque is one thing; staunching the march of dementia is another. Biogen used two standard tests, the Mini Mental State Examination and Clinical Dementia Rating Sum of Boxes, to measure cognitive decline.
Again, the effects on the patients—in this case, the score on the tests—were proportional to the step-up in dose levels.
For example, on the MMSE, the placebo group scored 3.14 points lower after one year. The 1 mg group declined by 2.21 points; the 3 mg group, .75; and the 10 mg group, only .58.
On the CDR-SB, the placebo group declined by 2.04 points over one year. The 1 mg group, 1.70; the 3 mg group, 1.33; and the 10 mg group, .59.
The differences in those scores compared to placebo will certainly be a point of discussion. Before the data were released, for example, analyst Michael Yee of RBC Capital Markets wrote that for the high dose, a 1 to 1.5 point “delta,” or difference, on the MMSE would be “very solid.” (It has come in above 2.5.)
No doubt the safety figures will spark discussion, too. Headache was a side effect in 22 percent of those taking aducanumab and five percent taking placebo. There were three deaths: two in the placebo group, and one in the 10mg group that Biogen did not consider treatment-related. (But the company did not specify the patient’s cause of death.)
The edema data were broken into two groups: Carriers of the apolipoprotein E-e4 (ApoE4) gene—which puts them at higher risk of developing Alzheimer’s—and non-carriers.
Carriers in the 1 mg and 3 mg dose groups had a five percent rate of edema; in the 6 mg group, 43 percent; and in the 10 mg group, 55 percent. Biogen said the edema caused 5 percent of the patients in the 1 mg group to stop treatment; 10 percent in the 6 mg group; and 35 percent of the 10 mg group. (No one in the 3 mg group discontinued treatment.)
Non-carriers in the 1mg group had no incidence of edema; the 3 mg group, 9 percent; the 6 mg group, 11 percent; and the 10 mg group, 17 percent. There were no discontinuations in the 1 mg and 3 mg dose groups; 11 percent of patients in the 6 mg group and 8 percent in the 10 mg group dropped out.
How those data affect Biogen’s dosing strategy is an open question, perhaps one to be answered in coming days.
Photo “My Mother’s Hands” courtesy of Ann Gordon via a Creative Commons license.