PRIME: Titration, 2-Year Data on Aducanumab Still Look Promising in Early Alzheimer's

Deborah Brauser

December 14, 2016

Building on positive fixed-dose findings at 1 year, aducanumab (Biogen Inc) also showed significant benefits for patients with mild Alzheimer's disease (AD) in the titration and 24-month data just released from the phase 1b trial known as PRIME.

Clinical, safety, and biomarker results were presented in separate papers at the Clinical Trials on AD (CTAD) meeting in San Diego, California.

The first presentation showed that a cohort of participants with doses titrated up to 10 mg/kg aducanumab (average dose, 5.3 mg/kg) had significantly more improvement in mean positron emission tomography (PET) standard uptake value ratio (SUVR; –0.17) at 1 year compared with those receiving placebo.

This was less improvement than the SUVR change from baseline shown originally in the 10 mg/kg fixed-dose group (–0.266) but was in between what was found for those receiving 3 and 6 mg/kg fixed doses, supporting the treatment's antiamyloid activity, note the investigators.

In addition, there was a significant slowing of decline on the exploratory endpoint of Clinical Dementia Rating-Sum of Boxes (CDR-SB) in the titrated vs placebo group, along with a trend toward a slowing of decline on the Mini-Mental State Examination (MMSE).

Interestingly, titration may also reduce the incidence of amyloid-related imaging abnormalities with edema (ARIA-E) in ApoE ε4 carriers, which has been a problem with similar treatments. Fifty-five percent of carriers who received aducanumab at the 10 mg/kg fixed dose had ARIA-E vs 35% of those whose dose was titrated up to 10 mg/kg.

Dr Diana R. Kerwin

In the second presentation, Samantha Budd Haeberlein, PhD, vice president of clinical development at Biogen, told attendees that 24-month data showed continued and dose-dependent reduction of amyloid-β (Aβ), as shown on amyloid PET.

Results also "suggest sustained cognitive benefit" over the 2-year period, as measured on the CDR-SB and MMSE. And no new ARIA cases were reported between months 12 and 24.

Session moderator Diana R. Kerwin, MD, Texas Alzheimer's and Memory Disorders, Dallas, noted that although the study is small, there is reason for cautious optimism.

"They definitely showed a dose-response relationship to reduction in amyloid on amyloid PET. And they showed a dose-response in their cognitive endpoint," Dr Kerwin told Medscape Medical News after the presentations.

"So it looks really promising, and I think it looks more promising than anything else we've seen."

High Expectations

Initial PRIME results were first presented at last year's International Conference on Alzheimer's and Parkinson's Disease; subgroup results were presented at the American Academy of Neurology 67th Annual Meeting; and full 1-year fixed-dose results were published in September in Nature.

After negative topline results were released last month from the EXPEDITION3 trial of solanezumab vs placebo for mild dementia from AD, talk from the field moved toward aducanumab — another anti-Aβ monoclonal antibody.

The spotlight continued to shine after the full EXPEDITION3 failed results were presented at a special CTAD session the night before the scheduled aducanumab sessions — and was brighter still when the new PRIME results were leaked earlier than planned.

By the time Dr Haeberlein took the stage in front of a packed room, expectations were high for the small trial.

Although solanezumab and aducanumab "do have their differences," Dr Kerwin said that the way the PRIME investigators structured their study design shows that "they seem to have a better handle on dosing. And that could be in part because they seemed to figure out what their dose level toxicity was."

In PRIME, 197 patients aged 50 to 90 years who had a positive florbetapir (18F-AV-45) PET scan and who met prodromal or mild AD criteria were enrolled and randomly assigned to 1 (n = 31), 3 (n = 33), 6 (n = 30), or 10 mg/kg fixed-dose aducanumab (n = 32); titrated aducanumab (n = 23); or placebo (n = 48) every 4 weeks for 54 weeks. A subgroup of ApoE ε4 carriers was also assessed.

For the titration cohort, the schedule included 1 mg/kg of aducanumab for the first 2 doses, 3 mg/kg for the next 4 doses, 6 mg/kg for the next 5 doses, and then 10 mg/kg afterward. The weighted average dose by week 52 was 5.3 mg/kg, with a PET SUVR of –0.171 at month 12 (P < .001).

Dr Maria Carrillo

The placebo group had a significant worsening from baseline on the CDR-SB vs the titration group (average drop, 1.89 points vs 0.7 points, respectively; P < .05). Although the difference was not significant, the placebo group also worsened more on the MMSE (average drop, 2.45 points vs 0.99 points, respectively).

"I thought this titration study was interesting as it habituated the body slowly to higher doses. And it showed that this helped avoid ARIA over time, which was very promising," Maria Carrillo, PhD, chief science officer of the Alzheimer's Association, commented to Medscape Medical News.

"And the cognitive and other findings, though small, all showed that the previous hypothesis was still in place even in the face of titration of dose," added Dr Carrillo, who was not involved with the research.

Extension Data

After the initial 12 months of treatment, the placebo-controlled study was rolled into a 3-year extension study. All 117 patients participating in the long-term extension received 3, 6, or 10 mg/kg of aducanumab. A total of 91 of these participants completed the study through month 24.

The individuals who were originally randomly assigned to receive placebo received a 3-mg/kg fixed dose of aducanumab during the extension phase or a titrated dose from 3 to 6 mg. And those who originally received 1 mg/kg were moved to the 3-mg/kg fixed dose. All others continued with their original dosing assignments.

The primary endpoint for this analysis was safety and tolerability, as measured by adverse events (AEs). The most commonly reported AEs in the long-term extension were falls, headache, and ARIA. At 24 months, no new ARIA cases were reported for patients continuing to receive 3, 6, or 10 mg/kg.

However, among the 5 patients with ARIA, 1 had a concurrent serious AE of seizure and loss of pulse. Although 2 patients died during the trial (1 in the 10-mg/kg and 1 in the 6 mg/kg group), these were not deemed to be treatment related.

Aβ reduction on amyloid PET and cognitive change from baseline were exploratory endpoints. The "switchers" who originally took placebo for 12 months and then took 3 to 6 mg/kg aducanumab for an additional 12 months had an SUVR change of –0.16.

Compared with the overall placebo switchers, both the 10- and 6-mg/kg continuers showed significant decreases in amyloid plaque burden at 24 months (SUVR, –0.33 [P < .001] and –0.28 [P < .01], respectively). Both of these findings were better than those shown after the original 12 months (SUVR, –0.27 and –0.21, respectively).

The difference on the CDR-SB at 24 months between those receiving placebo and those receiving the 10-mg/kg treatment dose was 1.62 points.

"The data [presented] at CTAD support the positive results we have seen in our Phase 1B study of aducanumab and provide insight into the observed effects in patients treated for up to two years," said Dr Haeberlein in a release.

Dr Kerwin noted that the findings regarding the ApoE ε4 carriers were especially striking. "This does have downstream implications. If this were to ever come to a treatment, we're going to have to know the genetic makeup of our patient before we give them aducanumab and to figure out what dose is most appropriate for them."

In addition, "it was interesting that they were able to adjust dosages and still see the really nice showing of the decline on the amyloid PET and improvement on the cognitive endpoint," she said.

"They showed a fairly strong signal," added Dr Kerwin. "Now, we have seen strong signals in phase 1 trials before, such as with solanezumab. But I think [these investigators] have a little bit of a better handle, possibly because they've been able to learn from some of the mistakes of the past."

Moving Forward

For Dr Carrillo, one of the most interesting points of the trial centered on the placebo switchers in the extension phase. "These switchers showed some reduction in amyloid load. But it didn't bear out over a year in terms of cognition. They never caught up to the highest dose," she noted.

"I think this is very interesting because it's supportive of the hypothesis that the earlier you start, the better and more tractable the brain is to the medication — and the more tractable that the disease could be," said Dr Carrillo.

"Can they catch up later? We just don't know. The extension study has been approved for 3 years out, so it would be interesting to see how far out this effect on memory is sustained."

She added that each subgroup in the phase 1b trial was small, "so you can't really make huge statements. But there was supportive evidence that this treatment might work in the upcoming phase 3 studies."

That said, the phase 3 safety and efficacy ENGAGE and EMERGE trials are enrolling participants with early AD. According to ClinicalTrials.gov, each study is expected to include 1350 patients and is shooting for completion in February 2022.

The primary outcome measures for both trials will be change on the CDR-SB from baseline to week 78. Secondary outcomes include change from baseline on the MMSE, the 13-item AD Assessment Scale-Cognitive Subscale, and the AD Cooperative Study-Activities of Daily Living Inventory-Mild Cognitive Impairment version.

"We are committed to advancing our global phase 3 program…as well as the scientific understanding of Alzheimer's disease so we can help identify a treatment for the many people affected by this terrible disease," said Dr Haeberlein.

PRIME was funded by Biogen. Dr Haeberlein is an employee of Biogen. Dr Kerwin and Dr Carrillo have disclosed no relevant financial relationships.

9th Annual Clinical Trials on Alzheimer's Disease 2016. Abstracts OC21 and OC31, both presented December 9, 2016.

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