21 Dec 2016

Let down by solanezumab’s demise, researchers at the Clinical Trials for Alzheimer’s Disease conference, held December 8-10 in San Diego, were in sore need of some good news. They got a taste of it, albeit small, with the release of new data from PRIME, the Phase 1b trial of the anti-Aβ antibody aducanumab. Biogen researchers presented results of a titration arm of the trial, in which gradually upping doses in ApoE4 carriers not only limited the amyloid-related imaging abnormality (ARIA) that signifies edema in the brain, but also cleared more brain amyloid than seen in participants on either of the two lowest doses of the drug. Participants in a long-term extension study also saw their brain amyloid load continue to shrink. In a separate bit of hopeful news, researchers from Genentech showed data from a Phase 1b trial of their anti-Aβ antibody, crenezumab. They reported that higher doses were safe and reaffirmed the company’s decision to boost the dose in a Phase 3 trial. Results from Phase 3 trials of both immunotherapies are expected in 2020.

Suzanne Hendrix of Pentara Corporation in Salt Lake City commented that in terms of their trial results and potential as therapies, solanezumab and aducanumab are polar opposites: Results from the aducanumab trial were tantalizing yet fraught with large error bars and small sample size, while the solanezumab trial yielded statistically solid results whose effect size was underwhelming.

The monoclonal antibody aducanumab latches onto oligomeric and fibrillar forms of Aβ, whereas solanezumab preferentially binds soluble monomeric Aβ. Phase 1 results of aducanumab in people with prodomal and mild AD were gradually offered up in tasty morsels at conferences over the past two years, dazzling researchers and investors. Findings suggested dramatic reductions in Aβ burden—in some cases to near-normal in people who began the trial with a brain full of plaques (see Mar 2015 conference news and Aug 2015 conference news). To the chagrin of some researchers, Biogen teased the field with exploratory findings indicating a cognitive benefit, and a post hoc data analysis indicating that this happened only in people whose brain amyloid had shrunk (see Sep 2016 news). The sword of Damocles hanging over this antibody was widely seen to be its dose-related increase of ARIA-E, particularly in ApoE4 carriers.

In hopes of managing this problem, researchers hypothesized that gingerly nudging up the dose might reduce the occurrence of ARIA-E in those patients. To investigate, they added a titration group to PRIME, along with eight ApoE4 carriers in a new placebo group. Over 12 months, 23 ApoE carriers received two doses of 1 mg/kg, four doses of 3 mg/kg, five doses of 6 mg/kg, and three doses of 10 mg/kg aducanumab, while eight ApoE4 carriers received placebo. At CTAD, Biogen’s Vissia Viglietta superimposed data from this titration arm on the previously published data from the 1, 3, 6, and 10 mg/kg groups, as well as the pooled placebo group of 48 participants. Amyloid-PET scans revealed that, similarly to the placebo and 1 mg/kg groups, no significant reductions in amyloid burden had occurred in the titration group at six months, by which time they had just started taking the 6 mg/kg dose. However, by 12 months, Aβ took a nosedive in the titration group, ending up between the continuous 3 mg/kg and 6 mg/kg groups. On the clinical dementia rating scale sum of boxes (CDR-SB)—an exploratory measure on which the trial was too small to draw conclusions—slowed decline in the titration group seemed on par with that seen in the 10 mg/kg group.

Importantly, ApoE4 carriers in the titration arm experienced less ARIA-E than did ApoE4 carriers who continuously received 6 or 10 mg/kg. Eight out of 23 patients in the titration arm (35 percent) had ARIA-E, compared with nine out of 21 (43 percent) and 11 out of 20 (55 percent) in the 6 and 10 mg/kg groups, respectively. The eight ARIA-Es in the titration group surfaced early in the trial, during the 3 or 6 mg/kg dosing segments. The researchers stressed that all these imaging abnormalities, along with their possibly associated symptoms such as headache, resolved within four to 12 weeks. Six of eight participants with ARIA-E continued treatment.

Based on this data, Biogen decided to employ this titration strategy in the Phase 3 studies of aducanumab. ApoE4 carriers will start at 1 mg/kg and titrate up to 6 mg/kg, while noncarriers will titrate up to 10 mg/kg, Biogen’s Samantha Budd Haeberlein told Alzforum.

In a separate presentation, Budd shared results from the first year of a three-year extension study, in which PRIME participants could choose to continue open-label treatment. People who had received 3 mg/kg, 6 mg/kg, or 10 mg/kg doses during the first 12 months stayed on the same dose for the extension, while those who had received 1 mg/kg switched to 3 mg/kg. People in the placebo group during the first year of the trial upped it to 3 mg/kg or to a titration, which started with two doses of 3 mg/kg followed by 6 mg/kg for the rest of the extension.

Scientists packing the hall let out a collective gasp when Budd flashed the 24-month amyloid-PET results, revealing a further drop in brain amyloid in each continuous dose group between 12 and 24 months. The trajectory of the amyloid curves for participants who had been in the placebo or 1 mg/kg groups had been nearly flat for those 12 months, but kinked downward after participants switched into 3 mg/kg for the extension.

Their clinical endpoints were less clear-cut. Performance on the CDR-SB leveled out between 12 and 24 months for people taking the 10 mg/kg dose, while it continued to decline in the 3 and 6 mg/kg groups. Decline in the 3 mg/kg group was slower than in the 6 mg/kg group. People whose dose went up in long-term extension, i.e., those who switched to 3 mg/kg from placebo or 1 mg/kg, declined slightly faster than did the continuous 6 mg/kg group.

Of 117 participants who started the extension trial, 26 discontinued treatment. Of those, 12 discontinued due to adverse events—the most common ones being falls, headache, and ARIA-E. Among patients who continued on their same dose, no new cases of ARIA-E cropped up in the extension portion of the trial. However, perhaps unsurprisingly, five of 29 “placebo switchers” and three of 17 people who switched from 1 mg/kg to 3 mg/kg developed ARIA-E. Seven of these eight incidents occurred in ApoE4 carriers, and four of the 12 adverse event-related drop-outs from the extension trial were due to these events.

At CTAD, many researchers expressed cautious optimism about this latest release of aducanumab results. Some wondered about potential effects of the trial’s staggered enrollment. The 1 mg/kg, 3 mg/kg, and placebo groups started first, followed by a 10 mg/kg group along with another placebo group. After ARIA-E started cropping up in them, the researchers added the 6 mg/kg dose and later the titration arm, each along with another placebo group. For each separate enrollment, participants were randomized 3:1 to active versus placebo groups. The 6 mg/kg group did not fall neatly in line with the dose-response curve for cognitive endpoints—landing in between the 3 mg/kg and 1 mg/kg groups on the MMSE at 12 and 24 months, as well as on the CDR-SB at 24 months. Noting that raters of cognitive tests, who were privy to the timeline, might make assumptions about which dose group a person belonged to, Hendrix asked whether this could skew assessors to score participants with later start dates higher if they thought they were on higher doses. Comparing cognitive scores among the placebo groups could partly allay such concerns, Hendrix told Alzforum (see Nov 2015 news). 

Budd said that while investigators were indeed aware of the enrollment schedule, they were blinded to randomization to active treatment or placebo. She said investigators noted no obvious differences between the placebo groups but that because those groups were small, about eight patients each, the study was not powered to detect such differences. “Pooling the placebo groups was part of the prespecified analysis,” she told Alzforum. Several site investigators, including Larry Honig of Columbia University, New York, noted that with such small numbers of participants in each arm, they would like to see how individual patients performed over time, for example by way of spaghetti plots.

Jacking Up Crenezumab
With its own Phase 3 trial in the starting blocks and new results from Phase 1b, Genentech’s crenezumab program sits at a similar stage of development as aducanumab, though its Phase 3 program at present is smaller. Crenezumab—a humanized IgG4 monoclonal antibody—binds to oligomeric forms of Aβ. Because IgG4 antibodies exert little effector function, meaning they trigger fewer potentially destructive cytokine responses, researchers hope to be able to use higher doses without triggering neuroinflammation that may underlie ARIA-E.

At CTAD, Helen Lin, of Genentech in South San Francisco, presented results from a new Phase 1b dose-escalation study that the company is using to determine the best doses for its nascent Phase 3 trial, CREAD. Genentech tested the safety and tolerability of 40, 60, and 120 mg/kg doses after patients had received 15 mg/kg in a previous Phase 2 trial. The decision to jack up the dose stemmed from findings of a new drug-disease progression model, which accurately predicted cognitive decline the scientists observed in two Phase 2 studies. The simulation predicted that 60 mg/kg would produce the maximal treatment benefit without safety concerns.

Similar to the aducanumab Phase 1b design, the crenezumab dose-finding study staggered enrollment. The first cohort was randomized 5:1 to 40 mg/kg crenezumab or placebo, infused four times over 13 weeks, with safety and pharmacokinetic measurements at weeks five and 13. The other two dose groups (and corresponding placebo groups) started five and 10 weeks later. Following each cohort’s 13-week placebo-controlled phase, participants transferred into an open-label, long-term extension program. People on placebo switched to the dose taken by the treatment group in their cohort (except people in the 120 mg/kg cohort switched down to 60 mg/kg for the extension).

Lin described safety data for the 40 and 60 mg/kg doses for the placebo-controlled portion of the trial. She reported that none of the study’s 52 participants—mild to moderate AD patients ranging from 50 to 90 years of age—experienced ARIA-E. Six participants did have ARIA-H (hemosiderin), generally considered a less worrisome, asymptomatic abnormality. There were no severe adverse events. The adverse events that did occur tended to be mild and did not force an end to treatment. In the 60 mg/kg group, the serum concentrations of the antibody quadrupled over those observed in people who received 15 mg/kg infusions in the Phase 2 trial, as expected.

Lin told the crowd that Genentech is moving forward with its 60 mg/kg dose in a Phase 3 trial of 750 people with prodromal to mild AD, which is slated for completion in 2020.

Active Immunization: A More Cost-Effective Shot at Goal?
If aducanumab, solanezumab, or crenezumab succeed in Phase 3, most researchers agree that the earlier treatment begins, the better the chances of slowing neurodegeneration. Alas, an early start to treatment would mean years of costly infusions of a biologic therapy. Cynthia Lemere of Brigham and Women’s Hospital in Boston was impressed by the results from the PRIME aducanumab trial, but questioned whether long-term treatment would be cost-effective or even accessible to the common person. Lemere speculated that should an Alzheimer’s vaccine exist, plenty of middle-aged people, especially those with a family history of the disease, would rush to get those shots.

The standard-bearer in this area is Novartis’s CAD106, which is in a Phase 2/3 trial expected to last until 2023. But several other Aβ vaccines are coming up in its wake, and one was reported at CTAD.

Pedro Pesini of Araclon Biotech in Zaragoza, Spain, presented safety and immunogenicity data from a Phase 1 study of ABvac40, a vaccine directed against the C-terminus of Aβ40. The study enrolled 24 patients with mild to moderate AD who received three monthly subcutaneous injections, either of the vaccine (16 patients) or placebo (eight patients). Pesini reported no significant differences in adverse events between the treatment and placebo groups. Most people in the treatment group generated antibodies against the vaccine, with plasma titers ramping up more after each injection. These antibodies were still detectable in the plasma a year later, Pesini said. —Jessica Shugart

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References

Therapeutics Citations

1. Solanezumab
2. Aduhelm
3. Crenezumab
4. Amilomotide
5. ABvac40

News Citations

1. Biogen Antibody Buoyed by Phase 1 Data and Hungry Investors 25 Mar 2015
2. Aducanumab, Solanezumab, Gantenerumab Data Lift Crenezumab, As Well 10 Aug 2015
3. Paper Alert: Aducanumab Phase 1b Study Published 2 Sep 2016
4. Outcomes, Outcomes: Cognition is Crux of New Alzheimer’s Trials 24 Nov 2015

Other Citations

1. several other Aβ vaccines

Further Reading

No Available Further Reading