“There is a lot of bad news, but it’s useful bad news.” This line by Randy Bateman of Washington University, St. Louis, captured the mood at the AD/PD conference held March 27 to 31 in Lisbon, Portugal. Whereas in years past scientists filled a paucity of clinical data with educated guesses about what might work, at this meeting they got reams of data to process—all negative as far as the amyloid hypothesis goes. The prevailing attitude was one of learning from mistakes and pleading for patience. Usually after setbacks, the upbeat quotes come out, and so it was here. Some speakers quoted Winston Churchill’s “Success consists of going from failure to failure without loss of enthusiasm.” Others borrowed Benjamin Franklin’s “I have not failed. I’ve just found 10,000 ways that won’t work.”

  • Crenezumab had zero benefit in Phase 3, researchers showed soon after terminating trial.
  • A decade of gantenerumab research underpins its entry into Phase 3.
  • BAN2401 recalls its Phase 2 participants for a long-term extension.

This spring, scientists found three ways that won’t work. They include trying to slow cognitive decline in symptomatic Alzheimer’s with the anti-Aβ antibodies aducanumab and crenezumab, or with the BACE inhibitor lanabecestat.

On aducanumab, there is no data to report yet. Biogen halted the ENGAGE and EMERGE Phase 3 trials six days before AD/PD (March 2019 news), and in Lisbon did not present; indeed, a scheduled talk was withdrawn. Alas, scientists abide a vacuum no more than nature does, and by the time the 3,892 attendees had been convening for six days, they were trading word in the hallways that the futility analysis had shown not even a hint of efficacy for aducanumab, with placebo and treatment curves superimposed. They speculated why this was either surprising or predictable, but speculation is not data. Sometimes, futility analyses taken during a trial deliver surprises later, once researchers have a chance to dig into the data; this is how Roche resurrected gantenerumab after its SCarlet Road trial stumbled (see below). So by the end of AD/PD, scientists parted on reassurance by Biogen’s Samantha Budd Haeberlein that her company will share Phase 3 data as soon as possible. Soon after, though, any hope that Biogen would proceed with a secondary prevention trial it had been planning were dashed when, on April 24, the company announced an end to the program and removed aducanumab from its pipeline (Biogen Q1 Update). 

At AD/PD, attendees challenged pharma researchers. Why in the world would they try more anti-Aβ antibodies or BACE inhibitors when none have worked so far? The researchers defended their deliberative approach of taking time to learn from each other’s failures before scratching a class of drugs, or a target. They noted that the history of drug development is rife with instances where, when multiple companies pursued the same target with slightly different molecules, some stumbled but others learned from those stumbles and later found success. One example is using CETP inhibitors to raise HDL cholesterol, said John Sims of Eli Lilly and Company. Pharma scientists argued it can be difficult to disentangle right away whether a negative trial is due to the molecule, the trial, or the target. Referring to aducanumab’s news, Roche’s Geoffrey Kerchner said, “A press release does not lead the whole industry to stop trials with other molecules in the same class. It is a mistake to pull a drug out of well-designed trials before there is evidence that it does not work.”

Then what is the latest evidence on Aβ antibodies and on BACE inhibitors, the two main ways of targeting amyloid? AD/PD featured detailed data on Roche’s crenezumab and gantenerumab and a bit on Eisai’s BAN2401 (see below). It also featured ample data on Eli Lilly’s lanabecestat and tidbits on two BACE inhibitors currently in the running, Eisai’s elenbecestat and Novartis’ umibecestat (see Part 16 of this series).

Faster With ARIA. In this gantenerumab trial participant, an ARIA-E developed in the same brain region that saw fast and dramatic amyloid reduction. But even in participants who did not develop ARIA, amyloid scans went from positive to negative over the course of two years. [Courtesy of Roche.]

First, crenezumab. Roche announced the end of its two-trial Phase 3 program on January 30 (Jan 2019 news), and at AD/PD it showed the results it has gathered thus far. “Patients are still finishing their follow-up visits, and data are coming in. So the data are preliminary, but today I show what we have because we want to share rapidly,” Susanne Ostrowitzki of Roche/Genentech told the AD/PD audience.

Because this humanized anti-Aβ IgG4 has limited effector function, postulated to result in low risk of ARIA-E, it drew considerable note in the field during the early years of amyloid immunotherapy, before researchers learned that this type of edema is a manageable side effect, not an automatic show-stopper. Crenezumab binds to Aβ monomer and, reportedly at 10-fold higher affinity, to oligomers. It is seen in the periphery of plaques; an area thought to be rich in oligomers; this inspired hope that it might do away with toxic species of Aβ (Jul 2018 conference news). 

The two Phase 3 CREAD trials halted this year were evaluating a fourfold higher dose than had been used in Phase 2. Both Phase 2 trials had missed their primary endpoint and, as often happens in this field, post hoc and exploratory data digging hinted at numerically better outcomes in the earlier-stage patients and slower amyloid accumulation at the higher dose. That ray of hope was enough for Roche to go into Phase 3, testing monthly infusions of 60 mg/kg, i.e. three to five grams depending on a participant’s weight.

Two CREAD trials started a year apart; in Lisbon, Ostrowitzki showed data from CREAD 1. By the time of clinical data cut in January, 813 people with prodromal or mild AD had been randomized, 13 percent in both arms had completed the study, 14 percent had discontinued. The crenezumab and placebo groups were well-matched at baseline. At the time the clinical data were cut, each group still had about 300 people in it. Given that this was an interim analysis, the two treatment groups were about 400 strong at baseline and down to the mid-60s by their last, week 105 visit.

The result? Crenezumab did not work at all. On the primary outcome, the CDR-sum of boxes (CDR-SB), the drug and placebo curves sat on top of each other. Ditto for the ADAS-Cog, and for the MMSE. Nothing.

On a functional measure, the ADCS-activities of daily living, the curves looked as if people on crenezumab were doing slightly worse than those on placebo. When the researchers followed up on this by taking the functional aspects of the CDR-SB and broke open the total score into its parts, the differences fell on either side of zero and were inconsistent between timepoints. “The data does not support a drug-placebo difference,” Ostrowitzki said. In other words: It was noise.

Did people whose disease had progressed less respond any better than those who were further along? No. The researchers split the participants two ways: into prodromal versus mild cases as per baseline characteristics, and again by whether they fell below or above 24 on the MMSE alone. They got the same result each time: The cuts did split the trial population as expected, but the crenezumab groups progressed exactly as the placebo groups. “We saw no treatment signal at the earlier versus later stage,” Ostrowitzki said.

Did ApoE make a difference? No. And as an aside, “E4 carrier status had no prognostic effect,” Ostrowitzki said.

At the high dose used in this trial, in this preliminary dataset, crenezumab produced numerically more side effects than placebo but the differences were small. Nothing alarming stood out in the data Ostrowitzki presented.

In toto, crenezumab appears to have reached its target to the extent the researchers expected, but did nothing to treat AD. “Of course this was very disappointing to everyone,” Ostrowitzki said. The full set of CREAD clinical data, and its biomarker data, are not in yet, she added.

A head scratcher? “Crenezumab is quite similar to solanezumab in its binding,” commented Eric Siemers, formerly of Lilly. Siemers was surprised that crenezumab had no efficacy whatsoever, when solanezumab did have a tiny but real benefit at the same stage of AD. Was it affinity? Exposure in the brain? Even at this high dose, most crenezumab would have bound to Aβ in the periphery. Even of the smidgen of crenezumab that entered the brain—Ostrowitzki reported a CSF to serum ratio of 0.21—much would have bound monomer because monomeric Aβ is more abundant in the brain than oligomeric, Siemers noted.

Do You Need ARIA to Clear Amyloid?
With crenezumab biting the dust, scientists asked whether perhaps a clinical benefit cannot be had without plaque removal, and plaque removal cannot be had without ARIA-E, the edema that comes with rapid movement and clearance of amyloid deposits. At AD/PD, Greg Klein of Roche offered this answer: No, ARIA is not necessary. But it does speed things up.

Klein presented data on gantenerumab, Roche’s anti-Aβ IgG1 antibody, which, unlike crenezumab, binds amyloid plaques and strongly activates microglia to clear them. Gantenerumab itself wobbled in 2014, when a futility analysis ended the Phase 3 SCarlet RoAD trial in prodromal AD, but it did not fall. After halting SCarlet RoAD and its fellow Phase 3 trial Marguerite RoAD, Roche decided to convert both into open-label extension studies to gather more data. (Some scientists at AD/PD expressed misgivings about interim futility analyses, which save people from the risk and hassle of negative trials and cut costs, but also deprive scientists of the full set of results.)

In Lisbon, Klein showed results of the gantenerumab open-label extension amyloid PET sub-study. Sixty-nine people had scans at baseline and after one year on gantenerumab; 39 people had three scans, at baseline and after one and two years. Gantenerumab removed amyloid to below the 24 centiloid threshold in all cohorts, no matter whether they started out at 50 or 90 centiloids. “Regardless of baseline amyloid level, or prodromal versus mild subgroup, after two years on gantenerumab, the mean for all groups was below the positivity line,” Klein said.

But is ARIA-E required for this removal? This question can be answered because, while 93 percent of the ARIA-Es in this extension trial were asymptomatic, this type of localized swelling is easily visible on MRI. In Lisbon, Klein showed examples of focal ARIA-E at six months, which resolved by 12 months and, interestingly, occurred in spots where there was a dramatically large amyloid removal as well (see image above). Even so, when Klein compared PET and MRI across all participants, he learned that while ARIA-E marks “hotspots” of rapid amyloid disappearance, amyloid recedes brain-wide even without ARIA. After two years, people who had ARIA-E along the way shed 64 centiloids of amyloid; people without ARIA-E, 56. “It’s a timing issue: Amyloid removal happens fast with ARIA, and more slowly without. ARIA is not required for significant amyloid reduction with gantenerumab,” Klein said.

And no one wants this side effect, even if it is less serious than initially thought. Biogen designed its now-defunct Phase 3 aducanumab trials to minimize ARIA, and concern over this side effect threw a wrench into the 856-patient Phase 2b BAN2401 trial when European regulators ordered sponsors to keep ApoE4 homozygotes off the highest dose.

For its part, Roche again looked to its combined SCarlet and Marguerite RoAD open-label cohort to learn. For example, could they tell who might be most prone to ARIA-E? Looking across time, they saw that a person’s global amyloid load at baseline did not predict; however, regional amyloid offered a hint in that the incidence of ARIA-E was highest in people with a lot of amyloid in the back of their brain. The occipital region is where people with cerebral amyloid angiopathy tend to have the highest burden; CAA accompanies AD and is a risk factor for ARIA-E (Johnson et al., 2007; Gurol et al., 2016). 

Start Slow, Go Low
Klein’s colleague Nathalie Pross presented another insight gleaned from the SCarlet/Marguerite RoAD open-label extension cohort. The reason why the near-dead gantenerumab program was resuscitated after the 2014 SCarlet RoAD futility scare was that post hoc analyses suggested there had indeed been a dose-dependent slowing of cognitive decline, albeit only in fast progressors. Also, their CSF tau and neurogranin levels had separated dose-dependently from placebo.

Based on this and other data in the field, Roche decided to up the gantenerumab dose to 1,200 mg. Yet this time they did not rush into another Phase 3, but first explored this new target dose, along with titration schemes to minimize ARIA, in the participants they already had, i.e., the extension cohort, Pross said.

Roche’s in silico Alzheimer’s disease model had predicted that, when given from the start, this dose would cause ARIA-E in 58 percent of participants and that titration might cut this to 25 percent, a rate Roche considers manageable. After trying out titration schemes in the open-label cohort, the actual rate of ARIA across those schemes came in at 28 percent for SCarlet and 32 percent for Marguerite RoAD, Pross reported.

Notably, a person’s ApoE genotype did not affect their risk of ARIA-E during titration to the target dose. Hence Roche is conducting its ongoing Phase 3 GRADUATE trials with the same four-step, nine-month titration in all participants. From month nine until the end of the blinded two-year period, the treatment group will be on 1,020 mg. This slight lowering from the planned 1,200 mg target was enabled by a bioequivalent formulation change along the way, Pross said.

To ease study participants’ travel burdens, they can opt to have gantenerumab or placebo injected under the skin at home for a majority of “visits,” Pross said. The trials include the usual outcome measures, plus exploratory plasma markers as an additional endpoint.

This information is the latest piece of what Roche has learned in a decade of studying gantenerumab, with the trials starting in 2008. Pross said Roche tried to innovate, designing one of the first prodromal trials, first subcutaneous delivery, and embracing the DIAN-TU in 2012. Some participants have been on gantenerumab for nine years, Klein said. When pressed why Roche continues with gantenerumab in light of its prior woes and aducanumab’s downfall, Kerchner said: “We have not seen aducanumab data yet. I do not know why it failed. I do know that with gantenerumab we have put a great deal of work into understanding how dose relates to target engagement and took that knowledge into Phase 3. We have hundreds of patient years of exposure with gantenerumab, and have done our best to learn about the molecule before moving forward.”

Taking note, competing companies are increasingly offering open-label extensions, as well. They see how data collected that way helped Roche better understand their drug; besides, many prospective participants refuse to join a trial unless they get the opportunity to at least receive the drug after the placebo-controlled period is over.

Chad Swanson and colleagues presented at AD/PD that in February 2019, Eisai added a previously unplanned open-label extension to the 856-person Phase 2b study of their anti-Aβ protofibril antibody BAN2401 (Nov 2018 conference news), which ended in summer 2016. Participants from the original, placebo-controlled trial, regardless of whether they completed the 18 months of treatment—and regardless of their ApoE genotypes—are being invited back to receive the highest BAN2401 dose for up to two years total. This means they will come to their clinic dozens more times for biweekly infusions and assessments on top of 42 previous visits the core study already required.

In light of what companies have learned about managing ARIA, people who develop asymptomatic ARIA during this open-label extension can stay on BAN2401 uninterrupted, and people with symptomatic ARIA can go back on the antibody once their ARIA has stabilized or resolved. The researchers hope to learn more about safety and the time course of amyloid removal.

Because health economists agree that monthly antibody infusions won’t become lifelong therapy for millions of Alzheimer’s patients, Eisai scientists are also curious to see what happens after a “drug holiday.” Participants in the long-term extension will have been off BAN2401 for a few years. What did this do to their amyloid, to its downstream biomarkers, and indeed to the response that matters—cognition and function in life? Did the improvements last? And what happens when a person goes back on treatment?

Eisai researchers are hoping to enroll up to 250 people into the open-label extension. It will run until August 2021, alongside the BAN2401 Phase 3 trial, which started in March 2019 to enroll 1,566 people with early symptomatic AD and is set to run until 2024.—Gabrielle Strobel

Comments

  1. The clinical failures of drugs to treat AD may be explained by the formation of cytotoxic Aβ oligomers and their pleomorphism. Indeed, many monoclonal antibodies (mAb) have been directed against monomeric Aβ, while ignoring until recently the toxic oligomeric forms (AβOs). That the initial success of some mAbs against AβOs has been followed by failure in the long term can be explained by Aβ pleomorphism.

    There is significant evidence that AβOs are heterogeneous in structure, toxicity, and targets of action, a situation that has been compared to the different strains of an infectious agent. Treatment of AD with mAbs has always involved a single antibody against a specific conformational epitope. This approach may show initial success, until new AβO “strains” with different conformational epitopes (conformers) are produced and become predominant. Then these new conformers, resistant to neutralization by the original mAb, will proceed to damage neural cells aggravating AD.

    Therefore, a potentially effective treatment would require the use of a wide selection of mAbs against various toxic conformers—an approach that besides being very expensive, quite possibly would be of limited success.

    New evidence shows that plaque is a protection mechanism rather than AD causative agent. Plaque removal by mAbs that fails to neutralize the cytotoxic AβOs may aggravate AD by releasing toxic oligomers that were immobilized. This does not support the opinion that plaque removal translates into therapeutic benefits. The situation is blurred by a broad diversity of pathogenic AβOs, which makes them a moving target.

    Hence, a preventive approach to AD, i.e., interfering with the assembly of neurotoxic AβOs, and/or neutralizing and removing them by active immunotherapy, may be more effective than treatment. This observation may be also applied to BACE1 inhibitors.

    References:

    . The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade. J Alzheimers Dis. 2018;64(s1):S567-S610. PubMed.

    . Molecular subtypes of Alzheimer's disease. Sci Rep. 2018 Feb 19;8(1):3269. PubMed.

    . Prospects for strain-specific immunotherapy in Alzheimer's disease and tauopathies. NPJ Vaccines. 2018;3:9. Epub 2018 Feb 27 PubMed.

    . Promising results from Alzheimer’s disease passive immunotherapy supports the development of a preventive vaccine. Research, vol. 2019, Article ID 5341375, 14 pages, (2019)

  2. My comment will be primarily influenced by the structure of the Aβ 1-42 peptide DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA (PDB 2MXU) and its mechanistic implications.

    The hydrophilic N-terminus is a relatively poorly organized region where antibodies bind. Then, from LVFFAE... onward, the peptide forms highly organized stacks, with hydrophobic side chains creating the fibril's core. My question upon seeing this structure was: What are proteases supposed to do with this? The answer has an impact on both the chance of designing a dedicated, artificial protease (this was my actual goal) and the fate of the plaque in vivo. 

    The LVFFAEDVGSNKGAIIGLMVGGVVIA region is extremely well fortified against any nucleophilic attack. Proteases can likely only degrade the N-terminus fragment; this reduces the plaque's immunological signature, but the actual fibril avoids degradation.

    Hence my question: Do we have a definite proof that antibodies, by tagging the plaque for microglia, truly promote plaque clearance, or just help "shave off" the epitopes?

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References

Therapeutics Citations

  1. Aducanumab
  2. Crenezumab
  3. Gantenerumab
  4. BAN2401
  5. Elenbecestat
  6. Umibecestat
  7. Solanezumab

News Citations

  1. Biogen/Eisai Halt Phase 3 Aducanumab Trials
  2. BACE Inhibitors: Postmortem on One, Live Updates on Two
  3. Roche Pulls Plug on Two Phase 3 Trials of Crenezumab
  4. On Target: Crenezumab Reduces Aβ Oligomers in CSF
  5. Second Look at BAN2401 Data Still Positive, Despite Snafu

Paper Citations

  1. . Imaging of amyloid burden and distribution in cerebral amyloid angiopathy. Ann Neurol. 2007 Sep;62(3):229-34. PubMed.
  2. . Florbetapir-PET to diagnose cerebral amyloid angiopathy: A prospective study. Neurology. 2016 Nov 8;87(19):2043-2049. Epub 2016 Sep 7 PubMed.

External Citations

  1. pipeline 
  2. Biogen Q1 Update
  3. Phase 3 GRADUATE
  4. BAN2401 Phase 3

Further Reading

No Available Further Reading