The first successful clinical trial for a new Alzheimer’s drug is making big news.

Buck professor Julie Andersen weighs in on Lecanemab

Lecanemab is the first potentially disease-altering therapy for Alzheimer’s to make it through phase 3 clinical trials. It met its primary endpoint by reducing patients’ cognitive decline by 27% when compared to placebo.   But whether the drug is the “breakthrough” some are calling it, a small step in the right direction, or a yet another disappointment remains to be seen.  The drug’s developers, Biogen and Eisai, will present full scientific data at an Alzheimer’s meeting in November.   Buck professor Julie Andersen, a neuroscientist who studies Alzheimer’s, is eager to see the data.

Kris Rebillot, the Buck’s Senior Director of Communications, talked to Andersen about Lecanemab.

Julie, some of the researchers commenting on this article posted on the Alzheimer’s Forum were clearly excited, and some were downright giddy about the success of lecanemab.  What’s your take?

I understand the excitement.  This is the first time that there’s been a clearly successful trial for Alzheimer’s disease after two decades of trying. It’s been like walking through the desert in terms of developing new drugs for the disease. So that’s a big deal to the field. But even though I hope the drug works, I’m not ready to blow the trumpet yet.

You have concerns?

The 27% reduction in cognitive decline among study participants is statistically significant, but the question is whether that decline has any clinical meaning or not. For a patient with Alzheimer’s disease, would they really be able see or feel that they had a clinical improvement in terms of their cognition? It’s not clear, because if you talk to clinicians, lecanemab did not reach that particular threshold. We don’t yet know whether patients taking the drug are going to see or feel beneficial effects.

Clinicians have also made the point that even though the trial showed a lower drop in levels of cognitive decline within six months in those patients taking the drug versus those taking placebo, what happens later on? If somebody taking the drug continues to have reduced losses in cognition, then that would be clinically significant. But what if we look at the 18-month time point, which was part of the trial, and what if the patients taking the drug end up with the same level of cognitive loss as those taking the placebo? That would be less exciting. Yes, the drug might stave off cognitive loss for a year or whatever, but then you’re back to where you started from. Researchers are going to want to see data from the 18-month time point. It’s important.

Also 70% of the patients who were given lecanemab had an APOE4 mutation which is a genetic risk factor for the disease. Only about 25% of the general population carry such a mutation, If those with APOE4 are selectively showing a better affect, it might suggest that the medication is good for people who have an APOE4 mutation but maybe not for other forms of Alzheimer’s disease.

How about side effects with lecanemab?

About 20% of the patients who showed a slowing of cognitive decline on the drug had brain swelling. They had what’s called ARIA –background amyloid-related imaging abnormalities.  So those patients couldn’t continue to take the drug and it essentially unmasked the double-blind aspect of the trial for those patients because it became clear who was getting the drug.  

And there’s something else to bear in mind, which is a big issue with a lot of these antibody therapies: because the drug is given intravenously, it’s not just taking a pill. You have to go into a doctor’s office and have an IV and, more importantly, the drug has to efficiently cross the blood-brain barrier. In general, these antibody therapeutics don’t cross the blood-brain barrier very well. So you often have to give a very large dose to make sure that you’re getting a sufficient dose in the brain. And because you’re giving this huge dose of drug, you may end up with side effects due to the fact that the drug can also impact healthy cells not normally affected by the disease.  If you were giving the patients a drug that was specifically only going to the neurons that were dying or where the pathology was, that’s one thing, but if you’re giving the drug and it is also impacting healthy cells, then you end up with side effects like ARIA. So it’s not a targeted approach. It’s a little bit still of a sledgehammer.

Both lecanemab and Aduhelm, another drug for Alzheimer’s, are antibodies that are designed to clear amyloid plaques.  We talked about Aduhelm back in January, before it was given a very limited approval by the FDA due to concerns about both efficacy and safety.  What’s different about lecanemab?

It turns out that amyloid is a little bit more complicated than we thought, in the sense that there are various forms of amyloid. Beta-amyloids are proteins that actually clump together to form the plaques, but they start out as sort of small, soluble oligomer, small soluble proteins. And then they become what are called protofibrils, which are longer clumps of protein before they become fibrils, which are really what the plaques are made of.  And these different antibodies target different forms of amyloid.  In the case of lecanemab, it is targeting protofibrils; they’re no longer small soluble proteins but are starting to clump together more. It’s not completely clear what form of beta-amyloids are most associated with losses in neuronal function. There are a couple of other ongoing clinical trials which target different forms of amyloid using other amyloid beta antibodies, gantenerumab and oligomannate, which we’ll hear more about down the line.

Within the Alzheimer’s research community, we don’t completely understand which form of beta amyloid should be targeted to prevent disease.  We need to do some more basic research because we’re throwing drugs at all of these different forms and hoping they’re going to work, and they act in different ways.

As promising as this clinical trial appears to be and even if lecanemab shows clinical relevance, it’s not going to be a cure, right?

Probably not. Alzheimer’s disease is definitely not one-size-fits-all. People present with very different symptoms and levels of disability.  There are differences in how rapidly the disease develops. We don’t understand a lot of basics about the disorder. The lecanemab trial implies that a certain form of amyloid may be contributing to the disease.  But the trial doesn’t necessarily show that it’s the only form contributing to disease pathology. And there are other things we likely need to address, like tau tangles or neuroinflammation, the latter of which involves important immune cells within the brain called microglia.  More and more people are thinking about this, looking at multi-component therapies where we’d be dealing with all of the potential pathologies.

Well, that’s the perfect set up for me to ask you about the $2.4 million Transformative Research Award that recently went to your lab.  One of your lab members, Chaska Walton, is developing a “smart” drug delivery system that would provide targeted combination therapies to address all of the pathologies involved in Alzheimer’s. What’s that about?

We’re really excited about this.  Chaska has spearheaded design of a system that turns immune cells into mobile biological drug factories that can “decide” when to release drugs at the site of pathology and, once that pathology is cleared, can then move onto the next site of pathology.  These biological drug factories can be programmed to churn out combination therapies. And the drugs are not systemic, they’re targeted, which means we can likely avoid the side effects that have plagued the majority of previous clinical trials.  Chaska has for example developed a program in which the immune cells produce Aduhelm combined with zagotenemab, which failed a Phase II clinical trial aimed at clearing tau tangles, another feature of Alzheimer’s.  His system works in human cell culture and we’re now testing it in mice.

Update: The Food and Drug Administration (FDA) is already considering lecanemab for a conditional approval based on preliminary evidence from a smaller study.  Given the data from the recent trial, FDA approval is almost a certainty. A decision is expected by January 6, 2023. Assuming approval, the next big step will involve Medicare, which will decide whether to reimburse the cost of lecanemab, making it accessible for all patients. Eisai published a paper in June suggesting the drug’s price could range from a hefty $10,000 to $38,000 a year per patient.  Andersen says this highlights the need for continued research towards more targeted and perhaps less expensive AD therapies.