Biogen’s Alzheimer’s Drug Likely To Be Approved With Warning Labels

People can die from the side effects of drugs. It happens every day. Read the warning labels of your pharmaceutical products.

It’s not shocking that Biogen/Eisai’s (NASDAQ:BIIB) new Alzheimer’s medication causes some terrible side effects for a tiny fraction of the people who take the drug, known as Lecanemab. Up until December 20, there were two known deaths from use of Lecanemab in an extension study, post-Phase 3, for Lecanemab.

As reported by Science magazine by journalist Charles Piller, the third patient died of brain swelling and brain bleeding on September 19, 2022, approximately two months before the presentation of final results for Lecanemab’s Phase 3 drug trial. Biogen/Eisai did not mention this death in their Lecanemab presentation in November.

Information of the death has only emerged after the deceased’s relatives sent medical records and MRI images to the journal Science. The deceased was a 79 year-old Florida woman who was apparently in good health (outside of her Alzheimer’s diagnosis) before the drug trial. As reported by Science:

The newly revealed death comes on top [of] other reports of serious brain bleeding and swelling in the core clinical trial and two other deaths in the extension phase—the first reported by STAT and the second by Science—that some scientists have linked to lecanemab.

Biogen/Eisai apparently did not actively deceive. In their final presentation for Lecanemab, they stated that no deaths were caused by Lecanemab in the core study. Indeed, all three deaths occurred during the extension study, which involves 6 weeks of Lecanemab treatments after the core trial is finished.

Whether the woman received infusions of the antibody or a placebo during the core 18-month trial is unclear. But she did get the drug over 6 weeks in the extension phase—in which any participant can opt for treatment. Before the extension trial started, a brain scan revealed signs of a few microhemorrhages, but they were not serious enough to rule her out of the trial.

The woman’s family provided Science with MRI scans of the woman’s brain before and after use of Lecanemab. The MRIs are disturbing, as distinctive and much larger dark spots appear in the woman’s brain MRI after treatment with the Biogen drug. From the photos published in Science, it looks like the woman lost a considerable amount of brain matter as a result of only 6 weeks of treatment!

Most people who see the images of the MRIs would probably conclude that some people likely should not take Lecanemab, especially if there is no benefit from the drug. According to Science, “some large subgroups in the [Lecanemab] trial, including women and people under age 65, did not benefit to a statistically significant threshold” from the drug.

Biogen/Eisai stated in their presentation that the vast majority of patients’ brain swelling/bleeding problems occurred early in the use of Lecanemab. So, the fact that all three of the deaths occurred after the extension trial seems to indicate that the three who died were likely part of the placebo group and were being infused with the drug for the first time.

This may indicate that extra care must be taken after each of the first dozen or so Lecanemab treatments. One expert interviewed by Science suggested that 5 MRIs be taken each year while using Lecanemab.

Approval Still Likely

Nevertheless, I believe the FDA will approve Lecanemab. Why? Through its Phase 3 trial, Lecanemab demonstrated with high statistical significance that it can slow cognitive decline over the course of 18 months of treatment. In fact, it slowed cognitive-behavioral decline by an impressive 27% on the CDR-SB (Clinical Dementia Rating scale Sum of Boxes) measurement scale.

While some may see a 27% reduction in decline as clinically insignificant, from the perspective of someone whose mother suffers from Alzheimer’s, such a reduction in decline is valued to the extreme.

Furthermore, any given drug will affect different patients differently. It may benefit some people greatly. The average patient showed a 27% reduction in cognitive-behavioral decline. Perhaps some people will see a 50% reduction in decline.

Others, sadly, may potentially die from brain bleeding.

This is the case for most drugs; they help some people and for others, the side effects are too onerous.

Finally, because there has been no effective treatments approved for general use for Alzheimer’s patients, I believe the FDA will grant approval when the PDUFA is reported on January 6. It may be preliminary or conditional, but it will be an approval in my view.

AVXL’s Blarcamesine

But what if there are other effective treatments, without the brain bleeding? Anavex (AVXL) has presented initial results for a drug, Blarcamesine, which seems to be just as effective (actually better when using as a gauge the ADAS-Cog (Alzheimer’s Disease Assessment Scale-Cognitive subscale)). The side effects of Blarcamesine are dizziness and confusion, not brain bleeding.

For a full comparison of the two drugs, see my previous article.

The Anavex drug causes no brain swelling or bleeding because it operates differently. The Anavex drug Blarcamesine is a Sigmar-1 agonist, manipulating the production of the Sigmar chemical in the brain. The Biogen and Eli Lilly (LLY) Alzheimer’s drugs both clear amyloid from the brain, and in doing so they cause, for some, brain swelling/bleeding.

Anavex recently concluded a Phase 2b/3 trial for Blarcamesine. The FDA may wish to carefully examine the Anavex trial results before making a decision on the Biogen drug. After all, why approve a drug that has harsh side effects when there is another drug that works arguably just as well, without those deadly side effects?

Conditional Approval

NPR reported that

The [FDA] is expected to consider a conditional approval in early 2023 and a full approval later in the year. If approved, lecanemab is likely to be limited to people in the early stages of Alzheimer’s. They make up about 2 million of the 6 million people with the disease.

It’s not clear to me why Lecanemab would be limited to those people “in the early stages of Alzheimer’s.” It seems to me that the FDA would recommend use of Lecanemab for use in people who are least likely to suffer symptomatic brain bleeding.

The FDA may also require those taking Lecanemab to have MRIs done on their brains regularly. Furthermore, the FDA may require Biogen/Eisai to report the results of their extension study to the FDA, if they have not done so already.

By giving Lecanemab conditional approval, the FDA will give itself time to carefully examine Anavex’s Blarcamesine results. Depending on that examination, perhaps the FDA can further limit or expand the use-cases for Biogen’s Lecanemab. This seems the sensible path to me.

In its communication with Science, Biogen/Eisai already seems resigned to having numerous warning labels slapped on the drug. Eisai responded to Science inquiries in part by suggesting that “for many patients the benefits will outweigh the risks.” Hardly a ringing endorsement of its own drug.

The ICER report

The independent review board known as the Institute for Clinical and Economic Review (ICER) is taking the issue of brain bleeding among Lecanemab patients seriously. In their draft review of the drug, they noted that at the time of their writing, two people had died as result of “cerebral macrohemorrhage” in the Lecanemab extension study. I assume they will now examine the third death carefully.

ICER puts a high bar on what are called Minimal Clinically Important Differences (MCID), meaning the minimum difference a drug makes in a patient that can be considered clinically important.

No dementia drug in any Phase 3 trial has ever achieved a MCID by the standards put forth by ICER. The only drug that has come close is Anavex’s Blarcamesine. The MCID on the ADAS-Cog scale for Alzheimer’s patients is a reduction in cognitive decline by 2 full points. Blarcamesine, on average, reduced cognitive decline by 1.85 points over the course of 48 weeks (11 months). Biogen’s Lecanemab only reduced decline in their patients’ ADAS scores by 1.44 points over the course of 18 months.

ICER stated that Lecanemab had not met the MCID. To me, this does not mean much. If it were a headache medicine, Lecanemab may not cut the mustard. But because there are no effective treatments for Alzheimer’s, I believe the FDA will readily approve any drug that makes any difference.

The question is, how does the FDA take into consideration the side effects of Lecanemab?

Stock Price Predictions

If the FDA grants conditional approval of Lecanemab and tags it with a passel of warning labels, I believe Biogen’s stock value finishes the day above 300.

If it is unconditional approval, the stock may break 350.

If the FDA outright rejects Lecanemab, Biogen stock may break 200 on its way down.

If the FDA approves Lecanemab, it will send a signal that Anavex’s Blarcamesine, with similar qualities but without the terrible side effects, will certainly be approved in my opinion. The rally in that stock may be quite flagrant.

If the FDA approves but limits Lecanemab’s use due to its side effects, it will also likely send AVXL stock up.

If the FDA rejects Lecanemab but only because of its side effects, that may send AVXL stock the highest out of all scenarios presented here, as it will indicate that Lecanemab’s treatment results were good but that its side effects are unacceptable. With Anavex’s results being better but with no lethal side effects, and with Lecanemab eliminated as competition, AVXL will soar, in my opinion.

If the FDA rejects Lecanemab solely because the FDA believes the medicine is ineffective in treating the symptoms of Alzheimer’s disease, then it is unclear what will happen to AVXL stock. Some may buy, as the chief competition has been eliminated; others may sell, worrying that the FDA will also reject Blarcamesine.

Finally, Eli Lilly’s Donanemab, on which ICER seemed noncommittal with a negative tilt, will be seen in the same light as Lecanemab. If Lecanemab is approved, Eli Lilly may rally some; if Lecanemab is rejected, LLY will likely take a hit.

In my previous article, I said that I would consider taking Biogen’s Lecanemab only after taking Anavex’s Blarcamesine for the first two years of treatment. As more information comes out, I lean further on the side of focusing any dementia treatment plan around Anavex’s Blarcamesine. While that matter is not urgent, many of us whose parents suffer from Alzheimer’s would like to get our hands on safe, effective treatment as soon as possible.

We will learn of the Lecanemab news on January 6, and on January 12, we may learn crucial details about Blarcamesine. Our future health outcomes, if not our financial outcomes, will become clearer within a fortnight.