Monoclonal antibodies as a pharmacological therapy

The situation is escalating: While the number of Alzheimer’s patients in Germany and worldwide is increasing dramatically, a pharmacological breakthrough still seems to be far away. In recent years, a series of promising antibody preparations have been developed that have made it to the final stage of clinical approval. However, almost all of them have failed so far due to insufficient efficacy – and not a single one has succeeded in stopping mental decline.

According to the amyloid hypothesis, amyloid-beta protein (Aβ), a major component of extracellular deposits (plaques) in the brain, is the trigger of the Alzheimer’s disease process and therefore an attractive target for pharmacological intervention. Aβ occurs in various forms that differ in size and solubility, and thus in the neurotoxicity (toxic effect in the nervous tissue).

In recent years, drug research has specifically produced substances in the form of antibodies that act with very high precision against these different forms of Aß, with the aim of dissolving and removing the deposits via different mechanisms of action. Such immunotherapy with antibody preparations is considered a very promising pharmacological treatment option for Alzheimer’s disease. The suffix “-mab” in the names of these immunotherapeutics refers to “monoclonal antibody“. These are immunologically active proteins that are directed highly specifically against certain protein structures according to the lock-and-key principle. These are immunologically active proteins that are directed highly specifically against certain protein structures according to the lock-and-key principle.

Several years ago, anti-Alzheimer’s agents called solanezumab (Eli Lilly) and bapineuzumab (Janssen and Pfizer) already failed due to lack of clinical efficacy signals. In 2022, Crenezumab and Gantenerumab, two candidates from Swiss pharmaceutical company Roche, also failed to show effectiveness against the fatal brain disease and thus also dropped out of the clinical approval process.

Even the most promising drug candidate to date, Aducanumab (Biogen/Eisai), which made it to approval in 2021, albeit in a highly controversial approval process and only in the U.S., has questionable efficacy. In Europe, its approval was rejected by the European Medicines Agency (EMA) due to “an unproven efficacy and possible serious side effects of the drug.” Approved in the U.S., aducanumab is the first new Alzheimer’s drug since 2003, and its slowing effect on cognitive decline has been reported at 22%, but with life-threatening side effects such as brain swelling and hemorrhage in more than 30% of study participants, and also extremely high therapy costs. The patient benefit is therefore questionable. Read more about the approval fiasco concerning Aducanumab here.

Currently, two monoclonal antibodies against Aβ are in the late phase of clinical development: Donanemab of the pharmaceutical company Eli Lilly (Trailblazer-ALZ2 study) and Lecanemab of the companies Eisai and Biogen (Clarity-AD study). Both are IgG1 monoclonal antibodies that target insoluble, or clumped, forms of Aβ.

In 2022, the result of the Clarity-AD study with lecanemab was published in a press release by the manufacturer Biogen: lecanemab slowed mental decline by 27% in patients, and a rapid market approval is being sought by the manufacturers Biogen and Eisai. How this study is to be evaluated, please read here.

The preliminary result of the TRAILBLAZER-ALZ-2 study with donanemab was also announced by the pharmaceutical company Eli Lilly in early 2023: the antibody was tested in 1182 early-stage Alzheimer’s patients. The deposits were significantly reduced in the majority of patients. At the end of the 18-month study, donanemab significantly slowed the deterioration of patients’ clinical condition by 35% compared to placebo. Read more about donanemab here.

Experts in Alzheimer’s research, on the other hand, view antibody drugs rather critically: despite proven reduction of Aß deposits, the benefit for the patient remains questionable, since no antibody has yet succeeded in halting or alleviating the disease. In all cases, the deterioration of cognitive decline is minimally slowed, but not slowed. Moreover, the proven “efficacy” in terms of reducing senile plaques is dearly bought with serious, sometimes fatal, side effects.

These side effects are referred to as ARIA(Amyloid-Related Imaging Abnormalities) in the medical community. They manifest as undesirable changes in MRI scans and occur with all anti-amyloid antibodies. In patients treated with these agents, study physicians observed ARIA in the form of brain swelling and cerebral hemorrhage or iron deposition, which in some cases was fatal. But even if the ARIA are clinically more harmless, this means an enormous additional diagnostic effort for the treating physicians, which is associated with high additional costs – and not least with immense stress for the patients.

ARIA do not appear to be the only side effect of these agents, as an Australian research group has discovered in a recent study: To do so, the scientists took a closer look at the side effects of anti-Aß drugs, i.e., their triggering potential for ARIA, and their effects on brain volume. The results of this scientific study were published in the highly respected medical journal Neurology in early 2023.

Paradoxically, the Australian research team found in this study that all representatives of this group of drugs also promoted a shrinking of the brain volume (brain atrophy), the structural cardinal symptom of Alzheimer’s disease. Since brain atrophy was accelerated, especially in the patients with the side effects, this would be more than concerning since a fairly high proportion of patients had these adverse side effects: with the newest agent, donanemab , about a quarter of participants suffered from brain edema and about a third from brain hemorrhage. These patients in particular are thus affected by brain atrophy. The authors therefore derive the following specific recommendations from their findings:

Recommendation of scientists for the treatment with monoclonal antibodies

1. Physicians prescribing anti-Aß monoclonal antibodies with the described side effects (ARIA) should inform current and new patients that these drugs have been shown to accelerate neurodegeneration (e.g., ventricular enlargement).
2. Clinicians should review volume-based MRI data from clinical trials of (ARIA-inducing) anti-Aß monoclonal antibodies to assess the risk-benefit profile of these therapies.
3. Physicians should monitor brain volume changes in individual patients receiving (ARIA-inducing) anti-Aß monoclonal antibodies to determine whether continued treatment is appropriate.
4. Data Safety Monitoring Boards (DSMBs) overseeing ongoing clinical trials of antibody drugs should review volumetric data to determine if patient safety is at risk, particularly in patients who develop ARIA.
5. Ethics committees approving studies for antibody drugs should require that volume changes in the brain be actively monitored. Long-term follow-up of brain volume should be included in study plans to determine whether brain atrophy progresses, especially in patients who develop ARIA.
6. Pharmaceutical companies that have conducted studies with antibody drugs should query previous brain volume data (e.g., stratification by ARIA, analysis of additional brain structures), report the results, and release the data to researchers for study.

The study data of the monoclonal antibody therapies are particularly disappointing in comparison with the clinical pilot study of the ReCode concept according to Dr. Dale Bredesen, which was published in 2021 (see figure). Here it becomes clear that the monoclonal antibodies are only able to slow the deterioration of cognitive decline somewhat, but cannot stop or cure it, and with a huge risk of fatal side effects. Dr. Bredesen’s individualized ReCode therapy, unlike monotherapies with the antibody drugs, detects and targets 36 potential risk factors causally associated with Alzheimer’s disease. As the figure shows, the ReCode pilot study has demonstrated in a direct comparison of efficacy that it is entirely possible to stop and even reverse the progression of Alzheimer’s disease, particularly in its early stages, through a multifactorial, lifestyle-oriented treatment approach.

Figure: Effectiveness of therapies with monoclonal antibodies in comparison to the multimodal treatment concept ReCode (modified after https://www.apollohealthco.com/alzheimers-reversal)

Conclusion:

In recent years, a new form of anti-Alzheimer’s drugs has been developed: monoclonal antibodies (ending in “-mab”) that specifically target Alzheimer’s-specific amyloid deposits. Even though these plaques in the brains of Alzheimer’s patients have been reduced significantly in some cases after treatment with these new agents, the clinical efficacy of all the preparations tested so far remains extremely low and the benefit for patients questionable. On the other hand, the risk of fatal side effects such as brain swelling and cerebral hemorrhage, as well as the cost factor for the therapy, are enormously high.

A recent study has also shown that the reduction of brain volume is promoted by all representatives of this group of drugs. Thus, even the new Alzheimer’s drugs are not, as expected, the drug breakthrough that can stop this terrible disease – they have the potential to promote dementia in the long term.

In addition, there is a reasonable assumption that Aβ deposits in the brain are a natural protective function of the body and have little to do with the progression of Alzheimer’s disease. The “mabs” may therefore be driving out the devil with the Beelzebub, as the above-mentioned side effects suggest

All this seems almost ironic since effective, side-effect-free and significantly less costly lifestyle-oriented prevention and therapy concepts are available. Fortunately, with this knowledge, you have the choice to decide on the right therapy for your mental health!

References:

1. Söderberg L, Johannesson M, Nygren P, Laudon H, Eriksson F, Osswald G, Möller C, Lannfelt L (2022) Lecanemab, Aducanumab, and Gantenerumab – Binding Profiles to Different Forms of Amyloid-Beta Might Explain Efficacy and Side Effects in Clinical Trials for Alzheimer’s Disease. Neurotherapeutics 2022 Oct 17. doi: 10.1007/s13311-022-01308-6.
2. https://clinicaltrials.gov/ct2/show/NCT03367403
3. https://www.clinicaltrials.gov/ct2/show/NCT04437511
4. https://clinicaltrials.gov/ct2/show/NCT03887455
5. Mintun M, Lo AC, Evans CD et al. (2021) Donanemab in Early Alzheimer’s Disease. N Engl J Med 2021; 384:1691-1704, DOI: 10.1056/NEJMoa2100708
6. https://www.alzforum.org/therapeutics/aduhelm
7. https://investors.biogen.com/news-releases/news-release-details/lecanemab-confirmatory-phase-3-clarity-ad-study-met-primary
8. K Toups, A Hathaway, D Gordon, H Chung, C Raji, A Boyd, BD. Hill, S Hausman-Cohen, M Attarha, WJ Chwa, M Jarrett, DE Bredesen (2021) Precision Medicine Approach to Alzheimer’s Disease: Successful Pilot Project. Journal of Alzheimer’s Disease 88 (2022) 1411–1421 DOI 10.3233/JAD-215707
9. Lilly’s Donanemab Significantly Slowed Cognitive and Functional Decline in Phase 3 Study of Early Alzheimer’s Disease. Press Release Eli Lilly, May 3, 2023
10. Alves, F., Kalinowski, P., & Ayton, S. (2023). Accelerated brain volume loss caused by anti-β-amyloid drugs: a systematic review and meta-analysis. Neurology, 100(20), e2114-e2124.