Despite the difficulties and setbacks, research and development in Alzheimer's is making progress. Advances in clinical development keep the hope alive of having new drugs in the not-so-distant future to complement the currently limited therapeutic arsenal.
In recent years, the focus of clinical development has been on immunotherapeutic compounds aimed at clearing brain beta-amyloid deposits. Today, the first monoclonal antibodies, lecanemab and donanemab, are available, showing that their reduction effect on these plaques correlates with a slowing of cognitive decline.
Currently, in Europe, the first of these two drugs, lecanemab, has not received approval from the regulatory agency EMA, which in the summer opposed its approval citing that its modest clinical efficacy does not outweigh the risks related to amyloid-related imaging abnormalities (ARIA), including brain inflammation and possible hemorrhages, which can be fatal.
However, there are more biological drugs targeting beta-amyloid in research, and many other treatments in clinical development aiming to change the natural course of this dementia or, at least, alleviate its symptoms. In total, there are 81 therapies in clinical development, with 16 in phase III and II/III of clinical trials according to Phrma data, the U.S. pharmaceutical industry association.
For now, after obtaining approval for early stages of cognitive decline and dementia, lecanemab and donanemab continue their phase III clinical development in patients with presymptomatic Alzheimer's. The results from these studies will determine if the very early use of these treatments is more effective against dementia. Other next-generation beta-amyloid-targeting biologicals, remternetug and sabirnetug, are being tested in phase III and phase II/III.
Targeting the Tau Protein, one of the targets
Alongside beta-amyloid, the second major target of drugs in development for Alzheimer's is the tau protein, responsible for the formation of intracellular neurofibrillary tangles, a process also identified in the disease's origin.
In phase II and phase III, there are several compounds targeting tau, especially monoclonal antibodies (such as E2814, BMS-986446, posdinemab, and bepranemab) and antisense oligonucleotides (such as BIIB080).
There are also oral medications in phase III based on a possible action against tau, such as simufilam and hydroxymethylthionine mesylate, considered a tau aggregation inhibitor and a derivative of methylene blue, used in Africa against malaria.
There are more drugs nearing the end of their clinical development belonging to families used in diverse diseases such as obesity, erectile dysfunction, malaria, or rheumatoid arthritis. The most well-known is semaglutide, attributed with protective effects against neurodegeneration and neuroinflammation.
The phosphodiesterase 5 inhibitor mirodenafil, a drug from the Viagra family, could have beneficial effects on cognition through multiple mechanisms of action, including an effect on amyloid and tau.
Another drug with a known mechanism of action, in the area of autoimmune diseases, is BHV-8000, a TYK2/JAK1 inhibitor in phase I showing high brain penetration capacity and considered to have potential application in Alzheimer's.
Among the list of drugs in development for Alzheimer's compiled by Phrma, there is an interesting proposal, the protease inhibitor atzuginstat, which by targeting the periodontal pathogen Porphyromonas gingivalis aims to benefit cognitive decline.
Combating Insomnia and Dementia
In the group of small molecules in advanced stages of development are fosgonimeton and NA-831, believed to promote neurogenesis; bezisterim, acting through the inflammation pathway; buntanetap, considered a neurotoxic protein inhibitor, and piromelatine, aiming to improve insomnia and cognition.
There are dozens of compounds in research exploring pathways other than beta-amyloid. Raquel Sánchez Valle, coordinator of the Behavior and Dementia Group of the Spanish Society of Neurology, reveals that therapies targeting tau and inflammation predominate, along with symptomatic treatments acting on different neurotransmitters, followed by those aiming to eliminate toxic substances.
The expert warns that it is too early to expect disease-modifying treatments targeting tau. "The therapies currently being developed are similar to the first drugs against beta-amyloid; some don't even modify tau, making it difficult to achieve a clinical effect."
Among the treatments believed to be useful for their anti-inflammatory effect is semaglutide, but the expert believes it is still unknown if the potential protective effect against dementia observed in long-term follow-ups is due to this effect: "From a pathophysiological point of view, it makes a lot of sense, but once the patient has symptoms, we will have to see if these drugs have an impact, as the inflammation process seems to be quite early."
Designing Bispecific Antibodies for Specific Targets
Xavier Morató, Director of Clinical Trials at the Ace Alzheimer Center Barcelona, highlights the interest in research with bispecific antibodies capable of improving certain properties compared to other biologicals, such as compound penetration into the brain. One of these candidate drugs is ALIA-1758, expected to significantly reduce cerebral amyloid burden with a low antibody dose, allowing monthly subcutaneous administration.
Another interesting approach, Morató emphasizes, is therapies targeting the TREM2 receptor, aiding microglial cells in reducing inflammation in the nervous system. He mentions that there is much "anticipation" for the upcoming publication of phase II results of the Invoke-2 trial with the monoclonal antibody AL002, "expected by the end of this year." There are also small molecules targeting TREM2, such as VG-3927, a TREM2 agonist.
The recent history of lecanemab in Europe shows that, despite the great need for Alzheimer's treatments, demonstrating clinical efficacy is not enough to reach the market. For this reason, Morató understands that molecules with a higher likelihood of reaching the market in the short term would be those resulting from repositioning and those already approved for other indications, with oral or subcutaneous administration, and fewer adverse effects than biologicals.
Combining Therapies to Increase Efficacy
Given the complexity of Alzheimer's, it is assumed that future treatment will consist of a combination of therapies administered in early stages. "There probably won't be a single magic solution for Alzheimer's disease. In the case of cancer and HIV, success has come from combining early diagnosis with combined treatments that modulate different disease processes," Morató points out.
Sánchez Valle agrees: "With monoclonal antibodies targeted against beta-amyloid, it is being seen that the sooner they are administered, the better. It is likely that we will need to advance in the timing of treatment initiation to have a relevant impact, and that we may need combined therapies, perhaps targeted against amyloid, tau, and inflammation," adds the expert from the SEN.
In the short term, the neurologist from the SEN highlights the challenge of introducing anti-amyloid biologicals in Europe. The negative opinion of the EMA on lecanemab may not be the end of its story in Europe. Regarding donanemab, she indicates that there are certain differential characteristics with lecanemab that may facilitate approval; especially, that in its development, it was conceived as a time-limited therapy until the clearance of cerebral amyloid, as opposed to the chronic treatment with lecanemab.
If it reaches clinical practice in countries like Spain, "there will be a need to change the dynamics for early detection, treatment, and patient selection. If they are intravenous, they will require day hospitals, plus monitoring for adverse effects. Additionally, there are certain elements such as early diagnosis through biomarkers, which are starting to move and will accelerate in case they are approved in Europe."
For Mercè Boada, medical director of the Ace Alzheimer Center Barcelona, despite the safety and cost issues of lecanemab, "the benefits that this molecule can offer to a person are invaluable."
For now, the medication has been approved in the United States, Japan, China, South Korea, Israel, the United Arab Emirates, and the United Kingdom, although the National Institute for Health and Care Excellence (NICE) in the UK has rejected coverage by the public health system (NHS). Australia has also currently rejected it.
"For the EMA and the Therapeutic Goods Administration (TGA) in Australia, the medication's efficacy does not outweigh the safety risks. While for NICE, the medication's benefits do not outweigh its costs. The debate is ongoing," observes Boada.