Upcoming Alzheimer’s Medicines Currently in Development

The landscape of Alzheimer's disease treatment is evolving rapidly. There are several therapies currently in different stages of development. Some of them might be worth keeping an eye on.

In this article, we'll explore various innovative approaches to Alzheimer's treatment. We'll also look at specific treatments that may soon receive regulatory approval. And as soon as they do, Alzheimer's patients in the Netherlands (and elsewhere) will be able to access them. Perhaps with a bit of help from our expert team.

Current directions in Alzheimer's medicine research

All the newest approved Alzheimer's medicines are anti-amyloid therapies. However, there are other approaches to treating Alzheimer's disease as well. Including:

• Anti-tau therapies. They are aimed at the tau protein, which forms tangles within neurons and contributes to neurodegeneration.

• Anti-inflammation therapies. They are targeting neuroinflammation, which also plays a role in Alzheimer's disease.

• Neuroprotective agents. They aim to shield neurons from damage and, in doing so, to preserve brain functions.

• Symptomatic treatments. Treatments that help alleviate Alzheimer's symptoms are also a promising research direction. Such treatments are, for example, cognitive enhancers and combination therapies.

Here are some of the most promising medicines in each research direction.

Anti-amyloid therapies in development

Gantenerumab is an investigational monoclonal antibody targeting amyloid-beta (Aβ) plaques. It's emerging as a potential contender in the quest for effective treatments for early Alzheimer's disease. This therapy is being studied for its ability to reduce amyloid plaque burden and influence the progression of the disease.

The efficacy of gantenerumab has been evaluated in the GRADUATE I and II trials ². While these studies demonstrated a decrease in amyloid plaque, they did not show a statistically significant slowing of clinical decline. Currently, the trial NCT05552157 aims to clarify whether gantenerumab can effectively halt or slow the accumulation of Aβ plaques and positively impact disease progression. The study is specifically focused on early-onset Alzheimer's caused by a genetic mutation (DIAN-TU) ¹. Results are expected in 2034.

Tau-targeting therapies in development

Another critical area of research on Alzheimer's medicines focuses on tau protein. Tau tends to form tangles within neurons, thus contributing to neurodegeneration. Some of the tau-targeting medicines being studied are:

• Tau vaccines

  Tau vaccines are an emerging therapeutic strategy aimed at eliciting an immune response against tau proteins. Recent studies have shown that these vaccines can promote the production of antibodies that target tau tangles. In this way, they could potentially slow disease progression and improve cognitive function.

  Several tau-targeting vaccines are in development. For example, AADvac1 and ABBV-181, which aim to provoke an immune response against tau tangles. These are currently in early-phase clinical trials.

  Furthermore, researchers are exploring the possibility of combining tau vaccines with other treatments to enhance overall therapeutic efficacy. One possible combination is with anti-amyloid therapies ³.

   

• Anti-Tau Monoclonal Antibodies

  Multiple therapies have been studied over the last years for their potential to reduce tau levels. Some have had less success. For example, semorinemab, tilavonemab, and gosuranemab have all failed to show any consistent results in improving cognitive function or affecting tau buildup in the brain ⁴.

  However, there are more anti-tau monoclonal antibodies in development. Some have shown some more promising results in clinical trials so far. For example:

  • Bepranemab: In the Phase 2a TOGETHER (AH0003) study, bepranemab showed a 33%-58% reduction in tau accumulation and a 21-25% slower cognitive decline (ADAS-Cog14 score) at Week 80. In participants with low tau burden or non-carriers of the APOε4 gene, high-dose bepranemab slowed tau accumulation by 63%-67% and clinical progression by 29%. The treatment was generally well tolerated, with comparable safety profiles to placebo ⁵. Further clinical trials will be needed in order to confirm these results.

Anti-inflammation therapies in development

Neuroinflammation plays an important role in Alzheimer's disease. Microglia, some of the brain's immune cells, can help remove amyloid-beta (Aβ) but can also cause harm when they become overactive due to the buildup of Aβ. Targeting how microglia work, especially through the TREM2 pathway, could lead to new treatments for Alzheimer's. Here are some currently being studied:

• AL002: AL002 is an antibody that targets TREM2, a protein important for brain health. In mouse studies, it helped activate TREM2 signaling, clear amyloid plaques, and improve cognitive function. A phase II trial is currently testing AL002 in early Alzheimer's patients, with adjustments made to exclude certain high-risk individuals. The study is set to continue until December 2025 ⁶.

• Pepinemab: Pepinemab targets semaphorin 4D (a protein that plays a role in the regulation of cell signaling and communication in the nervous system). By doing so, it aims to reduce inflammatory cytokine release. In a recent Phase 1b/2 clinical trial, showed a positive result in slowing down disease progression in patients with mild cognitive impairment ⁷. Further clinical studies are needed to confirm pepinemab's potential role as a treatment for Alzheimer's.

Neuroprotective agents and symptomatic treatments in development

Neuroprotective agents aim to protect neurons from damage and preserve brain function. Symptomatic treatments aim to alleviate symptoms of Alzheimer's and enhance cognitive abilities.

Among these, several innovative treatments are under investigation:

• Cognitive enhancers. Medicines like donepezil and rivastigmine are currently used to treat symptoms of Alzheimer's (also in the Netherlands).
  Other cognitive enhancers are also in development - e.g. phosphodiesterase inhibitors (PDE-Is). These medicines work by enhancing the levels of signaling molecules, cAMP and cGMP, which are important for brain functions like neuroplasticity and protection. Some PDE inhibitors are still under investigation. Time (and data) will show if they eventually lead to cognitive improvements ⁸.

• Combination therapies: Combination therapies in Alzheimer’s disease include pharmacodynamic approaches. This means combining agents to influence the disease biology or symptoms. There are also pharmacokinetic strategies, where one medicine enhances another’s delivery or mitigates side effects.

  One example of a combination therapy under investigation is AMX0035. This therapy combines sodium phenylbutyrate and taurursodiol. It aims to protect neurons by addressing mitochondrial and protein-folding dysfunctions. In the Phase 2 PEGASUS trial, AMX0035 showed no significant cognitive impact over the 24-week trial. However, it showed a reduction in tau proteins and amyloid beta ratios. These findings encourage further exploration of AMX0035’s potential for Alzheimer’s ⁹.

When will new treatments for Alzheimer's be approved?

It's hard to say, as experimental medicines are at different stages of development. It may take a couple more years before we see the next Alzheimer's treatment approval. When we do, it's likely going to be in the USA first. However, if your treating doctor advises starting a treatment with a novel medicine, remember you can access it before it's available in the Netherlands. You have the right to do so as a Named Patient.

In the meantime, there are already some treatments approved in the world, but not yet available in the Netherlands. If you or a loved one are eligible for treatment with Leqembi or Kisunla, you can get them right away, as long as you have a prescription. Get in touch with our expert team for more information.

References:

1. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset AD Caused by a Genetic Mutation (DIAN-TU). ClinicalTrials.gov, Accessed 05 November 2024. 
2. Two Phase 3 Trials of Gantenerumab in Early Alzheimer's Disease. PubMed, 16 November 2023.
3. Development of an anti-tauopathy mucosal vaccine specifically targeting pathologic conformers. Nature.com, Accessed 05 November 2024. 
4. TANGO: a placebo-controlled randomized phase 2 study of efficacy and safety of the anti-tau monoclonal antibody gosuranemab in early Alzheimer’s disease. Nature.com, Accessed 05 November 2024. 
5. UCB Presents Encouraging Data on Bepranemab in Early Alzheimer's Disease in Phase 2a Study at CTAD 2024. UCB, 31 October 2024.
6. A Long-term Extension Study to Evaluate Safety, Tolerability, and Efficacy of AL002 in Alzheimer's Disease. ClinicalTrials.gov, Accessed 05 November, 2024. 
7. Vaccinex Reports New Findings for SIGNAL-AD Phase 1b/2 Trial of Pepinemab at Clinical Trials on Alzheimer's Disease (CTAD) Conference in Madrid, Spain. BioSpace, 31 October 2024.
8. Cummings, Jeffrey. New approaches to symptomatic treatments for Alzheimer's disease - Molecular Neurodegeneration. Molecular Neurodegeneration, 13 January 2021.
9. Amylyx Pharmaceuticals Announces Results from PEGASUS Trial of AMX0035 in Alzheimer's Disease at the Clinical Trials on Alzheimer's Disease (CTAD) Conference. Amylyx, 9 November 2021.