How can dementia drug development be improved?

By Rachel Arthur

- Last updated on GMT

Dementia research lags behind the disease burden, says the WHO report. Pic: getty/nopparit
Dementia research lags behind the disease burden, says the WHO report. Pic: getty/nopparit

Related tags Dementia Alzheimer's disease Aducanumab Alzheimer Clinical trial Clinical trials WHO Patient centricity Patient recruitment

The WHO has set out a new blueprint for dementia research: outlining the potential of precision medicine, repurposed drugs and revamped clinical trials. “Addressing dementia is one of the greatest health challenges of our generation,” says the organization.

Dementia is set to reach 78 million people by the end of the decade. It is already the seventh leading cause of death globally; and yet research in the area accounts for less than 1.5% of total health research output.

In publishing its blueprint for dementia research, the WHO sets out the challenges in drug development and clinical trials: giving policy makers, funders, pharmaceutical companies and academics guidance on how dementia research can become more efficient, equitable and impactful.

“During the COVID-19 pandemic, we have learned how fast we can advance research and development if we act in a coordinated manner," ​says Dr Soumya Swaminathan Chief Scientist World Health Organization. "It is now time to translate these learnings to address another global health challenge that we’ve been confronted with for years: dementia.”

Among other goals, the WHO wants to see the development of a disease-modifying therapy for Alzheimer’s Disease that is ‘safe and affordable and has a clear clinical benefit’ by 2030.

The dementia drug pipeline

There are few effective drug treatments for dementia. Only four drugs are currently available internationally for Alzheimer’s Disease: three acetylcholinesterase inhibitors and one N-methyl-D-aspartate receptor antagonist, and all are symptomatic treatments, with no disease-modifying properties.

In 2002, memantime was approved for moderate-to-severe AD, but there has been little since. The only exception is the US accelerated approval of Biogen’s Aduhelm (aducanumab), a monoclonal antibody against amyloid β, in 2021, on the basis that it removes amyloid from the brains of people with AD and may have cognitive benefits.

But this approval has proved to be controversial: ‘not the least because cognitive benefits have not been conclusively established, adverse effects are significant, and there is no strong evidence in this specific case that the removal of amyloid is associated with clinical benefits’, ​observes the WHO. While Aduhelm remains in a Phase 4 trial, Biogen has severely cut back its efforts on the drug.

The attention is now on other Phase 3 drugs such as Eisai and Biogen's lecanemab​ (an FDA decision is expected in January​) and Lilly’s donanemab.

A 2021 review​ identified 143 agents in 172 clinical trials on AD listed in the database, of which 83.2% were putatively disease modifying drugs, 9.8% cognitive enhancers and 6.9% for treatment of neuropsychiatric symptoms.

Of the different drugs, 31 were in phase 3 trials; 84 in phase 2 and 30 in phase 1. 

Research gaps

Dementia is associated not with one but with many diseases that may have different causes and potentially an additive effect. Better understanding, therefore, of these associations is essential to develop effective therapies – perhaps with several targets.

dementia getty andrewbrookes

Furthermore, ‘major gaps’ remain in understanding the pathophysiological process and the relation between pathology and clinical presentation.

“Although non-amyloid pathways in AD, including tauopathy, neuroinflammation, oxidative stress and synaptic loss, are also being addressed with diverse strategies, the interaction of these pathways and how different treatment strategies should be combined for synergistic effects are not well understood," ​notes the WHO report.

"Better understanding of the mechanisms, including the underlying causes of the diseases, and the biological causes of behaviors and psychological symptoms associated with dementia is required to identify targets and ensure effective treatments.”

With better understanding of how underlying disease contributes to dementia development, this could take drug development to the next level: with precision medicines and combination therapies offering the promise to tackle disease with greater efficacy.

“The approaches to treatment development have thus far largely focused on single molecules or other treatments with a specific disease focus, such as immunotherapy for specific disorders or targeting specific enzymatic pathways," ​says the report.

"However, different underlying diseases often contribute to dementia development, progression and disease phenotypes. Even when one, such as AD, is the cause, many pathways are involved. It might therefore be necessary to intervene at several pathways or several points on the same pathway to achieve clinically meaningful benefits. Consideration should therefore be given to developing combination treatments delivered simultaneously or sequentially.

“More attention should also be paid to the precision medicine approach, whereby a treatment is tailored to a patient’s specific condition. Much of the delay in this field is due to pooling patients with different conditions and testing the same drug in all of them (e.g., amyloid-negative individuals in amyloid-lowering trials).

"Addressing this requires the use of disease-specific biomarkers and their development for other dementia-related conditions is essential.”

Repurposing drugs is another potential route for dementia drug research and development. In fact, of the drugs currently in clinical trials, 37% are repurposed.

As a result, the WHO wants to see cognition as a secondary outcome of trials for treatments of NCDs (such as diabetes, stoke and coronary artery disease) to explore the potential of these treatments in cognitive disorders and to identify new drugs and drugs that could be repurposed for the treatment of dementia.

WHO: Strategic goals for the development of novel therapies

  • Develop next-generation therapeutics that target the cell, gene or nucleotide and treatments that target brain networks for resilience, maintenance and repair for dementia in general as well as specific pathological processes. Other novel approaches such as antimicrobial treatments, the gut–brain axis (including nutritional interventions), stem cell therapy, brain stimulation and parabiosis should be further investigated.
  • Increase investment in the development of treatments for diseases beyond Alzheimer’s: such as Lewy body disease and frontotemporal dementia.
  • Promote research to investigate both amyloid and non-amyloid targets
  • Apply the principles of precision medicine in dementia research to verify both the efficacy of a treatment and the reliability of specific biomarkers.
  • Include cognition as a secondary outcome of trials for treatments of NCDs (e.g., diabetes, mellitus, hypertension, coronary artery disease, stroke) to explore the potential role of these treatments in cognitive disorders and to identify new drugs and drugs that could be repurposed for the treatment of dementia.

'Drug development is an intensely collaborative exercise'

One of the biggest problems in dementia drug development the ‘prohibitively high’ cost of bringing a new drug to market, prompting many large pharmaceutical companies to cut back their efforts in the field.

But interest is being renewed by collaborations among industry, academia and governments. Examples are the Alzheimer’s Prevention Initiative, the United Kingdom Dementia Consortium, the Accelerating Medicines Partnership – Alzheimer’s Disease, the European Union Joint Programme – Neurodegenerative Disease Research and the Davos Alzheimer’s Collaborative.

The WHO wants to see more of such collaboration. “Drug development is an intensely collaborative exercise,"​ it says. "It requires partnerships among scientists, pharmaceutical companies, clinical trialists, health specialists and service providers. Collaborative networks should include academia, industry and government, and trials should be truly international. Such collaboration and networks are only just starting to be established.”

Improving clinical trials

Getting dementia drugs through clinical trials has proved to be a problematic area for dementia drugs to date. Reimagining the standards and norms for dementia clinical trials, therefore, will be key to getting drugs from the pre-clinical stage to approval.

“Due to the slow evolution and progression of dementia symptoms, clinical trials for assessing the prevention, treatment or cure of dementia are naturally long. This makes clinical trials very expensive and prone to high rates of attrition," ​notes the report.

“More adaptive clinical trials should be conducted, and clinical trial networks should be established to make trials more feasible, equitable and inclusive. This will require engagement of research beneficiaries and the general public.”

Clinical trials often lack population and geographical diversity – for example, women are under-represented in Alzheimer’s trials, despite being at greater risk of developing dementia.

By 2027, the WHO wants to see standardized expert guidance on the design of clinical trials for drug development.

WHO: Strategic goals for dementia clinical trials

  • Adaptive, efficient trial designs: Design more adaptive trials of two or more treatments for use in combination.
  • Recruitment of patients and timing of interventions: As the pathological processes that cause dementia often predate the onset of clinical symptoms by many years, design trials to recruit patients as early as possible when relevant to the therapeutic strategy.
  • Harmonized international outcome measures: Improve international collaboration for identifying and validating outcome measures for clinical trials, including cognitive and functional outcomes and biomarkers.
  • International trial infrastructure: To ensure equity and develop infrastructure for trials in both HIC and LMIC, so that trials are international, gender-balanced, include all populations, are fully transparent and provide equal access to the data and results by researchers in all settings. A national registry and a database of people who are interested in trial participation should be established, and the research workforce should be trained to ensure that they have the required skills and competence.

The WHO blueprint for dementia research can be found in full here.

Related topics Bio Developments Pipelines

Related news

Show more

Follow us