What’s next for Alzheimer’s Disease?
Following the FDA approval of Eli Lilly’s anti-amyloid drug Kisunla (donanemab) for the treatment of Alzheimer’s disease, first-time patients and clinicians now have two disease-modifying treatment options, Eisai’s Leqembi (lecanemab) or Eli Lilly’s Kisunla.
Accompanied by their associated risks and benefits, both drugs are redefining the treatment of Alzheimer’s in the short-medium term and this article will explore what patients and HCPs can expect next.
Improved diagnostics and access
Despite both Leqembi and Kisunla having shown meaningful clinical benefits, neither is curative and only slows the disease’s progression. With both drugs targeting the same hallmark pathology known as amyloid (which starts to accumulate ~20-years before clinical symptoms), early treatment initiation is paramount to their efficacy, with significantly diminished outcomes seen the later treatment is started.
To ensure patients start treatment as early as possible, a quick and accurate diagnosis is needed. This proves more challenging than perhaps expected, due in part to the stigma associated with the disease’s early symptoms (memory abnormalities, mood swings and cognitive deficits). Patients are often hesitant to admit their symptoms or avoid consulting a primary care physician.
While health care professionals and patient advocacy groups have championed the education of the public on the importance of early diagnosis for appropriate early treatment, a full destigmatisation of this disease (historically viewed as a burden on families) will be critical.
Another limiting factor remains that, despite recognition of the symptoms, there’s a lack of access to specialised physicians who can impact the likelihood of a confirmatory diagnosis. This is driven by the requirement of complex, and often invasive, diagnostic tools like amyloid PET imaging and CSF biomarker analysis which are unavailable in GP and community settings. In some instances, it has become clear that only 2% of patients currently have access to these “gold standard” diagnostics in the UK, with similar access issues prevalent in the US and EU.
To address this, an emphasis has been placed on the development of novel diagnostics assays with particular interest devoted to blood-based biomarkers. Whilst there are several options already available as either exploratory or confirmatory assays (the Mayo Clinic’s pTau217 assay for instance) these are not currently covered by insurance. This results in sizeable out-of-pocket costs and they are largely unused as a consequence.
Ongoing developments from Roche and Eli Lilly look to address this. Having received breakthrough device designation for its pTau217 BBBM in 2024, an FDA approval is expected within the next few years and will increase the chances the assay sees full coverage, allowing patients in community settings access to less invasive and more accessible blood-based diagnostic tools.
Beyond diagnostics, a major step to increase the accessibility of these therapeutics, is to improve their dosing and route of administration. Currently, both Leqembi and Kisunla require access to transfusion centres, which in community settings limits access and places a great burden on patients who are required to visit bi-weekly or monthly. Innovations in drug administration mean that as early as January 2025, subcutaneous injectors of Leqembi may be available allowing for more convenient dosing. Similarly, the development of Eli Lilly’s remternetug is expected to offer another accessible option at a less frequent dosing schedule.
Expansion of the Alzheimer’s pipeline and clinical options
Following a positive diagnosis, patients will, having met the required eligibility criteria for Leqembi and Kisunla, start treatment. However, while ongoing studies are working to determine the long-term benefit of these drugs, so far clinical data has shown benefits over ~18-months. As neither option is curative, there remains a significant unmet need for additional therapeutic options to slow down or target different stages of the disease.
This is where much of the now over 164 ongoing clinical trials, assessing ~127 drugs across the Alzheimer’s pipeline and spanning >13 different MOAs beyond amyloid come into play. Each trial builds on the wealth of academic knowledge of the pathophysiology of Alzheimer’s disease.
Among those in development, there are now assets targeting Tau, Complement, TREM2, neuroinflammation, metabolic dysregulation, insulin signalling pathways, cellular senescence, poly-genic risk mutations and many more. Two examples of these modalities include:
- Tau, an intercellular microtubule associated protein that forms in Alzheimer’s as hyperphosphorylated tangles and leads to neuronal dysfunction. Historically, this has been challenging to target clinically. Eisai’s E2814, an ASO are now looking to change the narrative on Tau therapeutics through the Phase 2/3 DIAN-TU trial with the trial expected to conclude April 2028. It is worth noting that in Tau pathology there is a stronger correlation seen to the clinical decline seen in patients, more so than amyloid, suggesting an intrinsic relationship and likelihood or driving greater clinical benefits.
- TREM2, a receptor expressed on microglia, which acts as the resident immune cells of the brain clearing amyloid depositions and maintaining a homeostatic environment. This was first linked to Alzheimer’s pathology through genome wide association studies which demonstrated loss-of-function polygenic risk factors, such as R47H, some of the most strongly correlated to the eventual development of the disease. Addressing these polygenic mutations would be an ideal treatment strategy, but currently, most developments focus on increasing TREM2 activity through monoclonal antibodies or small molecule agonism, including Alector’s AL002, with topline Phase 2 data expected Q4 2024, Vigil’s Phase 1 investigation of VG-3927 and Muna’s preclinical mAb.
Although these different modalities are being investigated as monotherapies, the most promising approach will be the potential to use them as combination therapies. By synergizing different therapies, it is possible to target different pathways for an enhanced clinical effect. Nonetheless, these combinations are years away from clinical use, and any current issues, such as potential adverse events, cost of therapies and difficult access need to be address before being able to fully harness their potential.
For a space which was at a standstill for such a significant period, the Alzheimer’s space is seeing an emphatic rejuvenation. Patients and clinicians are offered greater hope that one day the disease will be manageable, if not preventable.
To get more insights into the Alzheimer’s pipeline, feel free to reach out to us at info@lifesciencedynamics.com
