Alzheimer’s Disease Therapeutics and Diagnostics – Parallel Advancements for Patient Care

Alzheimer’s Disease Therapeutics and Diagnostics – Parallel Advancements for Patient Care

2023 has already been a landmark year in Alzheimer’s disease (AD) therapeutics: lecanemab (Leqembi), co-developed by Biogen and Eisai, received FDA accelerated approval in January, and Phase 3 results for donanemab (Eli Lilly) are expected in 2Q23, with submission for FDA full approval shortly thereafter (accelerated approval was rejected in January). With the potential for widespread availability of novel treatments in the coming years, enabling timely, accurate diagnosis of Alzheimer’s disease should be front of mind for commercial strategy teams. Alzheimer’s complexity can make early diagnosis difficult, and misdiagnosis is common1. Fortunately, there is a burgeoning neurodiagnostics field aiming to offer clinicians and patients more certainty in their condition through a variety of CLIA-certified or FDA-approved diagnostic tests. The thoughtful selection and use of neurodiagnostics in clinical trials and the larger marketplace will be critical in the coming years to enable expanded access for Alzheimer’s Disease therapeutics.

Novel AD Treatments Necessitate Improved Diagnostics

Looking at the Alzheimer’s Disease (AD) therapeutic pipeline, there are over 30 disease-modifying therapies in late-stage clinical development2 with Eisai’s lecanemab (Leqembi) and Eli Lilly’s donanemab garnering the most attention. In their confirmatory phase 3 trials, both treatments included patients suffering from early symptomatic disease or mild cognitive impairment (MCI) due to AD and aim to measure an improvement from baseline in cognitive function tests using different metrics and brain amyloid plaque deposition using PET scans. Summarized in the table below, lecanemab relies on Clinical Dementia Rating scale Sum of Boxes (CDR-SB) as the primary outcome measure while donanemab utilizes the Integrated Alzheimer’s Disease Rating Scale (iADRS):

 Testing Approaches for Diagnosing Alzheimer’s Disease

Test CategoryStrengthsDrawbacks
Cognitive, Functional, and Behavioral Tests: Evaluate an individual’s mental abilities to identify changes in cognitive function
 
Notable examples: Clinical Dementia Rating scale Sum of Boxes (CDR-SB); Integrated Alzheimer’s Disease Rating Scale (iADRS)
Familiar and good track record
 
Low cost and quick administration
 
Able to detect disease progression
Relies on HCP consistency in application and interpretation; errors are common among PCPs
 
Relies on heterogenous clinical symptoms; CFB tests alone lead to misdiagnosis and cannot detect pre-clinical AD
Structural Brain Imaging: Segments and measures volumes of key brain structures; used for the detection of AD biomarkers

Notable examples: Volumetric Magnetic Resonance Imaging (vMRI); PET scan; CT scan
Well-established for AD diagnosis, particularly PET scans
 
Provides an objective measure
 
Differentiates AD from other forms of dementia (such as vascular dementia and frontotemporal)
High cost and large footprint scanning machines required
 
Not suited/accessible to primary care settings
 
False positives; brain changes may not be indicative of AD
 
Patient experience; potential sedation risk to achieve needed stillness
Cerebrospinal Fluid (CSF) Tests: Detection of AD biomarkers in CSF samples, such as β-amyloid, t-tau, and p-tau

Notable examples: Lumipulse® Aβ42/40 assay (Fujirebio); Elecsys CSF phospho-tau181/Aβ42 assay (Roche)
Accuracy improvements (when used alongside other tests)
 
Routine use in specialist healthcare settings
 
Differentiates from other forms of dementia (such as Lewy body and frontotemporal)
Invasive procedure required (lumbar puncture); risk of side effects and some patients are contraindicated (e.g., anticoagulants use)
 
Limited accessibility in primary care settings
 
Not validated in diverse populations
Blood Tests: Detection of AD biomarkers in blood samples, such as levels of β-amyloid, tau protein and neurofilament light (NfL) protein

Notable examples: PrecivityAD® (C2N Diagnostics); Quest AD-Detect (Quest Diagnostics)
Low cost
 
Easy to administer/minimally invasive
 
Routine across relevant healthcare settings
Currently less accurate /definitive than brain imaging or CSF analysis
 
Requires more sensitive measurement due to low biomarker concentrations
 
Lower specificity in later stages of AD when biomarkers are more indicative of general neurodegeneration
Genetic Testing: Detection of genetic variants associated with an increased risk of developing AD

Notable examples: APOE ε4 variant (for early- and late-onset AD); PSEN1, PSEN2 and amyloid precursor protein (APP)
Identifies risk of developing AD, supporting earlier diagnosisLimited predictive power
 
Limited use for diagnosis of late-onset AD; no strongly associated mutations
 
Ethical considerations; potential for psychosocial impact of test results

Both primary endpoints, CDR-SB and iADRS, diagnose behavioral symptoms rather than biomarker measurement in their scoring. CDR-SB is frequently chosen as an endpoint as it detects disease progression by assessing cognition and function in personal care, problem-solving, memory, and other functions; however, it has been criticized for its inconsistent reproducibility in detecting treatment differences. 5 On the other hand, iADRS is argued to reliably detect disease progression and treatment effects in participants across the spectrum of disease by measuring similar cognition and function categories through a composite score of ADAS-Cog-13 and ADCS-iADL.5 A point of concern is that payers may require biomarker data to supplement these cognitive tests to approve access to costly AD therapy and restrict access when inconsistencies arise. Forward-thinking therapeutic developers should consider now which sources of biomarker data will remove barriers to access to therapeutics and how best to validate this ability.

Breadth of Innovation in Diagnostics Development

Recently, diagnostics companies have collaborated with key players in AD therapeutics trials by measuring inclusion criteria and endpoint biomarkers. In November, C2N Diagnostics announced the PrecivityAD test’s use in the AHEAD trial, a lecanemab extension study, as part of the inclusion criteria of quantifying elevated brain amyloid.6 Specifically, PrecivityAD, a blood test, satisfies the requirement to show a plasma, cerebrospinal fluid (CSF), or positive PET result predictive of intermediate or elevated amyloid before screening. Neurodiagnostics contribute to endpoint measurements as well. When Eisai presented their ClarityAD results, all the target engagement and drug activity data from a panel of fluid biomarkers- including plasma pTau-181, GFAP and NfL – were from Quanterix Corporation’s ultrasensitive Simoa assay kits. 7 Overall, diagnostics are already useful at the clinical trial stage and may supplant less accessible and expensive gold-standard testing like amyloid PET in the future.

Outside clinical trials, the emerging neurodiagnostics landscape is rife with innovation, using various modalities testing for different biomarkers. Fujirebio’s Lumipulse Aβ42/40 and Roche’s Elecsys CSF phospho-tau181/Aβ42 assay both offer FDA approved Aβ42/40 measuring tests using cerebrospinal fluid (CSF) to assist clinicians in making diagnoses beyond clinical examination.8,9 This advance comes at the cost of the patient’s comfort due to the invasiveness of CSF collection. Quest Diagnostics and C2N Diagnostics address this through their CLIA-certified plasma blood tests, Quest-AD and PrecivityAD respectively, whose results approximate that of amyloid PET scan findings. Will we soon see a “Test and Treat” future in AD? Not so fast. Considerable work remains before widespread clinical adoption of plasma tests can occur.10 One major barrier is the lack of plasma test performance data in diverse patient populations with comorbidities like chronic kidney disease or a history of stroke that may boost AD biomarkers in the blood. Researchers also stress that CSF and plasma tests shouldn’t be used in cognitively healthy individuals since the disease has a long preclinical phase and may not manifest in the patient’s lifetime, causing undue distress and financial ramifications. All these companies face the current headwinds of defining and achieving their reimbursement strategy in an environment where therapeutic clinical utility is still evolving. The definition of coverage policies and diagnostic criteria by CMS and major commercial payers will drive the adoption and utilization of tests moving forward.

Future Challenges Facing AD Patients

It is unclear how many patients will receive the benefit of Leqembi and other anti-amyloid therapies. In April 2022, CMS effectively denied Medicare coverage of any anti-amyloid therapies, a decision they recently re-iterated after denying petitioning from the Alzheimer’s Association.11 Despite this, the Veteran’s Health Administration has determined it will cover access to Leqembi to veterans who fit the VHA’s criteria and the FDA label indication. In response to Aduhelm’s accelerated approval, CMS’s Chief Medical Officer left the door open to broad access if a therapeutic shows evidence of clinical benefit through the traditional full FDA approval process. 12 A decision on full approval for Leqembi is expected in July, preceded by an FDA Advisory Committee meeting scheduled for June 9th. Once a therapeutic overcomes this hurdle, questions about clinical utility for both a therapeutic and a diagnostic will be more settled and replaced with a simple one: what diagnostic tests can help accelerate access for an AD disease-modifying therapy?

In the near future, partnerships between diagnostics companies and drug developers can make a big difference for the millions of people grappling with the impact of dementia on their health and families. Early collaborations like the one between Eisai and C2N Diagnostics in the AHEAD study may mark the beginning of new and deeper partnerships between these two fields. New therapeutics will benefit from a robust diagnostics industry helping patients get an earlier diagnosis and diagnostics manufacturers will receive wider adoption and uptake. Future joint commercial partnerships can allow caregivers and physicians to test an individual and match them to the most appropriate treatment available.

How Kx can help

We at Kx are monitoring the Alzheimer’s Disease space evolution closely and see opportunities for commercial planning teams to meet the technology of the future through concrete, forward-looking steps today. To join us and discuss further, contact Brett at brett.larson@kxadvisors.com.

Contact Our Team Today

 

 

Thank you to Jean Santos for his contributions in the development of this piece.


References

  1. Gaugler JE, Ascher-Svanum H, Roth DL, Fafowora T, Siderowf A, Beach TG. Characteristics of patients misdiagnosed with alzheimer’s disease and their medication use: An analysis of the NACC-UDS database – BMC geriatrics. Characteristics of patients misdiagnosed with Alzheimer’s disease and their medication use: an analysis of the NACC-UDS database. https://bmcgeriatr.biomedcentral.com/articles/10.1186/1471-2318-13-137. Published December 19, 2013. Accessed February 2, 2023.
  2. Alzheimer’s Disease Therapeutics. https://www.alzforum.org/therapeutics/search?fda_statuses%5B%5D=851&target_types=&therapy_types=&conditions%5B%5D=145&keywords-entry=&keywords=. Accessed January 29, 2023.
  3. Commissioner Oof the. FDA grants accelerated approval for Alzheimer’s disease treatment. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment. Accessed January 29, 2023.
  4. Rogers MB. No accelerated approval for Donanemab. No Accelerated Approval for Donanemab. https://www.alzforum.org/news/research-news/no-accelerated-approval-donanemab. Accessed January 29, 2023.
  5. Wessels AM, Rentz DM, Case M, Lauzon S, Sims JR. Integrated alzheimer’s disease rating scale: Clinically meaningful change estimates. Alzheimer’s & Dementia: Translational Research & Clinical Interventions. 2022;8(1):197-210. doi:https://doi.org/10.1002/trc2.12312.
  6. Consortium ACT. New blood test to identify people at risk of developing Alzheimer’s symptoms will be used in clinical trial aiming to prevent memory loss. New Blood Test To Identify People At Risk Of Developing Alzheimer’s Symptoms Will Be Used In Clinical Trial Aiming To Prevent Memory Loss. https://www.prnewswire.com/news-releases/new-blood-test-to-identify-people-at-risk-of-developing-alzheimers-symptoms-will-be-used-in-clinical-trial-aiming-to-prevent-memory-loss-301422214.html. Published November 11, 2021. Accessed January 29, 2023.
  7. Quanterix’s Simoa® technology drives advances in Alzheimer’s disease research presented at 2022 clinical trials on Alzheimer’s disease (CTAD) conference. Quanterix’s Simoa Technology Drives Advances In Alzheimer’s Disease Research Presented At 2022 Clinical Trials On Alzheimer’s Disease (CTAD) Conference. https://www.quanterix.com/press-releases/quanterixs-simoa-technology-drives-advances-in-alzheimers-disease-research-presented-at-2022-clinical-trials-on-alzheimers-disease-ctad-conference/. Published December 6, 2022. Accessed January 29, 2023.
  8. FDA permits marketing for new test to improve diagnosis of alzheimer’s disease. FDA Permits Marketing for New Test to Improve Diagnosis of Alzheimer’s Disease. https://content.govdelivery.com/accounts/USFDA/bulletins/3165b47. Published May 4, 2022. Accessed January 29, 2023.
  9. Zinkovich C. Roche alzheimer’s Disease Cerebrospinal Fluid (CSF) assays receive FDA clearance, supporting more accurate and timely diagnosis. Roche Alzheimer’s disease Cerebrospinal Fluid (CSF) assays receive FDA clearance, supporting more accurate and timely diagnosis. https://diagnostics.roche.com/us/en/news-listing/2022/roche-alzheimers-disease-cerebrospinal-fluid-assays-receive-fda-clearance.html. Published December 8, 2022. Accessed January 29, 2023.
  10. Rogers MB. FDA approves Fujirebio’s CSF test for ad-quest diagnostic offers plasma test. FDA Approves Fujirebio’s CSF Test for AD—Quest Diagnostic Offers Plasma Test. https://www.alzforum.org/news/community-news/fda-approves-fujirebios-csf-test-ad-quest-diagnostic-offers-plasma-test. Published May 21, 2022. Accessed January 29, 2023.
  11. Fact sheet Medicare coverage policy for monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease. Medicare Coverage Policy for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease. https://www.cms.gov/newsroom/fact-sheets/medicare-coverage-policy-monoclonal-antibodies-directed-against-amyloid-treatment-alzheimers-disease. Published April 7, 2022. Accessed January 29, 2023.
  12. Press release CMS finalizes Medicare coverage policy for monoclonal antibodies directed against amyloid for the treatment of alzheimer’s disease. CMS Finalizes Medicare Coverage Policy for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease. https://www.cms.gov/newsroom/press-releases/cms-finalizes-medicare-coverage-policy-monoclonal-antibodies-directed-against-amyloid-treatment. Published April 7, 2022. Accessed February 7, 2023.

Key Insights & Takeaways: American Association for Clinical Chemistry Annual Scientific Meeting & Clinical Lab Expo

The Clinical Chemistry Annual Meeting did not disappoint with great attendance, engaging talks, and some innovative exhibits. After digesting all our notes (and a bit of Chicago’s finest culinary fare) from the busy week, we walked away with five key takeaways:

Innovative culture on display

If new products and technologies capture your attention, the Clinical Expo did not disappoint. Headlined by the Disruptive Technology Award winner, Nanopath, who led with a solid-state biosensing platform that removes the need for nucleic acid amplification. However, the Clinical Expo was full of new product launches, with some breaking new ground, such as Angle, plc with a system for harvesting cancer cells from patients’ blood for analysis. As expected, a stream of Monkeypox virus controls and assays were starting to be announced to address the now declared public health emergency. With promising innovations come questions about their ability to displace existing technologies, improve testing workflows, the size of addressable markets, and go-to-market plans. Members of the Kx team support clients by answering these types of questions every day and can assist you in thinking through how best to tackle these issues.

Still have VALID fears

On the heels of Europe having a regulatory shakeup in diagnostics (In-Vitro Diagnostic Medical Devices Regulation (IVDR) implementation), it seems likely the United States is about to follow suit with the Verifying Accurate Leading-edge IVCT Development Act (VALID Act) coming to a vote in Congress as early as next month. With so many clinical laboratorians converging on the conference, we expected to hear various positions and forecasts. AACC organizers did an excellent job putting forward an update through a session titled “Valid Vital LDTs: Current State of Regulation Legislation of Laboratory-Developed Tests.” However, we are left with the impression several laboratorians are upset with the impact this legislation could have on their business. Kx Advisors is keeping a close eye on this legislation and will be providing an update as the situation evolves. Get in touch if you would like to be kept informed and up to date on the latest developments.

Tech influences testing

Algorithms, connectivity, and smartphones were highlighted not only on the main stage, but across the Expo floor. Artificial intelligence and machine learning were featured in Dr. George Church’s plenary session discussing how machine learning will support a laboratory’s desire for multiplex testing, simultaneously gathering anywhere from tens up to billions of data points. On the show floor, we saw several connectivity products and features on display falling into two basic categories. First, solutions, such as Planet Innovation’s NeoSync(TM) and BrightInsight’s Connected Diagnostics Platform, focus on flexible configurations that may integrate into existing or future medical devices. The second category leverages smartphones as a connectivity conduit, with applications spanning from mobile phlebotomy to test analysis for blood clotting, infectious disease and more. Implementation of connectivity and algorithm-driven testing schemes as either products or product attributes require a strong understanding of testing behaviors and user segmentation. Kx Advisors utilizes novel behavioral modeling, and environment/user segmentation frameworks to support prioritizing the ideal tech-enabled features and products.

Character matters

As an industry, we all watched the collapse of Theranos, and the subsequent convictions of Elizabeth Holmes and Ramesh Balwani on fraud charges. These events surfaced discussions on the intersection of startup culture and clinical diagnostics, public trust in laboratory medicine, and the role of government oversight. AACC organizers wisely “read the room” and highlighted a discussion on ethics and accountability with Theranos whistleblowers, Erika Cheung, and Tyler Shultz. As a part of the diagnostics community, I applaud the efforts of AACC to facilitate these discussions.

Thank you, Chicago!

Chicago offers more than hot dogs and pizza – If you read our previous post about the hot topics of AACC, Bob Serrano and I voted for our favorite Chicago signature foods. Well, thank you Chicago for some amazing food and great hospitality— even if we missed grabbing a dog.

How Kx Can Help

Discuss more on the latest developments in diagnostics and life sciences or our key takeaways from the 2022 American Association for Clinical Chemistry Annual Scientific Meeting & Clinical Lab Expo. Contact Brian McNally, PhD brian.mcnally@kxadvisors.com.

Contact Our Team Today

Q&A with Kx: Spotlight on AACC 2022

Q&A with Kx: Spotlight on AACC 2022

American Association for Clinical Chemistry (AACC)
2022 Annual Scientific Meeting & Clinical Lab Expo
July 24 -28, 2022
McCormick Place Convention Center
Chicago, Illinois USA

Before they head off to the Windy City for this year’s AACC Annual Scientific Meeting & Clinical Lab Expo, we asked Bob Serrano and Brian McNally for their insights on what they hope to learn, see, and are excited to discover at this year’s conference!

Q: What takes life science growth strategy consultants to the American Association for Clinical Chemistry Annual Meeting?

Bob: At Kx Advisors, we focus on partnering with life sciences clients to deliver actionable insights that fuel growth. Clinical diagnostics has always been a market with technical innovations, but now more than two years since the start of the COVID-19 pandemic, we see significant investments being made. Those investments are in a market where patients demand greater value from testing. Models that decentralize molecular diagnostics right into our homes or adding genome sequencing to doctor’s visits, are both examples of those new models. Conferences like AACC are a great venue for us to listen to various perspectives and share our own insights.

Brian: As a former bench scientist, I find myself drawn to new products and technologies. After all, new gadgets in clinical diagnostics hold the promise of a healthier future for all of us. With almost 300 new exhibitors since 2019, I’m excited to see the future of diagnostics in the lab and at home. So, you can expect to find me talking to exhibitors about their new study results and how they expect it will bring greater value to labs.

 

Q: What do you expect to be the hot topics in laboratory medicine?

Brian: While COVID testing is here to stay given the endemic-like nature of SARS-CoV-2, we see three outcomes of the pandemic impacting the labs. First, pandemic preparedness. We see this being tested with the spread of new SARS-CoV-2 variants as well as monkeypox. Second, advances in characterizing host-pathogen interactions, brings a new dimension to supporting clinical practice from diagnosis through treatment. Lastly, we expect labs will be sharing their perspectives on how to support patients with post-COVID syndromes.

Bob: I expect a hot topic for attendees will be what the inclusion of Verifying Accurate Leading-edge Development (VALID) into the Medical Device User Fee Amendments (MDUFA) will mean for innovation. VALID establishes a risk-based framework for in vitro clinical test (IVCT) regulation, which would give the FDA authority over LDTs (laboratory-developed tests). AACC has asked its membership to oppose VALID’s inclusion, while the industry group AdvaMed has endorsed VALID. So, while VALID’s language is not yet finalized, and there is a proposed five-year phase-in, we still expect to hear a lot from the Expo attendees on how VALID is going to impact them. Specifically, how will a risk-based regulatory structure be applied to new testing models that are less hypothesis-driven, and more proactive?

 

Q: What technologies do you see making headlines on the Expo floor?

Bob: While the headlines might be from earlier this year, the news surrounding decreasing costs of next generation sequencing will resonate with clinical laboratories. Costs are a key barrier to the recent push we see for comprehensive genomic profiling (CGP). At this past month’s American Society of Clinical Oncology meeting, Illumina hosted a networking event where a panel of clinicians shared case studies where CGP was transformational for the patient. The panelists went on to describe reimbursement as a barrier to adoption; so obviously, if costs keep decreasing, we could see CGP’s growth accelerate.

Brian: AACC does a fantastic job of providing some built-in technology headlines with the Disruptive Technology award. This year, there are three finalists who we expect will be getting a lot of attention moving forward. First, the Verita™ lab-on-a-chip platform by Biological Dynamics offers a nanoparticle-based isolation solution for streamlined multi-omic testing. This type of platform technology should garner broad appeal with biomarker discovery groups as well as assay developers. Next, Nanopath has focused their attention on women’s infectious diseases and looks to use their expertise in nanotechnology to offer a compelling physician office testing platform. Lastly, Visby Medical has launched a palm-size PCR testing platform for COVID and sexually transmitted infections. All these finalists are great representatives for the trends we have seen coming in the molecular diagnostic space, so now we need to find what’s next.

 

Q: What do you expect to share with your clients when you get back from the Meeting & Expo?

Brian: With COVID bringing diagnostic testing into our homes, we have all participated in the adoption of decentralized diagnostic testing. Now we are looking at the next wave of patient-focused testing, both in the home as well as distributed throughout the healthcare setting. The innovations we see coming are not only from the test technology, i.e., how fast can PCR be done, but how the tests fit into these new environments, and how they communicate with the broader healthcare system.

Bob: An event like AACC is a great way to share perspectives and gather experiences firsthand from the clinical laboratory. The insights I expect to share with our clients will then be focused on how laboratories are going to deliver value to patients. As an example, how can labs deliver greater clinical insights in a post-VALID environment? And what impact will greater competition in the genomics space have? So, we look forward to hearing perspective of the labs, the diagnostic developers and partnering with them to help identify the best way to help patients and clinicians.

 

Q: Last question for you both, Deep Dish Pizza or Chicago Dog?

Brian: Chicago Dogs for me. No way to pass up all those toppings.

Bob: Deep Dish all the way! More specifically, Deep Dish from Pizzeria Due, the original chain restaurant of Pizzeria Uno. This is the true pride and soul of Chicago. 🍕

 

How Kx Can Help

Discuss more on the latest developments in diagnostics and life sciences (or the great pizza vs. hot dog debate of 2022), join us in Chicago for AACC Annual Scientific Meeting & Clinical Lab Expo.  Contact Bob Serrano bob.serrano@kxadvisors.com or Brian McNally, PhD brian.mcnally@kxadvisors.com

Contact Our Team Today