THE LATEST

Read The 2020 Hot Indications List

How can companies determine where to focus as they develop their pipelines and determine new growth opportunities? Kx Advisors’ 2020 Hot Indications List can help. In our 6th annual analysis of global R&D investment, our experts identified the top indications for industry focus.

Download The White Paper

Tag: market access

Blood Biomarkers in Alzheimer’s Disease

Posted on by Juan Valdez-Capuccino

Blood Biomarkers in Alzheimer’s Disease

The AD landscape is complex but evolving addressing diagnosis bottlenecks, infrastructure support/access issues, and cost considerations is crucial for improving patient outcomes.

Barriers to address for improving patient outcomes

Diagnosis
  • PCPs are not set up for success to provide adequate workup.
  • Current cognitive and functional tests have limitations and require repeat testing to detect decline over time.
  • Blood biomarkers (BBMs) can address some of these limitations but have had a slow uptake.

Infrastructure
  • Hiring and training required personnel needed to carry out all required steps for diagnosis and medication administration (e.g., staff at infusion and MRI centers).

Support/Access
  • Patients’ access to HCPs is limited (e.g., geographic location, HCP limited time).
  • Caregiver support is essential and is often overlooked when setting up patient appointments.

Cost
  • High cost of approved therapies is a barrier to access for patients even though they are most effective and offer cost savings when introduced early.
  • Other factors should be considered, such as care partners’ ability to continue working while the patient remains in the earlier stages longer.

On this page, we will provide an overview on diagnosis with a specific focus on BBMs, including the landscape, available tests, accessibility, accuracy of data, and upcoming pipeline and industry trends.

EXECUTIVE SUMMARY – THE BBM SPACE TODAY

Despite rapid expansion in BBM development, significant hurdles remain to reach broad adoption in AD1

Challenges with Current AD Biomarker Tests2,3

  • The gold standard for Aβ and tau measurements involves costly and invasive PET and CSF tests.
  • There is a need for less invasive and cost-effective alternatives.

 

BBM tests1,2,4

  • Have the potential to address unmet needs because they:
    • Limit the number of patients that require a confirmatory PET scan.
    • Help with earlier diagnosis of AD.
  • Current limitations include:
    • Age-dependent accuracy.
    • Results influenced by comorbidities such as hypertension or CKD.

Did you know?

Because of the multiple steps in the diagnosis of AD, the average predicted wait time between clinical diagnosis and treatment is 18.6 months4
4.

EXECUTIVE SUMMARY – THE FUTURE BBM LANDSCAPE

Slow adoption of BBM tests is poised to shift, driven by outcomes of combination targets, greater coverage and reimbursement, and increased investments, reflecting growing confidence in BBMs in AD diagnosis.

BBM Tests Icon

Testing for multiple targets yields the most promising outcomes

Previous BBM tests examined individual targets. Recent approvals in the market show a shift toward a stronger emphasis on simultaneously assessing various targets (i.e., Aβ and p-tau 217).

Wider insurance coverage and improved reimbursement will enhance BBM accessibility for AD diagnosis

With the emergence of DMTs, we anticipate that more BBM tests will secure CPT codes, insurance coverage, and reimbursement protocols, accelerating their adoption.

Increasing investments and strategic partnerships underscore a high level of confidence in the potential of BBM testing

These collaborations not only demonstrate a commitment to advancing BBM technologies, but also indicate a growing belief in their ability to make a meaningful impact on AD diagnosis.

Despite an initial sluggish adoption, emerging trends point toward the anticipated expansion of BBMs in clinical practice.

Detailed Findings

Amyloid beta and tau are the primary biomarkers of Alzheimer’s disease, which are currently measured via CSF or PET scans2,5

Amyloid beta (Aβ)6

Doctor Icon

Plasma Aβ42/40 levels are abnormal during the presymptomatic disease stages making earlier screening and diagnosis possible.

Chart Down Icon

A lower Aβ42/40 ratio corresponds to Aβ presence in the brain.

P-tau

Doctor Icon

Plasma p-tau levels are related to both the density of Aβ plaques and tau tangles.

Chart Down Icon

P-tau levels increase across the AD continuum, including the asymptomatic phase in sporadic and genetic forms of AD7

Given the multistep nature of AD diagnosis, more accessible testing methods are needed to help with timely and accurate AD diagnosis and intervention

Doctor Icon

AD often isn’t diagnosed until a patient has progressed to the mild dementia stage of the disease8

People Icon

About one-third of people with MCI due to AD develop AD dementia within 5 years, and each day >2000 adults may transition to moderate AD9

Hourglass Icon

Progression past the MCI stage can lead to ineligibility for certain AD treatments10

Patient presents with suspected cognitive changes | Assess cognition with diagnostic tools sensitive to MCI and mild AD dementia (eg, MoCA, MMSE, Mini-Cog) | Use structural imaging to rule out other conditions that may cause symptoms similar to AD (eg, MRI and CT scans)

Routine screening of adults >65 or individuals with risk factors for AD could identify more patients before they progress to mild dementia.

More affordable and accessible testing could reduce time from initial cognitive changes to formal diagnosis.

Did You Know Icon

Did you know? Because of the multiple steps in the diagnosis of AD, the average predicted wait time between clinical diagnosis and treatment is 18.6 months15.

Assessment via BBMs have the potential to be an important part of the path to treatment and are a growing focus area

Overview of BBMs

Drivers:

  • Enable earlier diagnosis for patients over 65, particularly in mild cognitive impairment (MCI) and early Alzheimer’s disease (AD)1
  • Reduce misdiagnosis
  • Provide greater access to biomarker-based measures compared to expensive and invasive PET/CSF tests

Barriers:

  • Lack of regulatory approval for BBMs
  • BBMs should complement, not replace, clinical assessments16
  • High variability in disease progression among individuals with positive biomarkers17
  • BBMs are not yet established in clinical practice, requiring physician education

As the field’s understanding of BBM use and limitations in the AD space increases, so does the number of in-development and commercially available tests

TestManufacturerAvailabilityTargetAccuracy Data
AD-Detect18QuestAvailable for useAmyloid beta, p-tau181, p-tau 217Sensitivity: 71
Specificity: 89%
PrecivityAD19C2NAvailable for useAmyloid beta 42/40 ratioSensitivity: 88%
Specificity: 89%
Accuracy: 86%
PrecivityAD220C2NAvailable for useAmyloid beta 42/40 and p-tau 217/np-tau 217 ratioSensitivity 88%
Specificity 89%
ALZpathDx21ALZpathAvailable for useAmyloid beta and p-tau 217Accuracy: 92%
P-Tau 21722,23Mayo ClinicAvailable for useP-tau 217Accuracy: 94%
ALZmetrix TM24PharmaKureCompleted clinical trialAmyloid beta, α-synuclein, p-tau 181, and p-tau 217Accuracy: 97%
Elecsys25,26Roche/LillyOngoing clinical trialsAmyloid beta or p-tau 217Data not yet released
LucentAD27QuanterixResearch use onlyP-tau 217Accuracy: >90%
AB42 and TTAU28Siemens HealthineersN/AAmyloid beta and tauData not yet released
ALZpath p-tau 21729,30AlamarN/AResearch onlyAccuracy: >90%
Equipment dependent test31FujirebioResearch use onlyAmyloid beta (1-40,1-42) and tau (p-181, p-217)N/A

Did you know?

A breakthrough device must file for FDA 510(k) clearance when there is low to moderate risk for the device and there is a legally marketed predicated device32.

Scientific evidence has driven companies to offer tests that measure both Aβ and p-tau to obtain a more accurate assessment of AD

TestManufacturerCLIA certifiedAvailabilityTargetAccuracy Data
AD-Detect18QuestYesAvailable for useAmyloid beta, p-tau 181, p-tau 217Sensitivity: 71%, Specificity: 89%
PrecivityAD19C2NYesAvailable for useAmyloid betaSensitivity: 88%, Specificity: 89%, Accuracy: 86%
PrecivityAD220C2NYesAvailable for useAmyloid beta 42/40 and p-tau 217/np-tau 217 ratioSensitivity 88%, Specificity 89%
Simoa® ALZpath21ALZpath, QuanterixYesAvailable for useP-tau 217Accuracy: 95%
ALZmetrix TM22PharmaKureN/ACompleted clinical trialAmyloid beta, α-synuclein, p-tau 181 and p-tau 217Accuracy: 97%
Phospho-Tau 21722,23Mayo ClinicYesAvailable for useP-tau 217Accuracy: 94%
Elecsys23,24Roche/LillyN/AOngoing clinical trialsAmyloid beta or p-tau 217Data not yet released

Earlier developed tests were primarily designed to screen for Aβ.

There has been a shift toward the development of tests screening for p-tau 217 and others that simultaneously screen for multiple markers.

C2N, ALZpath, and Quanterix, and Roche and Eli Lilly’s plasma tests for Aβ and p-tau 217 have received the FDA Breakthrough Device Designation23-26,33.

Did you know?

The average review time for breakthrough devices with 510(k) clearance is 152 days34.


Lack of insurance coverage hinders the adoption of BBMs, but the promise of expanded coverage and reimbursement in the future can spur their acceptance and use

CPT CodeDescription
0206UNeurology (Alzheimer’s disease); cell aggregation using morphometric imaging and protein kinase C-epsilon (PKCε) concentration in response to amylospheroid treatment by ELISA, cultured skin fibroblasts, each reported as positive or negative for Alzheimer’s disease DISCERN™, NeuroDiagnostics, NeuroDiagnostics
0207UNeurology (Alzheimer’s disease); quantitative imaging of phosphorylated ERK1 and ERK2 in response to bradykinin treatment by in situ immunofluorescence, using cultured skin fibroblasts, reported as a probability index for Alzheimer’s disease DISCERN™, NeuroDiagnostics, NeuroDiagnostics
0289UNeurology (Alzheimer’s disease); mRNA, gene expression profiling by RNA sequencing of 24 genes, whole blood, algorithm reported as predictive risk score MindX Blood Test™, MindX Sciences™ Laboratory
0346UBeta amyloid, Aβ40 and Aβ42 by liquid chromatography with tandem mass spectrometry (LC-MS/MS), ratio, plasma QUEST AD-Detect™ Beta Amyloid 42/40 Ratio, Plasma, Quest Diagnostics
0358UNeurology (mild cognitive impairment); analysis of β-amyloid 1-42 and 1-40, chemiluminescence enzyme immunoassay, cerebral spinal fluid, reported as positive, likely positive, or negative Lumipulse® G βAmyloid Ratio (1-42/1-40) Test, Fujirebio Diagnostics, Inc, Fujirebio Diagnostics, Inc
0361UNeurofilament light chain, digital immunoassay, plasma, quantitative Neurofilament Light Chain (NfL), Mayo Clinic, Mayo Clinic
0393UNeurology (e.g., Parkinson’s disease, dementia with Lewy bodies); cerebrospinal fluid (CSF), detection of misfolded α-synuclein protein by seed amplification assay, qualitative SYNTap® Biomarker Test, Amprion Clinical Laboratory
0412UBeta amyloid, Aβ42/40 ratio, immunoprecipitation with quantitation by liquid chromatography with tandem mass spectrometry (LC-MS/MS) and qualitative ApoE isoform-specific proteotyping, plasma combined with age, algorithm reported as presence or absence of brain amyloid pathology PrecivityAD® blood test, C2N Diagnostics LLC, C2N Diagnostics LLC
0443UNeurofilament light chain (NfL), ultra-sensitive immunoassay, serum or cerebrospinal fluid (Effective 04/01/2024)
0445Uβ-amyloid (Abeta42) and p-tau (181P) (pTau181), electrochemiluminescent immunoassay (ECLIA), cerebral spinal fluid, ratio reported as positive or negative for amyloid pathology Elecsys® PhosphoTau (181P) CSF (p-tau 181) and βAmyloid (1-42) CSF II (Abeta 42) Ratio, Roche Diagnostics Operations Inc (US owner/operator)
83520Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative; not otherwise specified
84999Unlisted chemistry procedure [when specified as tau protein, amyloid beta peptide testing other than long form Aβ, Aβ1-42, Beta-amyloid (1-42), and Abeta42 in CSF specimen or neural thread protein biochemical testing]

Coverage & reimbursement is restricted

  • BBMs currently lack medical necessity status and require stronger evidence for clinical use
  • Due to their novelty, private insurance payers, Medicare, and Medicaid do not currently provide coverage for BBMs
  • BBM test manufacturers are actively pursuing reimbursement for their products

BBM CPT codes are limited

Only 2 BBM tests currently have corresponding CPT codes35,36

High OOP Costs for tests

  • Patients need to pay out-of-pocket for biomarker tests since they are not covered by insurance
  • The cost per test varies by manufacturer; the QUEST-AD Detect test is priced at $399 plus a physician service fee, while the PrecivityAD test costs approximately $1,20037-39
  • C2N Diagnostics emphasizes potential cost savings of $643 per identified case of Alzheimer’s disease

The use of BBMs to detect and diagnose Alzheimer’s disease early could lead to an increase in the number of patients receiving potentially life-changing treatment.


The use of BBMs to detect and diagnose Alzheimer’s disease early could lead to an increase in the number of patients receiving potentially life-changing treatment.

BBMs can have a significant impact on the diagnosis and monitoring of Alzheimer’s disease, benefiting both patients and physicians, if current challenges are overcome by:

Patient Identification Icon

Allowing for patient identification at the PCP level

Early Detection Icon

Detecting patients in the earliest stages of AD

PET Scan Icon

Limiting the need for a confirmatory PET scan

Early Intervention Icon

Leading to early intervention, maximizing the effectiveness of approved therapies

Caregiver Burden Icon

Reducing the burden on caregivers

BBM tests have the potential to shape the AD neurodiagnostic landscape46

Diagnosis Icon

When used in combination with clinical and cognitive evaluation, the role of BBM in clinical practice may assist in diagnosis/prognosis and in monitoring changes related to the disease-modifying treatment, supporting the safe and effective use of treatment in the future, while PET/MRI is expected to only be necessary for borderline BBM measures.

Research Icon

While BBM tests are not ready to be a stand-alone diagnostic in any clinical setting, more research and clinical trials may improve these tests to the point where they can be widely used to screen for AD risk.

Screening Icon

BBM tests, along with diagnosis dynamics and advances in screening, could change the way AD is detected, resulting in earlier detection and improved patient outcomes.

References

  1. Yu M. Presented at the American Academy of Neurology. April 2024. Session C5
  2. Hampel et al. Neuron. 2023;111(18):2781-2799.
  3. Masdeu JC. Presented at the American Academy of Neurology. April 2024. Session C5
  4. Mielke et al. Nature Medicine. 2022;28(7):1398-1405.
  5. Jack CR Jr. Lancet Neurol. 2010;9(1):119-28.
  6. Hansson O et al. Alzheimers Dement. 2022;18(12):2669-2686.
  7. Janelidze S et al. JAMA Neurol. 2021;78(11):1375-1382.
  8. Mayo Clinic. 2023. Accessed May 13, 2024. https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/in-depth/alzheimers-stages/art-20048448.
  9. Alzheimer’s Association. Alzheimers Dement. 2024. doi:10.1002/alz.13809.
  10. LEQEMBI (lecanemab-irmb) [Prescribing Information]. Nutley, NJ: Eisai Inc.
  11. Alzheimer’s Association. 2022. Accessed May 13, 2024. https://www.alz.org/alzheimers-dementia/diagnosis/medical_tests.
  12. O’Caoimh R et al. J Alzheimers Dis. 2016;51(2):619-629.
  13. Tariq SH et al. Am J Geriatr Psychiatry. 2006;14(11):900-910.
  14. Usarel C et al. Int Psychogeriatr. 2019;31(2):223-229.
  15. Liu JL, et al. RAND Corporation; 2017. https://www.rand.org/pubs/research_reports/RR2272.html.
  16. Angioni D, et al. J Prev Alzheimers Dis. 2022;9(4):569-579.
  17. Dubois B, et al. Alzheimers Res Ther. 2023 Oct 13;15(1):175.
  18. MedPageToday. 2024. Accessed May 13, 2024. https://www.medpagetoday.com/neurology/alzheimersdisease/109142
  19. C2N. 2023. Accessed May 13, 2024. https://c2n.com/news-releases/cns-precivityad-blood-test-which-identifies-amyloid-pathology-as-an-aid-to-alzheimers-disease-diagnosis-further-demonstrates-its-high-accuracy-in-newly-published-research/
  20. Meyer MR et al. Alzheimers Dement. 2024. doi: 10.1002/alz.13764.
  21. Ashton Nj et al. medRxiv. 2023:2023.07.11.23292493.
  22. Mayo Clinic. 2023. Accessed May 23, 2024. www.mayocliniclabs.com/test-catalog/Overview/621635#Overview
  23. Arranz J, et al. Diagnostic performance of plasma pTau 217, pTau 181, Ab 1-42 and Ab 1-40 in the LUMIPULSE automated platform for the detection of Alzheimer disease. Preprint. Res Sq. 2023;rs.3.rs-3725688. doi:10.21203/rs.3.rs-3725688/v1
  24. Pharmakure. 2023. Accessed May 13, 2024. https://pharmakure.com/world-alzheimers-day-using-ai-to-diagnose-early-stages-of-the-disease-2/
  25. Roche. 2023. Accessed May 13, 2024. https://diagnostics.roche.com/us/en/news-listing/2023/roche-collaboration-lilly-enhance-early-diagnosis-alzheimers-dis.html
  26. FierceBiotech. 2024. Accessed May 13, 2024. https://www.fiercebiotech.com/medtech/alzheimers-blood-test-roche-eli-lilly-nabs-fda-breakthrough-tag
  27. Quanterix. 2023. Accessed May 13, 2024. https://www.quanterix.com/press-releases/quanterix-launches-high-accuracy-p-tau-217-blood-biomarker-test-to-aid-physician-diagnosis-of-alzheimers-disease/
  28. SIEMENS Healthineers. 2020. Accessed May 13, 2024. https://www.siemens-healthineers.com/en-us/press-room/press-releases/novartiscollaboration.html
  29. PR Newswire. 2024. Accessed May 13, 2024. https://www.prnewswire.com/news-releases/new-study-published-in-jama-neurology-affirms-high-diagnostic-accuracy-of-alzpaths-ptau217-test-in-identifying-amyloid-and-tau-in-the-brain-302040568.html
  30. ALAMAR Biosciences. 2024. Accessed May 13, 2024. https://alamarbio.com/alamar-biosciences-and-alzpath-inc-announce-strategic-supply-agreement-for-ptau217-antibody-to-advance-alzheimers-disease-research/
  31. FUJIREBIO. 2024. Accessed May 13, 2024. https://www.fujirebio.com/en-us/products-solutions/neurodegenerative
  32. Medical Device Safety and the 510(k) Clearance Process. Accessed June 6, 2024. https://www.fda.gov/medical-devices/510k-clearances/medical-device-safety-and-510k-clearance-process
  33. C2N Diagnostics. 2024. Accessed May 13, 2024. https://c2n.com/news-releases/2019/01/29/2019-1-24-c2n-diagnostics-receives-breakthrough-device-designation-from-us-fda-for-blood-test-to-screen-for-alzheimers-disease-risk
  34. Medical Device Academy. 2024. Accessed May 13, 2024. https://medicaldeviceacademy.com/breakthrough-device-designation/
  35. Blue Cross Blue Shield. 2023. Accessed May 13, 2024. https://mn-policies.exploremyplan.com/portal/web/medical-policies/-/mp-200
  36. Healthy Blue. 2024. Accessed May 13, 2024. https://provider.healthybluenc.com/dam/medpolicies/healthybluenc/active/policies/mp_pw_E001583.html
  37. EmblemHealth. 2023. Accessed May 13, 2024. https://www.emblemhealth.com/content/dam/global/pdfs/provider/reimbursement-policies/biochemical-markers-alzheimer.pdf
  38. Precivity. 2024. Accessed May 13, 2024. https://precivityad.com/news/study-finds-cn-diagnostics-precivityad-blood-test-provides-opportunities-for-robust-cost-savings-in-the-evaluation-of-patients-with-cognitive-impairment
  39. Canestaro et al. Popul Health Manag. 2024. doi: 10.1089/pop.2023.0309
  40. SIEMENS Healthineers. 2020. Accessed May 13, 2024. https://www.siemens-healthineers.com/press/releases/ms-novartis.html
  41. Quanterix. 2022. Accessed May 13, 2024. https://www.quanterix.com/press-releases/quanterix-announces-new-agreements-with-lilly-to-advance-alzheimers-disease-diagnosis-and-treatment/
  42. Beckman Coulter. 2023. Accessed May 13, 2024. https://www.beckmancoulter.com/about-beckman-coulter/newsroom/press-releases/2023/q3/2023-jul-17-beckman-coulter-and-fujirebio-partner-to-bolster-access-to-alzheimers-disease
  43. Quanterix. 2023. Accessed May 13, 2024. https://www.quanterix.com/press-releases/quanterix-announces-new-agreement-to-advance-blood-based-alzheimers-disease-detection/
  44. PR Newswire. 2024. Accessed May 13, 2024. https://www.prnewswire.com/news-releases/alamar-biosciences-and-alzpath-inc-announce-strategic-supply-agreement-for-ptau217-antibody-to-advance-alzheimers-disease-research-302075376.html
  45. EISAI. 2024. Accessed May 13, 2024. https://www.eisai.com/news/2024/news202414.html
  46. Schindler SE, et al. Nat Rev Neurol. 2024. doi: 10.1038/s41582-024-00977-5. Epub ahead of print.

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

Posted on by Bob Serrano

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.

5 Misconceptions for MedTech Market Access Strategy

Posted on by Jenna Riffell, PhD

5 Misconceptions for MedTech Market Access Strategy

Market access in MedTech is a complex and rapidly evolving environment, with increasingly intense scrutiny on the costs and benefits of new technologies as the pressure on budgets increases globally. The ability to prepare for and navigate market access strategy is, now more than ever, crucial to the success of a new product, and is frequently assessed by potential partners and acquirers with the same priority as the scientific rationale or potential for favourable regulatory approval.

During the recent MedFit 2022 event in Grenoble, we discussed the most common pitfalls that may affect market access planning and strategy with leading European experts and start-up companies. Here are the top five misconceptions for market access strategy we identified.

“We want to get the approval first, then we will plan for market access”

Engagement with payers early in product development is essential. Companies should define a path to reimbursement, and understand how payers will assess their product, as early as the concept stage to use payers’ feedback to shape the technology into a marketable product and create patient and company value. Leaving engagement with payers until late in development, or after approval, can often lead companies to:

  • overlook crucial requirements
  • mistarget patient populations
  • fail to expectations to gain market access
  • fail to gain critical pricing insights to size the commercial potential

Missing the opportunity to treat payers as your sounding board can cause delays and significant restrictions in access, while timely and iterative payer engagement has the potential to speed up the development process.

“The evidence we are generating for regulators will be sufficient for our market access strategy”

Regulatory decisions are at the top of priority lists for MedTech entrepreneurs both in the US and Europe. Selection of the right pathway and preparation of required submission dossiers are time-consuming and costly and constitute a necessary condition for market access. Late-stage start-ups agree, nonetheless, that it is far from sufficient, and payers themselves corroborate this perspective. In a recent Kx Advisors study, 100% of interviewed executives for major US payers agreed going beyond the evidence required for regulatory approval is key for market access strategy. Payers increasingly require demonstration of patient value not only with differentiated clinical efficacy and safety but through increased compliance and improved patient outcomes and satisfaction. They are also seeking additional sources of data, such as real-world evidence, insurance claims, and adverse event reports. MedTech companies should plan and pre-empt these requirements by carefully designing their studies for a payer-targeted set of endpoints as early as possible and generating evidence with not only regulators but also payers in mind.

“There is an established price for devices like ours”

Existing pricing and reimbursement benchmarks provide valuable insights for market access strategy, as showing cost-effectiveness in comparison to the current standard of care is an important part of any MedTech company’s economic narrative. However, payers’ focus is shifting towards a more holistic view, with greater interest in:

  • improved patient outcomes
  • demonstrated longer-term value
  • ease of use
  • adherence to treatment
  • patient satisfaction

Four out of every five payers recently interviewed by Kx Advisors indicated a preference for increased value over purely lower cost of treatment and were ready to assess pricing based on a complete view of benefit for the patient and healthcare system. The approach MedTech companies take to frame, measure, and present this value becomes a tactical choice, and a key element of a broader commercialisation strategy, that should not be dismissed or made based on a simple competitive analysis.

“We will focus on a market we know and aim for broad market access”

Many MedTech companies decide to first target their home geographic market, building on their familiarity with it, knowledge of the local language and system, and network of contacts. This approach, while easier from a product development perspective, may not allow companies to fully capture their commercial potential. In conversations with Kx Advisors, start-ups with prior product launch experience highlighted the need for fast market deployment and the value of testing the product with first adopters (and getting the product paid for early on) typically outweighs the breadth of market access. The choice of the first markets in which to launch is a strategic decision, and market access becomes one of the key drivers that should be considered in careful prioritisation of the highest potential markets. Entrepreneurs should be aware of both regional (e.g., US vs EU) and intrinsic (e.g., openness to innovative technologies) differences among payers, as well as differing patient population structures and accessibility, and explore avenues that expedite first market access, such as targeting research institutions or venturing into new geographies.

“Payers are not willing to consider innovative reimbursement models”

Getting paid for innovative technologies is notoriously difficult, especially when there is no easy way to make them fit within the established market access pathways for medical devices. The emergence of digital therapies and connected health, as well as the ongoing shift towards at-home therapies accelerated by the COVID pandemic, have only made the landscape more complex. At the same time, the awareness and urgency to address these challenges is on the rise among payers. Approximately 60% of payers recently interviewed by Kx Advisors stated they are exploring value-based reimbursement options and new, alternative pricing models for medical technologies (e.g., subscriptions or device-as-a-service arrangements) will be an increasingly welcome element of future coverage decisions. Building a differentiated market access strategy that accounts for multiple possible business models and reimbursement scenarios and exploring those early with key stakeholders can allow MedTech companies to create and leverage these opportunities.

 

Has your commercialisation strategy ever been impacted by any of these common misconceptions? Or are you currently facing other strategic decisions that will be crucial for your MedTech company’s growth? Feel free to contact Kx Advisors for a follow-up discussion.

Contact Our Team Today

 

Jenna Riffell is a Managing Partner at Kx Advisors, based in London.

Przemek Czerklewicz is a Principal at Kx Advisors, based in London. During the recent MedFit Event 2022 he led an expert panel titled “Innovators’ checklist for market access”.