EXECUTIVE SUMMARY – THE AI LANDSCAPE SPACE TODAY

AI-powered software tackling some of the main unmet need have already been developed and are currently awaiting FDA 510(k) approval

Current AI-powered software are designed for a broader usein neurology

• Current AI-powered software have been developed for not only Alzheimer’s disease but for a larger number of neurodegenerative diseases, such as looking at changes in white and grey matter and volumetric changes
• The approval of ATTs has created a new set of needs and challenges that current approved products do not address, like the need for centiloid count on PET scans

 

Adding functionalities such as ARIA monitoring can help address some of the unmet needs created by ATTs

• Software addressing some of the unique unmet needs like detecting and monitoring for ARIA are currently awaiting FDA 510(k) approval and could be granted as early as Q1 2025
• Different pricing models, such as subscription-based models or pay-as-you-go models, could help with the adoption of these technologies in large and small healthcare systems

Did you know?

ARIA is one of the side effects of monoclonal antibodies directed to amyloid beta aggregates such as lecanemab and donanemab​

EXECUTIVE SUMMARY – THE FUTURE AI IMAGING LANDSCAPE

Ease of integration and additional features that can aid with image interpretation and diagnosis will be key moving forward

Unmet need: Testing for multiple targets yields the most promising outcomes

Future trends: Ability to detect ARIA-E and ARIA-H events and additional features, such as the ability to detect the potential risk of developing ARIA, could help improve the safety of ATT

Unmet need: Most companies currently only offer one payment system, although some have shifted to provide multiple options

Future trends: Having different pricing models for different healthcare systems could help those with large or small volume of patients

Unmet need: The need to integrate with a cloud-based AI could help with faster computation and analysis but have the risk of not being available if there are connectivity issues

Future trends: Products that don’t over-rely on an internet connection for some of their key features could bypass this issue, although computational analysis could be compromised

There is great potential for the use of AI in helping neurologists and radiologists with diagnosis and monitoring for safety, yet FDA approval is critical for their adoption in the real world

AI imaging could be used alongside BBMs to reduce the need for CSF testing in AD; however, it is unlikely to replace CSF testing as a standalone modality in the near-term

Drivers of AI-Driven Imaging Adoption

Driver

Decreased Scan Time

Description

Studies have shown up to 4x faster scan times with AI processing tools¹.

Stakeholder Benefit*

Increased machine availability would allow imaging centers to scan a greater volume of patients

*Benefit: Gain to stakeholder resulting from increased MRI/PET usage

Driver

Increased Confidence in Scan Quality

Description

Real-time motion tracking and gating optimization, and post-processing AI tools could correct for motion artifact in MRI and PET scans

Stakeholder Benefit*

Greater scan quality would reduce the need for repeat scans and patient callbacks, minimizing unnecessary strain on imaging facilities

Movement correction would allow for roomier, less restrictive scanners, reducing patient discomfort

Driver

Enhancement of Weaker Scanners

Description

Improved accuracy and resolution may enable 1.5T magnetic field strength scanners to approach the quality of 3T scanners, which are 30%-40% more expensive^2,3.

Stakeholder Benefit*

A broadened network of capable scanners would improve patient access to minimally-invasive diagnostics.
¹NYU Langone Health NewsHub; ²Siemens Healthineers; ³LBN Medical

Critical Implication Given current capabilities, AI-driven imaging is expected to be used alongside BBMs in the near term

With an increase in AI-powered software, the ability to integrate with imaging devices, unique software features, and pricing models will help differentiate currently available options for AD

As the number of AI-powered software solutions continues to increase, so does the competition with these three areas being key components that will help differentiate products in the space

Integration

Most software offers the ability to integrate with Picture Archiving and Communication Systems (PACS), but not all are accompanied by additional stand-alone/third-party or web-based platforms that could help differentiate themselves from the competition by offering seamless user experiences

Software features

Key features like the ability to detect ARIA in patients undergoing ATT, volumetric measurements of white or grey matter, or to perform contrast weighted images, or multi-time-point or normative comparisons will also determine which software can offer the best set of features that respond to healthcare system needs

Pricing models

Accommodating pricing models can be matched to needs of institution type; for example, subscription based for large institutions or pay as you go for smaller radiology centers

Product Capabilities

Product	Detection/diagnosis	Prognosis	Monitoring	ARIA detection
Pixyl.Neuro.BV1
ARIAscore structure2
QyScore3
Trace4AD4

FDA Clearance and Pricing

Product	Noise reduction	Detection/diagnosis	Monitoring
SubtlePET1
Neurocloud PET2
Neurophet SCALE PET3
PalRe™4

Detection and Monitoring

Product	Key features	Detection/diagnosis	Monitoring
Neurocloud PET3	Identify and quantify regions with abnormal metabolism, positive/negative amyloid result, customizable report
Neurophet SCALE PET4	Quantifies SUVR of biomarkers (e.g., amyloid, tau) targeted by various radiotracers using PET images; Accurately measures atrophy of white matter and grey matter caused by neurodegenerative disorders to provide analysis results and SUVR calculation for 91 brain regions

ARIA Detection Capabilities

Product	Key features	ARIA detection
Neurophet AQUA AD1	Brain region segmentation, volume quantification, normative comparison, report generation, white matter hyperintensity quantification, multi-time-point analysis, ARIA monitoring
icobrain aria2	Automated quantification of ARIA-E and ARIA-H

Key Benefits

Faster Results

Objective and Comparative Analysis

Improved Accuracy of Diagnosis

Comprehensive and Organized Reporting

Methods for Tracking Disease Progression

Standardization

OSET 2024: The All-in-One Ortho Industry Meeting
Event Recap and Key Takeaways
By Masha Dumanis, Senior VP

This year the Orthopaedic Summit for Evolving Techniques (OSET) welcomed its most diverse set of faculty and attendees and hosted sessions across 14 different subspecialties and groups in addition to its inaugural Investor Day hosted by Healthpoint Capital and its Business of Medicine course. Over 6 days at the incomparable Fontainebleau Hotel, Las Vegas, attendees got to participate in nonstop morning to night learning and unprecedented networking opportunities. What was abundantly clear is that there was a definitive desire among physicians to cross-pollinate with their peers and counterparts across specialties.
This year’s joint Spino-Pelvic course and joint Trauma-Shoulder sessions were very well received. OSET also broke down barriers as it welcomed both podiatric surgeons and foot and ankle orthopedists to its Foot and Ankle sessions. What makes this meeting truly unique for those who have not attended is its intentionality in bringing together industry with clinicians to further innovation in the industry.
Attendees also got to hear moving keynotes – stories of triumph, of overcoming hardships, and of celebrating the spirit of healthcare from Trina Spear, founder of FIGS scrubs, tennis legend Andre Agassi, and hockey and football heroes, Mike Eruzione and Joe Theismann.
For those who didn’t get to attend, I will share a few themes and findings:

• The realities of operating in an ASC (ambulatory surgical center) – which the majority of clinicians are doing at least on a part-time basis – means doing things differently and it also means needing something different from your vendors
• JnJ MedTech sponsored a panel with some of its surgeons that echoed this exact point – the importance of “finding the right partner” who can provide not just implants, but complete solutions, and understands the needs of your ASC
• Clinicians touted the use of the right technologies – for instance automation for scheduling, notes dictation, and maybe even coding automation
• Others advocated for simple solutions like reducing instruments, consolidating to fewer (or yes, in some cases, one) vendor(s) and various sterilization solutions – outsourcing or pods/cubes to avoid wrapping (see Turbett Surgical and SteriCUBE)
• One of the powerful points made was that lots of the work that used to be done post-op is now done pre-op: patient education and communication is critical – several surgeons touted their use of Zimmer’s mymobility platform to enable this
• Post-op pain management and elimination of opioids continued to be a hot topic, especially with the imminent arrival of the hard fought “NOPAIN” act which will provide separate reimbursement to qualifying treatments
• In addition to Pacira and Heron, Gate Science presented on its novel RELAY technology (nerve block port and PNS device) and digital pain management with the GateKeeper app, while newcomer Synaptrix presented about its novel pre-op neuromod administration Novabloc that is slated to provide 20+ days of post op pain relief

• There is an avalanche of revision surgeries coming in the next decade whose growth will far outpace the growth rate in primary joints
• Solutions that address complex revisions while lowering complications and costs and improving outcomes will be highly valued, including instruments that help remove stubborn implants while being bone sparing, technologies to help rapidly diagnose and treat periprosthetic joint infections, and technologies to reduce infections (for instance, the new antibacterial coating from Onkos Surgical)
• A discussion topic: Will revisions move outpatient and to ASC too? Likely yes, but a lot is necessary on the enabling side first.
• On the sports medicine side, biologic augmentation has very much become a household term and there seems to be consensus that soft tissue-to-bone fixation and healing is made better by one of the now many available options (synthetics, collagen, hyaluronic acid, etc)
• The indications for biologic augmentation, anecdotally, seem to be spreading beyond rotator cuff – hip/labral repair, foot and ankle/achilles repair – what fixations are not yet optimized?
• Other regenerative topics included ACL repair and cartilage restoration with the MACI arthro launch, and S+N CartiHeal promotion
• While Trauma doesn’t get a lot of airtime, several notable topics came up. Fragility fractures are associated with significant morbidity and mortality, and so is the standard of care – conservative treatment – for many patients, leading to death within a year.

• There are new options for treatment which can get patients back to mobility and reduce pain rapidly – specifically, CurvaFix for fixation of the pelvic ring.
• Additionally, surgeons discussed adjunctive treatments of IlluminOss to aid in fixation.
• Across ortho – and particularly in trauma and sports medicine – compartment syndrome is a devastating complication that is both hard to catch and very invasive to treat the later it is caught.
• Newcomer MY01 is bringing awareness to compartment syndrome with their minimally invasive continuous pressure monitoring technology that can reduce staff time and be limb saving – it definitely garnered a lot of interest.
• The “war on technology” – whether its robotics, custom guides, or even custom implants, navigation, AR, or smart implants was ON throughout OSET – not just at this eponymous evening session, but throughout the whole conference.
• As many surgeons as there were at the conference, there were equally as many opinions about the role of robotics and which robot is appropriate.
• In attempting to answer whether robotics should be used in orthopedics broadly, but spine, and the ASC specifically, Dr Roland Kent turned to general robotics experts asking where robots make sense. The answer: “Robots shine in completing human tasks that require accuracy, redundancy, and reproducibility”
• Arguably, we are heading in the right direction, but it’s refinement and data that may help improve the performance.
• The reality is that technology continues to be more of a menu of options, rather than a need for some “death match” in which there is a conclusive winner. Surgeons not only pick what they each prefer, they often switch between technologies depending on case, setting, and patient needs.
• AI was perhaps subtly or overtly a topic throughout the conference. We now have machine learning built into so many of the tools that clinicians are using and its power grows exponentially. While some scoff at AI’s potential in healthcare, I believe that we are just at the precipice of seeing its power.
• Dr Isador Lieberman opened his session on the use of predictive analytics in spine with a critical point – “the decision is more important than the incision.” Today, robots are only as effective as the plan inputted by the surgeon. Similarly, cuts by a guide, or the fit of a custom implant will only be as good as the plan from the surgeon and engineer. Over the last several years this pre-operative planning demanded a completely new skill set of surgeons.
•  Today, aided by technology, and not just their own clinical experience, but machine learning capabilities, its facetious to say our plans are getting incrementally better. Driven by AI – our understanding of biomechanics and ability to plan cases are getting exponentially better.
• AI is likely to be the tool that finally makes robotics in MSK a value-add, rather than an expensive toy that adds time.
• AI will help streamline efficiency – everything from patient scheduling optimization, risk scoring and predictive analytics, and AE and readmission prevention, to improvements in treatments, and better understanding of the body’s inter-relatedness
• While it seems ironic to close with the basics, there was more discussion this year on how optimizing patients’ baseline health through exercise, nutrition optimization (check out Xcelerated Recovery and Mend), and chronic disease management will have outsize impacts on outcomes in MSK
• What is not as simple is that this requires coordination across sub-specialties and care-coordination tools – to steal the words of Dr Benjamin Schwartz, – what we really need is an “MSK Medical Home”
• Some mechanisms that could help patients don’t exist yet – the notable clinician Dr Bob Sallis said “I can’t refer my patients to an exercise professional. Insurance pays for surgery but not personal trainers.” He went on to talk about how Kaiser has used physical activity as a “vital sign” for 15 years in its EMR and the impact on population health management
• The availability of GLP-1s has helped surgeons offer actionable next steps to patients who otherwise would not have qualified for surgery

This is barely scratching the surface of all that was happening across 5-6 conference halls and the exhibit hall for six straight days (if you happen to invent something that allows me to be in multiple places at once – please call me first 😉).

To learn more about our insights on MSK, the growth in enabling tech, shifts in site of service, and more, reach out to Masha Dumanis, Senior VP and co-lead of the MedTech Practice at masha.dumanis@kxadvisors.com

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

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 9^th. 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.