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Metal’s New Rival Why PEEK Knee Implants Have Big Players on Edge by EOS Intelligence
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Metal’s New Rival: Why PEEK Knee Implants Have Big Players on Edge

Healthcare providers performed around 3.6 million knee replacement procedures globally in 2023, according to LSI’s Global Procedure Volumes Database, which covers 37 countries. This substantial volume highlights the massive clinical demand and shows a strong opportunity to innovate beyond traditional metal-on-polymer implant technologies. As more people age and joint problems from lifestyle become more common, the orthopedic field is turning to new, improved solutions that better meet what patients and healthcare systems need today. Will all-polymer implant technology drive the next breakthrough in total knee arthroplasty (TKA)?

Breaking the mold: Is metal-on-polymer TKA still the best we can do?

Healthcare community widely regards metal-on-polymer implants as the gold standard in TKA as these implants effectively handle the knee joint’s high load-bearing demands. Compared to all-polymer alternatives, metal-on-polymer designs provide greater mechanical strength, enabling them to withstand daily use and maintain long-term joint stability. According to the American Academy of Orthopaedic Surgeons, ~90% of total knee replacements continue to function effectively 15 years after surgery.

Maxx Orthopedics and Invibio (a Victrex PLC company) are set out to challenge this conventional view with the Freedom Total Knee System using PEEK-OPTIMA femoral component (PEEK standing for Polyether Ether Ketone).

In 2025, a research study (Cowie et al., Bioengineering 2025, 12(3):261) reported that PEEK-OPTIMA polymer-on-UHMWPE (Ultra-High-Molecular-Weight Polyethylene) knee implants showed UHMWPE wear comparable to metal-on-UHMWPE. Researchers based this conclusion on their evaluation of PEEK-OPTIMA and cobalt-chrome femoral components paired with polyethylene lower knee component in a knee simulator mimicking real walking and movement. Findings from this study address the key concern that all-polymer knee implants might wear out too fast.

Another research paper (ORS 2025 Annual Meeting Paper No.275) concluded that the wear behavior (including wear factor, rate, and volume) of PEEK-on-UHMWPE was comparable to cobalt-chrome-on-UHMWPE and met ASTM (Advancing Standards Transforming Markets) wear standards.

Overall, the collective evidence demonstrates that all-polymer PEEK implants could match the wear performance of metal-on-UHMWPE systems over millions of cycles, alleviating concerns about rapid degradation. Further research and clinical trials must still confirm real-world durability.

Beyond metal: could PEEK be the future of knee implants?

PEEK’s practical advantages are vast and include faster manufacturing, onsite customization, lower allergy risk, clearer imaging, and better bone compatibility. This could address longstanding issues with metal-based knee implants and reshape the TKA landscape, potentially becoming the new benchmark for knee implant materials.

Faster, lower-cost production

Studies show that manufacturers can injection-mold PEEK components in about three minutes and can have them ready for use within a week, in contrast to custom cobalt-chrome pieces, which often require months to finish. This rapid production cuts manufacturing costs and reduces hospital inventory requirements, making implants more affordable and improving access for patients facing long waitlists. Surgical centers can also benefit from greater flexibility to adjust designs quickly.

If PEEK adoption grows, patients, healthcare providers, payers, and PEEK producers will surely benefit. However, traditional metal-implant makers would face major disruption, forcing them to adapt or partner with polymer experts to stay relevant.

On-site 3D printing and customization

PEEK’s compatibility with high-temperature 3D printing allows hospitals to create patient-specific implants on demand. Such implants can fit the anatomy more precisely, potentially improving recovery and function. On-site implant printing also eliminates shipping delays and the need for large warehouses for hospitals and solution providers.

However, acquiring industrial-grade PEEK printers and training staff require significant investment, which will likely act as a factor slowing adoption. On the supply side, implant makers will be challenged with additive manufacturing (which they will likely have to bring in-house) and the need to forge partnerships with 3D-printing players. All players, whether established or start-ups, will have to navigate strict and demanding regulatory approval before hospitals adopt these materials.

Minimizing metal-related risks

As PEEK does not release metal ions into surrounding tissue, it eliminates the risks of irritation or hypersensitivity that affect up to 25% of patients with implants. This is a considerable benefit for patients with metal allergies. Hospitals may see fewer allergy-related follow-ups, fewer revision surgeries, and lower long-term costs. This is again challenging metal-implant makers, who will have to address this shift by developing hypoallergenic alternatives or risk losing market share as patients and healthcare professionals move to polymer-based options.

Enhanced imaging transparency

PEEK’s radiolucency produces clear standard imaging (X-rays, CT scans, and MRIs) without metal artifacts, enabling earlier detection of misalignment, loosening, or infection. This means a reduced need for specialized scans, lowers costs and radiation exposure. Change in implant materials will affect radiology solutions vendors, as they may have to adjust protocols to optimize scans for polymer implants.

Bone-friendly mechanics

PEEK is isoelastic and mimics the mechanical properties of natural bone, spreading pressure more naturally through the bone around it. This reduces stress shielding that can cause bone loss around stiffer metal implants. Patients may experience fewer long-term complications and easier revision procedures if needed.

Those bone-friendly mechanics offer a great benefit for several hospitals and payers, thanks to lower costs of managing bone-loss issues. Implant developers must consider whether newer low-modulus metal alloys can match PEEK’s bone-preserving properties at all, as polymer-based solutions can redefine TKA standards.

Considering these benefits, PEEK presents a compelling alternative to metal-based knee implants. Each benefit comes with practical considerations, including upfront equipment costs, regulatory challenges, and strategic shifts for established manufacturers. As clinical trials progress and real-world data accumulate, stakeholders across orthopedics will need to monitor the impact PEEK will have on reshaping the implant market.

Is all-polymer TKA entering the home stretch?

FDA Investigational Device Exemption (IDE) approval, global feasibility trials, and dedicated research funding signal that PEEK-based knee implants are on the verge of commercialization.

FDA approval accelerates clinical testing

In September 2024, the FDA granted an IDA for the Freedom Total Knee System using Invibio’s PEEK-OPTIMA femoral component in partnership with Maxx Orthopedics. This authorization clears the way for systematic safety and efficacy data collection under controlled conditions. IDA gives legitimacy to the solution, and hospitals and surgeons can begin preparing for a polymer-based alternative entering mainstream in the future.

Decades of collaboration accompany ready manufacturing

Invibio recognized PEEK’s medical potential in the early 2000s, and by 2024, over 15 million PEEK-OPTIMA devices were implanted worldwide. Since 2012, Invibio and Maxx Orthopedics have co-developed an all-PEEK femoral component paired with a UHMWPE tibial insert. Invibio can probably consider scaling its existing PEEK production facilities (although it already maintains large-scale PEEK-OPTIMA manufacturing facilities). Similarly, other PEEK producers might follow suit to offer reliable availability and cost predictability once approvals are in place. Incumbent metal-implant manufacturers may need to forge similar partnerships or invest in polymer capabilities to avoid losing market share.

Early trial results build confidence

Feasibility studies in India, Belgium, and Italy, ongoing since 2021, have shown no device-related adverse events with the PEEK-OPTIMA component in small patient cohorts. This suggests strong biocompatibility and mechanical resilience. Healthcare providers will continue watching further study results and might alter their component purchasing decisions. Established TKA suppliers will face renewed pressure to rethink their own implant solutions if studies show continued positive results.

India leads the commercial charge

Maxx Orthopedics plans to file for regulatory approval in India with a 2025 commercial launch target. India’s large patient base and growing demand for joint replacements create an ideal environment for initial commercialization. For players, early market entry here could build clinical experience and generate real-world data to support subsequent approvals in Europe and the USA.

Academic funding fuels long-term validation

In 2023, Invibio and academic partners, including the University of Leeds, secured a £1.7 million UK EPSRC grant for TKA patient outcome research. This funding will support ongoing research into wear patterns, revision rates, and other outcomes. Robust academic data will likely affect clinical decisions and payer coverage, while boosting evidence for PEEK implant solutions makers.

The momentum around all-polymer TKA continues to grow, thanks to regulatory milestones, scientific studies, strategic manufacturing alliances, and academic validation.

EOS Perspective

The ongoing developments from Invibio and Maxx Orthopedics mark a potentially transformative era in TKA, moving beyond conventional metal-on-polymer implants. However, all-polymer implants have yet to reach a point where they can directly compete with metal implants, which have demonstrated reliable durability over five decades. Although PEEK shows promise as a metal-free alternative, additional real-world studies are needed to validate its long-term effectiveness.

Nevertheless, the emergence of all-polymer knee implants will likely prompt a counter-response from incumbent players, further accelerating innovation in the field. The stakes are high, as LSI’s Global Market Analysis & Projections database shows that Zimmer Biomet, Stryker, and DePuy Synthes still dominated the TKA market in 2023, collectively accounting for about 80% of the overall market.

Zimmer Biomet, for instance, in March 2025 secured FDA clearance of Persona Revision SoluTion Femur, a revision knee implant component made of Tivanium (Ti-6Al-4V) alloy, offering an alternative for patients with metal sensitivities. This development reflects their strategic effort to address concerns around metal allergies and to strengthen their trusted metal implant offerings to stay competitive.

Most established market players have the know-how and infrastructure to drive R&D in all-polymer implants for TKA, given their experience with implant polymer technologies and the inclusion of PEEK-based implants within their broader portfolios and other applications. For instance, both Zimmer Biomet and Stryker successfully commercialized customized solutions for PEEK-based cranial implants. Their existing R&D pipelines and clinics networks position them to act fast. With this, they might be able to considerably stifle disruption from startups or niche players. The challenge for these large companies will likely be the execution.

Smaller competitors often innovate faster, while established players can be slowed by internal processes or reliance on existing metal implant revenue streams and supply chains. How they handle this transition will shape the future of knee replacements, either reinforcing their market leadership or allowing newer companies to gain a foothold.

Anti-Obesity Drugs – Pharma Companies Race to Grab a Bite of the Pie by EOS Intelligence
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Anti-Obesity Drugs – Pharma Companies Race to Grab a Bite of the Pie

For many years, bariatric surgery has been the go-to option for people struggling with obesity and obesity-induced conditions. However, for the last couple of years, another easier option has become available in the form of GLP-1-based weight loss drugs. This class of medicine mimics a hormone that helps reduce food intake and control appetite. These drugs have revolutionized the weight loss market, which was previously dominated by gimmicky and fad-based OTC solutions. Due to GLP-1’s proven effectiveness, there is soaring demand for these drugs, outstripping its current supply capacity. While only two players operate in this market, several leading drugmakers have been racing to develop their own version of the drug. Moreover, with additional proven merits of the drug beyond just weight loss, it has become more appealing for pharma players to invest in.

GLP-1 anti-obesity drugs make big waves in the pharmaceutical sector

Over the past few years, anti-obesity drugs have received immense attention from healthcare professionals, pharmaceutical companies, and the general public. A new class of medication that stands out is glucagon-like peptide-1 (GLP-1) agonists, traditionally used for treating Type 2 diabetes. But along with managing diabetes, these drugs also suppress appetite and lower calorie intake by mimicking the GLP-1 hormone (a gastrointestinal hormone), which causes the patient to feel fuller longer and thereby prevents overconsumption. Regular intake of such drugs is deemed to result in a weight loss of about 15-25% of body weight in obese people.

GLP-1 agonists received FDA approval as anti-obesity drugs in 2021. Given their promising results, the demand for these drugs has increased immensely. However, despite the patient’s high out-of-pocket price of US$1,000 plus, there are severe shortages in the market.

Anti-Obesity Drugs – Pharma Companies Race to Grab a Bite of the Pie by EOS Intelligence

Anti-Obesity Drugs – Pharma Companies Race to Grab a Bite of the Pie by EOS Intelligence

Only two players operate in this highly-coveted market

The GLP-1-based medication is now marketed in two categories – one for managing diabetes and blood sugar levels and the other as a weight loss drug. The GLP-1-based weight loss drug market is highly consolidated, as only two players operate in this space. These are Denmark-based Novo Nordisk and US-based Eli Lilly.

Novo Nordisk, the market leader, received FDA approval for its weight loss injectable, Wegovy, in June 2021. This drug uses the same active ingredient as Novo Nordisk’s diabetes drugs, Ozempic and Rybelsus (oral); however, it has a different dosage and can also be used for weight loss in patients who do not have diabetes. That being said, Ozempic has also been used off-label for weight loss.

On the other hand, Eli Lilly’s injectable drug for weight loss, Zepbound, received FDA approval in November 2023. Eli Lilly’s glucose-dependent insulinotropic polypeptide – GIP/GLP-1 injectable drug for diabetes, Mounjaro, has the same composition and dosage as Zepbound and is often prescribed off-label for weight loss as well.

While Novo Nordisk’s drugs, which use semaglutide as an active ingredient, result in weight loss of about 13 to 22 lbs, the drugs by Eli Lilly have tirzepatide as an active ingredient. They are stated to result in a weight loss ranging between 15 and 28 lbs.

From a price-point perspective, Wegovy has an out-of-pocket cost of US$1,349 per month, compared to Zepbound, which has an out-of-pocket cost of US$1,060 per month. Thus, while Novo Nordisk’s Wegovy has the first-mover advantage, Eli Lilly’s Zepbound is considered more effective and better priced.

Currently, both weight loss drugs by Novo Nordisk and Eli Lilly come in the form of injectables. However, both companies are developing oral versions of the drug as they are easier to administer and more convenient to prescribe. They may also help ease supply constraints currently impacting the injectables. In June 2023, Novo Nordisk conducted Phase 3 trials for its once-daily oral Wegovy drug, according to which the drug helped obese adults lose about 15% of their body weight. Similarly, in June 2023, Eli Lilly conducted Phase 2 trials for its oral GLP-1 receptor for weight loss. The drug helped obese adults lose up to 14.7% of their body weight. Both companies are optimistic about the outcomes of their trials; however, the expected launch timelines for these drugs have yet to be determined.

Leading drugmakers race to compete in the growing anti-obesity drug market

Currently, Novo Nordisk and Eli Lilly are the only two players operating in this market. However, several other leading pharmaceutical players have joined the race and are working towards developing their own version of the drug, either through in-house R&D or through strategic acquisitions.

Moreover, they are targeting their research towards developing and marketing a new generation of GLP-1-based medications that are administered orally, are longer lasting, and have additional health benefits and limited side effects.

In February 2024, US-based biopharmaceutical company Amgen successfully completed a Phase 1 clinical trial for its GLP-1 agonist drug, MariTide. As per the trials, the drug produced a 14.5% weight loss in patients administered the highest dose. Moreover, the company claims that the trial indicates that patients may need to take less frequent doses of MariTide (compared with current competition), and the weight loss achieved stays significantly longer. The company has begun its Phase 2 trial, with results expected by late 2024.

In December 2023, Swiss-pharmaceutical giant Roche acquired US-based Carmot for US$3.1 billion (US$2.7 billion upfront cash and US$400 million on certain milestones). This acquisition has helped put Roche on the map for obesity drug development. Carmot has two GLP-1 agonist molecules for weight loss, which are currently being tested in the mid to advanced stages of clinical trials. The first drug, CT-388, is a once-weekly injectable and has completed Phase 1 clinical trial, while the other drug, CT-996, is an oral drug currently undergoing Phase 1 trials.

In November 2023, UK drugmaker AstraZeneca entered into an agreement with Shanghai-based Eccogene, wherein the former licensed an oral once-daily GLP-1 receptor agonist called ECC5004 for the treatment of obesity, Type 2 diabetes, and other cardiometabolic conditions. For this, AstraZeneca agreed to pay Eccogene an upfront fee of US$185 million for the drug and a further payment of US$1.83 billion in future clinical, regulatory, and commercial milestones and tiered royalties. The drug is currently in Phase 1 development, and the company hopes to enter Phase 2 of clinical studies by the end of 2024. In the past, AstraZeneca stopped the development of two GLP-1 agonist drugs that were being developed in-house. The development of an injectable called Cotadutide was halted in April 2023, and an oral drug called AZD0186 was halted in June 2023 after their respective Phase 2b and Phase 1 clinical trials did not yield the desired results.

Pfizer, one of the most active companies in this regard, has faced multiple failures in their endeavor to develop a competitive obesity drug. In 2020, it started a clinical trial for its GLP-1 agonist weight loss drug, Lotiglipron. However, in June 2023, the company stopped developing the drug after its Phase 1 and Phase 2 drug interaction studies indicated a rise in liver enzymes in patients who took the drug once a day. In 2021, the company simultaneously began working on another GLP-1 receptor agonist, Danuglipron, which was to be taken twice daily. While the Phase 2a trial for the drug in June 2023 showed promise, the company halted the development of the drug post its Phase 2b trial in December 2023. The drug was scrapped as, despite significant weight loss, the trial patients experienced high rates of common gastrointestinal and mechanism-based adverse side effects. The company is now conducting a pharmacokinetic study with a once-daily version of the Danuglipron drug that will provide guidance on future development plans.

Pfizer’s failure with these two drugs demonstrates the struggle the leading pharma companies face to develop a safe, effective, and tolerable GLP-1 agonist for weight loss.

GLP-1 agonist drugs have benefits beyond diabetes and weight loss

Despite multiple setbacks, leading pharma companies are investing heavily in this space, as they understand the potential of these drugs. While currently, GLP-1 agonists are poised as diabetes and weight loss drugs, they have far more benefits. Data from ongoing clinical trials and independent studies suggest that GLP-1 agonists also help improve cardiovascular health and kidney function and help treat addiction and dementia.

In March 2024, Novo Nordisk’s Wegovy received FDA approval for reducing the risk of serious cardiovascular complications in adults with obesity and heart disease. This is based on the results shared from the company’s three-phase trial SELECT, which indicated that Wegovy reduced patients’ risk of major cardiovascular problems by about 20% during the five-year trial period.

Similarly, in 2019, the company started another clinical trial, FLOW, to determine the impact of GLP-1 agonists on kidney function. As per the interim results in October 2023, the trial displayed that Ozempic (Wegovy’s diabetes counterpart) reduced the risk of kidney disease progression and kidney and cardiovascular death in diabetes patients by 24%. Given its success, the company has halted the trial at the interim stage.

An initial study conducted on animals in March 2023 reportedly showed positive results for curbing addictive tendencies, such as drinking and smoking, with Ozempic. Currently, two trials are being undertaken to validate the use of GLP-1 agonists in humans to manage drug and alcohol addiction. Given the testimonies from current users of the drug, it is indicative that the drug has been helping users curb their addictions.

In addition to this, several researchers are also suggesting that GLP-1 could be used in the treatment of dementia and other cognitive disorders. This is based on the claim that GLP-1 agonists reduce the build-up of two proteins, amyloid, and tau, in the brain. These two proteins are known to be responsible for Alzheimer’s disease, which is the most common form of dementia. In February 2022, a new trial at the University of Oxford was initiated to test people with high levels of amyloid and tau and at risk of developing dementia to determine if the use of GLP-1 agonists would result in a reduction in tau accumulation and brain inflammation. The interim results from the study have not yet been disclosed.

High prices and limited coverage pose as speedbumps for obesity drug adoption

While these obesity drugs have exploded in popularity in recent times and are only expected to grow further as their case use increases, they do have certain shortcomings and challenges that are important to address.

These drugs are known to cause several side effects, such as nausea, diarrhea, vomiting, constipation, and ulcers. They can also lead to severe complications, such as pancreatitis, in some extreme cases. While most of the common side effects of the drugs are manageable and justifiable given the risk-benefit ratio, one of the key issues with the drugs is that they need to be taken in perpetuity to keep the weight off. In other words, once a patient stops taking the drugs, the weight comes back. Given that these drugs are priced at more than US$1,000 per month at the moment, taking them constantly becomes a considerable challenge for patients.

Moreover, considered as ‘vanity-use’, these drugs are currently not covered by most medical insurance policies, and thus, patients have to pay for them out-of-pocket. While several employers in the USA are considering including these drugs in their health plans, they are still debating their merit. Employers acknowledge the benefits of these drugs as they help employees who battle with obesity improve their health and, in turn, improve overall performance and employee satisfaction. However, high costs and long-term use act as definite barriers, which make both employers and insurers reluctant to cover these drugs.

Insurers are slowly warming up to the inclusion of GLP-1 drugs in their plans

In March 2024, leading insurance company Cigna stated that it would expand insurance coverage to include weight loss drugs but would limit how much health plans and employers spend on the drug each year. As per Cigna’s benefits management unit, Evernorth Health Services, spending increases for these weight loss and diabetes drugs would be limited to a maximum of 15% annually. The plan offers a financial guarantee and enables employers and health plans to have greater predictability and control over their GLP-1 spending by offering clients (employers) a guarantee that the cost of weight loss and diabetes drugs would not increase by more than 15% annually.

As a part of the effort to limit how much employers spend on GLP-1-based drugs annually, Evernorth has entered into an agreement with Novo Nordisk and Eli Lilly. However, the details of the agreement have not been disclosed.

While this is a good start, the drug would need better coverage by many other insurance players to reach a wider audience.

EOS Perspective

Given that about 12% of the global population and more than 40% of the American population grapple with obesity (as per WHO and 2022 statistics by the National Institute of Diabetes and Digestive and Kidney Diseases, USA, respectively), weight loss drug manufacturers Novo Nordisk and Eli Lilly are sitting on pharma goldmines. The weight loss drugs market, expected to reach US$100 billion by 2030, is poised as one of the most promising sectors for the pharma sector. Thus, it is no surprise that several leading players are investing heavily to join Novo Nordisk and Eli Lilly at the top, either through in-house R&D or through acquisitions.

However, developing these drugs proves to be challenging for drugmakers, as evidenced by the failures of several companies in creating their own versions. We can expect the sector to consolidate further as larger pharma companies look to acquire niche players with their trials being in advanced stages.

Moreover, in a bid to find their footing in this promising sector, pharma players are trying to develop advanced versions of the drug that have benefits beyond just weight loss and offer long-term benefits. This is also because, at the moment, these drugs are not approved by most insurance companies, which makes them extremely expensive for the wider population to afford. This, in turn, is withholding these drugs from becoming mainstream and is thereby preventing them from tapping into their true growth potential. That being said, Wegovy’s recent FDA approval for reducing cardiac complications in people with obesity and heart disease will likely tip the insurers’ coverage scales. Insurance companies are likely to cover the drug in the near future.

Since no other drug in the market offers proven cardiac benefits along with weight loss (including Eli Lilly’s), it is safe to say that Novo Nordisk is way ahead in the race and will dominate the market for the foreseeable future. Thus, to be able to compete in the market, it is not enough for drugmakers to develop obesity drugs offering just weight benefits. They would need to develop drugs that offer higher efficiency or additional therapeutic benefits along with weight loss and price them competitively.

Metaverse Meets Medicine: Spatial Computing's Game-Changing Potential by EOS Intelligence
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Metaverse Meets Medicine: Spatial Computing’s Game-Changing Potential

Spatial computing, sometimes called the metaverse, will revolutionize healthcare by seamlessly merging the digital and physical worlds. Leveraging technologies such as augmented reality (AR) and virtual reality (VR), it offers exciting transformative possibilities, from enhanced surgical training and improved diagnostics to personalized treatment plans and remote care solutions. As the technology matures, it presents both opportunities and challenges for technology solution providers.

AR, VR, and Extended Reality solutions offer an immersive healthcare experience

Spatial computing uses technologies such as virtual, augmented, and mixed reality to interact with digital information in 3D space, fundamentally changing how healthcare is delivered. It is gradually finding applications across the industry. For example, surgeons can practice complex procedures in realistic, risk-free VR environments, improving their skills and preparedness. Doctors can visualize medical images in 3D for more accurate diagnoses.

Patients also become more engaged in their care through interactive tools that explain their conditions and treatment options. Holographic images expand the scope of remote care, providing patients with a stronger sense of connection to their doctors. VR can even be used for immersive therapy sessions, helping patients manage anxiety or PTSD in a safe, controlled setting.

The potential applications are vast. AR solutions can overlay medical imaging data (CT scans, MRIs) onto a patient’s body for improved diagnosis. Virtual patient models can simulate treatment scenarios for optimized treatment planning. Tools such as EnVisio provide continuous 3D surgical awareness, enabling surgeons to plan approaches from any angle for increased precision.

Virtual clinics promise to reshape care delivery models, while live surgeries can also benefit from this technology. Within six months of Apple Vision Pro’s launch in February 2024, surgeons at UC San Diego Health successfully performed minimally invasive operations using Apple Vision Pro headsets, which offered significant cost advantages over traditional surgical monitoring systems.

Surgery-specific applications and AI integration drive innovation

The field is attracting significant innovation. Companies such as Medivis and Osso VR are pioneering the development of spatial computing solutions for surgical planning and medical training. There are several solutions (such as Medivis’s Surgical AR and Surgical Theater) available that use real-time camera images to project 3D models in a surgeon’s headset for both surgical planning and rehearsal before the procedure. Other solutions include AR and VR to help surgeons and health professionals in their medical training.

Since the launch of Apple Vision Pro, several large solution providers and startups started developing software solutions that leverage Apple’s advanced capabilities, specifically for applications in the healthcare sector. Siemens Healthineers developed its ‘Cinematic Reality’ app in March 2024, which offers advanced imaging and visualization solutions, including 3D reconstruction and VR tools for surgical planning.

Several large surgical players are also developing solutions that help optimize the processes, making surgeries more efficient and cost-effective. For example, Stryker‘s Mako SmartRobotics app for Apple Vision Pro (launched in March 2024) enables surgeons to review and visualize patients’ surgical plans. Zeiss‘s Surgery Optimizer (launched in April 2024), an AI-powered app for cataract surgery preparation using the Artevo 850 microscope and Apple Vision Pro, is another example of this trend.

Epic‘s Spatial Computing Concept for Apple Vision Pro aims to streamline charting, lab review, and secure communication for physicians. This also enables real-time updating of patient information on the hospital’s EHR systems. Integration of AI with spatial computing is a likely next step, promising optimized procedures with spatial computing overlays. AI is also likely to aid in better processing and analysis of spatial data.

Growth in spatial computing is also likely to bring in further investments from venture capital and existing healthcare giants. Spatial computing startup XRHealth raised US$6 million in funding in January 2024, while Medivis raised US$20 million in Series A funding that would enable it to develop advanced surgical solutions that integrate AR technology.

Apple Vision Pro is a key enabler for startups to develop healthcare solutions

The competitive landscape is dynamic, with various players vying for market share. Established medical technology giants such as Siemens Healthineers, GE Healthcare, and Philips are integrating spatial computing into their existing platforms. Meanwhile, startups such as Osso VR, Surgical Theater, and Medivis are disrupting the market with innovative solutions.

Software and hardware specialists, including Microsoft (HoloLens) and Apple (Vision Pro), are crucial enablers. While Apple Vision Pro is currently prominent, other hardware and platform developers are likely to emerge.

We can anticipate mergers and acquisitions as larger companies acquire promising startups. There is an increasing focus on user experience and integration with existing healthcare systems. Apple’s launch of the Vision Pro has spurred interest in spatial computing, with startups developing for the mixed reality environment offered by AR/VR headsets such as the Vision Pro and Meta Quest.

Dependence on limited hardware ecosystems is a key challenge for developers

Solution developers face several key challenges. Dependence on hardware companies, including Apple and Meta, creates vulnerabilities. These companies have their own ecosystems for developing supported applications that limit the possibilities and options for startups.

Data privacy and security, particularly compliance with regulations such as HIPAA and GDPR, are paramount, especially as AI integration becomes more prevalent. Compatibility with legacy systems, including imaging systems and EHRs, is also essential to be successful.

Maintaining cost-effectiveness is crucial, as the high prices of devices like the Vision Pro and HoloLens pose a barrier. Funding, particularly for startups, remains a challenge, although recent successful funding rounds offer encouragement.

EOS Perspective

The spatial computing market in healthcare is poised for substantial growth, driven by the increasing demand for immersive technologies, the rise of AR/VR in medical training, and the growing need for remote healthcare solutions.

Spatial computing advancements are transforming areas such as clinical education, surgical planning, training, medical imaging, and behavioral health. We can expect even more applications to emerge, improving care delivery and surgical outcomes. Imaging data will become more interactive, detailed, and accessible. Increased deployment in surgical settings will drive further growth in the development of supporting software and hardware. We may also witness an increase in hardware companies developing spatial computing systems suitable for application in the healthcare sector.

As the technology matures and costs decrease, spatial computing is expected to become an integral part of the healthcare ecosystem, transforming patient care and revolutionizing how medical professionals work.

Recall Aftermath Who is Gaining Share in the Sleep Apnea Devices by EOS Intelligence
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Recall Aftermath: Who is Gaining Share in the Sleep Apnea Devices and Ventilators Market?

In recent years, the number of ventilator recalls has increased considerably, primarily due to product quality issues, software malfunction, and manufacturing defects. This affected manufacturers such as Philips, Medtronic, and Vyaire Medical, leading to brand damage, financial losses, and a shift in the market competition. Existing players and new entrants such as Getinge and Nihon Kohden are stepping in to fill the gap with innovative and non-invasive products. The recalls caused challenges for manufacturers and patients, highlighting the need for strong quality control and regulatory oversight.

Recalls of its sleep apnea devices and ventilators hit Philips the hardest

The medical device industry has recently experienced many product recalls, particularly in the ventilators segment, impacting major market players such as Philips, Medtronic, Baxter, GE Healthcare, Hamilton Medical, and Vyaire Medical.

Philips (Philips Respironics) faced a series of class I respiratory product recalls, including CPAP and BiPAP machines, and ventilators, due to health risks caused by the polyester-based polyurethane (PE-PUR) sound abatement foam breakdown in the devices. Industry experts consider Philips’ sleep apnea devices and ventilator recalls among the most significant since 2021. As of January 2024, the company experienced a recall of over 15 million sleep apnea devices and ventilators, and reportedly hundreds of deaths. The recall seriously hurt the company’s reputation, weakened its position in the market, and caused significant financial problems.

The recalls led to a decline in the company’s share price by 60-70% in 2021, and it is still about 50% lower than its peak in April 2021 (US$ 53.45). Comparable sales of the connected care segment, including sleep apnea devices and ventilators, declined by about 19% in 2021 in comparison to 2020. This happened primarily due to sleep apnea devices and ventilators recalls, and the normalization of demand for hospital ventilators and monitoring systems following the COVID-19 surge. Recalls continued to drive down ventilator and sleep apnea device sales in 2022 and 2023.

The considerable impact on sleep apnea devices and ventilator sales resulted in a decline in Philip’s share in the sleep apnea device market, dropping to an estimated 20% between 2021-2023 from over 30% before the recall. The company also experienced a notable decline in market share in the ventilators market. Despite the decline in market share, Philips maintained its position as one of the leading players in both the sleep apnea devices and ventilators market.

However, in January 2024, Philips agreed to halt the sales of 19 sleep and respiratory products in the USA as a part of the consent decree with the US Department of Justice (DOJ). These products included hospital ventilation, certain home ventilation, sleep diagnostic devices, and portable and stationary oxygen concentrators. This affected the company’s brand image greatly and resulted in a further loss of market share in both ventilators and sleep apnea devices markets. Since the company will continue to sell consumables and accessories, including masks, it is anticipated to maintain a portion of its market share in both segments.

In April 2024, the company agreed to pay US$1.1 billion in legal settlement to resolve injury-related cases caused by sleep apnea devices and ventilators in the USA. Overall, sleep apnea device recalls cost the company over US$5 billion, likely including charges such as provisions for Philips Respironics-related litigation, consent decree, remediation costs, legal settlements, workforce restructuring, and quality remediation action. In addition, Philips cut 6,600 jobs by 2023 and is likely to reduce its workforce by a total of 10,000 by 2025.

Several companies bore the brunt of their own ventilator recall setbacks

Other prominent manufacturers such as Drägerwerk (Draeger), Medtronic, Vyaire Medical, Hamilton Medical, and Baxter also experienced various ventilator recalls due to manufacturing and quality defects. Although the FDA classified these recalls as serious, these companies did not face the same severe consequences as Philips, as these recalls did not result in major injuries.

All these manufacturers also witnessed a drop in ventilator sales largely due to the stabilization of demand for ventilators following the COVID-19 surge, with product recalls also contributing to the downturn.

In February 2024, Medtronic completely exited the ventilator market due to unprofitability. Similarly, in June 2024, Vyaire Medical filed for bankruptcy and was subsequently acquired in October 2024 by Zoll, an Asahi Kasei company engaged in the manufacturing of medical devices and related software solutions. This caused a profound impact on the ventilators market.

Market players are introducing products with advanced features to gain market share

The ventilator market encountered a radical shift in competition due to numerous product recalls. The suspension of sleep and respiratory product sales cost Philips its leading market position in sleep apnea devices and ventilators (except for certain home ventilators). It remains unclear when or if Philips will be able to resume sales of these devices. However, the company is unlikely to leave its presence in the sleep apnea devices and ventilators market entirely due to its commitment to service and supply of parts of ventilators in use, as well as its decision to continue the sale of consumables and accessories.

Existing market players such as Getinge, Hamilton Medical, Drägerwerk (Draeger), ResMed, and GE Healthcare, and newer entrants such as Nihon Kohden, are likely to fill in the gap left by Philips, Medtronic, and Vyaire Medical in the USA.

Market players such as Getinge, Drägerwerk (Draeger), and Nihon Kohden are focusing on introducing technologically advanced ventilators with features such as enhanced patient comfort, advanced monitoring capabilities, portability, and adaptive ventilation modes, to grab a slice of the pie. They are also increasingly focusing on expanding their portfolio of non-invasive ventilators with different interfaces, including face masks, nasal masks, helmets, and mouthpieces.

For instance, in October 2024, Nihon Kohden introduced a new ventilator system that combines invasive and non-invasive ventilation and high-flow oxygen therapy in one device, offering adaptability and eliminating the need to switch between machines. It also features a customizable, app-based touchscreen interface with advanced monitoring capabilities. Similarly, in January 2024, Getinge introduced ‘Servo-air Lite’, a non-invasive ventilator with high-flow therapy that offers optimal respiratory support, enhanced patient comfort, and ease of use for clinicians.

ResMed, a leading player in both the sleep apnea devices and ventilators market, is estimated to have grabbed over 10% of Philips’ market share in the sleep apnea devices market in the USA. ResMed witnessed a substantial increase in demand for its sleep and respiratory care products, including sleep apnea devices and ventilators, for various reasons, including Philips’ product recalls. The demand for its sleep and respiratory care products in the USA, Canada, and Latin America increased by 16%, 25%, and 10% in 2022, 2023, and 2024, respectively.

Companies engaging in sleep apnea devices and ventilator rentals, sales, and distribution, such as Trace Medical, also started adding brands from different companies to their product mix to meet the demand for these devices.

Patients experience delays in treatment and struggle to switch to other brands

Philips’ foam degradation issue has exposed patients to severe health risks, leading to respiratory complications and even cancer. Recalls of many ventilators and sleep apnea devices have left hospitals struggling to replace them, causing delays in patient treatment.

Patients relying on a specific brand faced reduced treatment options. Many patients found it difficult to switch to other brands due to cost and differences in machine settings or interfaces. With Philips halting sales of various sleep apnea devices and ventilators, patients have no choice but to switch to other brands.

The recall of various products from different companies has created significant demand and supply chain pressures for existing companies. These pressures will likely drive up ventilator and sleep apnea device prices, further burdening patients.

EOS Perspective

Product recalls in the sleep apnea devices and ventilator segment brought quality issues to the limelight. This highlights the need for stronger quality control processes and technologically advanced sleep apnea devices and ventilators incorporating virtual monitoring and AI integration, which can help detect defects earlier.

While the FDA received complaints about Philips’ degradation of the sound abatement foam in the sleep apnea devices and ventilators before the recall initiation, decisive action to force correction was not taken immediately. Also, despite knowing that Philips had been aware of the foam degradation issue for many years, the FDA did not take stronger enforcement measures against the company sooner. This situation highlights the importance of assessing and enhancing the FDA’s oversight process to ensure timely response to medical device complaints.

Philips suffered lasting brand damage due to the recalls. Although the company is trying to regain shareholder and consumer trust after settling US claims for an amount much lower than anticipated (US$2-5 billion) by analysts and the public, it faces a long road ahead.

Regarding market competition, ResMed is estimated to continue to lead and strengthen its dominant position in the sleep apnea devices market. The exit of well-established players from the ventilator market will intensify competition among existing companies and new entrants seeking to capture market share. However, it will be a gradual process as customers slowly transition from existing products to new brand ones. On top of that, the new entrants are likely to face stricter regulatory norms and product approval processes aimed at reducing the number of product recalls and enhancing patients’ safety.

Mind over Matter How Non-invasive Neuromodulation Is Becoming the Future of Pain Management by EOS Intelligence
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Neuromodulation: The Electric Shock to Traditional Pain Management

Scientists have been researching the possibility of using electrical impulses to treat many health conditions. The starting point was the introduction of the first TENS (transcutaneous electrical nerve stimulation) device in the 1970s in the USA. Its goal was to test the tolerance of chronic pain patients to electrical stimulation. In recent years, non-invasive neuromodulation has emerged as a promising field for treating various neurological disorders. This field will likely experience significant growth in the coming decade, thanks to technological advancements, such as AI-powered sophisticated wearables.

Non-invasive neuromodulation is emerging as a novel treatment for several diseases

Non-invasive neuromodulation is a technique that uses external devices to apply electromagnetic fields, electrical currents, or other forms of stimulation to the brain to enable targeted modulation of neural activity.

The technique is effective in treating a range of conditions. Currently, several devices are available in the market for treating illnesses, including chronic pain, tinnitus, diabetic neuropathy, and functional disorders such as bladder and bowel control.

The non-invasive neuromodulation market encompasses a diverse array of devices that can modify neural activity without the need for invasive procedures. This includes transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and TENS.

TMS therapy sessions typically require the presence of a physician. An example is MagVenture Pain Therapy, a TMS device developed by a Denmark-based company, MagVenture, for treating chronic pain.

TENS and tDCS devices are portable and, hence, suitable for at-home treatments. The FDA has not yet approved tDCS in the USA for medical use. However, its use falls under the Investigational Device Exception (IDA) regulations. Though it is marketed for non-medical uses in the USA, it is used for medical treatment in regions such as the EU, Singapore, and Israel.

TENS devices are small, battery-powered devices that consist of leads that connect to electrodes, sticky pads placed on the skin in the area that needs stimulation. An example is Cefaly, an FDA-approved TENS device developed by the US-based Cefaly Technology for pain management. This device works by stimulating and desensitizing the primary source of migraine pain, the trigeminal nerve, using a precise electrical impulse.

Mind over Matter How Non-invasive Neuromodulation Is Becoming the Future by EOS Intelligence

Mind over Matter How Non-invasive Neuromodulation Is Becoming the Future by EOS Intelligence

The non-invasive neuromodulation market is showing rapid growth

The global non-invasive neuromodulation devices market for neurological and psychiatric disorders was approximately US$1.2 billion in 2022. According to a 2023 report by Report Prime, an India-based market research firm, the market is projected to grow at a CAGR of 7.2% from 2023 to 2030, reaching US$2.1 billion by 2030.

Several reasons fuel this rapid growth in recent years, including the increasing prevalence of chronic pain and other neurological conditions (especially in older patients), the numerous advantages this technique has over invasive neuromodulation, breakthroughs in non-invasive technology, and a surge in investments.

Increasing incidence of neurological disorders is a major driver

The increasing incidence of debilitating disorders such as chronic pain, Parkinson’s disease, diabetic neuropathy, etc., is creating a pressing need for new and efficient treatments to address these conditions. A 2023 study by the CDC indicated that 20.9% of American adults suffered from chronic pain, and 6.9% experienced chronic pain that significantly limited their daily activities.

Similarly, Parkinson’s disease affects nearly 1 million people in the USA as of 2023, with this number expected to rise to 1.2 million by 2030. These statistics indicate a rising trend of neurological disease burden in the USA.

One major issue that many patients and physicians face is that the current treatments for many of these conditions fall short, leaving a significant gap in the care of patients. Typically, doctors treat people suffering from chronic pain, including that of diabetic neuropathy, using painkillers. Most patients develop medicine tolerance, experience drug-wearing-off effects, or suffer from severe side effects, diminishing the overall treatment effectiveness.

Some patients may even consider drastic and irreversible surgical procedures, such as nerve amputation, due to inadequate treatment results. However, even these may not always provide the desired relief. This indicates the need for a reliable and effective solution for managing the pain, discomfort, and other neurological symptoms associated with the primary disease.

As non-invasive neuromodulation stimulates the brain areas responsible for pain processing, it alters the patient’s perception of pain. With the growing incidence of neurological disorders, this desired neuromodulation effect will continue to be in high demand, contributing to the growth of the non-invasive neuromodulation devices market.

Non-invasive treatments offer advantages over other techniques

Typically, conditions such as chronic pain are treated using a combination of prescription medicines. However, these medications, including NSAIDs, opioids, etc., come with a variety of side effects, such as digestive issues, ulcers, drowsiness, etc. Long-term use of opioids can lead to a range of negative consequences, including the development of tolerance, physical dependence, and opioid use disorder, increasing the risk of overdose and death. Conventional treatment methods also need frequent hospital visits.

Invasive neuromodulation is an effective treatment option for various neurological conditions. However, it also carries significant risks, such as site infections, perioperative and postoperative complications, blood clots, and device malfunctions. Additionally, these techniques often require multiple hospital visits.

In contrast, non-invasive neuromodulation offers several advantages over invasive methods. These wearable devices provide drug-free treatments that do not require surgery or complex installation. As a result, they are easy for patients and physicians to use.

A comprehensive study about the efficacy of various non-invasive devices is not yet available. However, controlled individual studies by companies and developers have shown promising efficiency in treating various diseases.

Moreover, a 2019 report published in BMJ, a peer-reviewed medical journal, indicated that non-invasive neuromodulation offers a potential solution for patients who are sensitive to traditional treatments. This includes patient groups such as pregnant women, adolescents, and those who experience poor tolerability or lack of efficacy from pharmacological treatment therapies.

The need to treat health conditions of these patient groups may drive the use of non-invasive devices to treat health conditions.

Scientific advancements help improve efficacy and expand applications

The non-invasive neuromodulation field has seen several breakthroughs in recent years, showing promise for accelerated R&D and new and improved devices potentially entering the market in the future.

One example is the proprietary magnetic peripheral nerve stimulation (mPNS), marketed as Axon Therapy, developed in 2023 by US-based Neuralace Medical for managing painful diabetic neuropathy.

Another example is vibrotactile stimulation (VTS), currently under development by an interdisciplinary research team from the University of Minnesota as a treatment for spasmodic torticollis or cervical dystonia. This is a painful neurological condition that affects the neck. Though the product is not yet marketable, the clinical trials are showing significant promise.

VTS devices are also being developed for conditions other than pain. An example is the VTS glove, a wearable device developed by researchers at Stanford University and the Georgia Institute of Technology in 2024. The device applies high-frequency vibrations to the hands and fingers to relieve uncontrollable arm and hand spasms. In clinical trials, patients who used the device experienced significant improvements in symptoms, with some even reporting a reduction in their use of oral medications. The team is now working to develop the device further and make it available to patients as a publicly available therapy.

Furthermore, a new treatment for tinnitus, known as bimodal neuromodulation, which involves stimulating two sensory pathways in the brain, has been developed. Ireland-based company Neuromod offers the Lenire device, which combines headphones and a mouthpiece to deliver auditory and tactile stimuli to alleviate symptoms. Patients wear the device for an hour daily, for at least six weeks, to stimulate the tongue with electrical impulses while listening to tones.

These new developments are likely to give momentum to the ongoing R&D in the sector.

Increased investment signals growing market potential

The sector has also seen an uptick in investments. For example, Nalu Medical, a US-based company, secured US$65 million in funding in 2024 to advance its neurostimulation technology for treating chronic pain.

Similarly, Avation Medical, a US-based company focusing on treating bladder issues, raised over US$22 million in 2024 to launch the Vivally System. This wearable device treats patients with urge urinary incontinence (UUI) and overactive bladder (OAB) syndrome.

Massachusetts–based Cognito Therapeutics, a company focused on developing a new therapy for Alzheimer’s disease, raised around US$73 million in 2023.

This increasing trend in R&D investments shows investors’ rising interest in the field of non-invasive neuromodulation, indicating promising market prospects.

Integration with AI is expected to pave the way for future developments

Non-invasive neuromodulation is seeing considerable success in developing closed-loop systems that leverage artificial intelligence (AI) and machine learning (ML) to give customized therapeutic output. This trend is likely to see more growth, especially with the rapid advancements in the field of AI.

An example is Avation Medical’s Vivally System, a wearable neuromodulation device that uses closed-loop, autonomously adjusted electrical stimulation to treat patients with UUI and OAB syndrome. The device uses a smartphone app to calibrate itself for each patient and then delivers a constant current of electrical stimulation through a wearable garment. It also uses an advanced AI-powered closed-loop algorithm and electromyography (a medical test that measures the electrical signals sent by nerves to muscles and received back from them) to enable continuous real-time monitoring and therapy adjustment, ensuring uniformity and safety.

Non-invasive neuromodulation device companies are forming partnerships with research institutes to develop safe ways to treat various disorders using generative AI neuromodulation.

One such collaboration started in June 2024 between US-Swiss generative neuromodulation firm, Dandelion Science and Geneva-based research institute Wyss Center for Bio and Neuroengineering. The goal is to develop a generative AI neuromodulation platform for treating neurodegenerative and neuropsychiatric disorders.

Similar collaborations are likely to commence in the future, as it is clear that the combination of neuromodulation and AI is set to impact various treatment fields significantly.

Expansion of insurance coverage could boost treatment accessibility

Conventionally, chronic pain treatment involves a combination of drugs and physical therapy. The US patient usually pays 20% of their Medicare-approved amount. People with severe pain spend about US$7,700 on annual healthcare expenditures, and with insurance, they have to spend around US$1,600 annually. For the management of pain conditions such as migraine, the out-of-pocket expense can increase to 30% of their Medicare-approved amount.

Non-invasive neuromodulation treatment has proved to be more cost-effective than conventional treatments. Although many non-invasive pain management devices are not covered by insurance, some are eligible for reimbursement.

For instance, Nerivio, a wearable device for treating migraine, is covered by Medicaid and Highmark Insurance. Moreover, Theranica, Nerivio’s Israel-based parent company, introduced the Nerivio Savings Program in October 2020 to help US patients access the device. It is a reimbursement plan that allows patients to receive their first device for a copay of up to US$49 (for 18 treatments), depending on their insurance coverage. The refill costs US$89 for those without insurance.

Additionally, patients may be able to use Health Savings Accounts (HSAs) or Flexible Spending Accounts (FSAs) to pay for specific approved devices. An example is Cefaly, for which, though not covered by insurance in the USA, consumers can use HSA and FSA funds or finance their purchase with Affirm (a US-based financial technology company that offers flexible payment options) for US$36 per month upon qualifying. Without insurance or other financial aid, the upfront cost varies from US$330 to US$430, and an additional US$25 for three reusable electrodes, each usable up to 20 times each.

Non-invasive neuromodulation devices’ high upfront cost remains the key barrier to broader adoption 

Overall, non-invasive neuromodulation devices offer a more cost-effective option than other treatments. The most significant barrier for patients opting for non-invasive neuromodulation is the high upfront cost, especially with no insurance coverage.

For example, Israel-based Zida Therapeutics’ Zida Control Sock, a device to treat urinary incontinence, comes with an upfront cost of US$750. Without insurance, many people may find it challenging to cover this cost. This is particularly true for older adults whom conditions such as chronic pain and urinary incontinence affect the most. According to 2023 data released by the US Census Bureau, 14.1% of Americans aged 65 and older live in poverty, making these devices less accessible to them without insurance coverage.

However, this situation may improve as several companies are now in talks to receive insurance coverage for their devices. With an increase in R&D, companies can also offer robust evidence to demonstrate the effectiveness and long-term safety of the devices, prompting insurance companies to provide coverage.

With reimbursement available for companies such as Theranica and Zida, and with several other companies such as Neurovalens planning to enter discussions with insurance providers to achieve reimbursement status, the accessibility has a chance to improve in the near future. This will likely drive adoption in the coming years.

EOS Perspective

Adopting non-invasive devices will likely increase as a standalone treatment and adjunct therapy. While non-invasive treatments currently focus on conditions such as chronic pain, tinnitus, urinary incontinence, etc., experts believe that this will soon expand into other neurological conditions, including ALS, and Parkinson’s disease.

Currently, there are only seven FDA-approved drugs for ALS treatment, all of them with limited effectiveness. The significant unmet need in this field presents a compelling opportunity for non-invasive neuromodulation companies. PathMaker Neurosystems is among the few companies conducting feasibility studies and developing non-invasive neuromodulation treatment options for ALS patients.

Research is also underway to develop a non-invasive treatment for Parkinson’s disease, which was previously treated using invasive techniques. Czech Republic-based STIMVIA has reported promising results from its initial pilot study of a new treatment for patients with Parkinson’s disease as an add-on therapy.

Several new non-invasive devices are also in the development pipeline, and their clinical trials are promising. An example that has shown positive results in a pivotal trial is a treatment for improving upper limb function by Netherlands-based ONWARD Medicals.

Non-invasive neuromodulation has the potential to revolutionize the treatment of chronic pain and other neurological disorders. As the field continues to evolve, with advancements in AI-powered wearables and increased investment in R&D, we can expect to see even more innovative solutions emerge in the coming years.

New Directions in Alzheimer’s Diagnostics Will Blood Tests Replace CSF and PET by EOS Intelligence
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New Directions in Alzheimer’s Diagnostics: Will Blood Tests Replace CSF and PET?

Around three-fourths of dementia cases continue to remain undiagnosed even though the incidence of Alzheimer’s disease (AD) is rapidly growing across the globe. AD affects about 60-80% of dementia patients worldwide. Early diagnosis of AD is critical in forging beneficial medical care strategies and enhancing patient outcomes. Current AD diagnostic tests, such as cerebrospinal fluid (CSF) and PET scans, are either invasive or associated with side effects and are generally expensive. This calls for developing less invasive, safer, faster, and more accurate AD diagnostics, such as blood tests.

Blood-based tests promise accurate and non-invasive AD diagnosis

Researchers are developing less invasive and less costly blood tests that are likely to be more accurate than contemporary tests. There are currently two types of AD diagnostics blood-based tests: the phosphorylated tau217 (ptau217) test and the amyloid beta (Aβ) 42/40 plasma ratio test.

The ptau217 biomarker has the potential to differentiate AD from other neurodegenerative diseases, as ptau217 levels can be high in AD patients before the onset of clinical symptoms. Studies have proved that ptau217 tests can detect AD early on and monitor disease progression.

The Aβ 42/40 plasma ratio tests detect amyloid beta protein plaques in the brain that cause cognitive impairment. Due to the lack of a certified reference standard for measuring plasma Aβ42 and Aβ40’s absolute values, ptau217 may be better than an amyloid beta ratio test. However, both tests are accurate enough to diagnose AD.

Notably, ptau217 blood tests are believed to give up to 95% accurate results when coupled with CSF tests as against 90% accuracy of CSF when used as a standalone method. At the same time, amyloid beta (Aβ) 42/40 ratio tests are known to give around 80% accuracy in detecting amyloid positivity.

Many laboratories and diagnostic companies have designed or are designing ptau217 assays. C2N Diagnostics, Quanterix, Quest Diagnostics, and Laboratory Corporation of America (LabCorp) offer ptau217 laboratory-developed tests (LDTs).

Low cost of blood-based AD tests can also be a growth-driving factor

A major push towards blood-based AD diagnostics comes from the tests’ lower cost in comparison to PET and CSF. The cost of blood tests typically ranges from US$200 to US$1,500, depending on the test provider.

The cost of PET ranges from US$1,200 to US$18,000, while the average price of CSF tests is around US$4,000 (in both cases, the actual cost depends on the type of facility, location, and the extent of insurance coverage).

As of 2023, Medicare and Medicaid covered PET scans for AD in the USA outside clinical trials. Therefore, AD patients need to pay around 20% of the PET cost, which translates to US$240-US$3,600, even after insurance coverage.

Considering the high share of dementia and AD cases remaining undiagnosed, there is a chance that the lower cost of blood-based tests can help contribute to higher accessibility to testing and ultimately improve the early detection rate.

Large AD diagnostic players partner with smaller ones to develop new tests

In an attempt to develop ptau217 assays, major diagnostics companies tend to recognize the development progress made by smaller players. ALZpath, a novel AD diagnostic solutions provider, is the pioneer of the ptau217 antibody, which helps in the early detection of the disease. Large players such as Roche and Beckman Coulter are enticed by the synergistic opportunities ALZpath offers.

In June 2024, Roche partnered with ALZpath, an early-stage biopharmaceutical company specializing in AD diagnostics, to launch the plasma ptau217 In-Vitro Diagnostic (IVD) test. As per the partnership, Roche will use ALZpath’s ptau217 antibody to design and commercialize an IVD test to detect AD with the help of Roche’s Elecsys platform.

In July 2024, Beckman Coulter also partnered with ALZpath to utilize ALZpath’s proprietary ptau217 antibody to detect AD on Beckman Coulter’s DxI 9000 Immunoassay Analyzer.

AD diagnostics firms receive funding from various sources, including drugmakers

Constantiam Biosciences, a bioinformatic analysis firm, received a US$485,000 Phase 1 SBIR grant (Small Business Innovation Research) from the National Institute on Aging to develop a tool for deciphering risk variants pertaining to AD and related dementias (AD/ADRD) in September 2024.

Biogen and Eli Lilly invested in the Diagnostics Accelerator, a funding initiative started in 2018, at the Alzheimer’s Drug Discovery Foundation (ADDF) in 2020. The Diagnostics Accelerator has invested over US$60 million across 58 projects, most of which are blood tests. In its Q4 2023 earnings call, Biogen emphasized its support for developing tau biomarker diagnostics and pathways. Its partner, Eisai, has invested around US$15 million in C2N Diagnostics and collaborated with IVD companies such as Sysmex, among others. In September 2024, ADDF invested US$7 million in C2N Diagnostics to further develop blood-based AD detection tests.

Other investors have also identified the opportunities AD diagnostic offers. A 2024 market research report by Market Research Future estimated that the AD diagnostic industry would nearly double, from US$4.5 billion in 2023 to US$8.8 billion in 2032.

FDA stands as an accelerating force for blood-based tests via breakthrough device designation

For a while now, the FDA has been granting breakthrough device designation (BDD) to devices that could address life-threatening diseases with unmet medical needs. BDD facilitates the expedited development, review, and assessment of medical devices, ensuring quicker access for patients and medical professionals. It would not be too ambitious to conclude that strong positive evidence from several uses and studies of ptau217 tests is likely to compel the FDA to approve them for use in the near future. The first sign of this is that the FDA is granting BDD status to multiple ptau217 blood tests.

In March 2024, the FDA granted BDD to Simoa ptau217 by Quanterix. This blood test can detect AD in patients with cognitive ailments even before signs and symptoms start to appear.

In April 2024, the FDA gave BDD to Roche’s Elecsys ptau217 plasma biomarker test to augment early diagnosis of AD. Roche partnered with Eli Lilly to develop this blood test that will widen and accelerate AD patients’ access to diagnosis and suitable medical attention and care.

In early 2019, the FDA gave BDD to C2N Diagnostics’ blood test to detect AD. The BDD status of AD blood tests will likely accelerate the development, review, and assessment processes of these tests, improving patient outcomes.

Some FDA-approved AD drugs have used blood tests in clinical trials. Eli Lilly’s Kisunla and Esai/Biogen’s Leqembi have successfully utilized C₂N Diagnostics’ Precivity-ptau217 blood biomarker in their clinical trials. The FDA approved both drugs to manage AD. This improves the chances of this blood test getting approved by the FDA.

Lumipulse G β-Amyloid 1-42 Plasma Ratio test by Fujirebio Diagnostics received BDD from the FDA in 2019. The company submitted an FDA filing for the Lumipulse G ptau217/β-Amyloid 1-42 Plasma Ratio IVD test in September 2024. If approved, this test will become the first commercially available blood-based IVD test in the USA to detect AD.

EOS Perspective

There has been considerable progress in developing blood-based assays for AD diagnosis by pharma and diagnostics companies. However, a good portion of the liability for their products not reaching market readiness faster lies (and will probably remain to lie) on the approving authorities that are unable to accelerate the administrative steps.

Some blood tests, such as PrecivityAD, are approved for safe use in the EU but are still not in the USA. While such approval is typically a time-consuming process and requires a thorough investigation, the blood tests will enter the market at a larger scale across several geographies only if the authorities fast-track their approvals. This is particularly applicable to blood tests previously successfully used in clinical trials for approved AD drugs and for tests that have already attained BDD status from the FDA.

As an example, PrecivityAD by C2N Diagnostics received BDD status in 2019 from the FDA. However, the FDA has still not approved the blood test for safe use in the USA. This is still despite the fact that PrecivityAD and other C2N Diagnostics’ assays have been utilized in over 150 AD and other research studies across the USA and abroad. FDA’s time-consuming and lengthy review procedures and bureaucratic reasons are some of the factors responsible for the delay in approval. In addition to this, C2N Diagnostics needs to submit some more evidential data pertaining to the accuracy of PrecivityAD, which is likely to take time to produce.

These procedural and administrative impediments, along with the time taken by the device makers to present the data to the FDA, will likely continue to put a brake on the blood-based tests becoming available to patients in the near future.

The situation will remain so, given the FDA’s recent decision to regulate new LDTs involving diagnostic tests that use body fluids such as blood, saliva, CSF, or tissue on similar lines as medical devices (meaning LDTs must comply with the same standards as medical devices). As per this regulation, LDTs need to prove the accuracy of their tests. This decision will have both winners and losers in the AD stakeholder ecosystem.

Researchers and physicians are looking at this regulation with a positive stride as this step will reduce the number of tests with unconfirmed accuracy from the market in the USA. This is undoubtedly a positive change for patients’ safety, reducing the number of misdiagnoses and accelerating correct diagnoses.

On the other hand, smaller start-ups and diagnostic companies are not likely to benefit from this decision as it will restrict the development of new innovative tests vis-à-vis large diagnostic companies. Overall, the decision will likely decelerate the approval of blood-based AD tests or at least will require much more paperwork and proof of accuracy from the device makers. This decision will take effect in multiple phases over four years, starting from July 2024.

On the research and development side of the Alzheimer’s disease diagnostics space, a certain level of symbiosis between drug producers and diagnostic solution providers will continue to impact the market positively. Drugmakers are partnering with or investing in diagnostic companies to leverage the latter’s innovative blood-based biomarkers (BBBM) technologies in the clinical trials of their own drug candidates. This trend is likely to continue.

Not only drugmakers but also more prominent healthcare diagnostics companies, such as Roche and Beckman Coulter, are partnering with early-stage biopharmaceutical companies, such as ALZpath, to develop and commercialize AD ptau217 tests. Collaborations such as these are a testimony to the fact that it is mutually beneficial for AD industry stakeholders to work in tandem to advance AD diagnostics research, a significant growth-driving factor for the market.

Phase 3 Drug Candidates - A Ray of Hope in Alzheimer’s Disease Bleak Treatment Landscape by EOS Intelligence
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Phase 3 Drug Candidates – A Ray of Hope in Alzheimer’s Disease Bleak Treatment Landscape?

Many biopharmaceutical companies, such as AriBio, Annovis Bio, Athira Pharma, Cassava Sciences, and Alzheon, specializing in treating neurodegenerative diseases, are developing drugs for Alzheimer’s disease (AD) that are currently in phase 3 of clinical trials. If approved, these drugs can ameliorate the AD treatment approaches to a considerable extent. A major prerequisite to this is for concerned authorities to take concrete steps to fast-track clinical trials and increase AD research investment.

With only a 1% success rate of clinical trials in drug development until 2019, the AD treatment gap is alarming. A 99% failure rate means there is a very limited influx of new, more effective, and more advanced AD drugs into the market, and the gap between available treatment options and the rising number of AD cases is increasing.

The disease burden of Alzheimer’s will rise from US$1.3 trillion in 2020 to US$2.8 trillion by 2030 globally. With the rise in the aging population across the globe, the estimated number of AD patients will increase from 55 million in 2020 to 78 million in 2030.

However, recent drug approvals, such as Elli Lilly’s Kisunla (Donanemab) in July 2024 and Biogen/Eisai’s Leqembi (Lecanemab) in January 2023, bring a ray of hope for a new approach to AD treatment.

Initial hopes for new drugs can be premature

New drugs do enter the market from time to time. However, their impact on AD treatment in the long term is not always significant. An example of this is Biogen’s Aduhelm. Based on its ability to reduce amyloid protein in the brain, the FDA approved Aduhelm (Aducanumab) in 2021 in an accelerated approval route for AD treatment.

However, in 2024, Biogen discontinued the drug in the alleged desire to reprioritize its resources in AD treatment. Experts cite weak clinical evidence for efficacy, serious side effect risks, a high price point, and poor sales among the many reasons for Aduhelm’s withdrawal from the market.

AD drug candidates succumb to clinical failures

Eisai and Biogen have been working together since 2014 to develop and commercialize AD drugs. However, they have faced clinical drug failures, similarly to many other pharmaceutical companies during that time. For instance, they had to terminate Elenbecestat, one of their AD drugs, in phase 2 clinical trial in 2019 following an unfavorable risk-benefit ratio finding by the Data Safety Monitoring Board (DSMB).

Eisai launched its first AD drug, Aricept, an acetylcholinesterase inhibitor, in the USA in 1997 in collaboration with Pfizer. The annual peak sales of Aricept were US$2.74 billion before its patent expiry in 2010. However, Pfizer exited neuroscience drug research and development in 2018 after the failure of its AD drug candidates, such as Dimebon and Bapineuzumab.

Clinical challenges in Alzheimer’s research and reallocation of resources were among the other reasons for Pfizer’s exit from neuroscience R&D and drug development. Nevertheless, Pfizer did not desert the neuroscience space completely, rather forged a spin-off company called Cerevel Therapeutics in partnership with Bain Capital.

Phase 3 Drug Candidates - A Ray of Hope in Alzheimer’s Disease Bleak Treatment Landscape by EOS Intelligence

Phase 3 Drug Candidates – A Ray of Hope in Alzheimer’s Disease Bleak Treatment Landscape by EOS Intelligence

Recent drug launches focus on amyloid beta targeting mechanism

In January 2023, the FDA approved Leqembi (Lecanemab), a drug by Biogen and Eisai, for AD treatment. It is a monoclonal antibody that clears away the amyloid beta plaques known to cause cognitive impairment in AD patients. With MHRA’s (Medicines and Healthcare Products Regulatory Agency) approval of Leqembi, Great Britain becomes the first European country to authorize the drug for the treatment of early-stage AD as of August 2024.

In July 2024, the FDA approved Kisunla (Donanemab) by Eli Lilly to treat early-stage AD. The drug’s mechanism of action is the same principle as that of Leqembi, an amyloid beta protein plaque targeting mechanism. Kisunla becomes the third anti-amyloid drug approved for AD treatment, following Aduhelm (now discontinued) and Leqembi. Both Kisunla and Leqembi drugs carry the risks of the formation of temporary lumps in the brain that can be fatal. Therefore, physicians advise regular brain MRIs to alleviate this risk. Neurologists and researchers are in disagreement over whether the benefits offered by these drugs are clinically meaningful.

Researchers are still studying the side effects of these two drugs. Prescribing them requires confirmation of the presence of amyloid protein in the brain. Therefore, PET scans and CSF tests are required before such a prescription.

The FDA has approved both drugs in the USA for intravenous infusions (IV) in the early stages of AD. Kisunla is administered every four weeks instead of every two for Leqembi. Therefore, Kisunla offers greater convenience compared to Leqembi.

Experts from Bloomberg Intelligence suggest that Eli Lilly will likely surpass Biogen and Eisai’s reign at the top of the AD drug market by capturing around 50% of the US$13 billion market globally by 2030. This is partly because of Kisunla’s convenient dosing and the fact that AD patients can stop taking the drug after the amyloid levels touch the clearance threshold.

Newer therapeutic approach-based drugs are in phase 3 clinical trials

Apart from the amyloid beta therapeutic approach, AD researchers are exploring the role of other mechanisms in AD treatment, such as anti-tau antibodies, neurotransmitter receptors, and synaptic plasticity or neuroprotection. Drugs based on these mechanisms are currently in phase 3 of clinical trials.

The Washington University School of Medicine’s DIAN-TU (Dominantly Inherited Alzheimer Network Trials Unit) trial is testing Lecanemab plus Eisai’s investigational anti-tau antibody E2814 in patients with early-onset AD caused by a genetic mutation. E2814 prevents the spreading of tau seeds in the brains of AD patients. This drug is in phase 3 clinical trial. The clinical study commenced in June 2024 and will complete by November 2029.

ACP-204 by Acadia Pharmaceuticals is also in phase 3 clinical trial for AD. The agent acts as an inverse agonist at the 5-HT2A serotonin receptor. FDA has approved Acadia’s previous 5-HT2A inverse agonist, Nuplazid, for Parkinson’s disease psychosis. ACP-204 will be the first drug for AD treatment in Acadia’s product portfolio if approved.

Another drug in phase 3 trial is AriBio’s AR1001, a phosphodiesterase-5 (PDE5) inhibitor. Apart from AR1001, two more AD drugs are in AriBio’s pipeline, AR1002 and AR1003 that are currently under the investigational new drug-enabling stage of clinical trials.

For better patient outcomes, researchers are attempting to develop AD drugs with non-invasive modes of administration that are likely to be less expensive and equally effective compared to AD drugs administered intravenously.

The safety and effectiveness of oral therapy candidate Buntanetap, developed by Annovis Bio, are comparable in people with early onset AD regardless of whether they do or do not carry a genetic risk factor APOE4. That is according to new data from a phase 2/3 clinical trial that tested three doses of Buntanetap against a placebo in more than 300 patients with the neurodegenerative disease. Buntanetap modulates protein production to reduce clumping. The competitive advantage of Annovis Bio over its peers is the fact that Buntanetap targets multiple proteins in the brain, such as amyloid beta, tau, alpha-synuclein, and TDP43, making it more effective than AD drugs that target a single protein.

Apart from Buntanetap, Annovis Bio has another oral drug to treat advanced AD and dementia in its pipeline, ANVS301, which is in phase 1 of clinical trial. In July 2024, Annovis Bio received FDA approval to transition to a new solid form of Buntanetap in future clinical trials allowing the company to refine its drug formulation, potentially improving its efficacy and safety profiles.

Another promising AD drug candidate, Fosgonimeton by Athira Pharma, is a small-molecule positive modulator of the hepatocyte growth factor (HGF) system, previously showing neuroprotective, neurotrophic, and anti-inflammatory effects in preclinical models of dementia. This drug is in phase 3 clinical trial. Athira Pharma ended 2023 with a strong balance sheet, signaling its better financial position to augment its ongoing pipeline development.

Eli Lilly’s new drug Remternetug works as pyroglutamyl (3)-amyloid beta-protein (3-42) inhibitors, positioning it as a promising AD drug. Remternetug will join Eli Lilly’s portfolio as a second AD drug if approved.

Simufilam by Cassava Sciences is a proprietary, small-molecule oral drug that restores the normal shape and function of altered filamin A (FLNA), a scaffolding protein, in the brain. It is now in phase 3 clinical study to test this new and promising scientific approach to treating and diagnosing AD. The mechanism of action of this drug involves stabilizing a critical protein in the brain instead of removing it. This novel approach distinguishes Cassava Sciences’ drug from other treatments that predominantly focus on amyloid-beta or tau proteins. In May 2024, Cassava Sciences raised US$125 million by selling its stock to shareholders. The funds will be utilized for the continued development of Simufilam.

Valiltramiprosate by Alzheon is potentially the first oral disease-modifying treatment for AD. Valiltramiprosate is well differentiated from plaque-clearing antibodies in development for AD due to its novel mechanism of action, oral mode of administration, and potential efficacy in a genetically targeted population. In October 2017, Valiltramiprosate/ALZ-801 received FDA Fast Track designation for AD investigation. Due to Alzheon’s significant progress in AD drug development, the company has attracted a lot of investors since 2022. Alzheon received US$100 million in June 2024 in Series E venture capital funding which will be utilized to further develop and commercialize Valiltramiprosate. This is in addition to US$50 million received in series D round of funding in 2022.

Big names dominate the competition, with clinical trials in progress by smaller biopharma players

On the competitive landscape front, the AD drug market is highly competitive, with many pharmaceutical companies financing R&D to engineer new drugs that could potentially delay the progression of AD and/or restore neuronal health. The global AD therapeutics market size was US$4.8 billion in 2023 and will surpass US$7.5 billion by 2031, as per Towards Healthcare, a healthcare consulting firm.

A couple of large players still dominate the global AD therapeutics market. Interestingly, they are not the only ones active in the AD treatment development, as several smaller biopharmaceutical companies that specialize in neurodegenerative disease treatment are working on AD drugs (many currently in phase 3 of clinical trials).

High R&D costs are a considerable factor in slowing the progress down

Between 1995 and 2021, the cumulative private spend (total R&D expenditure by pharmaceutical companies, does not include federal funding) on clinical stage R&D for AD was US$42.5 billion, with the largest share of 57% (US$24.1 billion) incurred during phase 3. During the same period, the FDA approved 878 drugs across all therapeutic areas; only six of these drugs were for AD treatment (four cholinesterase inhibitors [ChEIs], memantine, and aducanumab). These statistics speak volumes of the complex, expensive, time-consuming, and predominantly unsuccessful nature of AD clinical trials. This ultimately leads to exorbitant prices of AD drugs.

A range of factors drive the R&D costs and, in turn, the price of AD drugs. A significant component here is patient screening, which contributes to 50-70% of the cost. Patient recruitment and retention are also challenging, given the considerable length of such trials.

Moreover, patient recruitment challenges stunt the progress of AD clinical trials. The recruitment rate for AD clinical trials is as low as one patient per site per month. In terms of eligibility, 99% of AD patients who are eligible for participation in a clinical trial never consider taking part. This further increases the time taken to conduct AD clinical trials.

EOS Perspective

After decades of failure in clinical trials, two anti-amyloid AD drugs, Kisunla and Leqembi, are available in the market, forming a duopoly in the USA. There are several promising drugs in phase 3 clinical trials with a new mechanism of action apart from amyloid beta protein inhibitors. However, the disease management landscape is prone to unforeseen changes, such as the withdrawal of drugs owing to safety, efficacy, and pricing issues.

The AD treatment landscape faces challenges such as drug inefficacy, complex pathophysiology of AD, expensive and time-consuming clinical trials, delays in diagnosis by physicians, behavioral changes and deteriorating mental health of AD patients, and severe side effects of medications. These challenges will continue to impede the development of new disease management approaches.

An issue that is very likely to continue to challenge progress in developing better treatment options for AD is the severe lack of funding. Dementia research is extremely underfunded compared to HIV/AIDS, cancer, and COVID-19 in the USA. Irrespective of the fact that the deaths attributed to AD are on par with cancer, the difference between the annual US federal government funding for AD vis-à-vis cancer is strikingly huge.

AD drug development is a tough market to operate in. The ongoing issue with AD research funding persists, and there do not seem to be changes in federal funding soon. On top of that, the slow progress in successful R&D and many failed clinical research trials will likely make private-sector investors hesitate or withdraw.

In addition to this, AD drug manufacturers will also continue to face the challenge of low to modest drug sales due to poor adoption rates stemming from issues like restricted coverage.

As of June 2023, Medicare was covering AD drugs that slow down the progress of the disease provided a physician agrees to the collection of real-world evidence of these AD drugs, as per the Centers for Medicare & Medicaid Services (CMS). However, there is a significant underlying problem with drugs for AD treatment. When the drug finally enters the market, patients cannot afford the treatment, and the coverage is restricted and sometimes withdrawn. There is no foreseeable change to this impasse, and hence, the AD treatment development is likely to be slow.

If reimbursement of AD drugs is removed, patients are likely to stop administering AD drugs altogether and adopt alternative healthcare resources such as antidepressants, as found in a 2021 study by researchers from Paris-Saclay University and Memory Center of Sainte Périne Hospital in France.

The reluctance of payers to cover the treatment cost for AD is influenced by several factors beyond just the high cost of the drug. Factors include cost-effectiveness of treatments, uncertain long-term safety and efficacy benefits of treatments, clinical guidelines and recommendations, availability of alternative treatments including generics (from drug makers such as Cadila, Cipla, Dr. Reddy’s, among others), and regulatory and reimbursement policies.

The future of AD treatment approaches will continue to remain bleak, and patients will be left with only a few available drug options unless the right authorities set out a plan for fast-track clinical trial processes, increase AD research investment, and support broader insurance coverage.

Pharma Companies Navigate Their Way through Ac-225 amidst Supply Constraints by EOS Intelligence
by EOS Intelligence EOS Intelligence No Comments

Pharma Companies Navigate Their Way through Ac-225 amidst Supply Constraints

Pharma companies have been increasingly investing in developing targeted alpha therapies for cancer treatment, using alpha-emitting isotopes such as Ac-225. However, the current supply for Ac-225 is limited, and thus, companies are working towards securing their supply chain. The recent investment by Eli Lilly in isotope manufacturer Ionetix brings to light the increasing interest of large pharmaceutical companies in Ac-225 and its uninterrupted supply for their pipelines. Similar to Eli Lilly, several other companies have strategically invested in or partnered with manufacturers to ensure a guaranteed supply.

Ac-225 is pegged as a promising isotope for next-generation cancer treatment

Among the recent advances in cancer therapies, only a few have shown as much promise as targeted alpha therapies have. Targeted alpha therapies (TAT) involve using alpha-emitting isotopes to selectively target and destroy cancerous tissue without causing significant damage to surrounding healthy tissue. This is facilitated by the short range of alpha radiation in human tissue (less than 0.1 mm), which corresponds to less than 10 cell diameters. Moreover, they are characterized by high energy levels (5-9 MeV), which results in the selective destruction of malignant cells.

Several alpha-emitting isotopes are currently being explored for TAT, the most common among them being Ac-225, At-211, Pb-212, and Bi-213. Of these, Ac-225 (actinium-225) is considered the most potent medical-grade radioisotope as it has a high decay energy of 5.9 MeV and a half-life of 10 days. It is the isotope of choice in several clinical trials, with about 15 Ac-225-based ongoing clinical trials currently in the USA. However, despite having substantial potential for developing next-generation treatments in the cancer space, their adoption has been slow, given the short supply of the isotope.

Ac-225 is not naturally available and is derived from Th-229 (thorium-229), a byproduct of uranium-233 (U-233), which is a leftover from the production of atomic weapons in the 1950s and 1960s. The initial batch of Ac-225 has been supplied by the US Department of Energy (DOE). However, the supply cannot keep up with the growing demand for trials.

Isotope producers invest to accelerate Ac-225 supply in the future

Currently, there are two commercialized routes to produce Ac-225. As mentioned above, the first and traditional route involves separating Ac-225 from Th-229, derived from the US government’s legacy reserves of U-233. The US government holds about 453kg of U-233, of which only about 256kg is of high quality and will produce about 24g of medical-grade thorium.

The government had previously started a program that extracted a small amount (150mCi) of Th-229, which produced about 1.2 Ci of Ac-225 per annum, enough to treat 1,200 patients. However, in 2019, the US DOE entered into a public-private partnership with Terra Power and Isotek to downblend its stock of U-233 to extract Th-229, which can further be used to develop Ac-225. In 2021, TerraPower entered into an agreement with Cardinal Health, a US-based commercial alpha contract manufacturing organization (CMO), to develop and produce Ac-225 for drug development commercial sales. This will likely significantly improve the supply of Ac-225 in the long run.

The other route to produce Ac-225 is through cyclotron production, which involves irradiating a Ra-226 (Radium-226) target with a proton and knocking off two neutrons. Several isotope manufacturers are adopting this technology and are working on increasing their manufacturing capacity.

Niowave, a US-based supplier of medical and industrial radioisotopes, uses a closed-loop cycle to produce high-purity Ac-225 and other alpha emitters from Ra-226 using a superconducting electron linear accelerator. Similarly, Ionetix, a leading cyclotron technology innovator and isotope manufacturer, uses the same technology to produce Ac-225 and managed to produce its first batch of Ac-225 in June 2024. The company commissioned its first cyclotron at its current facility in 2023, while it aims to install and commission a second cyclotron there in early 2025. By 2025, it is expected that the company will be able to produce about 1Ci per week. The company also aims to establish another site in the USA for Ac-225 production in 2026.

While isotope manufacturers are strategically working to enhance the production of Ac-225 in the long run, the current supply, which is required to fuel the ongoing clinical trials using Ac-225, is quite limited. In 2024, the worldwide supply of Ac-225 is estimated to be about 2Ci per annum, which is merely enough to treat 2,000 patients.

Pharma companies invest in securing their Ac-225 supply chain

Given its currently limited availability and immense potential, leading pharmaceutical players are adopting various strategies to secure their Ac-225 supply to support their targeted alpha therapies drug pipelines. Several leading players, such as Fusion Pharmaceuticals, Telix Pharmaceuticals, and Bayer, are actively working on partnering with companies producing Ac-225 to overcome supply-related challenges for their trials. Recently, a leading pharmaceutical company, Eli Lilly, also joined the bandwagon and secured its supply of the actinium isotope.

Fusion, which has three Ac-225-based drugs currently under trial, was one of the first movers in this regard and has inked several partner agreements to ensure a smooth supply.

In December 2020, Fusion entered into a partnership with TRIUMF, Canada’s national particle accelerator center. In this partnership, Fusion would provide the latter with up to US$18.5 million (CA$25 million) to upgrade its production facilities and scale up production of Ac-225. In return, Fusion would receive preferred access and pricing to the resulting isotope.

In June 2022, Fusion collaborated with Niowave, a US radioisotope manufacturer. Under the agreement, Fusion would invest up to US$5 million in Niowave to further develop their technology to increase their production capacity of Ac-225. In return, Fusion will be guaranteed access to a pre-determined percentage of Niowave’s capacity of the resulting Ac-225, as well as preferred access to any excess stock produced.

In November 2023, Fusion entered into an agreement with BWXT Medical, a US-based supplier of nuclear components and a subsidiary of BWX Technologies. Under the agreement, the latter agreed to provide Fusion with a preferential supply of Ra-225 (parent isotope of Ac-225) and access to high-specific activity generator technology. This would enable Fusion to produce Ac-225 at its own manufacturing facility for use in clinical trials. In addition, BMXT Medical provides Fusion with predetermined amounts of its actinium supply needs under a preferred partner agreement.

Another leading radiopharmaceutical player, Telix Pharmaceuticals, entered into an agreement with Cardinal Health in May 2024 to supply Ac-225 globally.

Similarly, in February 2024, Bayer signed an agreement with PanTera (a Belgian radioisotope production JV created by Ion Beam Applications and SCK CEN) to secure large-scale production of Ac-225. PanTera uses both the Ra-226 and Th-229 production mechanisms to produce Ac-225. It is collaborating with TerraPower to supply Th-229.

Eli Lilly, the largest pharmaceutical company globally, has also recently invested in a nuclear isotope manufacturing company, Ionetix, in August 2024. Eli Lilly has made a US$10 million convertible loan investment in the company to secure its supply of Ac-225. Moreover, PointBiopharma, which was acquired by Eli Lilly in 2023, also had a previous US$10 million investment in Ionetix, resulting in Eli Lilly holding a total of US$20 million debt facility with Ionetix. The pharma giant has the option to convert this debt into equity when Ionetix’s valuation exceeds US$300 million.

These investments by Eli Lilly and Fusion Pharmaceuticals are rare cases where major pharmaceutical companies are investing up the supply chain to secure actinium availability for their cutting-edge drug pipelines.

EOS Perspective

While targeted alpha therapies are emerging as high-potential next-generation cancer drugs, they are plagued by supply constraints of alpha-emitting isotopes, especially Ac-225. Thus, companies seeing great promise in these therapies must work towards securing their supply of these isotopes to ensure the smooth running of their clinical trials.

In the past, large pharmaceutical companies such as BMS have had to halt enrolment in their clinical trials due to the non-availability of Ac-225. Such interruptions not only delay the entire clinical trial but also have significant cost implications and could jeopardize its overall success.

Considering these limitations, it is imperative that pharmaceutical companies with ongoing or planned Ac-225-based trials invest in ensuring a guaranteed supply of the isotope for the entirety of their trial and future production of the drug once approved. While several companies are merely entering into supply agreements with isotope manufacturers, others are taking it one step ahead and investing in their upstream suppliers. Moreover, some companies, such as Fusion and now BMS, are advancing towards building on-site production of Ac-225.

That being said, establishing a secure supply chain of Ac-225 comes with its own set of costs and risks. Most pharmaceutical companies are undertaking significant investments (ranging between US$5-25 million) to guarantee their supply of Ac-225.

However, as a cancer therapy, TAT is in the nascent stages of development, and most trials utilizing Ac-225 are still in either phase 1 or phase 1/2, far from FDA approval. Moreover, the only Ac-225-based trial in phase 3 is being conducted by BMS for neuroendocrine cancer and is currently halted due to supply issues. Given the nascency and early stages of development of this treatment, it is too soon to predict if these heavy investments into Ac-225 would result in the development of FDA-approved drugs and bring sufficient returns. This risk can have particularly dire consequences for small players.

Thus, while companies looking to develop targeted alpha therapies using Ac-225 must work to secure their supply, their level of investment must remain in sober relation to their size, pipeline, and financial position.

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