Spinwheel: The Connective Tissue for Credit Data

Most users are very willing to link their bank accounts with popular financial applications like Venmo, Coinbase, and Robinhood. However, the data exchange that underpins those seamless monetary transfers is merely the first iteration of a new paradigm in the financial world: open finance.

Open finance enables a world where consumers and financial service providers can access financial data like spending, investments, payroll, loans, and tax information via API. With it, they can understand their financial situation and make better decisions about budgeting, borrowing, lending, and financial products. With questions of technical capability and regulatory permission mostly settled, the ability of data aggregators to deliver timely, comprehensive consumer financial data now steers the industry’s movement towards a world of open finance.

Yet while open finance tools now provide consumers with access to information about their financial assets, information about their debts and liabilities remains far less accessible, more opaque, and more scattered. The consumer debt market is an enormous part of the US financial ecosystem. Federal Reserve Data reports $19T of outstanding consumer liabilities. Equifax data shows that Americans are on track to originate 134M consumer loans across auto, bank and private label cards, mortgages, HELOC, consumer finance, and student categories in 2025 alone. Consumer debt is also a critical source of stress for many American households.

Unlike the asset side of their lives, data about the average American’s debts and liabilities are spread across multiple loan providers running legacy tech stacks. All this in an industry where nuanced, granular, and real-time data is essential for consumers to know exactly how much they owe, to whom, and when it’s due. Consumers are eager to budget, manage debt, and improve their credit scores, and banks and FIs are eager to meet the need with budgeting applications, credit monitoring, and credit-building tools. All that’s missing is the data aggregation connecting the two.

At F-Prime, we’re proud to have backed foundational companies like Quovo, Even Financial, and Kensho that allowed consumers and financial services providers unprecedented visibility and access to users’ financial assets. Now, we’re excited to partner with Tomás Campos, Tushar Vaish, and the Spinwheel team to do the same for their liabilities. Spinwheel is an API for consumer liability data that provides consumers, banks, lenders, and fintech companies with the ability to aggregate, understand, and manage consumer debt. It uses proprietary direct integrations and agentic workflow to collect permissioned, consumer liability data across credit card transactions, mortgages, auto loans, student loans, personal loans, and more, with the highest degree of coverage and accuracy in the market today. We’re excited to lead Spinwheel’s $30M Series A and join them at the forefront of financial infrastructure.

RIP Old VC Playbook: How Investors Are Changing AI Startups Evaluation

Originally published in Forbes

The AI revolution is moving so much faster than previous technological shifts. While the mobile internet took nearly a decade to reach 90 percent household adoption, ChatGPT achieved the same user penetration in just two years. This accelerated cycle is creating companies that reach incredible scale in record time, but it’s also rewriting the venture capital playbook. The traditional rules of SaaS investing are being challenged, and the moats we once relied on are becoming less defensible. Based on recent discussions my Eight Roads Ventures colleague, Michael Treskow, and I have had with our team, here are ten ways investors are changing how they evaluate AI startups today.

1. Agents Are the Future — Not Just Co-Pilots

The first wave of AI applications was dominated by “co-pilots” — tools that assist humans. The next, more powerful wave is characterized by “agents” — autonomous systems that complete tasks from beginning to end. These agents are transforming traditional “systems of record” into “systems of action.” As an investor, the key question goes beyond the earlier paradigm of “does this make a workflow more efficient?” Now, investors must ask, “can this automate the workflow entirely?” How (and to what degree) humans are involved will depend on the AI-use-case fit, enterprise risk appetite, and the existing workflow. As an example, Roo Code has multiple modes, from code mode to architect mode, based on customers’ specific needs. Early breakouts are already emerging in specialized fields like cybersecurity (penetration testing agents), DevOps (debugging agents), and financial services (memo generation agents), showing the power of vertical agents.

2. Traditional SaaS Moats are Diminishing

The three defensive moats that defined the SaaS era are eroding:

Implementation Friction: In the past, the high cost and complexity of implementing enterprise software, especially in regulated industries, created stickiness. Today, AI agents can write code and automate implementation, drastically lowering switching costs.

Workflow stickiness: SaaS used to be the system of record, deeply embedded in the enterprise workflow. But now that agents are performing the workflow entirely, it could reduce the friction of migrating.

Data Gravity: The effort of migrating data from one system to another created a powerful lock-in. Now, AI models can automatically ingest and structure data from various sources (including emails, calendars, and documents) making it far easier to populate a new system, and thereby reducing the stickiness of the incumbent.

3. Enterprise Knowledge, Trust, and Observability Are the New Defensibility

With the underlying models increasingly turning into an API-accessible commodity, differentiation is shifting up the stack to the application layer. The most defensible companies are building new moats around enterprise knowledge, trust, and observability.

When considering workflow integration, investors must figure out how deeply the product is embedded within a customer’s core business processes, or how well the agents internalize the enterprise knowledge if there is forward-deployed engineering. Just like a service provider, the more an agent has absorbed the enterprise’s organizational and operational intricacies and preferences, the harder it is to replace. The second moat, centered on becoming a trusted, default partner, is related to an older sales and marketing principle: In a confusing market, enterprises are looking for a trusted guide to shape their AI strategy. The first vendor to gain a customer’s trust and become their “default” AI partner gains an immense advantage, with the ability to expand across the organization.

5. The “Incumbents Are Slow” Argument Is No Longer a Given

Two ideas — that incumbents will be slow to act and that customers building in-house solutions will fail — that once formed foundational pillars of venture investing have now been turned on their head.

Incumbents now have access to the same powerful APIs as startups. And while cultural inertia at enterprises remains a challenge, the technical barrier to entry has been lowered, and the proprietary data they have accumulated over the years will give them a head start. Similarly, with modern orchestration tools like Thread, Onyx, or n8n, it’s becoming more feasible for customers to build their own bespoke AI agents in-house. A startup’s competition is no longer just other startups, but also its own customers and the very incumbents it aims to disrupt.

6. TAM May Increase, but Advantages Become Less Obvious Once Pricing Normalizes

A critical shift in the AI era is the expansion of the total addressable market (TAM) beyond traditional software budgets. AI companies can now tap into two distinct enterprise spending pools. “Co-pilot” models, which assist human users, are typically sold on a per-seat basis and compete for existing software budgets. Autonomous “agent” models complete workflows end-to-end, are sold on a per-outcome basis, and hold more transformative potential.

AI agents are positioned to capture a share of the much larger services budget, effectively replacing costs previously allocated to human labor or outsourced services. However, while the opportunity to capture the services budget is immense, it is not a blank check. As some founders have noted, many are generating eight-figure savings while charging customers six-figure prices. As agent-based solutions become more common, the price for automated labor will inevitably face downward pressure and normalize, meaning the initial advantage of charging rates comparable to human labor may not be sustainable long-term.

7. Team Composition Looks Different at AI Companies

AI-native companies are operating with unprecedented efficiency. While a company like Cursor can have great PLG motion and reach $100M ARR with around 30 employees, most enterprise AI companies build a GTM team to reach scale. In a confusing market with intense competition where perceived product differentiation is limited, GTM makes all the difference. On the tech side, CTOs with an ML background will be more essential in the foundational model and middleware layer than in the application layer. Having a Head of AI to stay on top of the latest feature releases and skate to the right opportunity will create a nice complement as the CTO scales the technical organization and infrastructure.

8. SaaS Metrics Still Matter, but in a Different Way

LTV/CAC is still relevant, but velocity matters more. The “Triple, Triple, Double, Double, Double” (T2D3) growth model for top-tier SaaS is being replaced by an even more aggressive trajectory. Some have suggested the new top-quartile metric is “Quintuple, Quadruple, Triple.” For example, a company would grow from $1M to $5M, $5M to $20M, and $20M to $60M over three years. While this velocity is exciting, it can also be misleading. Rapid adoption in a hot market doesn’t guarantee a large TAM or durable revenue. While there is no public benchmark for churn metrics for AI companies yet, we know some of enterprise AI companies’ net revenue retention (NRR) at month 12 is well above 100 percent to compensate for the logo churns — see Glean at 120 percent, Writer at 160 percent, and Jasper for enterprise at 163 percent.

9. Scrutinize Gross Margins and Unit Economics

AI companies often have high compute and model inference costs. While we see margins improve over time, investors must be vigilant about how costs are reported. As others have noted, companies may claim impressive gross margins even though a closer look at their P&L reveals millions in API calls and compute costs categorized under R&D. When re-categorized correctly, their margin was actually negative. Investors must always dig into the P&L to understand the true cost of goods sold.

10. Customer Love Doesn’t Guarantee Retention. Product Usage Is The True PMF

In a normal market, a high net promoter score (NPS) is a strong signal of future retention, but not necessarily in the current AI landscape. Customers may unanimously love a product today, but the market is evolving so quickly that a better alternative may appear in six months. Many enterprises are intentionally building flexibility into their tech stacks to easily swap vendors, so founders and investors alike should beware of “vibe revenue.” Therefore, look beyond NPS to metrics like product usage, which is a leading indicator of retention. Beware of “stealth churn,” where customers who are still paying see less frequent usage, or use a product for a lower percentage of their entire workflow.

2025 State of Robotics Report

We’re incredibly excited to share our 2025 update to our annual State of Robotics report. The report is a comprehensive analysis of more than 1,500 robotics companies globally, including a company-by-company exploration of the use case each is pursuing.

We invite you to download the report here, and reach out to authors Sanjay Aggarwal and Betsy Mulé.

dataplor: The Gold Standard in Location Intelligence

Whether you are building an autonomous delivery robot, identifying the best-performing Zara in the Netherlands, or comparing visits to Starbucks versus Dunkin’ Donuts in Boston’s Back Bay, actionable insights hinge on clean, highly accurate, up-to-date point of interest (POI) data. Across so many sectors, these insights underpin expansion plans, demand forecasting, customer targeting, underwriting, partnerships and more.

And yet, high-quality location data remains elusive. Historically, only large enterprises had the resources to acquire and leverage location data in their strategic decision-making processes, often stitching together multiple sources, or paying consultants or outsourced clipboard armies to collect data on the ground. Even then, coverage gaps and stale information were common. Maintaining your own POI data is expensive, painstaking work that requires perpetual aggregation, validation, and enrichment, making it a great candidate for outsourcing.

However, none of the POI players that emerged have come armed with a truly comprehensive set of high quality, global location data — until now. Since meeting Geoff Michener and the dataplor team in 2023, we’ve been impressed by their relentless focus on delivering clean, reliable POI data across more than 250 countries and territories. dataplor’s solution is mission critical to Global 2000 companies in tech, consumer goods, logistics, retail, F&B, and finance for geospatial analyses, operational workflows, and growth initiatives. The company’s data service is refreshed regularly with rigorous quality checks, and goes far beyond basic business names and addresses, enriching each location with brand, transaction, persona, foot-traffic estimates, hours of operation, sentiment scores, popularity metrics, and more. It truly is an unmatched combination of depth, breadth, and global coverage.

At F-Prime, our investments in data platforms like Lighthouse, Quovo, 1uphealth, and Canoe have reinforced our conviction that outsized value is created by starting with exceptionally high-quality data. The difference between 95 percent and 99.9 percent accuracy is massive and consequential for discerning customers. dataplor is democratizing access to highly accurate, actionable POI data, empowering organizations to make better-informed decisions and personalize customer experiences at scale. With the team’s exciting vision and roadmap, we are honored to partner with Geoff, Ryan, and the rest of the dataplor team on their $20.5M Series B.

Women’s Health Symposium

On May 7th, F-Prime, RA Capital Management, and OrbiMed hosted a Women’s Health Symposium.

The event was co-organized by Tashy Rodgers, MD and Anastasiya Sybirna, PhD from F-Prime, alongside Hugo Arellano-Santoyo PhD from Raven (RA Ventures), RA Capital’s healthcare incubator and Natasha Shervani from OrbiMed. We welcomed an engaged audience of investors from top-tier VCs and strategics to hear from three fantastic speakers:

Dr. Parambir Bhangu shared insights on Organon‘s commitment to advancing Women’s Health

Prof. Linda Griffith (Massachusetts Institute of Technology) introduced her groundbreaking “organ-on-a-chip” disease models

Dr. Michael Rogers (Boston Children’s Hospital) presented new discoveries from his translational endometriosis mouse model

Our roundtable focused on high unmet-need areas such as endometriosis, polycystic ovary syndrome (PCOS), uterine fibroids, heavy menstrual bleeding, and female-prevalent conditions like osteoporosis. We discussed the chicken-and-egg problem in the space: a lack of investment leads to limited innovation, yet the complexities of clinical trials and sparse pipelines make it harder to attract investment in the first place. Crucially, we also explored solutions – from novel mechanisms and biomarkers to more translational disease models that can help de-risk programs earlier.

Some of the highlights:

  • Academic funding in women’s health remains heavily skewed toward oncology, leaving non-oncologic gynaecological conditions underfunded and with sparse pipelines.
  • Endometriosis non-invasive diagnostics and biomarkers are a top priority: current surgical confirmation requirements hinder trials, and most lesions are invisible to imaging.
  • Pain, while clinically meaningful in endometriosis, is a noisy and variable endpoint. Validated biomarkers are urgently needed to measure disease modification.
  • There is cautious optimism about the new draft FDA guidance for osteoporosis, which may allow accelerated approval based on improvements in bone mineral density (BMD) rather than fracture reduction. The field is eagerly awaiting the final guidance, particularly regarding safety database and confirmatory study requirements
  • We are incredibly grateful to our speakers and attendees for a stimulating and solution-focused discussion. Exciting follow-ups are already underway. If you are an entrepreneur or academic working on novel therapeutics, diagnostics, biomarkers, or models for underserved women’s health conditions – we’d love to hear from you!

Gold-standard Eating Disorder Treatment Delivers Lasting Recovery for Patients and Families at Home

In 2019, Kristina Saffran and Dr. Erin Parks came to us with a slide deck and a passion for helping those struggling with eating disorders (EDs).

We were drawn to their story and mission as many of our team members had been touched by EDs – either suffering from one themselves or having a loved one who had struggled with an ED. Some are surprised to learn that EDs are the most expensive and one of the deadliest behavioral health conditions in the U.S., second only to opioid addiction. Nearly 30 million Americans across all races, genders, body sizes, and sexual orientations will have an eating disorder in their lifetime. Despite their prevalence, only 20% of those struggling receive treatment, and even less have access to evidence-based treatment. Our shared commitment to address this critical treatment gap, coupled with our strong belief in Kristina and Erin, led to our partnership with Equip.

We were delighted to lead the seed round that helped bring Kristina and Erin’s vision to life and to support them through the early fundamentals of company creation, including advising them through decisions about how to incorporate the company. Our team also had the pleasure of helping name the company – we proposed “Equip” during the naming process, believing that it reflected the ethos of the company. Equip – based on equipe, meaning “team” in French and the idea that the company has a strong focus on helping patients figure out how to equip themselves with skills to turn to instead of harmful behaviors. One of our team members, Brooke Hammer, even ultimately joined the company as a key member of the leadership team.


“F-Prime was one of our original champions who truly allowed Equip’s bold vision to become a reality. We, and the eating disorder field, are forever grateful for them.”

Kristina Saffran, CEO and Co-founder


Equip is positioned to transform eating disorder treatment with compelling evidence that their clinical approach works for lasting recovery. A remarkable 96% of Equip’s patients on a weight restoration program are gaining weight, 7 out of 10 are seeing reduction in their ED symptoms and 80% of parents have reported an increased confidence in their ability to address their child’s ED.

Eating disorder treatment is complex and cannot be one-size-fits-all. Equip’s medical and behavioral health platform is built to meet patients and families where they are through virtual family-based therapy (FBT). There are still significant challenges in the space but Equip is leading the way to deliver accessible, effective, fully virtual care.

Science2Startup

On May 14th, F-Prime, alongside 5AM Ventures, Atlas Venture, Osage University Partners (OUP), and RA Capital Management hosted Science2Startup.

S2S is a forum for top scientists from around the world to present their ideas and interact with leading investors and executives in the Boston biotechnology hub.

S2S is a symposium featuring the most innovative therapeutics startup ideas from the world’s top research institutions. Submissions from researchers are reviewed by a senior advisory group composed of experienced biotech investors. Selected presenters work 1-on-1 with advisory group mentors to further refine their concept and prepare a 15-minute presentation. 200+ attendees include entrepreneurs, biotech investors (Angels / VCs), pharma scouts, academic investigators, TTOs, etc.

To learn more, visit the S2S website with this link.

The Four AI Agents of Your Health

With the advent of AI, we are only beginning to envision how dramatically it will change the management of our health.

Many people have already used Claude, Gemini or ChatGPT to evaluate symptoms or interpret lab results. As models, apps, and users evolve, the possibilities to alter how care is delivered, accessed, and financed seem limitless.

 

 

From Carbon to Silicon

To fully grasp how AI might change healthcare, we first need to understand how our current system — built around humans and analog methods — limits our potential. Our health system was constructed on the assumption that information is stored locally in proprietary archives (on paper or in locally controlled EHRs), and that knowledge is stored in the minds and hands of trained providers.

In 1999, The Institute of Medicine showed that more than 100,000 people were dying annually due to medical errors. Since then, clinicians and administrators have sought to resolve flaws in our system. With AI, we may be able to rethink care delivery to resolve these problems, freeing us from the bottlenecks of a limited human supply of trained clinicians. The architects of hospitals and insurance companies never imagined that silicon could transcend carbon, yet the early days of generative AI make it obvious that this technology will transform the way care is delivered. AI-related tools can play an important role in reducing patient harm, while making our system more affordable and accessible.

Overcoming the Limits of Imagination

With new technologies, there is often a failure of imagination; society has a collective inability to see how the world can be reshaped by breakthrough innovations. This can be because new technologies are immature and the infrastructure to scale them does not yet exist. It is also due to humanity needing time to understand how to take advantage of new things. As Chris Dixon has commented, when the film camera was invented, creators needed a long time to figure out you could do more than just film a staged play indoors. In healthcare, changes in the way physicians practice often require the retirement of one cohort of doctors and the rise of a new generation of providers, who are more comfortable with newer tools (as was seen with the adoption of less invasive, laparoscopic surgery).

Adaptation Requires Creative Destruction

Beyond the limits of imagination, administrators face practical barriers to change. How can one be sure it is safe, legal, or appropriate to use new AI technologies? If providers automate current processes, such as replacing in-person care with an AI-enabled app or digital therapeutic, how can they backfill lost revenue associated with redundant activities? Will the data AI depends on be available and exchangeable without sacrificing privacy and security?

Our healthcare system isn’t designed with accessible data as a core assumption. More than a pragmatic challenge, this is a business model issue: large health systems would prefer that you never leave their four walls (which they call “patient leakage”), because they operate as oligopolies, leveraging market power to get better rates from payers. And yet, our health journeys take us outside of those four walls, where our data is no longer available, integrated, or complete.

For the modern potential of AI to truly advantage everyone, there needs to be a new architecture for data that enables this future. Truly ubiquitous data will make services more readily available and of higher quality, while also enabling a marketplace of care solutions that are not held back by fear of data blocking. If data integration were simple, patients (and their primary care providers and navigators) could evaluate cost vs. quality and the forces of creative destruction would reshape services, lowering costs.

The Four AI Agents of Your Health

In an AI-enabled future powered by a new data architecture, four “agents” are likely to emerge, who will work together to improve our health – four different objective functions that will be part of each patient’s life in an efficient and effective health care future. This framework originates from a straightforward concept that one must analyze the state of events and then orchestrate actions based on that understanding. This was stated memorably by Jay Desai, who would tell his team to “figure it out” and “get it done.” Jay’s charge is a great way to organize the work of managing health: figure it out, and get it done.

In terms of “figuring it out,” two agents will be key.

Moving from the realm of “figuring it out” to “getting it done,” two other agents become important in your life.

Four Bots for the Win

One might note that the four bots could, in fact, be one larger AI system operating cohesively, and this is likely. The reason it’s helpful to separate these four agents initially is to emphasize that these are four different objective functions, which work together. The Archivist aims to ensure the record is always complete. Whenever new items enter the archive, this is a prompt for The Diagnostician to update the risk assessment, just as new medical knowledge continues to improve its foundation model. An updated risk assessment could then prompt The Planner to adjust the health plan for a given patient. In turn, a change in the plan will require The Guide to update the user accordingly. The sequence of tasks could go the other way as well. Perhaps The Guide is told by the user that a new bout of scalp pain is occurring, prompting it to alert the other three bots and make appropriate adjustments. Perhaps The Diagnostician calls next for a temporal ultrasonic study to sort things out, which would then need to be incorporated by The Planner into the user’s life, considering the user’s insurance status, physician networks, schedule, etc., all explained to the user by The Guide.

Example: Hematocrit Result Leads to Sleep Apnea Treatment

To show these agents in action, here’s how a real-world scenario might work, with the four agents collaborating to get to the bottom of an abnormal lab value.

This hypothetical example may or may not relate to how the author of this post spent the last two months figuring out a similar issue (thanks to the care team at Firefly). An agentic future would make this sequence even more seamless, ensuring that the archive, the risk assessment, the health plan, and the user’s mindset are cared for at every step of the journey, possibly without the need for human intervention. Importantly, an AI-driven model would remove much – if not all – of the human costs, liberating the model from process bottlenecks and resource constraints.

Innovation as the Path to this Future

This sci-fi vision of the future may be closer than one might think. Companies like Zus and Health Gorilla already handle much of the tasks of an Archivist, as does Apple Health to a large degree for consumers (for entities that are properly linked). The Diagnostician already exists in the form of Google’s MedPalm models, and its AI rivals are not far behind. One already can upload an archive to these models to seek medical analysis. The Planner has further to go, but the venture market is replete with pitch decks of companies aiming to deploy agents to take over every administrative task in healthcare from answering the phone (e.g., Clarion or Hyro), to preauthorizing care (e.g. Cohere), to handling the billing (e.g. Akasa).

If doctors can have a bots call patients to remind them of appointments, why can’t patients have bots take the call and schedule care for when its suits their busy lives (in sync with health plan requirements)? As for The Guide, this may be the most Black Mirror-esque component, but most people would benefit from an always-on agent like Scarlett Johansson in Her, who simply takes care of everything. The ChatGPT voice is along those lines; just imagine the power of that interface when linked to the other three agents, entities who can actually “figure it out” and “get it done.” It’s not too hard to imagine Apple rolling out an “Apple Health+”* service that leverages AI and the iPhone’s health archive to assess risks and help users get care; other wearables such as Oura Ring may also go down a similar path.

Linking Back to our Terrestrial System of Care

How this AI future will integrate with our existing “terrestrial health system” remains an open question. And by “terrestrial,” I’m referring to all the buildings, offices, devices, labs, imaging centers, insurance companies, pharmacies, and HR departments that make up more than 18% of U.S. GDP. Those organizations already have a head start adopting AI tools to make their work more efficient, effective, and scalable, aided by countless health tech startups and established companies. As noted in a prior post on The New Digital Care Architecture, in order for data to take a full seat at the table alongside doctorsdrugs, and diagnostics, a myriad of technologies and processes need to evolve, including advances in both AI and the interoperability enabled by APIs.

These Four Agents represent something more personal – a model by which each person can have guardian angels in the cloud, always thinking about their health, meeting them where they are, to get them the care they require; anticipating what they need next often before they realize it. The implications for how personalized agents would extend from, interact with, and refine our existing health system remain unclear and are an area ripe for innovation. Though much of the “how” in this vision is unclear, what is clear is that the advance of AI agents will make much of care radically cheaper, more accessible, and more convenient.

So What?

In the coming months, more of the “so what” will be explored, aiming to identify actionable projects that can bring about this much more active, effective, scalable, and affordable healthcare future. If we can create real markets for care, where providers and individuals manage budgets to optimize health in tune with the personal needs of users, creative destruction will be unleashed to reshape our system for the better.

Of course, manifold risks must be managed and dealt with as we build a new healthcare future, rooted in AI systems such as these. That’s why we need entrepreneurs, clinicians, regulators, and operators to collaborate in the pursuit of “doing well by doing good.” for the sake of us all. If venture investors can help pull this future forward faster by financing the work, all the better.

Pioneering Progress: The Vyndaqel®/Vyndamax™ Story

The approval of Vyndaqel®/Vyndamax™ is paving the way for an expanding landscape of approved and investigational treatments for transthyretin amyloid diseases.

F-Prime is dedicated to advancing pioneering science and technologies that redefine patient care and treatment. Since 2002, F-Prime has facilitated the regulatory approval and commercialization of 33 products and drugs. In this series, Pioneering Progress, we showcase success stories behind the approval of drugs and products from our portfolio companies.

Understanding Transthyretin Amyloidosis, a Rare and Fatal Disease

Transthyretin amyloidosis (ATTR amyloidosis) is a rare, progressive, and fatal disease caused by the accumulation of misfolded proteins, known as amyloid, in the peripheral nervous system, heart, and other organs. This occurs when transthyretin (TTR)—a protein that transports the thyroid hormone thyroxine and retinol—misfolds and forms amyloid deposits. Normally, TTR exists as a tetramer, a stable cluster of four identical protein units. However, with aging or inherited mutations, these units separate and misfold, resulting in the formation of harmful amyloid fibrils, which are insoluble and resistant to degradation. ATTR amyloidosis manifests in several forms, with the two most common types being ATTR amyloidosis polyneuropathy (ATTR-PN), which affects the nerves, and ATTR cardiomyopathy (ATTR-CM), which impacts the heart.

ATTR-PN, which is estimated to affect 10,000-40,000 patients globally, leads to amyloid fibril-based damage to nerves, resulting in muscle weakness, loss of sensation, tingling, numbness, pain, and digestive track issues.1, 2, 3 Without prompt intervention, ATTR-PN is typically fatal within 10 years and, until recently, the only effective treatment was liver transplantation.2

ATTR-CM, on the other hand, is characterized by amyloid fibril accumulation in the heart tissue and results in symptoms resembling that of other heart conditions such as heart failure, further complicating diagnosis.3 While ATTR-CM was once considered very rare due to the diagnostic difficulty, recent improvements in diagnostic techniques have significantly increased incidence estimates, now with 5,000-7,000 new cases identified annually in the US alone4. Historically, individuals with ATTR-CM faced a poor prognosis, often experiencing severe health complications and a high risk of death within two to six years of diagnosis.5

With limited treatment options that target the root cause of ATTR amyloidosis, F-Prime saw a tremendous opportunity to bring new therapies to patients and transform how these diseases are treated and understood.

Advancing the Fight Against ATTR Amyloidosis

 The understanding of ATTR amyloidosis took a major step forward with the work of Portuguese physician and leading ATTR amyloidosis researcher Teresa Coelho, Ph.D., who linked mutations in the TTR gene to the development of amyloid disease. Her research identified key disease-causing mutations, such as V30M and V122I, and uncovered a secondary mutation that interestingly led to TTR tetramer stabilization and better patient outcomes. Building on these findings, Jeff Kelly, Ph.D., a chemist at Scripps Research Institute and co-founder of FoldRx, proposed a new treatment approach—a small molecule drug designed to stabilize TTR and prevent misfolding.

By screening known drugs and applying structure-based drug design, Kelly’s team discovered Vyndaqel/Vyndamax, a small molecule drug that binds to TTR. By keeping the protein in its stable tetramer form, this approach helps prevent TTR from breaking apart, misfolding, and forming harmful amyloid deposits. With a unique molecule and promising early data, Kelly co-founded FoldRx in 2003 together with Susan Lindquist, Ph.D., former director of the Whitehead Institute for Biomedical Research.

“FoldRx came to us with a strong foundation of peer-reviewed scientific research supporting its hypothesis and a simple but innovative approach for addressing ATTR amyloidosis that offered curative potential,” said Stephen Knight, M.D., President and Senior Managing Partner at F-Prime. “Their solution made FoldRx an ideal investment opportunity that closely aligned with F-Prime’s goal to fund companies with transformative potential. Together, we were able to lay the foundation for Vyndaqel/Vyndamax’s eventual approval and bring forward a much-needed therapy for this life-threatening disease.”

Under the leadership of CEO Richard Labaudiniere, Ph.D., FoldRx initiated clinical development of Vyndaqel/Vyndamax, starting with a Phase 0 study to better characterize the typical ATTR-PN patient natural history—which at the time was entirely unknown—and continuing through completion of a Phase 2 study.

Based on encouraging data from the Phase 2 study, Pfizer acquired FoldRx and Vyndaqel/Vyndamax received European marketing approval in 2010 as the first therapy to treat ATTR-PN. Following additional clinical studies, Vyndaqel/Vyndamax was approved by the US FDA for the treatment of ATTR-CM in 2019.

From Breakthrough to Progress

The approval of Vyndaqel/Vyndamax as a first-in-class treatment for ATTR-PN and ATTR-CM set the stage for an influx of new drugs that address the diseases through various modalities. This growing list includes approved siRNA-based treatments Onpattro® (patisiran) and Amvuttra® (vutisiran), antisense oligonucleotide medicines WAINUA™ (eplontersen) and Tegsedi® (inotersen), small molecule drug Attruby™ (acoramidis), and an investigational CRISPR/Cas9-based approach, NTLA-2001.

Vyndaqel/Vyndamax highlights F-Prime’s role in advancing innovative treatments that transform patient care. Its success has helped drive progress in the field, paving the way for more life-saving treatment options for patients. This journey—from groundbreaking research to a first-in-class therapy—demonstrates the power of scientific innovation and strategic investment in changing the course of rare, fatal diseases.

References:

  1. Schmidt HH, Waddington-Cruz M, Botteman MF, et al. Estimating the global prevalence of transthyretin familial amyloid polyneuropathy. Muscle Nerve. 2018;57(5):829-837. doi:10.1002/mus.26034
  2. González-Duarte A, Conceição I, Amass L, Botteman MF, Carter JA, Stewart M. Impact of Non-Cardiac Clinicopathologic Characteristics on Survival in Transthyretin Amyloid Polyneuropathy. Neurol Ther. 2020;9(1):135-149. doi:10.1007/s40120-020-00183-7
  3. Pfizer. Understanding This Rare Disease Called ATTR Amyloidosis. Accessed January 22, 2025.
  4. Jain A, Zahra F. Transthyretin Amyloid Cardiomyopathy (ATTR-CM). StatPearls. 2023.
  5. Rozenbaum MH, Garcia A, Grima D, et al. Health impact of tafamidis in transthyretin amyloid cardiomyopathy patients: an analysis from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and the open-label long-term extension studies. Eur Heart J Qual Care Clin Outcomes. 2022;8(5):529-538. doi:10.1093/ehjqcco/qcab031
  6. Castaño A, Drachman BM, Judge D, Maurer MS. Natural history and therapy of TTR-cardiac amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs. Heart Fail Rev. 2015;20(2):163-178. doi:10.1007/s10741-014-9462-7