In the 1990s there was desperate need for better treatments for neovascular age-related macular degeneration (nAMD). As a young resident at Massachusetts Eye and Ear Infirmary, I, along with my classmates, became swept up in a wave of innovation involving antivascular growth factor (VEGF) therapy and imaging. Ultimately, these innovations disrupted treatment paradigms and benefited millions of patients.

Now, with the perspective of two decades as a retina specialist, an MBA and various roles in academia, private practice and industry, I realize that anti-VEGF therapies not only caused seismic shifts in treatment paradigms, but also disrupted business models, created value networks and altered relationships among academia, private practice and industry by facilitating collaboration among these three groups.

These blossoming collaborations and resulting innovations continue to foster convergence among academia, practitioners and industry, which also parallels my career transitions. In this article, I will review disruptive innovation theory, trace anti-VEGF therapy development through the lens of innovation theory and examine the transitions that made this all possible.

DISRUPTIVE INNOVATION THEORY

Clayton Christensen’s 1997 book, “The Innovator’s Dilemma,” explains how titans of industry (incumbents) fall due to previously unknown companies (challengers).¹ Dismissing claims that such failures were due to poor management, Christensen developed the “disruptive innovation theory” to explain how incumbents could fall to challengers offering seemingly inferior products.

Specifically, challengers enter the low end of the market — the low-margin portion that incumbent firms are willing to cede with little to no fight. They forfeit this ground because they are most interested in serving their current clients well, and using their institutional capabilities to sustain innovation and incrementally improve their current products and services.

Over time, the “challenger” moves toward becoming a “disruptor” when it masters the simple work at the low end of the market, and then gradually moves up the scale of complexity and profit margin. With every step up in mastery, the disruptor begins to increasingly challenge or threaten the incumbent. This threat is further compounded as the disruptor retains the advantages and lessons learned from its success at the low end of the market, while the incumbent firm is often large and lethargic, slow to react to such drastic changes.

Eventually, the disruptive firm makes its way to the top of the complexity and profit margin market, while still retaining much of the share below as well. It pushes the incumbent firm out of the way, as the disruptive firm has typically developed a cheaper, simpler and more efficient means of addressing customers’ needs.

DISRUPTIVE INNOVATION IN OPHTHALMOLOGY/RETINA

The development of anti-VEGF and other anti-angiogenic therapies in ophthalmology correlates in some ways with Christensen’s model. During the past two decades, ophthalmology has witnessed disruptive innovation in the form of anti-VEGF therapy, which has altered the entire landscape. In fact, the global market for anti-VEGF therapy exploded from nonexistence in 2004 to $7.8 billion in 2015, and is predicted to reach $10.4 billion in 2020, according to Cohen and Company Equity Research.

THE INCUMBENTS AND THE DISRUPTORS

Prior to the advent of anti-VEGFA therapy, we treated nAMD with focal laser therapy and surgical excision of choroidal neovascular membranes (CNV), but outcomes with these incumbents remained poor.

With poor outcomes, unmet needs were significant — nAMD treatment needed disruptors.

In the late 1990s, as codirector of the Retina Service and Angiogenesis Research Lab at Indiana University, the largest medical school in the country, I eagerly began work on anti-angiogenic steroids in animal models of CNV,^2,3 later co-authoring perhaps the first published U.S. randomized clinical trial (RCT) of intravitreal therapy.⁴ In the quest for better treatment, our group even retrofitted a physics cyclotron to perform a single-center RCT of proton therapy for nAMD.5 We discontinued this RCT when verteporfin photodynamic therapy received approval in 2000. At that time, I started to realize that partnering with industry facilitated the much greater scope of large multicenter RCTs, and I began serving as an investigator on most of the major retina RCTs that followed.

In 2004, Macugen (pegaptanib sodium, Bausch + Lomb), an aptamer designed to target the 165 isoform of VEGFA, was the first-of-its-class agent approved to treat nAMD. Registration studies (VISION-1) showed that subjects receiving Macugen experienced approximately half the vision loss as those receiving sham.⁶

Lucentis (ranibizumab, Genentech/Roche), a recombinant humanized monoclonal antibody fragment targeting multiple VEGFA isoforms, demonstrated a therapeutic improvement of vision for the first time in the ANCHOR and MARINA studies.^7,8 In 2006, Lucentis received approval for the treatment of nAMD, and rapidly displaced both Macugen and verteporfin. Sustaining innovation with Lucentis then followed, in the form of expanding indications into macular edema due to vein occlusions and diabetic retinopathy.

In 2011, Eylea (aflibercept, Regeneron) was approved for the treatment of nAMD, after less frequent dosing in the VIEW-1 and VIEW-2 studies were shown to be noninferior to monthly ranibizumab.⁹ Interestingly, Eylea was launched with a lower price than Lucentis, and by 2015 it surpassed Lucentis in market share. According to public documents from each company, Eylea’s US sales in 2016 were valued at $3.32 billion, compared to $1.45 billion for Lucentis.

This disruptive innovation spurred value networks. Imaging technologies, such as ocular coherence tomography (OCT), advanced alongside anti-VEGF therapy. These advancements mutually reinforced need and benefit in a virtuous cycle, and led to synergistic value creation.

DISRUPTING THE DISRUPTORS, COMMODITIZING THE DISRUPTIONS

Avastin (bevacizumab, Genentech), a full-length recombinant humanized monoclonal antibody that binds all isoforms of VEGFA, originally received approval to treat metastatic colorectal cancer but was used off-label in 2005 for the treatment of nAMD. Off-label bevacizumab 1.25 mg was found to be noninferior to Lucentis in the Comparison of AMD Treatments Trials (CATT, sponsored by the NIH)10 and the analogous IVAN Study performed in the United Kingdom.¹¹

In the United States, off-label compounded Avastin became the most commonly initiated anti-VEGF treatment due to its cost: It is approximately 40 times cheaper than Lucentis or Eylea. Avastin holds approximately 60% of the USA nAMD market by volume.¹² Innovations ultimately become commoditized, due to new entrants to the market, lower prices and wide access, and Avastin has some of these features.

I became increasingly involved in the fast-moving evolution of anti-VEGF therapies. Ultimately, I served as principal investigator, medical monitor and a member of scientific advisory, data safety monitoring or writing committees in more than 100 national clinical trials, including CATT and nearly all registration trials for retinal therapeutics. In 2015, when I had an opportunity to work at Ophthotech with those who commercialized the first anti-VEGF therapy (Macugen), I eagerly accepted. I was especially encouraged by strongly positive phase 2 data involving inhibition of a different growth factor, with its potential to begin the disruptive innovation cycle anew.¹³ Also, in a small biotech company, I could work across numerous functional areas and learn from many highly educated and committed scientists, biostatisticians, business experts and others.

CONVERGING PARTNERSHIPS

Anti-VEGF disruptive innovation was only possible through academic, clinician and industry partnerships. This early collaboration led to a substantial evolution in the overarching medical community.

While all three center on advancing the field, private practitioners had historically focused on the individual patient, academicians on the disease and industry on the therapy. Partnerships among these entities created synergies, and facilitated innovation. Ultimately, to scientifically demonstrate the efficacy of anti-VEGF therapies, public companies, with access to the large amounts of capital necessary to fund clinical trials, worked with the practitioners who recruited, treated and followed the patients in these trials.

Now, these margins continue to fade as more crossover occurs — an inevitable side effect, perhaps, of disruptive innovation like anti-VEGF and its progeny. Specifically, a greater number of academicians and practitioners conduct industry-sponsored RCTs, as I did, or work more closely with industry, as I do currently. A greater number of academicians have even started their own biotech companies to research and develop their intellectual property further.

ORGANIZATIONAL HIERARCHY AND PHYSICIANS’ ROLES

The drug development process is lengthy, risky, expensive and requires large amounts of human and financial capital, typically only available to industry. For example, a recent study from the Tufts Center for the Study of Drug Development calculated the mean length of time and cost for phase 1 studies at: 33 months and $25 million; phase 2 studies at: 38 months and $59 million; and phase 3 studies at 45 months and $255 million. Furthermore, the mean overall likelihood of successful approval once a drug enters clinical testing is estimated at 12%.¹⁴

I experienced this risk first-hand at Ophthotech, when the phase 3 study of its lead compound failed to replicate results of the phase 2 study. However, I was able to leverage my experiences into a new role at Spark Therapeutics, contributing to gene therapy development, a disruptively innovative concept with implications beyond ophthalmology.

Given the risk, time and expense, industry must scale and require complex hierarchy and management across multiple disciplines; this in turn affects physicians’ independence, activities and incentives. In private practice, a physician typically assumes the role of leader, historically as proprietor in solo practice, or as managing partner in a group practice. In academia, the same physician who might have been the leader in private practice must answer to the chairperson, but has far fewer managerial roles, instead focusing on research and teaching. In industry, that same physician is embedded into an even more complex hierarchy with limited direct control, which can deter those physicians contemplating working in industry, given the traditional preference for independence.

In industry, physician activity and incentives are tied to corporate goals, instead of patient volumes or research grants. While physician work in industry is patient-centered, it does not involve direct one-on-one patient care. Rather, their work focuses on a therapy that can benefit many patients; this can involve therapeutic trial management through clinical development, assessment of new therapies through business development and health economics outcomes research, providing subject matter expertise in regulatory affairs, or interpreting and communicating study results to colleagues through medical affairs. Through my work in these areas, I came to appreciate the enormous collaborative efforts required to deliver a promising potential therapy to patients.

THE FUTURE

Ophthalmology’s future excites me. Rapid innovation will continue, which will generate better therapies with greater efficacy and duration. Novel disruptive therapies on the horizon include topical anti-VEGF agents, sustained-release devices, new anti-angiogenic molecular targets, gene therapies and stem cell therapies. Regardless of one’s role in academia, practice or industry, convergence has created opportunity for physicians throughout this spectrum to contribute to the development of effective new patient therapies. OM

REFERENCES

1. Christensen CM. The Innovator’s Dilemma: When New Technologies Cause Great Firms to Fail. 1997, Boston, MA: Harvard Business School Press, 1997. P. 252.
2. Ciulla TA, Criswell MH, Danis RP, et al. Choroidal neovascular membrane inhibition in a laser treated rat model with intraocular sustained release triamcinolone acetonide microimplants. Br J Ophthalmol, 2003;87:1032-7.
3. Ciulla, TA, Criswell MH, Danis RP, et al. Intravitreal triamcinolone acetonide inhibits choroidal neovascularization in a laser-treated rat model. Arch Ophthalmol, 2001;119:399-404.
4. Danis RP, Ciulla TA, Pratt LM, Anliker W. Intravitreal triamcinolone acetonide in exudative age-related macular degeneration. Retina, 2000;20:244-250.
5. Ciulla TA, Danis RP, Klein SB, et al. Proton therapy for exudative age-related macular degeneration: a randomized, sham-controlled clinical trial. Am J Ophthalmol, 2002. 134: 905-906.
6. Gragoudas ES, Adamis AP, Cunningham, Jr. ET, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med, 2004. 351:2805-2816.
7. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med, 2006. 355:1432-1444.
8. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med, 2006. 355:1419-1431.
9. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology, 2012. 119:2537-2548.
10. CATT Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med, 2011. 364:1897-1908.
11. Chakravarthy U, Harding SP, Rogers CA, et al. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet, 2013. 382:1258-1267.
12. Syed BA, Evans JB, Bielory L. Wet AMD market. Nat Rev Drug Discov, 2012. 11:827.
13. Jaffe GJ, Ciulla TA, Ciardella AP, et al. Dual Antagonism of PDGF and VEGF in Neovascular Age-Related Macular Degeneration: A Phase IIb, Multicenter, Randomized Controlled Trial. Ophthalmology, 2017. 124:224-234.
14. DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: New estimates of R&D costs. J Health Econ, 2016. 47:20-33.

About the Author

Dr. Ciulla co-directed the retina service and ocular angiogenesis research laboratory at Indiana University School of Medicine, and remains a volunteer clinical professor of Ophthalmology.

He is the medical strategy lead – Ophthalmology at Spark Therapeutics. E-mail him at thomasciulla@gmail.com.