Q&A: Mark Enyedy, ImmunoGen

With a background in pharma and biotech, ImmunoGen president and CEO Mark Enyedy talks to Pharm Exec about his dedication to oncology and the lessons he’s learned along the way.

Pharm Exec: Antibody-drug conjugates, or ADCs, have seen a lot of activity in terms of approvals and deals in recent years. How are you involved in that market, and what potential do you see for it?

Mark Enyedy: Founded in 1981 as a spinout from the then Sidney Farber, now Dana Farber Cancer Institute, ImmunoGen pioneered the field of ADCs with the goal of creating more effective and better-tolerated therapies by exploiting the targeting ability of antibodies to deliver potent anti-tumor agents directly to cancer cells. Over the last 40 years, we have developed one of the industry’s most comprehensive portfolios of ADC technologies, with four products in development and unmatched depth and breadth of expertise in new payloads, linkers, and methods of conjugation.

Mark Enyedy

Our business model initially focused on levering our platform to pursue R&D collaborations with large-cap biotech and pharma companies to deliver ADC development candidates that our partners would advance through the clinic and bring to market. These relationships have produced two marketed products and multiple ADCs currently in development.

• Developed as part of a collaboration with Genentech established in 2000, KADCYLA® (ado-trastuzumab emtansine) was approved in 2013 for the treatment of HER2-positive metastatic breast cancer. This was the first ADC approved for a solid tumor indication and leveraged ImmunoGen’s DM1 payload, and now enjoys blockbuster status with more than $1 billion in annual sales last year, becoming the first ADC to do so.

• While not an ADC, SARCLISA® (isatuximab-irfc, marketed by Sanofi) also employs ImmunoGen technology—our unconjugated anti-CD38 antibody—and is approved for the treatment of multiple myeloma.

When I joined the company in 2016, we transitioned ImmunoGen from a platform model supporting our partners to a company focused on developing and commercializing its own ADCs to capture greater value from our innovation. Today, we are on the cusp of becoming a fully integrated oncology company with the potential to have two ADCs (mirvetuximab soravtansine and IMGN632) on the market by the end of next year.

Looking at the broader market, with targeted anti-tumor activity and favorable tolerability profiles, ADCs are playing an increasingly important role in cancer care, both as monotherapies and in combination with existing and novel agents. To date, FDA has approved 11 ADCs, with more than half occurring in just the last two years as the pace of development has accelerated. Analysts estimate that these therapies alone could generate more than $20 billion in revenue by the end of the decade. With more than 50 companies actively working in the space today, we expect continued innovation and additional near-term approvals, including our two lead programs.

ImmunoGen had a failed Phase III trial in ovarian cancer in March 2019. What did you learn from that experience?

Our Phase III randomized trial compared the safety and efficacy of mirvetuximab soravtansine (mirvetuximab), our anti-folate receptor alpha (FRα) ADC, head-to-head against physician’s choice single-agent chemotherapy, the standard of care in platinum-resistant ovarian cancer, with the primary endpoint of progression-free survival (PFS). From a safety perspective, the results demonstrated that mirvetuximab was well tolerated with a differentiated safety profile. Looking at efficacy, although the study did not meet the primary endpoint, we observed that outcomes were correlated with FRα-expression.

Having a negative outcome in a Phase III study is a punishing experience, but we learned a few things in the process that we have applied to our ongoing registration studies. First, we saw the most benefit in patients with high levels of FRα expression; our ongoing studies include only this population. Second, we had introduced a simplified scoring system to assess FRα expression, but this scoring system inadvertently introduced a population of patients with lower levels of FRα than intended. For subsequent studies, we have reverted to our previous scoring system, which has demonstrated it is a robust and reliable approach to identifying patients. Finally, for our randomized confirmatory study MIRASOL, we have increased the power and used a more conservative design.Taken together, these steps give us a high degree of confidence that the outcomes of our registration program will be positive.

With the benefit of the lessons learned from our Phase III study, we developed a clear view of those patients who benefit most from mirvetuximab and how to best identify those patients. We then worked closely with FDA to design two trials: SORAYA, a single-arm pivotal trial evaluating mirvetuximab monotherapy in women with high FRα platinum-resistant ovarian cancer who have been previously treated with Avastin® (bevacizumab), and MIRASOL, a randomized, Phase III confirmatory trial evaluating mirvetuximab monotherapy in women with high FRα platinum-resistant ovarian cancer who may or may not have been previously treated with bevacizumab.

Despite the Phase III setback in 2019, we have made significant progress with the business and have taken the right steps to advance the mirvetuximab program. With top-line data forthcoming in Q4, we are on the path toward accelerated approval, and with confirmatory data slated for Q3 next year, we look forward to exciting near-term catalysts for the business.

What need does your potential new product in ovarian cancer fulfill?

Each year in the US, roughly 20,000 women are diagnosed with ovarian cancer, and 14,000 will die from the disease. With just a 50% five-year survival rate, ovarian is one of the deadliest cancers affecting women today. Based on our clinical experience, having tested samples from more than 2,000 patients, our data suggest that approximately 40% of ovarian tumors express high levels of FRα, which is the target patient population for mirvetuximab.

Despite advances in earlier-line settings, the majority of ovarian cancer patients relapse and become resistant to platinum-based chemotherapy. Treatment options for these patients are limited, with poor outcomes and diminished quality of life.

Against this discouraging landscape, our goal is to establish mirvetuximab as the standard of care for patients with high FRα advanced ovarian cancer by demonstrating a differentiated safety profile, higher overall response rates, and longer progression-free and overall survival. With positive data from SORAYA, we anticipate mirvetuximab’s initial indication will cover second- through fourth-line patients with high FRα, platinum-resistant ovarian cancer who have been previously treated with bevacizumab. We believe this represents more than 2,000 patients in the US. With confirmatory data from MIRASOL, our label would expand to over 4,000 patients in the US as bevacizumab-naïve patients would also be eligible.

We also continue to generate highly encouraging data supporting the potential of mirvetuximab to become the combination agent of choice for ovarian cancer. We believe the publication of these data, in addition to the mirvetuximab plus bevacizumab cohort published in 2019, could support compendia listing in close proximity to the initial monotherapy approval for mirvetuximab ahead of formal label expansion for this combination.

How have your experiences at Shire and Genzyme helped you in your current role?

Those experiences have proven invaluable to me at ImmunoGen. In roles both as outside counsel and working for the company, it was my privilege to work with and for Henri Termeer for over 20 years at Genzyme. Henri taught me what it meant to be a patient-centric business, the value of culture, and the connection between those two concepts. Working in healthcare is special; we don’t make widgets. Rather, when we succeed, we can make a profound impact on the lives of our patients. It is fundamentally the job of the CEO to remind employees of that connection every day to ensure the delivery of our products to the market with dispatch.

Henri was also Dutch, which meant an intense focus on financial and operational discipline and a global view of product development. I have carried those lessons over to my subsequent roles to ensure that we allocate capital efficiently and execute effectively to reach patients around the world.

In addition, at both Shire and Genzyme, I served as a general manager, which is great training for a CEO role. During my last eight years at Genzyme, we built the Transplant and Oncology business from 50 employees and no commercial products to more than 500 employees with over $800 million in revenue from product sales in more than 50 countries. That experience has proven particularly instructive as we look to transition ImmunoGen to a commercial company with our first two product launches starting next year.

Finally, during my last two years at Shire, I led the Corporate Development team, which included strategy and M&A. During that period, we effected over $50 billion in transactions, which has given me a deep appreciation for the impact that deal-making can have on the transformation of a business.

As a Board member of several biotech companies, what do you think big pharma can learn from biotechs?

No segment of the industry has a monopoly on good ideas or strong execution and, as most recently evidenced by the collaboration between Pfizer and BioNTech, some of the industry’s most prolific outcomes come from combining the strengths of each sector. We have much to learn from each other and, in my view, the keys to success in building a company and collaborating with others are bringing an open mind; valuing innovation, discipline, and rigor; being a bit humble and introspective; and having a good sense of humor. I look to apply these lessons to our business at ImmunoGen and to Boards on which I sit.