Strategy

Henri: N of 1

How the late Genzyme CEO Henri Termeer created the Orphan drug industry

Gaucher’s disease had swollen Brian Berman’s spleen to the size of a basketball and physicians at NIH told the three-year-old’s parents that it had to be removed.

It was 1984, there was no effective treatment for the rare genetic disorder, and the surgery would do nothing to change a prognosis that was grim and certain: years of deformity and unremitting pain relieved only by death.

Brian’s mother knew NIH was collaborating with a tiny biotech company called Genzyme to develop an experimental medicine for Gaucher’s disease. She pleaded with the research team to enroll her son as the first patient in a trial of the experimental enzyme replacement therapy.

Within a few months, the formerly listless boy was racing around the halls of NIH’s clinical center. Brian’s response to the treatment astonished his doctors and delighted his mother. It also transformed the life of Henri Termeer, Genzyme’s president.

Witnessing Brian’s recovery turned Termeer from a man determined to succeed at business into one dedicated to creating life-altering drugs. He needed a successful company do this, and was relentless -- some would say ruthless -- about creating that company. But from the moment he saw an experimental drug bring a child back to life, business became the means and creating life-saving medicines his goal.

“We wanted to make a big difference, not a small difference.”

Henri Termeer

Over the following seven years Termeer pursued the commercialization of what became Ceredase alglucerase with a persistence that at the time looked to many people like irrational stubbornness. His conviction that the therapy could and must be developed -- in the face of clinical evidence that it didn’t work, and despite daunting scientific, financial and regulatory challenges -- was fueled by images of Brian Berman’s exuberance.

In retrospect, the path that led from witnessing a small dying boy regain his life to building a multibillion dollar biotech company looks logical and premeditated. In fact, Termeer had no grand plan, many of his best moves were improvisations, and there were many instances where good fortune intervened to save his company from failure.

As news spread that Termeer had died suddenly on the night of May 12, Berman, now 37 and president and CEO of the National Gaucher Foundation, was among the patients and colleagues who remembered him as a visionary who overcame immense obstacles to launch the Orphan drug industry.

Termeer’s fundamental insight was that drugs for extraordinarily rare conditions had to be priced at levels that made developing them a viable, financially sustainable business. The way he did this was immensely controversial in the 1990s, and that controversy has exploded beyond the boundaries of markets for very rare conditions and has become the biggest challenge facing the biopharma industry.

Termeer was a member of a small group of entrepreneurs who grew a disparate group of fledgling businesses into a biotech industry that has become the world’s biomedical innovation engine. Along the way he pioneered patient-centered drug development, helped forge biotech’s public policy agenda, and inspired a generation of entrepreneurs to pursue the toughest, most important challenges.

A ‘Baxter boy’

Termeer was born in 1946 in Tilburg, the Netherlands, which he described in oral history interviews conducted by the Life Sciences Foundation as the “eighth-largest town in a very small country.”

After setting aside dreams of becoming a chess grandmaster, Termeer’s ambition starting as a teenager was to become a business leader. While studying economics at Erasmus University Rotterdam he traveled to a shoe company in the U.K. to write a thesis about how computers could be applied to inventory control. The company liked the plan so much that it hired him to implement it, so Termeer didn’t graduate.

Termeer learned that American business schools were recruiting international students, enrolled in the University of Virginia’s Darden School of Business and graduated with an MBA in 1973.

He caught the attention of a recruiter from Baxter Travenol Laboratories Inc. (now Baxter International Inc.). The company had created a program to recruit MBAs from leading business schools and fast-track them into senior management positions. In doing so, Baxter inadvertently provided the biotech industry with a cohort of early leaders.

A Harvard Business School study has noted that a disproportionate number of the CEOs of early biotech companies were former Baxter employees. More than one in five biotechs that went public between 1979 and 1996 had what the study dubbed a “Baxter boy” on the IPO team.

Baxter alumni included Gabriel Schmergel, who became CEO of Genetics Institute Inc.; Ted Greene, who when on to lead Hybritech Inc. and later founded Amylin Pharmaceuticals Inc. and Robert Carpenter who jumped from Baxter to become CEO of Integrated Genetics Inc.

17 men and a horse

After a decade at Baxter, in 1983 Termeer received a call from venture capitalists who were backing Genzyme Corp., which at the time consisted of 17 full-time employees, several academic consultants, and a race horse named “Genzyme Gene.”

Genzyme’s funders had an intuition that advances in genetic engineering could be translated into some kind of a business, but had little idea of what sort of business, and no plan for figuring it out.

Creating and executing that plan would be Termeer’s task if he accepted the position as president. He jumped at the opportunity.

“Henri believed you could make important decisions based on an N of 1.”

Richard Moscicki, FDA

Between Christmas 1983 and New Year’s Day 1984, Termeer met with the company’s scientific advisors and founders, including scientists George Whitesides and Harvey Lodish and venture capitalist Sheridan Snyder, to chart a path for Genzyme. In a talk given at the Darden School in 2012, he recalled that the group decided that “we wanted to do important stuff. We wanted to make a big difference, not a small difference. This was about really treating a disease, making a really big disease change, not an incremental difference.”

Crucially, the team also decided Genzyme would be operated on a pay-as-you-go basis and own whatever it created. The company would not serve as a research lab for pharma and it would only take on a project if it could raise sufficient money to see it through to completion.

Henry Blair, one of Genzyme’s founders and a scientist at Tufts University, brought the start-up a contract to supply glucocerebrosidase to NIH researchers who hoped that infusing the enzyme would reverse the symptoms of a rare lysosomal storage disorder, Gaucher’s disease.

The glucocerebrosidase Genzyme supplied to NIH was derived from human placentas.

The NIH team led by Roscoe Brady, who had spent decades unraveling the causes and exploring potential treatments for Gaucher’s, gave millions of units of Genzyme’s glucocerebrosidase to Gaucher’s patients -- and it had absolutely no effect.

Brady determined that it wasn’t getting absorbed, so he and colleagues at NIH and Genzyme came up with a strategy for chemically tweaking the enzyme so it would be preferentially absorbed by macrophages.

Genzyme received a contract to produce the modified enzyme, alglucerase.

Anecdote or n of 1?

Berman was the first patient to receive alglucerase.

After two months of treatment, the young Brian started running around the halls at NIH.

In his 2012 talk at the Darden School, Termeer recalled his reaction. “I can tell you that of all of the things all of us engaged in, those are the moments I remember the most. Those motivated me forever. That moment of saying ‘Wow! It works!’”

But in the early months of the trial, Genzyme had trouble producing enough alglucerase.

Every morning a Genzyme employee traveled to Boston area hospitals in Termeer’s car to collect placentas and lugged them up to the fifteenth floor of the company’s office on the edge of Boston’s “combat zone” red light district. The entire building vibrated when the placentas were spun in centrifuges.

Decades later Termeer remembered that the smell of the human tissue lingered in his car as he drove home.

Termeer watched as Brian’s health improved, declined when supplies of the therapy ran out, and bounced back quickly after Genzyme scraped together another batch. While the experience was hard on Brian and everyone involved with his care, it seemed to add weight to the argument that enzyme replacement worked. Brian was, effectively, his own control.

The NIH researchers quickly enrolled an additional seven adult patients in the alglucerase trial. Not a single one of them benefited from the treatment. The trial report concluded that enzyme replacement therapy for Gaucher’s disease didn’t work.

In 1985, Termeer pulled together Genzyme’s scientific advisors, an eminent group that included Lodish and Whitesides from Massachusetts Institute of Technology (MIT). They told Termeer that Berman’s response was just an anecdote, the patients who had failed to benefit represented the true lack of efficacy, and that it would be foolhardy to risk the company on alglucerase.

Even if it worked, the advisors pointed out it would be next to impossible to collect enough placentas to make commercial quantities of alglucerase. About 22,000 placentas were required to obtain enough enzyme to treat a single patient, so millions of human placentas would be required to treat the 2,000 Gaucher’s patients in the U.S. and the estimated 4,000 to 6,000 in the rest of the world.

Even developing a recombinant version of the enzyme was a waste of time, Termeer’s advisors said, because “gene therapy was just around the corner,” he recalled in the oral history interview. (Of course, more than three decades later, it remains just around the proverbial corner.)

Termeer disregarded their advice.

“Henri believed you could make important decisions based on an N of 1. Brian Berman is a great example,” said Richard Moscicki, deputy director for science operations at FDA’s Center for Drug Evaluation and Research.

Moscicki joined Genzyme in 1992 as medical director and over the next 19 years served as the company’s SVP, head of clinical development and CMO.

“That one boy’s response when other patients were getting less of the enzyme on a per weight basis helped him decide that he should go all in on the development of this,” Moscicki told BioCentury.

Subsequent experience showed that alglucerase doses had to be adjusted by the patient’s weight.

The seven patients who received the enzyme after Brian failed to benefit because they had been given the same dose as a three-year-old.

A mother’s story

To finance clinical development of alglucerase, Termeer decided in 1987 to raise $10 million through an R&D limited partnership. He had four months to get the deal done and traveled the country trying to sell 200 $50,000 warrants.

All of the patients in the U.S. known to have Gaucher’s disease could fit into four 747 airplanes. At a time when biotech companies were creating products for common diseases like stroke and diabetes, few investors could see how such a tiny market could be profitable.

After three and a half months on the road, Termeer was getting desperate. In mid-September he traveled to Albany, N.Y., with Robin Ely, Brian’s mother, to pitch the investment yet again.

Ely was 8 1/2 months pregnant, and after telling the potential investors about Brian’s response to enzyme replacement therapy, she revealed that her unborn child would also have the disease. In the absence of a therapy, her kids’ prospects were bleak.

“There’s nothing more convincing than a mother talking about her child,” Termeer recalled in the oral history interview.

The individuals in the room placed orders, they called their colleagues, and by Oct. 1 the $10 million had been raised.

Two and a half weeks later the stock market crashed. The Dow Jones Industrial Average fell 25% in a single day, cutting off the supply of capital for the foreseeable future. If he hadn’t raised the money through the R&D partnership, Termeer later said he would have given up on alglucerase.

The near-death experience left a mark. Termeer relentlessly raised capital whenever there was an opportunity, aware that the window could slam shut without warning at any moment.

Money alone didn’t solve the logistical nightmare of acquiring access to vast numbers of human placentas.

The answer lay in the Rhône Valley’s vineyards.

“I screamed so loud she could have heard it in Washington without a telephone.”

Abbey Meyers, founder of NORD

It turned out that France, unlike every other industrialized country, obtained blood plasma products from human placentas, not plasmapheresis. The process involved squeezing the placentas on wine presses to extract the liquid. The tissue, which contained the enzymes Genzyme needed to make alglucerase, was discarded.

Genzyme paid the Pasteur Merieux Institute (now part of Sanofi) $5 million to build a plant to process the discarded placentas.

“We processed almost 70 percent of placentas from all births in Western Europe, and 30 percent of placentas from all births in the United States,” Termeer recalled. “They found their way, through mechanisms that are a long, long story to explain, to our plant in this little town in France outside of Lyon.”

The next hurdle was designing the clinical trial.

Termeer was informed that 144 patients would be needed to reliably demonstrate efficacy, and that the trial would have to be placebo-controlled.

He told FDA that Genzyme only had enough enzyme for a 12-person trial, and it would be unethical to include a control group given the absolute certainty that untreated patients would progress. Instead, Genzyme presented data about an unmatched comparator group.

The trial was conducted by NIH researchers. The four adults and eight children in the study all benefited from the treatment.

FDA approved Ceredase in 1991. Because it had been designated an Orphan drug, Genzyme received seven years of market exclusivity.

An audacious price

Celebration in the patient community was tempered by shock after Genzyme announced the price for Ceredase.

The cost of the enzyme to treat an average patient came to about $380,000 annually. And patients would need to be treated for the rest of their lives.

While the price was astonishing, Genzyme coupled it to a unique commitment. Anyone who truly couldn’t afford Ceredase would get it free of charge.

Over the years Termeer made several arguments to justify the price of Genzyme’s enzyme replacement therapies, including the high cost of manufacturing, the need to reward successes to incentivize companies to take big risks, and the inherent value of the medicines.

In 1993 Ceredase was the poster child for drug price control advocates, including then-first lady Hillary Clinton and members of Congress.

Termeer never wavered on the price, or on the company’s commitment to provide its products free to patients who couldn’t obtain them through insurance or other means.

Genzyme’s commitment to provide drug to patients who lacked coverage through insurance did impose a toll on patients, according to patient advocates and the Office of Technology Assessment (OTA), an independent agency that advised Congress.

Ceredase was approved at a time when many private insurance policies had lifetime caps, meaning a policy would be terminated after a patient’s covered healthcare expenses exceeded that limit. If a child taking Ceredase blew through the cap, the entire family could lose coverage.

“Because the vast majority of private health insurance policies impose a limit on total benefits payable for each insuree, somewhere between one-third and one-half of all alglucerase recipients face a significant risk of exhausting or critically reducing their available insurance benefits over time,” OTA reported. “Although Genzyme supplies the drug free to those patients who exhaust (or otherwise lack) insurance benefits, for the rest of their lives such patients remain uninsured for the cost of administering alglucerase and any other medical expenses they may incur.” (Editor’s note: Italics in original).

Abbey Meyers, the founder of the National Organization for Rare Disorders (NORD), was a fierce critic of Genzyme’s pricing of Ceredase.

Lisa Raines, the head of Genzyme’s Washington office, said the price reflected the company’s heroic and expensive efforts to obtain and process millions of placentas, Meyers told BioCentury in an interview after Termeer’s death.

Meyers said she had expected the price to be reduced when FDA approved Cerezyme imiglucerase, a recombinant form of Ceredase, in 1994.

“I got a call one day from Lisa saying ‘you’ll be so proud of me. We just got the biotech version approved by FDA and I convinced Henri not to charge more for the biotech drug,’” Meyers recalled. “I was standing in my office in Connecticut and I screamed so loud she could have heard it in Washington without a telephone. I was so furious.”

Her fury was fueled by stories from desperate families, Meyers said. “I heard from people who were denied because Genzyme said their income was high enough to afford another insurance policy, or that they could afford the $5,000 deductible. These things still hurt today.”

Berman, who cinches a tourniquet with his teeth and self-infuses Cerezyme at home every two weeks, told BioCentury that the system works for Gaucher’s patients in the U.S.

“Companies do a good job making sure people are taken care of,” either through insurance or free drug programs for the uninsured, he said.

Nevertheless, patients think about the cost of their treatment -- and the consequences of losing access, he said.

“On the one hand, we are flabbergasted by the price of these drugs,” Berman said. “On the other hand, I went to the funeral of a young man who was born five years before me and didn’t have access” to an enzyme replacement therapy. “In that context it is hard to keep a level head. This is life or death for us.”

Termeer contended that because Cerezyme and other drugs for very rare conditions affected so few patients, healthcare systems and society as a whole could absorb high prices. And, he argued, those prices would serve as incentives for companies to continue creating life-saving treatments for the rarest diseases.

While she still doesn’t think Cerezyme’s pricing or the prices of other enzyme replacement therapies are fair, Meyers concedes Termeer unleashed a tidal wave of R&D by setting a high price.

“Other companies looked at Cerezyme, a drug that could only be used for a disease that maybe affected 5,000 patients worldwide, and they saw that he’s making billions of dollars,” she said. “So the rest of the industry said there’s gold in them thar hills. That did attract the industry to Orphan drugs that didn’t have alternate uses.”

Before Ceredase, there was no business model that would support investment in the science needed to create therapies for patients with very rare diseases unless the medicines could be used for other, more common conditions.

Richard Pops, chairman and CEO of Alkermes plc, credits Termeer with making the Orphan drug industry possible by pricing Genzyme’s therapies at a level that made it clear that creating drugs for rare diseases was a business endeavor, not charity.

Pops worked with Termeer on product development financing in Genzyme’s early days.

“In my mind reasonable people can have disagreements about whether the pricing is correct or not, but it is inarguable that what he did with Ceredase and Cerezyme ushered in a new era of discovering medicines for Orphan diseases that didn’t exist before,” Pops told BioCentury.

“I believe unequivocally that [the pricing of Ceredase] was definitely the most important event for the Orphan disease community,” said David Meeker, who is EVP and head of Sanofi Genzyme.

Termeer “gave not only Gaucher patients hope when he priced the drug where he did, he gave all rare disease patients hope,” Meeker told BioCentury.

According to Meeker, Genzyme’s precedent has been misunderstood and the underlying premise has been distorted.

“The pricing and the model was about rare disease. It wasn’t about any drug with an Orphan designation instantly being eligible for very, very high prices,” he said.

Meeker noted that the economics of pricing a drug with a total market of a few thousand patients worldwide differs substantially from the pricing of a drug that qualifies as an Orphan and treats a condition that affects hundreds of thousands of patients.

Termeer often was heard to say that if it were possible to create a medicine to treat a serious condition, there was a moral imperative to make it happen. “Henri felt that if the science provided the solution, then the genie was out of the bottle, you had to do this,” Moscicki told BioCentury. “We as a society had no choice but to provide those solutions for these people.”

That imperative included paying prices that were high enough to sustain businesses like Genzyme’s.

Moscicki recalled that he decided to leave an academic career to join Genzyme because Termeer “was a man I could really work for and be comfortable with. He was a charismatic visionary. He was an optimist, and he cared deeply about patients.”

Termeer “saw the importance of biotechnology and the industry which was still young at that time,” Moscicki said. “He felt strongly that it was important for biotechnology to move forward because it was willing to take risks that large pharma at that time wasn’t willing to take.”

“It wasn’t about making money or his ego. He truly believed these medicines were important,” Pops told BioCentury. “I never heard Henri gushing about the science for its own sake. It was all about the medicines.”

The Cost of Miracles

The need to defend the price of Ceredase and Cerezyme forced Termeer to focus on Washington at a time when most biotech companies had little or no interest in public policy.

In the fall of 1993 the Clinton administration was proposing the creation of a committee to review and approve the prices of breakthrough drugs as part of its healthcare reform program. Separately, Congress was holding hearings on drug prices.

Termeer pushed back in a commentary The Wall Street Journal published in November 1993 under the headline “The Cost of Miracles.”

“The real danger,” he wrote, “is not that the prices of new drugs will be too high, but that government controls, whether direct or indirect, will discourage investors from taking risks on biotechnology companies that develop new drugs.”

“The pricing and the model was about rare disease. It wasn’t about any drug with an Orphan designation instantly being eligible for very, very high prices.”

David Meeker, Sanofi Genzyme

Termeer cited Genzyme’s experience with Ceredase. “The CEO of another major biotechnology company had considered and rejected the idea of developing a treatment for such a rare disease because he could not imagine how his company could get an adequate return on a product intended for a few thousand patients,” he wrote.

Termeer also portrayed Genzyme’s hold on the Gaucher’s disease market as tenuous.

“Today, companies such as mine that develop breakthrough drugs can expect to have meaningful market exclusivity for only a few years.” He argued that patent protection or Orphan exclusivity did not “preclude others from designing and selling substantially similar products.”

In fact, Cerezyme sales peaked at $1.2 billion in 2008, before Genzyme suffered debilitating manufacturing setbacks in addition to the entry of Vpriv velaglucerase alfa from Shire plc and Elelyso taliglucerase alfa from Pfizer Inc. and Protalix BioTherapeutics Inc. Cerezyme booked $789 million in sales in 2016.

Taming the lion

Termeer’s public policy profile expanded in 1993, when two fractious biotech trade associations merged to form BIO. Termeer was elected as the new organization’s first vice chairman for health and in 1996 became chairman.

To fend off congressional attacks on the pricing of Ceredase, Cerezyme and other drugs, Termeer invented tactics that have become part of biopharma’s playbook in Washington.

“He built an architecture where every interested party would go in and weigh in,” said Carl Feldbaum, BIO’s first president. “It was a multi-layered, multidimensional army that went in on his behalf. He invented that.”

“When he went up on Capitol Hill, he was the point man, the top of the pyramid,” Feldbaum said. “He had the patients, their parents, the nurses, the docs, the hospital organizations coming in before him and plastering the Hill with the story of why this or that had to happen. He came in to close the deal.”

In those days Massachusetts Sen. Ted Kennedy, known as the Lion of the Senate, was the most important politician for the biotech industry. Kennedy was skeptical of industry, but Termeer persuaded him that patients would suffer if government enacted policies that disincentivized drug R&D investment.

“He had Ted Kennedy in his thrall,” Feldbaum remembered.

In addition to Congress, Termeer understood the importance of FDA and devoted enormous attention to supporting and improving the agency. He led BIO’s negotiations on the reauthorization of PDUFA, forging a close relationship with then-FDA Commissioner David Kessler.

The PDUFA reauthorization effort resulted in additional financial resources for FDA, but more importantly, it was coupled to the FDA Modernization Act of 1997, a bill that created FDA’s fast track procedures for accelerating the review of drugs for serious unmet medical needs.

Feldbaum remembers Termeer as improvisational, irrepressible and inspirational. But while he was extraordinarily organized, Genzyme’s leader had little use for detailed plans.

“This is a guy who told me, ‘If you have a strategic plan, put it in your desk drawer, I don’t want to see it,’” Feldbaum told BioCentury. “He left all his options open all the time. He could pivot on a dime.”

Patient-centered before it was cool

Developing, testing and selling products to small populations created an intimacy between Genzyme and its patients that was completely foreign to companies outside the rare disease space.

“Henri created a culture that was patient-centered long before any other company was talking about being patient-centered,” Moscicki said.

“In the rare disease world it is almost possible to know the name of every patient you are treating,” he added. “It becomes very personal. Patients would visit Genzyme. People had pictures of patients at their desks and in the hallways, so you knew that what you were doing was directly impacting patients you had met. That created a very different sense of mission” from other companies.

“He was very focused on the individual patient who was depending on our innovation,” Meeker recalled. “He made you focus on the patient as an individual.”

A quality failure

Ceredase, Cerezyme, and enzyme replacement therapies for other lysosomal storage disorders were only part of a broad portfolio of products and services Genzyme commercialized under Termeer’s leadership.

Along with the successes, there were expensive failures, including attempts to develop gene therapy for cystic fibrosis and cell therapy for Parkinson’s disease.

There was also an almost bewildering display of financial engineering, including a period in which three Genzyme entities each traded as individual tracking stocks, an arrangement which ended in 2003.

In 2001, 19 years after it was founded, Genzyme’s annual sales reached $1 billion. In 2008 sales hit $4.2 billion.

But Genzyme didn’t build manufacturing capacity fast enough to keep up with demand. Inventories dwindled, and the company decided to manufacture two additional products at its flagship facility, a plant in Allston, Mass., that had been built to make Cerezyme. A factory that was the physical embodiment of Genzyme’s accomplishments -- it looks more like a cathedral than a factory -- became a disaster scene.

FDA started ringing alarm bells in October 2008, warning Genzyme of manufacturing quality problems at the Allston plant.

Disaster struck in June 2009 when Genzyme discovered that a virus, Vesivirus 2117, had invaded bioreactors at the facility. The virus wasn’t harmful to humans, but it impaired the growth of the Chinese hamster ovary (CHO) cells used to produce Cerezyme and Fabrazyme agalsidase beta for Fabry’s disease.

Termeer made the decision to close Allston and have it taken apart, cleaned, disinfected and put back together. Because the company had been running flat out to keep up with demand, the interruption meant it would be unable to meet its commitments to patients.

Gaucher’s disease patients were hit hardest. Cerezyme had to be rationed and despite the availability of alternative products, some experienced worsening of symptoms, according to several published reports.

By the end of 2010 Gaucher’s patients had returned to normal dosing levels, but supply shortages continued. EMA continues to include Cerezyme on a drug shortages list. Fabry’s disease patients faced shortages of Fabrazyme until March 2012 and EMA didn’t remove the drug from its shortage list until July 2016.

Ultimately, the U.S. government forced Genzyme to pay a $175 million penalty and enter into a consent decree that put control of the facility in a third party’s hands.

Patients’ confidence in Genzyme was shaken, and so was Wall Street’s. The company’s market cap fell $4.4 billion (27%) from the day before disclosure of FDA’s first warning letter related to the plant to the final consent decree deal.

The weakened company became a target.

Activist investor Carl Icahn disclosed in November 2009 that he held 1.5 million shares of Genzyme Corp., a 0.6% stake in the company. At the time, the company’s shares had fallen about 40% from mid-August 2008, and was down around 25% on the year.

In February 2010, Icahn announced he would nominate himself and three others for election to the company’s board.

Termeer settled on a strategy of fighting an activist with an activist. Genzyme named activist investor Ralph Whitworth to its board in April and agreed to appoint another director chosen by Whitworth at an upcoming shareholder meeting.

Icahn took the gloves off in May, stating in a proxy submission to the SEC that Termeer was among three directors he planned to replace on the Genzyme board. Icahn upped his stake in the company to 3.9%.

By June Termeer had come to terms with Icahn, working out an arrangement for the company to retain all of serving board members, including Termeer, and enlarge the board by adding two of Icahn’s nominees.

The peace didn’t last. In the summer of 2010, Sanofi announced a hostile bid to acquire Genzyme after private efforts to reach a deal were rebuffed.

Looking back on it in a Life Sciences Foundation interview, Termeer said the “strategic fit of the two companies was obvious. Once it was clear that [Sanofi CEO Chris] Viehbacher wasn’t going away, it was really a matter of price.”

After nine months of haggling about the company’s value, Sanofi won Termeer’s crown jewel in 2011 for $20.1 billion plus a contingent value right (CVR). The CVR, originally valued at up to $14, has missed its first three milestones but has up to $11 in possible payments remaining. It closed on NASDAQ at $0.40 on Friday.

A busy time

Termeer stayed on for a few months to help with the transition. But he wasn’t the retiring type.

After leaving Genzyme, he remained active and visible as a co-founder, investor and director of biotech companies that pursued innovation from cystic fibrosis to autoimmune diseases (see “Life After Genzyme”).

Everyone who spoke to BioCentury had expected Termeer to continue his life’s work for many years. As time dulled the edges of their disputes and provided perspective on the magnitude of his accomplishments, some individuals who had been adversaries expressed deep sadness at Termeer’s death -- and disappointment that he hadn’t had the opportunity to create more new medicines.

“I was expecting him to make a few more miracles,” Meyers said.

Companies and Institutions Mentioned

Abiomed Inc. (NASDAQ:ABMD), Danvers, Mass.

Alkermes plc (NASDAQ:ALKS), Dublin, Ireland

Arrakis Therapeutics Inc., Waltham, Mass.

Artax Biopharma Inc., Cambridge, Mass.

Aura Biosciences Inc., Cambridge, Mass.

Aveo Pharmaceuticals Inc. (NASDAQ:AVEO), Cambridge, Mass

Baxter International Inc. (NYSE:BAX), Deerfield, Ill.

Biogen Inc. (NASDAQ:BIIB), Cambridge, Mass.

Biotechnology Innovation Organization (BIO), Washington, D.C.

Erasmus University Rotterdam, Rotterdam, the Netherlands

European Medicines Agency, London, U.K.

Exelixis Inc. (NASDAQ:EXEL), South San Francisco, Calif.

Genzyme Corp., Cambridge, Mass.

Life Sciences Foundation, San Francisco, Calif.

Lysosomal Therapeutics Inc., Cambridge, Mass.

Massachusetts General Hospital, Boston, Mass.

Massachusetts Institute of Technology (MIT), Cambridge, Mass.

Moderna Therapeutics Inc., Cambridge, Mass.

National Gaucher Foundation, Rockville, Md.

National Institutes of Health (NIH), Bethesda, Md.

National Organization for Rare Disorders (NORD), Danbury, Conn.

Partners HealthCare Systems Inc., Boston, Mass.

Pfizer Inc. (NYSE:PFE), New York, N.Y.

ProQR Therapeutics N.V. (NASDAQ:PRQR), Leiden, the Netherlands

Protalix BioTherapeutics Inc. (NYSE-M:PLX; Tel Aviv:PLX), Carmiel, Israel

Regulus Therapeutics Inc. (NASDAQ:RGLS), San Diego, Calif.

Sanofi (Euronext:SAN; NYSE:SNY), Paris, France

Shire plc (LSE:SHP; NASDAQ:SHPG), Dublin, Ireland

Tufts University, Medford, Mass.

University of Virginia, Charlottesville, Va.

U.S. Food and Drug Administration (FDA), Silver Spring, Md.

X4 Pharmaceuticals Inc., Cambridge, Mass.

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