Long before the word “multitasking” morphed from the world of IBM mainframe computers to human behaviors, Arthur Sackler had an innate ability to juggle multiple projects simultaneously. While engrossed in the New York art world, he remained as busy as ever with Purdue Frederick, medical advertising, and publishing. There was a sea change under way in some key aspects of the pharmaceutical industry. He and his brothers monitored it closely; they did not want to be left behind.
Nixon had declared a “war on cancer” and Congress responded with the National Cancer Act in 1971. Oncology did not exist as a medical specialty and doctors knew remarkably little about the disease they were tasked to cure. Well into the 1970s, most physicians thought cancer was a single disease, defined by the organ in which it was discovered (for instance, breast or brain or lung cancer). No one understood the role gene mutations played. Today, cancer is recognized as approximately two hundred different and distinct diseases, each identified by unique molecular alterations, no matter where in the body it is found.1
The drug industry had been mostly a bystander in cancer treatment. The prevailing medical wisdom was that cancers could not be cured. However, the federal government’s “war on cancer” created a big inducement for pharma: a lot of available research money. A year after Congress passed the act, the National Cancer Institute budget exceeded a billion dollars for the first time (the NCI’s first budget in 1950 was a measly $2.1 million).2
Eighty-five percent of the new funding went to investigator-initiated research, mostly clinical testing for advanced chemotherapy drugs. Some promising earlier studies that had stalled for lack of funding restarted.3 Those trials demonstrated that for early stage breast cancers chemotherapy after surgery was far more effective in eradicating tumors than either chemo or surgery alone.4 Two follow-up studies showed the same was true for colorectal and testicular cancer.5
Some Arthur Sackler–minded promotion executives tried euphemistically calling chemotherapy “anti-tumor antibiotics.” It never stuck. Seven new chemos, however, were developed from the new research, and the first reached the market in 1973.
The federal funding also led to breakthroughs outside of drugs. New diagnostic tools included colonoscopies for the early detection of colorectal cancer and CT scans and improved mammography for more precise tumor images. There was also noticeable progress on less invasive treatments once cancers were diagnosed. Radioactive seeds to treat prostate cancer replaced some surgeries, as did limited mastectomies for early stage breast cancer and targeted radiation for testicular cancer.6
The significance of some of the findings would not be apparent for a decade or more. Monoclonal antibodies, for instance, a technology for identical copies of an immune cell, was discovered in the lab in 1975. (It was not until the 1990s they were proven clinically useful in boosting the body’s immune response to fight some cancers; the two scientists who discovered them won the Nobel in Medicine.)
Although many of the 1970s cancer treatments seem rudimentary in comparison to the targeted gene therapies that arrived decades later, the burst of research on the causes and treatments of cancer laid the foundation for what ultimately became significantly longer survival prognoses and lower death rates.
Not every drug firm was interested in producing a cancer drug. Some had grand ambitions in unrelated fields. Squibb had begun investigating in 1968 whether it was possible to create a synthetic compound that mimicked the peptides found in the venom of a poisonous Brazilian viper. It caused a fatal drop in blood pressure. Researchers discovered that the venom inhibited the production of a kidney chemical that regulated blood pressure. Squibb’s researchers tested hundreds of chemical compounds before making a breakthrough in 1974 when they synthesized a molecule that mimicked the viper venom. They had put it together atom by atom.7 The result was an orally active drug that in clinical trials showed promise at controlling blood pressure and treating congestive heart failure.
When Squibb put Capoten (captopril) on sale, it was the first ever ACE inhibitor.8 Before its introduction, the medical advice for patients with congestive heart failure had been bed rest, diuretics (to help the heart pump fluid from the body), and digoxin (to relieve chest pain). Capoten was not a cure but it reduced the mortality rate and improved the quality of life for most patients.9 Within a decade, half a dozen other pharma companies marketed competitive ACE inhibitors, transforming what had been a nonexistent market to more than 150 million annual prescriptions.10
While ACE inhibitors were big news, they paled in comparison to a new blockbuster class of medications targeting peptic ulcers. Doctors had for years known that ulcers, at times painful and in some cases deadly, were caused by excess acid in the digestive tract. Researchers were stumped, however, in how to treat them. The bland diets advised by most doctors did little to help. Over-the-counter alkalis, like Alka-Seltzer, provided temporary relief.11 In severe cases, surgeons removed part of the stomach in the hope they excised the ulcerated portion.12
Ulcers were one of the conditions for which Sackler and Roche had pushed the limits of what the FDA had approved as the indications for its benzodiazepines. However, since the early 1960s, a growing number of researchers believed that the culprit was organic rather than emotional. They had discovered a single histamine molecule activated the production of acid when it locked on to a receptor in the stomach lining.13 Doctors were familiar for decades with histamines, hormones produced by the immune system. They were mostly protective but sometimes caused inflammation, increased heart rate, allergies and hay fever, even pulmonary complications. A Swiss doctor, Daniel Bovet, had won the Nobel in Physiology and Medicine in 1957 because of his pioneering work in isolating and producing “histamine antagonists” (antihistamines to the lay public).14
A group of Smith Kline researchers knew that nothing stopped the histamine-stimulated acid that caused peptic ulcers. The team was led by Dr. James Black, a Scottish pharmacologist and physician. Black had won fame for developing the first beta blocker in 1962 while he was researching the effects of adrenaline on the heart (his discovery, called propranolol, was the first drug capable of controlling high blood pressure). Smith Kline had asked Black to find a cure for ulcers. That meant discovering, isolating, and then synthesizing an effective histamine antagonist. The problem was that the histamine responsible for ulcers bound itself to a type of receptor (the H2) that did not respond to antihistamines. After five years, in 1968, they had created more than seven hundred chemical composites but had nothing to show for their efforts.15
No one had ever produced a medication with a targeted biological pathway. The project was spared cancellation at the last moment when Black’s team isolated some minor antagonist properties on a retest of one of their early compounds. It took another two years (1971) before the project produced a drug called metiamide. Black marveled as the ulcers on most test patients completely healed over several weeks of clinical trials in 1973. However, a third of those patients developed a serious blood disorder. Their white cells plummeted and made them susceptible to infections.16 Back in the laboratory, Black’s team made molecular alterations that produced a close chemical cousin to their original compound.17
Black and his researchers team gave it the generic name cimetidine. It passed clinical trials as effectively as had its predecessor in healing ulcers. This time there were no adverse effects. With a trouble-free approval process from the FDA, Smith Kline put Tagamet on the market in November 1976 in the U.K. and the following year in America (Smith Kline chose TAG from antagonist and MET from cimetidine). It was a panacea for the millions suffering from peptic ulcers. Tagamet set a new standard by which to define a blockbuster. Black won a Nobel in Medicine. And Smith Kline was rewarded with spectacular profits. Tagamet became the first drug in history to sell a billion dollars in a single year.18
The receptor site medications would in another decade result in a series of other breakthrough drugs, including statins to lower cholesterol, nucleoside reverse inhibitors for HIV-AIDS, proton pump inhibitors for gastrointestinal reflux, and selective serotonin reuptake inhibitors for depression.19 However, before the next wave of receptor site drugs arrived, research under way in northern California was about to open a window into technological and scientific advances that would be much more important for the pharmaceutical industry than any single blockbuster.
Since the discovery of penicillin, drug innovation in the laboratory had been a hit-and-miss process grounded in organic chemistry. Laboratories operated by so-called random drug discovery. Backbench scientists spent months looking for signs of biological activity in plants, soil, or other natural sources. The molecules that showed some possibility were isolated as potential compounds. For every 5,000 of those, 250 on average got to the next stage, testing on lab animals. That eliminated another half. Of the drugs that began human clinical studies, only 20 percent got FDA approval for sale to the public.20
In 1971, a Stanford biochemist, Paul Berg, developed a gene-splicing technique called recombination. Berg created a molecule from two different species (the results were not published until October 1972).21 A year later, another Stanford professor, Stanley Cohen, teamed with Herbert Boyer, a University of California at San Francisco biochemist. They relied on Berg’s gene-splicing method to clone genetically engineered organisms in foreign cells. The modified cells began replicating the new DNA as if it were its own. It was the birth of recombinant DNA (rDNA) technology.22 Scientists mark the Cohen-Boyer discovery as the official beginning of genetic engineering. It kicked off a biotechnology revolution.
Many researchers, though, worried that there were unknown dangers to inserting rDNA from one organism to another. The science was moving fast and there were no restrictions on what could be done in a lab. What if some rDNA molecules later proved biologically hazardous? Much of the early focus was on E. coli, the intestinal bacterium that in one strain causes food poisoning. Its small genomic size, uncomplicated single set of chromosomes, and fast replication rate made it a versatile host for a range of recombinant DNA research. Would E. coli exchange genetic data with pathogenic bacteria, leading to unforeseen results in the gene combinations that might unintentionally unleash a human catastrophe?
The National Academy of Sciences’ newly created Committee on Recombinant DNA Molecules comprised eleven of the world’s leading biotech researchers, including Cohen and Boyer. Paul Berg was its chairman. In the July 1974 issue of Science, they signed a remarkable open letter titled “Potential Biohazards of Recombinant DNA Molecules.” It warned of “emerging capabilities” risked the “creation of novel types of infectious DNA.” One danger was if the rDNA in the lab contained a cancer-causing gene that metamorphosed into a transmissible human bacterium.23
A moratorium on genetic engineering went into effect.24
The Sacklers were convinced that the milestones in genetic research held the promise of big returns for any pharmaceutical company that could master recombinant DNA. They agreed to watch for opportunities so they might participate as investors. Writing a check to back a start-up was the most they could do. The brothers were barely keeping up with their own business demands.
The eldest sons of Arthur and Raymond found a way to have more time with their fathers. They went to work for them. Raymond’s twenty-nine-year-old son, Richard, joined Purdue in 1971. He was also a physician, having graduated from New York School of Medicine and passing the licensing exams in both New York and Connecticut. Just before starting at Purdue with the newly created position “assistant to the president,” he took Harvard Business School’s intensive two-week Management Development Program. It was a crash course in how to hone “the skills to succeed in complex roles and shifting institutional and cultural landscapes.” One of his first assignments was dealing with the FDA’s determination that an antibiotic Purdue had in one of its eardrop products was not potent enough to treat any infection. The FDA recalled those drops. Purdue blamed the manufacturer, Yonkers-based Bard Pharmaceuticals, which was covertly owned by the Sacklers.
As for Arthur, his son, Arthur Jr., had decided after graduating from Wisconsin’s Lawrence College to join the family business. Arthur put his son to work in the McAdams marketing department. As opposed to Richard, who flourished under his father’s guidance at Purdue, young Arthur was not as driven as his father and had difficulty meeting the high expectations set for him. Marietta thought that Arthur was too hard on his son. Soon he left McAdams and joined Medical Tribune. When that did not work out, Marietta arranged for her family firm, Dr. Kade Pharmaceutical, to sponsor Arthur Jr. for a certificate program in business administration at NYU. Following that, he accepted a director’s position at Dr. Kade.25
Both sons knew how hard their fathers worked. There had been long periods growing up when they saw little of them. Still, it was not until they became employees that they realized how much was on the brothers’ to-do list. Along with many other drug companies, the Sacklers were looking into opening a branch in Puerto Rico. A change in the tax code in the early 1970s exempted manufacturing firms from corporate income taxes on profits made in U.S. territories.26 “There was a rush by many drug companies to set up manufacturing plants there,” said Richard Sperber, a former Glaxo and Wyeth marketing director. “They would make the active substance of their drugs in Puerto Rico, then jack up the price and ‘sell’ it to another subsidiary that put it into final dosage form. Because the price on the drug’s active ingredient was so expensive, little if any profit was earned. All the real money was at the untaxed manufacturing source.”27 In a few years the Sacklers opened Purdue Pharma in the capital of San Juan.I
The brothers, however, had bigger ambitions than creating subsidiaries to take advantage of changes in the tax code. They had long been interested in innovative delivery systems for oral and rectal medications. In the 1960s they had started researching technologies that might slow the rate at which a drug dispersed in the body, a rudimentary time release formula.28 The author discovered ten patents Raymond and Mortimer had filed related to sustained release formulas for suppositories and tablets. The Sacklers were not alone. Plenty of pharmaceutical companies were pursuing some type of controlled release for medications.29
In 1969 and 1970, the Sacklers had also put the biochemists and pharmacologists at Mundipharma AG, their Swiss-based company, on a project to develop a time release technology. Mortimer and Raymond assigned all their 1960s patents to Mundipharma in Basel. That was also true of the legal rights for a co-inventor on four of those patents, Dr. Alfred Halpern (Halpern worked at Arthur Sackler’s Pharmaceutical Research Associates, at 17 East 62nd Street, the address listed for half a dozen other Sackler businesses).30
The patents assigned by the Sacklers helped the Mundipharma team make progress in the lab. In 1971, Mundipharma filed for its own patent. The filing attracted little attention, even inside the pharma industry. As with many medical and science-related patents, it had a virtually indecipherable name: “Slow Release Formulation for Pharmaceutical Composition Containing a Fusible Carrier and Method for Producing the Same.” Mundipharma soon filed two related patents for “Composition in Solid Dosage Form.”31
That patent, and the underlying Mundipharma research, was the ideal complement to research then under way at two U.K. Sackler companies, Napp Pharmaceuticals and Bard Laboratories. The following year, Napp developed the first working compounds that the Sacklers believed might be adaptable as a controlled release formulation applied to oral medications.32
The value of those Mundipharma patents, combined with others Napp subsequently filed, would not be evident until 1980 when Napp introduced a drug that had the first-of-its-kind sustained release coating. It was an invisible-to-the-human-eye chemical layer made of a dual-action polymer mix that turned to a gel when exposed to stomach acid. That allowed the drug, MST Continus (continuous), to release pure morphine at a steady rate over twelve hours.33 Napp could adjust the release rate by fine-tuning the density of the coating’s water-based polymer.34
MST Continus was the breakthrough painkiller for which Cicely Saunders had been searching for her end-of-life cancer and hospice patients since the mid-1960s. Its coating was also the technology that in the 1990s would help convert Purdue’s opioid painkiller, OxyContin, into a much more widely prescribed medication. Doctors expected that a sustained release narcotic was less prone to addiction and abuse.
I. Mortimer hoped that his twenty-year-old son, Robert, would also work for the family when he graduated from college. He died in an accident in 1975, at the age of twenty-five.