The role of serendipity in drug discovery is well-recognized, the canonical example of which is Alexander Fleming’s 1928 discovery of penicillin in the bacteria-free circles surrounding mould on an agar dish. However, luck also plays a significant role in drug development.
After reading up on the history of some of the most (financially) successful drugs of all time, I was struck by how often chance events made the difference between success and failure, and how often the programs that went on to define a company were underappreciated for long periods of time. Often the only thing keeping these programs alive was the fierce advocacy of a few true believers.
On this page I’ve collected some of the more interesting examples of “unplanned successes” and initially underappreciated blockbusters, which I will update as a I find more. I recommend reading the full stories linked in the sources.
Keytruda (pembrolizumab) for multiple oncology indications
Global product revenue: $14,380m (2020)
Companies involved: Organon, Schering Plough, Merck
Merck seems as if they can do no wrong with Keytruda; the drug is effective against almost every solid tumour, benefits thousands of patients a year and is soon to be the highest revenue drug in the world.
However, as David Shaywitz says in the (highly recommended) article linked below:
“The success of pembro was anything but inevitable. It was discovered accidentally, by biotech scientists looking for drugs that would tamp down the immune response in patients with autoimmune disease, and would stimulate, not block, PD1. Even after a potent PD1 inhibitor was identified and recognized as a potential cancer drug, the research program had to fight for funding through two mergers and acquisitions. After the program finally wound up at Merck, in 2009, it was considered such a low priority that it was shut down and placed on the out-license list. A term sheet (valuing the program at next to nothing) was reportedly in place, but pulled at the last minute, as promising results from competitor Bristol-Myers Squibb (BMS) motivated a reconsideration of the mechanism.”
Revlimid (lenalidomide) for multiple myeloma (MM)
Global product revenue: $12,153m (2020)
Companies involved: Celgene
In 1991, years after the thalidomide scandal and its withdrawal from the market (1961 in Europe1), Dr. Gilla Kaplan’s experiments at Rockefeller university demonstrated a potential role for the disgraced drug in the treatment of HIV/AIDS. Following this proof of concept, Celgene in-licensed thalidomide from Rockefeller, eventually obtaining approval for leprosy in 1998 (an indication with a historical precedent dating back to a 1971 WHO-sponsored trial2).
Independently of Celgene, Beth Wolmer sought out a treatment for her husband Ira’s multiple myeloma, and based on discussions with researchers and her reading of the medical literature, persuaded their hematologist Bart Barlogie to try thalidomide. While it unfortunately didn’t work for Ira, Dr. Barlogie went on to try it in 84 other patients with impressive results3.
After seeing the results of Dr. Barlogie’s trial, Celgene funded additional trials and developed lenalidomide, a structural analog of thalidomide. In 2006, both thalidomide and Revlimid were FDA approved for multiple myeloma. Revlimid subsequently became the new standard of care in multiple myeloma, and one of the highest revenue drugs of all time.
However, the story of these compounds doesn’t end there. Despite decades of use, the unique mechanism of action of thalidomide analogs as a recruiter of E3 ubiquitin ligase and driver of proteosomal degradation was only recently elucidated4. This discovery has inspired a new and promising class of targeted protein degraders that may allow the drugging of previously “undruggable” targets in the near future.
Herceptin (trastuzumab) for HER2+ breast cancer
Peak annual global product revenue: $7,137m (2018)
Companies involved: Genentech, Roche
In the late 1980’s Herceptin was controlled by Genentech but development had stalled - oncology research was ironically a low priority at the time. Little development progress was made until a Genentech senior VP’s mother was diagnosed with breast cancer, upon which they became a champion for further investment in the product. After a successful phase 3 Roche finally opted to license the drug after passing on it twice before, despite modest revenue expectations at the time. Roche only changed their mind on the opt-in once it was clear that other companies were interested in acquiring it, as told by Rod Ferguson who led Herceptin’s outlicensing auction in 1997:5
Roche, which at that time owned and controlled Genentech, passed on this product not just once but twice. We had letters from Roche insulting us, telling us that Genentech was so stupid, that we should have killed this product off years before and this was a mistake.
Ibrance (palbociclib) for breast cancer
Global product revenue: $5,392m (2020)
Companies involved: Warner-Lambert/Parke-Davis, Pfizer
Palbociclib, known internally as PD-0332991, was synthesized internally at Parke-Davis in 2001 as part of an effort to make selective inhibitors of cyclin-dependent kinases (CDK) to treat cancer. While many other CDK’s were in already trials, they were non-selective, toxic and weakly effective - dampening enthusiasm for the class.
After a series of mergers in which Pfizer acquired Warner-Lambert/Parke-Davis (primarily for Lipitor) and Pharmacia, palbociclib was lost in the post-acquisition strategic reprioritizations and site closures. In 2004, Pfizer ran a phase 1 trial of palbociclib but didn’t conduct a follow-on phase 2, citing a lack of antitumour effect. Pfizer finally started clinical development proper with a phase 2 in 2009, after the UCLA oncologists Dennis Slamon and Richard Finn reported promising results with palbociclib in a small investigator initiated trial enrolling 12 patients with ER-positive metastatic breast cancer. Following compelling data from Pfizer’s phase 2 trial, Ibrance received an accelerated FDA approval in early 20156.
Soliris (eculizumab) for paroxysmal nocturnal hemoglobinuria (PNH)
Global product revenue: $4,064m (2020)
Companies involved: Alexion
Alexion was founded in 1992 to develop C5 complement inhibitors “for the treatment of autoimmune and cardiovascular diseases”7. At the time of their 1996 IPO Alexion was developing the short acting C5 inhibitor 5G1.1-SC and the long acting eculizumab (then known as 5G1.1)7. Although it is now the archetypical example of a high-priced rare disease drug, eculizumab started out as a potential treatment for relatively common “chronic disorders such as nephritis and rheumatoid arthritis”7.
2003 to 2004 was a pivotal period for the company, with 5G1.1-SC failing key trials in coronary artery bypass graft surgery8 and eculizumab disappointing in rheumatoid arthritis and membranous nephritis9. Facing bankruptcy, Alexion pivoted to PNH after promising results from an 11 patient open label study10, which eventually led to the FDA approval of Soliris in 2007 and initiated Alexion’s rare disease focused business model. Notably, it was the advocacy of the external hematologist Dr. Peter Hillmen and the Alexion scientist Russell Rother which persuaded the company to run trials of eculizumab in PNH, despite skepticism from the CEO that the PNH market would be big enough to secure a return on investment11.
Sources: Alexion SEC filings, How A $440,000 Drug Is Turning Alexion Into Biotech’s New Innovation Powerhouse
Velcade (bortezomib) for multiple myeloma (MM)
Peak annual global product revenue: $3,103m (2014)
Companies involved: ProScript, LeukoSite, Millennium, Takeda
Velcade (PS-341) was initially developed for muscle wasting diseases by the small biotech ProScript. After the sudden death of the venture capitalist who was funding their trials in 1997, ProScript lost access to capital and struggled to raise additional funds, as most investors considered the drug to be too risky a prospect. Without the ability to fund further trials, ProScript was eventually sold off to LeukoSite for only $2.7m.
When Millennium pharmaceuticals acquired LeukoSite in late 1999 for their lead program CamPath, it also incidentally gained control of PS-341. The former ProScript chemist Julian Adams and Dr. Kenneth Anderson of Dana-Farber were able to convince Millenium to invest in trials of PS-341 in multiple myeloma, which generated impressive early results and enabled the rapid FDA approval of Velcade in 2003. With Millennium’s inhouse discovery platform failing to generate important marketed drugs of its own12, Velcade became the company’s most important product and the primary reason for its eventual acquisition by Takeda for $8.8bn in 200813.
Avonex (interferon beta-1a) for multiple sclerosis (MS)
Peak annual global product revenue: $3,013m (2014)
Companies involved: Biogen
In the early 1990’s Biogen had two lead programs in late stage development: its novel antithrombotic Hirulog for cardiovascular diseases, and interferon beta-1a for hepatitis B. Meanwhile, the NIH was sponsoring a small trial for Biogen’s interferon beta-1a in MS that was “considered a long shot by all concerned”14. After data from the lead indications disappointed, Biogen went all-in on trials of interferon beta-1a in MS, the results of which successfully demonstrated a slowing of MS progression, and positioned Biogen’s drug favourably against the first-to-market Betaseron (US launch in 1993). Avonex launched in the US in 1996, founding Biogen’s massively successful MS franchise and establishing a company-wide focus on neurological conditions that persists to this day.
Viagra (sildenafil) for erectile dysfunction (ED)
Peak annual global product revenue: $2,051m (2012)
Companies involved: Pfizer
The story of Viagra is fairly well-known, but illustrative nonetheless. Originally developed as a treatment for high blood pressure, sildenafil’s results were poor and the program was on the verge of being shut down when Pfizer scientists became aware of a common side effect among trial participants; increased erections. As recalled by Ian Osterloh, then in Pfizer R&D:15
“At the time, no one really thought, ‘This is fantastic, this is great news, we’re really onto something here. We must switch the direction of this program.’”
Although initially skeptical, Pfizer did invest in trials of sildenafil for male impotence in 1993. In 1998 Viagra became the first FDA approved drug to treat erectile dysfunction, and Pfizer had essentially created a new indication.
Kalydeco (ivacaftor) for cystic fibrosis (CF)
Peak annual global product revenue: $1,008m (2018)
Companies involved: Aurora, Vertex
These days Vertex is known for its cystic fibrosis franchise, however, its first launch was a short-lived hepatitis C blockbuster called Incivek that launched in the US in 2011. However, a few short years after launch Incivek was made obsolete by the more effective nucleoside analogues, and in 2014 it was withdrawn from the market16.
Vertex’s CF story goes back to 2001, when it acquired Aurora Biosciences to gain access to its high throughput screening capabilities16. At the time, Aurora was running a small screening project instigated and paid for by the CF foundation. Following the acquisition, Vertex inherited the CF program, although it was considered a low priority by Vertex management at the time and would likely have been canceled if not for the CF foundation funding.
While the company was focused on Incivek, a few passionate holdouts from Aurora kept the CF program alive despite management opposition, even working on it in their spare time. Eventually their persistence paid off with the approval of their first CF drug Kalydevo (ivacaftor) in 2012 - just in time to help the company compensate for the loss of Incivek revenue.
Source: The Antidote