Making Drugs at the Edge of Reason

Vicki Sato, chair of Denali Therapeutics and VIR Biotechnology

Editor’s Note: This essay is excerpted from “Biotechnology in the Time of COVID-19” edited by Dr. Jeremy M. Levin. It is printed with permission from RosettaBooks. The book is available exclusively on Amazon.

A few days ago, I Zoomed with a Hollywood Squares display of faces on my laptop: the top 60 leaders of VIR Biotechnology, a young company founded with the intent to arm the world against infectious disease. Not a popular vision in 2017, as far as investment was concerned.

But on this day, these employees were working across nine time zones to identify new treatments for COVID-19; working from home, working in labs in San Francisco and Bellinzona, Switzerland, to identify and isolate human antibodies that might treat this new pandemic disease.

I am the chair and a co-founder of VIR, and George Scangos, our CEO, had invited me to answer questions from these smart, committed, and stressed leaders.

Early on, someone asked if I had experienced anything like this before.

I answered somewhat reflexively.

“No, there hasn’t been anything of this scope or speed; it’s a unique time.”

Then some older neurons kicked in. I practically struck my forehead in self-reproach. How could I have forgotten about HIV and AIDS?

Today, a generation is unaware of the terror of HIV infection; it is a disease that is “managed” because of medicines that were created in the 1990s and beyond.

What lessons did we learn in creating that medical advance?

In 1984 I joined Biogen as a lab rat, an immunologist fussing about interferon and IL-2, but also cognizant of a puzzling and deadly disease — Acquired Immunodeficiency Syndrome — because of my recent academic days reviewing grant applications on a profound immunodeficiency affecting primarily homosexual men. This condition was a tornado, obliterating the immune systems of healthy, young men and killing them within months of diagnosis with opportunistic infections that ravaged their bodies. We didn’t know where it came from and we didn’t know where it would take us.

We had just learned that this havoc was caused by a new virus, likely from Africa, that infected and killed T lymphocytes, destroying the very physiology designed to protect us from lethal pathogens. Could we imagine anything more diabolical, more deadly, more obscene?

Oh…and it was a retrovirus, one of the first described with an affinity for human cells, not monkey or chicken, or mouse. Viruses of this type can uniquely embed themselves permanently into the DNA of the host. They can do this because they have an enzyme, reverse transcriptase, that converts the genetic information of the virus, which is RNA, into DNA, the double-stranded form that comprises our own genetic material. They could drive the normal biochemistry of “DNA makes RNA” backward, from RNA to DNA, hence retroviruses.

It all seemed rather daunting, and the speed of postgenomic analytical techniques and computer-accelerated modeling, which we take for granted today, were still in our future.

But at Biogen, working on a strategy for a virus-receptor blockade, and later at Vertex working on HIV protease inhibitors, I was able to be part of the scientific anschlag that took on the challenge of treating this disease. They were experiences that shaped my outlook on the drama and melodrama of infection.

What did I learn?

Your drug is only as good as your assay

At Biogen, we worked to develop a soluble version of the CD4 receptor, the initial portal for HIV. The idea was to create a decoy that would lure virus away from cells. This engineered molecule worked remarkably well in the in vitro replication assays that measured viral p24 antigen, the gold standard at the time. It did not work so well in patients, though, in part because those early assays employed strains of virus that had adapted to laboratory conditions—strains whose molecular mechanisms had drifted in critical ways from the actual strains infecting people. In addition, we learned that HIV also had co-receptors that figured significantly in viral tropism and entry. Our assays, the most current at the time, had misled us.

Successful and persistent pathogenic viruses are complex

They have evolved efficient genomes to subvert the workings of host cells in ways that enhance their own replication and survival. Single silver bullets rarely work. At Vertex, we worked hard to develop a potent, highly selective inhibitor of the viral protease, an enzyme that controlled one essential step in viral replication. It was a powerful drug, but it wasn’t enough. Over time, mutational drift and selection created new strains resistant to the drug. Combination strategies, incorporating drugs that targeted multiple steps in viral pathogenesis, were needed to ensure a durable and sustainable response. Inhibitors of viral protease, when added to inhibitors of reverse transcriptase, another protein essential for the virus to multiply, finally tipped the balance toward more durable responses. The combinations were game changers; the individual components were the essential and encouraging steps along the way.

Patients need to be heard and respected

The first generation of drugs were poorly tolerated; the treatment was potentially as bad as the disease, with debilitating side effects and an upside of only weeks to months of prolonged life.

Was this enough?

Doctors and scientists fretted about doing more careful studies, more innovative studies, before approving the drugs for use. Patients clamored for a voice in that decision, pointing out that their lives were the ones at stake; their lives the ones complicated by handfuls of drugs that caused disfiguring lipid growths, or commandeered their lifestyles with difficult-to-manage, often-contradictory dosing schedules. Maybe weeks or months of life were enough for the moment, if even more effective treatments could emerge in that interval. Patients wanted a seat at the table at the FDA, a seat at the table inside of drug companies, offering insights to teams of scientists.

What impressed me so much about this patient engagement was the diligence and sense of community that sustained this effort. Patients who hadn’t taken a science class since high school made themselves experts at immune regulation; journalists used to covering crime beats or Broadway shows or financial markets were writing newsletters to keep fellow patients and families informed of the latest discoveries. Patient-activists chained themselves to fences at pharmaceutical companies to demand better access and better medicines. Gay physicians opened neighborhood clinics where patients could find information, advice, and treatments as they emerged, because not all hospitals or physician practices would take on patients infected with HIV.

It all made a difference.

Lots of other lessons were learned as well, but these all came rushing back after the figurative forehead slap in front of those leaders at VIR that morning. I believe the lessons are important to us today: know what your assays are telling you and keep making them better. Don’t expect a silver bullet cure, but build on steady victories. Be engaged with the breadth of patients affected.

During the time of HIV and AIDS, the biotech industry was in its infancy. It is startling to look back. The only drugs approved from our companies in 1987 were recombinant human insulin, somatotropin, and alpha interferon. Our viability as a set of businesses, let alone as an industry, remained a determined dream for the founders but a “show me” for the rest of the world. We hadn’t flexed our muscles yet.

For COVID-19, we aren’t newbies anymore. Our industry delivers the majority of game-changing drugs to patients. The speed at which young companies and old have joined hands to test older drugs for rapid efficacy, to launch vaccine trials using a technology only invented a half-dozen years ago, and to map the changing face of this complex virus is breathtaking. We are showing we can do the science and drive the medicine, and that we can invent even as we discover and learn new things about the virus and the multifaceted disease it causes.

But with our maturity comes a heightened responsibility for social equity and responsibility: we must ensure not only that our science is sound but that our medicines are accessible to everyone who needs them. Society is already predicting that we will engage in price gouging, exclusivity, and competition for “credit,” the attributes that make our industry one of the least respected globally. Some of our remarkable medicines in other disease areas are better known for their prices than their medical impact.

As we continue to “science the hell” out of this pandemic, let us match our scientific prowess with humility and a commitment to the patients we pride ourselves on serving.

Plagues, it has been noted, have a way of leveling the playing field. Medicines should do that, too.

Vicki L. Sato, PhD, is chair of Denali Therapeutics and VIR Biotechnology. She has spent many years in leadership roles within the biotechnology industry. More recently, she has served on the faculties of Harvard University and Harvard Business School. Sato is also a director of Bristol-Myers Squibb, Akouos, and BorgWarner Corporation.

This essay is excerpted from BIOTECHNOLOGY IN THE TIME OF COVID-19 edited by Dr. Jeremy M. Levin and is printed with permission from RosettaBooks. The book is available exclusively on Amazon:  https://www.amazon.com/dp/B089JGDZNC    


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