Biotech's Barnum and his Covid cures

Patrick Soon-Shiong knows when he realised the Covid-19 pandemic was going to pose a serious threat. It was February 24, and the part-owner of the LA Lakers was at the Staples Center in Los Angeles for Kobe Bryant’s memorial service.

With the player’s sudden, untimely demise on his mind, he found himself thinking about the emerging pandemic. Even though Covid-19 hadn’t yet caused a single reported death in the United States, Soon-Shiong was worried. He recalls turning around to California Governor Gavin Newsom and telling him, “We’re in trouble.”

His sense of urgency hasn’t gone away. “If I thought I was scared on February 24,” he says, “I’m more scared now.” The reason, he explains, is that “what we’ve learned is that this virus acts like cancer.” He says he has left his house only once since Bryant’s memorial, and that was to film a video about the coronavirus for the Los Angeles Times, which he bought, along with The San Diego Union-Tribune, for $600 million two years ago. “I shut myself off from the world,” he says.

And so one of the planet’s richest medical doctors, who made a $6.7 billion fortune developing breakthrough treatments for cancer and diabetes, seeks to battle the pandemic. The weapons in his arsenal: The cancer treatments he has spent the past decade and a half developing. He’s aiming them at all aspects of the coronavirus, from a vaccine to treatments for mild cases to therapies targeted towards patients on ventilators.

It’s an enormously ambitious plan from a man who has often been accused of being a hype artist. In an earlier incarnation, Soon-Shiong was a respected surgeon and professor at UCLA Medical School, but throughout his wildly successful entrepreneurial second act, he has been derided as more showman than scientist, thought guilty of overinflating results and taking undue credit. A few years ago, for example, he boasted about using a breast cancer drug to treat a patient with cervical cancer—but other groups were already seeing similar successes. As we wrote in a 2014 cover story, “While he’s undeniably brilliant, Soon-Shiong is equally undeniably a blowhard.”
 
But he also has fierce defenders, including former Senate majority leader Harry Reid, who says the 68-year-old “saved my life” in 2019 by providing an experimental treatment for his stage IV pancreatic cancer. Researchers say his methods are conceptually grounded in good science, though the verdict will ultimately depend on results.

“We’ve been tracking and seeing an increase in the number of these cell-based therapies, whether they’re being repurposed from oncology or even other disease conditions,” says Esther Krofah, a senior analyst who monitors the clinical development pipeline for Covid-19 vaccines and therapies for the Milken Institute. A number of them are going into clinical trials.

It may seem counterintuitive, but advances in knowledge about the immune system, and how it might help kill cancer, have real applications for infectious diseases. “To me, a cancer cell and a virus-infected cell are one and the same,” says Dr Wayne Marasco, an immunologist at Harvard Medical School who is researching coronavirus treatments. The immune system, he adds, seems to think the same way. Which is a good reason to take Patrick Soon-Shiong seriously.

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Born in Port Elizabeth, South Africa, in 1952, Soon-Shiong is no stranger to the intersection of the immune system, cancer and infectious disease. Having graduated from medical school at age 22, he focussed his early surgical career on transplants and cancer, both of which involve a complex pas de deux with the immune system. Crossing disciplines, he says, led him to look at the “body as a system, not a single little cell. We are a biological system.”

Such interdisciplinary thinking may be what led to the medicine that made his fortune: Abraxane, which took an existing chemotherapy drug, Toxol, but wrapped it in protein that made it easier to deliver to tumours. It’s now used to treat advanced cases of lung, breast and pancreatic cancer. In 1998, to develop Abraxane, he purchased Fujisawa, a small, publicly traded business that sold injectable generic drugs. Soon-Shiong used its revenues to quickly move Abraxane through the regulatory process. The FDA approved it in 2005, and in 2007 Soon-Shiong split the business in two, spinning out a company called Abraxis that focussed on the new cancer drug. He sold the generics business to Fresenius in 2008 for $4.6 billion. Two years later, he sold Abraxis to Celgene for $4.5 billion. Celgene, itself acquired by Bristol Myers Squibb in November 2019, reports that sales of Abraxane exceed $1 billion annually.

The complex business deals that went into Abraxane, however, left Soon-Shiong with “a reputation as more of a wheeler-dealer than a scientist”, as we noted in 2014. Back then, he posted to Twitter under the grandiose handle @solvehealthcare, but today he simply uses his name. Over several recent Zoom conversations, he evinces very little showmanship. He’s visibly tired, exhibiting the most excitement when he starts talking about intricate scientific details. “I’m burning out a little bit,” he admits, adding that he’s been getting only about four to six hours of sleep a night since February. Over that time, he says, his companies have concentrated on both continuing to develop his cancer treatments and working to employ them against Covid-19. He peppers his statements about his company’s approach to both cancer and the coronavirus with qualifiers about the results of pending studies, carefully avoiding seeming to overpromise.

Soon-Shiong has multiple interrelated businesses organised in a complex corporate structure. But his Covid-19 efforts come from the two companies he founded that work on developing cancer immunotherapies: NantKwest, a publicly traded outfit based in San Diego, and the privately held ImmunityBio.

Cancer immunotherapy is based on the notion that the body’s own immune system can be stimulated to treat the disease. That idea dates to the 19th century, when scientists first observed tumours getting smaller after patients developed a type of skin infection. This led to some of the first experiments in which the immune system of cancer patients was stimulated. Early efforts proved difficult to reproduce, though, and the field got sidetracked by advances in chemotherapy and radiation. Interest spiked anew in 1959, when a paper showed that the tuberculosis vaccine inhibited tumour growth in mice. After decades of intense research, the first cancer immunotherapy was approved by the FDA in 1986.

Other types of immunotherapies followed, ranging from purified antibodies that attack cancer to drugs that turn off the chemical switches that let tumour cells hide from the immune system. The latest advances involve CAR-T cell therapy, which first gained FDA approval in 2017 and involves genetically engineering immune cells from patients so that they attack certain targets found in tumour cells.

Founded in 2002, Soon-Shiong’s company NantKwest focuses on developing so-called “natural killer” (NK) cells, which the immune system uses to destroy virally infected cells as well as early-stage tumours. The company has been working to develop a line of “off-the-shelf” NK cells called NK-92, which can be used to treat certain cancers as well as viral infections.

The company, which has yet to post any meaningful revenue, has lost nearly $400 million since it went public at $25 a share (a $2.6 billion market cap) in 2015. The stock has recently traded in the $10.50 range, off a bottom of around $1 a share in 2019. One reason for the stock’s surge, says Jefferies analyst Biren Amin, is the company’s reported research into the coronavirus pandemic. The second, he suggests, involves former Senator Reid’s cancer treatment.

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Harry Reid, who represented Nevada in the upper chamber from 1987 to 2017, was diagnosed with pancreatic cancer in 2018 and started chemotherapy that July. He didn’t respond well. “I was so sick they stopped the chemo” that October, he says. In July 2019, a scan of his liver showed that the cancer had spread. That meant his only option was more chemotherapy. Around the same time, Joe Kiani, founder and CEO of Irvine, California–based health IT company Masimo, met with Soon-Shiong to discuss acquiring $50 million worth of assets from NantHealth. During that initial meeting, the conversation turned to Soon-Shiong’s other projects, which later led Kiani to phone the former senator. “I called up Harry and said, ‘This person could have the cure. I don’t know if he does, but what do you have to lose?’ ” Kiani recalls.

Two weeks later, Soon-Shiong and a doctor from NantKwest named Leonard Sender were working with Reid, using treatments from NantKwest as well as Soon-Shiong’s ImmunityBio. Those treatments aren’t yet approved but were permitted under the FDA’s compassionate-use rules. Reid was treated with a combination of Abraxane, NantKwest’s natural killer cells and a drug from ImmunityBio called N-803, which stimulates the immune system to produce its own killer cells. Soon-Shiong compares it to the “triangle offence” often employed by the Lakers. In November 2019, Reid reported that his scans were completely clear, showing no signs of cancer. 

Reid’s is an extraordinary story, as pancreatic cancer remains one of the deadliest forms of the disease. Within five years of diagnosis, it kills some 90 percent of patients, accounting for 7 percent of cancer deaths globally. Jeopardy! host Alex Trebek, who also suffers from pancreatic cancer, has received the same treatment, as have two other unidentified patients. But Sender cautions against declaring a cure. “It’s too early to tell, because this is a very nasty form of cancer,” he says. That’s why NantKwest is now focussed on a new randomised clinical trial.

As part of these projects, Soon-Shiong has spent the past five years working with the National Cancer Institute. His companies have a collaborative agreement with the NCI involving several types of treatments. Dr Jeffrey Schlom, chief of the NCI’s laboratory of tumour immunology and biology, recalls being in sync with Soon-Shiong from the start. “At our first official creative meeting, we presented our slides of our approach,” he says. “And then he got up and presented his approach, and they were almost identical.” Schlom’s group has since published in peer-reviewed journals 15 papers regarding Soon-Shiong’s treatments.

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Since February, NantKwest and ImmunityBio have redirected some of their attention towards the coronavirus pandemic, using a number of weapons in their collective arsenal. The first is a vaccine, based on the system Soon-Shiong’s companies are developing for cancer, that has already shown positive results against Covid-19 in a study involving mice. It’s also being studied in monkeys as a part of the federal government’s “Operation Warp Speed”. As for human trials, Soon-Shiong says he’s ready to go. “My timeline is now dependent on the FDA letting me get out of the gate,” he says. “I’m in the gate, the bell hasn’t rung and the racehorse is frothing at the mouth.”
 
This vaccine is delivered to the body in a common cold virus called an adenovirus that has been stripped of all the parts that can cause harm to people. That modified virus contains two individual segments of the Covid-19 coronavirus: The spike protein, the surface protein on the virus that triggers an antibody response; and a nucleocapsid protein, which is found in the centre of the virus. Most of the more than 100 vaccines that are currently in clinical development for Covid-19 focus on the spike protein to generate an immune response. Soon-Shiong thinks that won’t be enough, though, which is why he’s including the nucleocapsid protein. “My concern is that the spike protein mutates,” he says. “It’s mutated even through this pandemic.”

Beyond potential mutations, another concern about merely eliciting an antibody response is that, from the data seen so far, antibodies to the Covid-19 virus just don’t last very long. Levels of antibodies in the blood are “really low after a few months”, says Marasco, who’s not associated with Soon-Shiong’s companies or their vaccine research. “I think it’s uncertain how long immunity will remain after successful vaccination.” Using the nucleocapsid protein “couldn’t hurt”, he adds, and it could elicit not only antibodies but virus-killing T-cells as well.

The second weapon is the application of NantKwest’s NK-92 and ImmunityBio’s N-803. NK-92 is being adapted to directly attack virus-infected cells, while the N-803 stimulates the patient’s immune system to produce its own natural killer cells against the virus. The treatments might be used either together or separately depending on the patient, Soon-Shiong says. Human trials have already begun. “It’s a fantastic thing they’re applying them to infectious disease to see how patients fare,” says Gigi Gronvall, an immunologist at Johns Hopkins Center for Health Security, who is not involved in the research. “The concept is great but we need to see what the data says.”

The third weapon NantKwest and ImmunityBio are developing to combat Covid-19 involves the use of mesenchymal stem cells, which are derived from bone marrow. This type of stem cell has been investigated over the past decade for diseases—like Covid-19—that can cause the body’s immune system to go into overdrive and attack itself. This treatment would be for the most severely sick Covid-19 patients, who are experiencing a “cytokine storm”, in which the immune system overreacts. Small-scale studies have suggested this might be an effective treatment, and several companies, including Melbourne, Australia–based Mesoblast, are already in late-stage clinical trials. Soon-Shiong’s companies are working with hospitals to recruit patients for human trials.

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If Soon-Shiong’s approaches to Covid-19 bear fruit in clinical trials, the next step may prove harder still: Getting those treatments to needy patients. This is especially so for the vaccine, because at the moment neither NantKwest nor ImmunityBio has the resources to scale up manufacturing. “I’m now behind the eight ball,” Soon-Shiong admits, “because there’s no way I could have 100 million doses unless somebody supports me. Maybe I have a million or 2 million doses.” He expresses some frustration at the government: “Billions are going to companies that have billions [in] revenues.” He’s not wrong. In July, pharma giant Pfizer (2019 revenue: $51.8 billion) received a $2 billion federal contract to manufacture a vaccine it’s developing.

Things are brighter for the companies’ N-803 and NK-92 products, as NantKwest has the ability to manufacture at scale, but these treatments will face competition from others being developed by pharmaceutical companies. “I think there are a lot of alternatives that are more practical than a cellular therapy for an acute infectious disease,” Marasco says, though he does acknowledge that the companies’ plans to use stem cells against the more severe cases have potential.

Despite his frustrations, Soon-Shiong appears determined to do his part in the war against the coronavirus. “This is the crisis of our time,” he says. “It’s almost existential.”