In pharma, cancer is king

March 23, 2020
Inside the industry's quest for its next crowning achievement in oncology

Pharma’s pursuit of innovative oncology drugs has hit a fever pitch like the industry has never felt. On the heels of a treatment revolution that has fundamentally changed how we understand, fight and, in some cases, can cure cancer, pharma is mobilizing at a dazzling speed to develop the next holy grail in oncology.

Much of the frenzy has been brought about by the rise in immunotherapies that, for the first time, have made it possible to outsmart a disease that’s masterful at evading destruction. Advances in cell and gene therapies have also given pharma companies an unprecedented set of groundbreaking tools for crafting more effective treatments. By many measures, these recent advances have paid off.

According to the American Association of Cancer Research, the number of cancer survivors in the U.S. increased by 1.4 million to 16.9 million in January 2019. The average life expectancy in the U.S. also rose in 2018 for the first time in several years, partly due to a drop in deaths from cancer.

Yet, when it comes to improving patient outcomes in cancer, there’s still plenty of room for new therapies to reign.

The total number of those diagnosed with cancer in the U.S. is growing. Estimates from PwC show that the number of cancer patients in the U.S. this year will swell to about 18 million — up 31 percent over 2010. And of course, cancer actually consists of hundreds of different diseases, giving the industry a wide array of oncological indications to target.

The current generation of cancer treatments is also still stymied by a number of challenges including manufacturing issues, limited therapeutic benefits for many patients and sky-high prices that have drawn public ire.

All told, oncology has become a segment of the industry that is both bursting at the seams and begging for further innovations. Recognizing the potential to help both patients and business, pharma has become obsessed with oncology.

PwC estimates that 34 percent of the 15,267 pharma assets in development are related to cancer — a 30 percent increase over 2013 — as companies target a mushrooming global oncology market that could reach $230 billion by 2024.

With its resources mobilized at an unprecedented rate, pharma is gearing up to usher in the next generation of cancer treatments that are smarter, more targeted and potentially more curative than ever before.

The blockbuster bonanza

Just 10 years ago, only two cancer drugs had surpassed the threshold required for blockbuster status. Now, all of the top 10 oncology drugs are selling well over $1 billion each year. The road for innovating new cancer drugs is still long (around 10 years on average from patent filing to regulatory approval), and the cost is still high (about $650-700 million per approval, according to analysis by JAMA Internal Medicine). But the payoff for pharma companies in oncology is reaching altitudes like never before.

EvaluatePharma estimates that the $91.9 billion the industry has currently invested into clinical oncology drug development will result in $78.2 billion in net present value (NPV).

Much of the value in oncology is being driven by pharma companies shifting away from the “big five” tumors — breast, lung, colorectal, prostate and gastric — and instead targeting rarer cancers. The McKinsey Cancer Center estimates lower-incidence tumors will account for about 50 percent of oncology revenue this year.

Common sense would suggest that drugs targeting high-prevalence diseases would net bigger returns, but Zachary McLellan, the therapeutic area director of oncology and respiratory diseases at Informa Pharma Intelligence, points to a number of reasons pharma has found value in rarer cancers.

“There is significant unmet need in many rare diseases due to a lack of effective treatments, which lowers the bar in what may be considered a viable therapeutic approach. This creates opportunity as companies become better at developing therapies that target specific genetic subpopulations,” he says. “We’ve also seen that regulatory bodies are willing to expedite the process for these niche applications, so there are potential timeline advantages as well.”

No matter how you look at it, there’s a lot of value on the line for oncology treatments in pharma, which has helped trigger a massive wave of M&A activity. Cancer-driven deals have taken the industry by storm over the last five years, accounting for nearly half of the money pharma spent on acquisitions and licensing. But winning at this game requires developing a new regime of innovative oncology drugs.

New-wave cancer treatments

Tumor agnostic
The idea of weaponizing the body’s own immune system to fight cancer has deep roots in medical history, and researchers have long toyed with different ways of achieving this goal. But the scientific momentum behind today’s top-selling immunotherapies picked up speed just decades ago.

The big turning point came when researchers honed in on the ability of antibodies to unleash the immune system’s killer T-cells on cancer. In particular, scientists discovered that certain “checkpoint” proteins, such as PD-1, are found on T-cells. Cancer cells then cleverly release a protein that binds to PD-1, creating a reaction that stops the T-cells from attacking cancer. Today’s generation of “checkpoint inhibitors” are now able to bind to proteins like PD-1, and block the cancer’s own proteins, to kick the immune system back into gear.

Merck & Co.’s Keytruda, a PD-1 checkpoint inhibitor, wasn’t the first approved drug to use this mode of action, but in the last few years, it has become the most dominate. Although it was first approved to treat melanoma, Keytruda has since racked up approvals for a number of notable indications such as non-small cell lung cancer, gastric cancer and esophageal cancer. Some analysts predict that annual sales for Keytruda could one day reach $27 billion — a higher mark than any other drug in history.

Keytruda was also one of the first drugs approved by the U.S. Food and Drug Administration for a tumor agnostic indication, meaning that it can be used to treat tumors with a specific biological makeup, regardless of where in the body the cancer originated. As the market for checkpoint inhibitors has become increasingly crowded — with competing treatments approved that target PD-1, PD-L1 or CTLA-4 proteins — some drug developers are setting their sights on finding new kinds of drugs that take the tumor agnostic approach.

In late 2018, Bayer’s Vitrakvi became the first treatment with a tumor-agnostic indication at the time of initial U.S. Food and Drug Administration approval. Called a “new paradigm” in cancer care by the FDA, Vitrakvi works by targeting solid tumors that have an NTRK gene fusion. The NTRK genetic biomarker is rare — the alteration occurs in less than 1 percent of all solid tumors — but the approval for Vitrakvi has been widely heralded as a game changer.

According to Dr. Scott Fields, Bayer’s head of oncology development, Vitrakvi, which Bayer co-developed with Loxo Oncology, is one of the most ground-breaking cancer therapies to come along in the last 10 years. Fields says that part of what makes Vitrakvi especially exciting is its efficacy — around 75 percent of patients in clinical trials showed a response to the treatment. It has also been shown to have a lower toxicity — an area of emerging focus for drug developers.

“During studies, we had no treatment-related deaths and a few patients came off of the treatment due to toxicity. Many patients have a limited life span, so making sure they have a good quality of life is critical,” he says. “It’s very specific for the target — that’s why we believe it’s so well tolerated. To me, that is a big achievement.”

Historically, Bayer has not been one of Big Pharma’s top players in oncology — but in the last few years, the company has been busy expanding its reach. Just a decade ago, Bayer had only one oncology product on the market. Now, it has six approved in the U.S. and another 15 in development.

Rather than targeting the well-trodden paths in cancer care, Bayer has leap frogged over the “first-generation” immuno and cell therapies and is instead targeting the incoming wave of cancer treatments. In addition to Vitrakvi, Fields listed a number of leading edge treatments Bayer has in development, including immunotherapies that will target new checkpoints, as well as targeted thorium compounds (TTC) therapies. Like all Big Pharma companies, Bayer has also gobbled up several smaller biotech firms in the last few years to expand its development pipeline and get its hands on emerging technologies.

Last year, Bayer also invested over $200 million in Century Therapeutics, a Philadelphia-based startup looking to make its mark in oncology with a cell therapy platform based on induced pluripotent stem cells (iPSCs). Bayer is also partnering with Khloris Biosciences to develop anti-cancer vaccines using iPSCs. These deals, along with others made in 2019, have helped Bayer firmly establish its footing at the forefront of the rapidly changing realm of cell therapies — arguably the buzziest area of oncology.

Cell therapies
When a group of researchers recently reported from Cardiff University that they had found a new type of T-cell receptor that could help eradicate many types of cancers, the media frenzy was swift. Had someone done it? Was this finally the “one-size-fits-all” cure for cancer?

Although the idea of a universal cancer treatment seems far-fetched, many believe that if it’s going to happen, it will be a kind of cell therapy.

The Cardiff discovery was serendipitous. Originally, the researchers had been analyzing blood and looking for bacteria-fighting immune cells. But what they found was a never-before-seen receptor molecule called MR1. In lab tests, the scientists showed that immune cells equipped with MR1 were able to kill a wide range of solid-tumor cancers — including lung, skin, blood, ovarian, kidney, prostate and more — while bypassing healthy cells.

The breakthrough was notable because it demonstrated the curative potential of T-cell therapies (encouragingly, MR1 does not vary in humans). But if developed — human trials harnessing the MR1 receptor are slated for later this year — this type of “off the shelf” treatment could also solve one of the major logistical issues that has dogged the industry for T-cell therapies.

So far, the FDA has approved two CAR T-cell therapies for cancer — Yescarta, developed by Kite Pharma (now owned by Gilead Sciences) to treat a type of lymphoma, and Novartis’ Kymriah, which targets advanced acute lymphoblastic leukemia. Both treatments have shown impressive response rates in a large number of patients. But they’ve only been developed to treat blood-based cancers, limiting their application to a smaller patient population. They are also mired in logistical manufacturing challenges.

To administer the therapy, T-cells have to be extracted from the patient, engineered with artificial CAR receptors added to their surface and then infused back into the patient. It’s a complicated process with lots of room for error.

In December, Novartis reported that it is unable to ship Kymriah to patients 10 percent of the time either because of out-of-specification issues or manufacturing failures. Often, the company has to petition the FDA to let the patient use the therapy anyway because of the imminent risk to the patient’s life.

According to Jason Bock, vice president of Therapeutics Discovery and head of Biologics Product Development at The University of Texas MD Anderson, the ongoing manufacturing issues associated with Kymriah show “the complexity of the problem” with CAR T-cell therapies.

“The manufacturing of these therapies is more complicated than anything pharma has ever tried,” Bock says.

Although the difficulty in producing cell therapies is still great, the potential is also so large that MD Anderson recently launched its own internal Biologics Development group, which acts as a biotech within MD Anderson’s Therapuetic Discovery division. The goal is to robustly accelerate cell therapies from the research lab to industrial-scale manufacturing.

“MD Anderson has been doing cell therapy in an academic setting for more than 18 years, so we have a lot of experienced staff. We’re going to combine that with our industrial know-how…to solve these manufacturing challenges,” Bock says.

Earlier this year, MD Anderson invested in a 60,000-square foot facility to help Therapeutics Discovery have direct control of cell therapy manufacturing to better develop the products. Bock says they are also working with a number of pharma vendors to co-innovate needed technologies.

“The vendors are really all-in with cell therapies,” he says. “They are putting a lot of effort into new products and equipment.”

When it comes to developing the next generation of cell therapies, the name of the game is “off the shelf” treatments, that, unlike existing CAR T-cell therapies, would not require the patient’s own harvested cells. The MR-1 discovery could lead to one type of off the shelf cell therapy, and recently, MD Anderson was the site of clinical study that could ultimately deliver another.

In February, MD Anderson released the results of a phase 1/2a clinical trial using a cord blood-derived CAR natural killer (NK) cell therapy targeting the CD19 antigen to treat patients with a type of lymphoma. The trial involved 11 patients, seven of which showed a “complete response.” Importantly, the NK-cell therapy was shown to have a much better safety profile than standard CAR T-cell therapies, which trigger a painful side effect called cytokine release syndrome — caused by an overactive immune system — in 70-90 percent of patients.

“We didn’t have any cases of neurotoxicity or cytokine release syndrome,” says Katy Rezvani, a professor of Stem Cell Transplantation and Cellular Therapy at MD Anderson, and the lead researcher on the study. “To us, that was pretty amazing.”

MD Anderson has already licensed its CAR NK-cell platform to Takeda Pharmaceuticals, who now have the rights to develop and commercialize up to four CAR NK therapies.

Some of the innovative cell therapies in development such as CAR NK and iPSCs are also being explored alongside CRISPR, a high-precision gene-editing tool that Rezvani says could be another game-changer in oncology.

“We live in exciting times,” she says. “The progress that is being made in the fields of cell therapies, genetic engineering and gene editing is likely to result in the generation of extremely potent cells for the treatment of cancer.”

Bock echoes Rezvani’s enthusiasm for cell therapies, saying that it’s the area of oncology with the most potential to create longer-lasting cures for cancer.

“There’s too much investment and momentum for it not to happen,” he says. “This is going to be the next big step forward.”

Immunogene therapies
Another hallmark of today’s cancer research climate is the increasing interest in marrying different treatments. Much like chemo and radiation, today’s generation of cancer drugs can provide miracle cures for some, but leave swaths of patients without any benefit. Even if some patients show a response to a treatment such as a checkpoint inhibitor in the short term, remission rates among today’s cancer drugs remain high. Thus, many of the emerging cancer treatments — including MD Anderson’s CAR NK therapy — are being tested in combination with chemo or other therapies.

This idea that cancer treatments are “better together” has driven the clinical research for Oncoprex, a new immunogene therapy treatment being developed by Austin-based Genprex. Not only does Oncoprex combine several innovative approaches to treating cancer — immuno and gene therapies plus a nano-based delivery system — it is also slated to be tested with AstraZeneca’s Tagrisso, a blockbuster targeted therapy for tumors with EGFR mutations, and Merck’s Keytruda.

According to Genprex’s CEO, Rodney Varner, therapies like Oncoprex have the potential to improve the outcome of existing therapies.

“When patients go on drugs like Tagrisso, many get a real benefit,” Varner says. “But they inevitably relapse. For Tagrisso, the average time is 14 months.”

Genprex’s Oncoprex, which is currently being tested as a treatment for non-small cell lung cancer, contains a tumor-suppressing gene called TUSC2 that is encapsulated in a positively charged nanovesicle made from lipid molecules. After being injected, it targets and penetrates cancer cells, interrupts the cancer’s replication pathways, re-establishes pathways that induce programmed cell death and creates an immune response to cancer.

Varner says that Oncoprex is the first cancer drug that has made it to clinical trials using this kind of nanopartical delivery system, which helps the treatment find tumors in difficult-to-reach parts of the body. It also comes with a better safety profile for patients and fewer manufacturing burdens than viral vectors, the typical vehicle for gene therapies.

“Manufacturing this therapy is complicated — but not as complicated as viral vector manufacturing,” he says. “It doesn’t require as much clean space…and there is a backlog of virus manufacturing in the U.S.”

So far, Oncoprex has been tested in a phase 1/2 clinical trial at MD Anderson with one EGFR inhibitor. It also won the FDA’s Fast Track designation to be tested with Tagrisso, and recently secured funding to begin a trial combo-ing the treatment with Keytruda. 

Although the drug’s development is still in the clinical stage, Varner says the company could have a blockbuster on its hands.

“Virtually every patient that gets an immunotherapy for lung cancer is going to get Keytruda or something like it,” he says. “If we combine with the two largest selling lung cancer drugs, Tagrisso and Keytruda, and show that patients can benefit, that would be a large selling drug.”

Getting ahead in the onco-race

Although the market for cancer drugs is exploding, success won’t be a given for every company. Here are what experts suggest are keys to success in oncology:

Co-develop needed tools
One of the biggest lessons Fields says that Bayer learned from bringing Vitrakvi to market was that when you’re a pioneer in a new indication area, you may have to help build the infrastructure around the drug’s development.

“The challenge of developing a treatment for a very rare tumor type is that you have to have a strategy to find the patients,” Fields says.

Ultimately, Bayer struck partnerships to develop and become experts in diagnostics tools for cancer. Last year, Bayer announced a deal with Roche’s molecular information company, Foundation Medicine, to commercialize a next-generation sequencing (NGS) test that screens patients’ tumors for genome information. The partnership will help expand the availability of genome sequencing to more patients, which Fields says was not performed routinely in the past.

Rework clinical trials
Patient recruitment for clinical trials is a growing problem for oncology drug development. If a company is targeting a high-incidence tumor, the population for patients is bigger, but the competition for patients can be fierce. For rarer indications, a smaller patient population makes it tougher to find and recruit patients. One emerging strategy has been the creation of “basket trials,” which enroll patients with various types of cancer into one study (Bayer took this approach to test Vitrakvi). But as McKinsey notes, it’s important to be prepared for “extensive planning and collaboration” when using basket trials.

Think digital
Being innovative in oncology shouldn’t just relate to drug development. According to McKinsey, “Different sources of health care information will be connected. Innovative companies will make progress in mining the information to gain more nuanced insights to optimize outcome.” How might this strategy play out?

In its 2018 report, “New dynamics in the pharmaceutical oncology market,” PwC points to Pfizer’s Oncology Together program as a case study in how pharma can leverage emerging technologies and data. The program connects cancer patients with “care champions,” who can assist with overcoming various daily challenges, such as transportation or cost issues. With its LivingWith app, Pfizer’s program also helps patients take notes at doctor appointments, track data from wearable devices and see inspirational stories from other cancer patients. Although the app can be used by patients using  any treatment, Pfizer is still able to leverage the data to develop a better understanding of the patient experience and outcomes.

“Companies can strengthen their relationships with oncology patients by surrounding them with digital support. Tracking more health data ... can help pharma companies understand where new opportunities lie,” PwC states.

Stick with what you’re good at
Part of what Fields says has shaped Bayer’s oncology strategy is keeping a targeted portfolio.

“There are so many interesting approaches now available to study in oncology,” he says. “If you try to do everything, that may not be the best approach.”

Rather than casting a wide net, Bayer has honed in on three areas, which limits the company’s exposure to potential failures, and has helped improve Bayer’s know-how.

“We can’t become experts in everything, but we are developing expertise in what we do,” Fields says.

Can pharma cure cancer?

Will all of this investment in oncology ever pay off in a universal cure? In reality, the word “cure” isn’t used often in pharma’s oncology vocabulary — instead the focus is on improving “patient response” or “outcomes.” Of course, that doesn’t stop the world from wanting to know when someone is going to bottle up a cure for cancer.

“We’re not necessarily going to come up with one cure for everyone,” Bock says. “But we’re seeing that some indications now have a dramatically increased survival rate. As we continue to understand how to better develop and manufacture these living drugs, cell therapies offer us the long anticipated ambition of talking about cures.” 

About the Author

Meagan Parrish | Senior Editor