Oncology

Less than a month into her role as CEO of the nonprofit Cancer Research Institute, Alicia Zhou has some big ideas for the future of the organization.

The CRI has funded cutting-edge oncology research, primarily in the field of immunotherapy, since 1953, when the approach was considered experimental and unorthodox. Cut to present day and immuno-oncology has become a major pillar in cancer treatment and research, resulting in some of the world’s biggest blockbusters. 

And Zhou sees more opportunities for evolution in the field, as well as CRI’s role in encouraging and establishing routes of partnership between the many stakeholders in drug development. One way Zhou, who is CRI’s first new CEO in more than 30 years, is looking to update the nonprofit’s model is by taking a page out of Silicon Valley’s book.

For instance, when the CRI doles out grants for academic research — like the Star Award that offers $1.25 million for an investigator over five years — the support is aimed at an individual’s talent in the field rather than specific projects. Zhou, who worked in leadership at a healthcare startup before taking the reins at CRI, sees an opportunity to bring a talent-based model to cancer research.

“What’s interesting about that model is it reminds me of the way that in Silicon Valley, which is where I come from, the old adage is, ‘invest in founders, not the company,’” Zhou said. “We’re investing in these scientists, not necessarily their project, and that’s quite different from the way anybody else funds.”

Under Zhou’s leadership, CRI will focus on data-driven research efforts that require collaboration across the board, from pharma to government to nonprofits and academics. 

Here, Zhou explains the vision she brings to CRI, how she plans to allay the “fragmentation” happening within cancer research and where the walls can be broken down so scientists and the industry can create a more cohesive, data-driven effort toward cancer cures.

This interview has been edited for brevity and style.

PHARMAVOICE: You’re succeeding Jill O’Donnell-Tormey, who led CRI for more than 30 years. How do you plan to keep her vision alive while bringing your own experience to the role, especially with the cancer field evolving so rapidly?

ALICIA ZHOU: I have really big shoes to fill. One of the things that attracted me to the CRI is the fact that it has such a longstanding legacy of supporting some of the best scientists in the field of immunotherapy research.

What I have in front of me is to ask, what is the next evolution for CRI? How do we broaden our reach and our influence? I love to think about how a nonprofit can change the landscape of research by potentially investing in and building data-driven research assets. As a newcomer, I’m seeing that the science that’s happening is becoming more fragmented. Folks are pulling off little pieces of the pie and saying, OK, we’re going to treat this particular cancer, these types of patients with this particular kind of molecular genotype. If you’re a patient, you want to be treated holistically to determine the treatments you should consider. I would love for CRI to actually play a role in defragmenting the space a bit and bringing people together to discuss how to treat the whole patient and not just a specific part of their tumor.

How do you plan to tackle that defragmentation effort?

Nonprofits are uniquely positioned to convene players for these kinds of conversations. Pharma companies have to be driven by what is going to drive revenue, and there’s nothing wrong with that — but it makes sense that they become very focused on where they believe their portfolio is going to be the strongest. At a nonprofit, we’re not looking for the success of a single agent or a single pathway, and we can drive toward the broader mission of bringing immunotherapy to every cancer. With that in mind, we can contemplate collaborations and partnerships across the for-profit and nonprofit space.

In immunotherapy, we have this problem right now where all the data is fragmented, so we have different patients who have undergone different types of immunotherapy treatment — information like what the tumor microenvironment looks like before they receive treatment, during treatment, after treatment, who responded, who didn’t, who developed resistance. We know that the answer to why that happens is probably somewhere in the data, and something that CRI could do is bring all that together. That's something that a for-profit entity wouldn't want to spend the time or funding on, but could be something that a nonprofit entity could really move the field forward with.

You mentioned taking lessons from Silicon Valley. What are some aspects you would bring in from that world, and which ones wouldn’t translate as well?

What's interesting about having worked in the Silicon Valley environment is the fundamental ways we've tackled the problems. When you're in a large incumbent organization, there's a sense of, this is just how things are done. But a startup can ask the question, why are they done that way? I like that way of questioning. What Silicon Valley does well is bring together expertise from very different areas to solve a single problem. And with basic cancer research becoming more data-driven, that’s important. You’re never going to get a biologist to become a machine learning expert, and you’re never going to get a machine learning expert to become a biology expert. So you want to figure out how to bring those two to the table.

But there are limits. As a startup in consumer technology, the stakes are ultimately not that high — in healthcare, the stakes are much, much higher. So I think we can learn to move more quickly, but we also have to proceed more cautiously when it comes to any kind of new, disruptive technology. In healthcare, there’s less room to iterate and break things.

How can CRI build up the influence to foster further collaboration within the industry?

At the end of the day, we have to demonstrate our unique value to every stakeholder in the space. Pharma companies, academic centers, donors. I’ve taken on this role because I believe CRI has the potential to do that, and to do it, we have to be more collaborative and think of new models for partnerships.

All scientists are in pursuit of the exact same thing, regardless of where they sit, and that’s discovery toward a cure. And that’s whether you’re on the academia side or on the industry side. There has got to be a model that allows pharma scientists to collaborate with academics that doesn’t destroy their ability to have proprietary IP but still allows everyone to move forward. If you can open that door and have that conversation, you’d be surprised how many pharma-based scientists have all sorts of ideas, and I’m willing to start those conversations.

At a company the size of Johnson & Johnson, it would be easy for departments to become siloed, accomplishing only their own objectives without a vision of the bigger picture. But even in the earliest stages of science, units as fundamentally divided as clinical research and commercial strategy work together to achieve the pharma giant’s common goal.

As J&J pursues clinical results, Dr. Craig Tendler, vice president of late-stage development, diagnostics and global medical affairs in oncology, has to consider not only what’s happening in a non-small cell lung cancer trial but what the commercial landscape will look like so patients can ultimately benefit.

“The way I look at the commercial contribution before we even get on the market is trying to define those key attributes that are important to physicians and patients and being able to integrate that into a development program where the results will hopefully support that profile,” Tendler said. 

So he teams up early with Biljana Naumovic, J&J’s president of U.S. solid tumor oncology, to ensure everyone is on the same page. Along with the research teams, Naumovic aims to define those key attributes at the outset.

“The primary end goal is to transform the lives of patients by changing the standard of care and supporting a long, fruitful quality of life,” Naumovic said. “We’re part of this discussion at the very beginning, so that before we go into the clinic, we’re defining where we want to go — for the past 20 years, we have done just that with very informed, passionate debates.”

If a program looks like it’s not going to change the standard of care, “we stop things that we do not think are going to hit the mark,” Naumovic said.

‘A huge responsibility’

When the baton makes its way from the clinical research teams to the commercial department, everyone needs to be on the same wavelength, Naumovic said.

“Bringing really strong data to then manage patients better is a huge responsibility,” Naumovic said, referring to the August FDA approval that stemmed from overall survival data in a late-stage study for EGFR-mutated non-small cell lung cancer with the drug combo of Rybrevant and Lazcluze compared with AstraZeneca’s Tagrisso, the current standard of care.

On the research side, patients stayed on the Rybrevant and Lazcluze combination treatment longer than with Tagrisso, Tendler said, noting that the combo provided better disease control, which is a selling point down the road. And that arises from early representation of the commercial perspective in clinical program design, he said.

“The beauty of having the commercial representation is that we have better insight as to what attributes should be integrated into the comprehensive development program,” Tendler said. “This idea that we have to look to not just bring a regimen that has enhanced progression-free survival but the factor that will convince physicians to use it in a higher proportion of patients is the survival data.”

At a conference with clinical experts like this past weekend’s annual conference of the European Society for Medical Oncology, Naumovic’s job is to distill the next steps into a commercial plan.

“Once the data is out, the oncology community has a million ideas for where to take it next,” Naumovic said. “And so we can create that together.”

In bladder cancer, for instance, J&J reported mid-stage data for a device called TAR-200 designed to sit in the bladder and release chemotherapy from within, showing a response rate of more than 83%.

“It’s a very clear example of an innovation being able to deliver an older drug in a new delivery device and having it get much more effective levels throughout the treatment cycle,” Tendler said.

Results like that give Naumovic some buzz to work with when the commercial strategy comes into play.

“This has never been seen before in localized bladder cancer, and to get there with a beautifully engineered device that stays in the bladder will be a radical change to what bladder cancer looks like once we bring it to the U.S. market in the beginning of next year,” Naumovic said.

The commercial influence

While science can only be done at its own pace, commercial demand can sometimes influence the direction in which a research team takes aim. A rise in colorectal cancer among young patients has troubled oncologists and caused companies like J&J to investigate new treatment options.

In a phase 1b/2 study for patients with metastatic colorectal cancer, a combination of Rybrevant and chemotherapy resulted in an almost 50% overall response rate.

“There has been no innovation in colorectal since [Eli Lilly’s Erbitux], and we’re talking several decades,” Naumovic said. “So like we did in bladder cancer and lung cancer, we’re coming to colorectal cancer the same way — there certainly is a resurgence of higher incidence in a younger population across the developed world because of diet, and we want to make sure we’re embracing that opportunity with the results that we have.”

Overall, J&J’s clinical and commercial teams have the same endpoints in mind — finding the right approaches to move the oncology field forward while keeping today’s patients at the center of the equation.

“We are a company that aims to put chemotherapy into the history museums where it belongs and focus on targeted therapies that will allow patients to live a longer and better life,” Naumovic said. “That’s where we think the field of oncology is going.”

Sponsored content

By Quest Diagnostics

As the Chief Medical Officer at Quest Diagnostics, I've had the privilege of witnessing and contributing to the remarkable evolution in oncology care. A significant aspect of this transformation, as detailed in our recent white paper, “The Evolving Role of Diagnostic Labs in Oncology: Navigating Biomarker-Driven Therapies,” is the rising influence of biomarker testing in the field of precision medicine. 

Traditionally, diagnostic labs have played a crucial, albeit less visible, role in healthcare, focusing primarily on providing diagnostic services. Today, as our understanding of cancer’s molecular underpinnings deepens, labs have become central to the development and implementation of personalized therapies. Our white paper explores this important shift, including how diagnostic labs are transitioning from traditional service providers to proactive partners in oncology care. 

A key element of this shift is biomarker-driven therapy. These therapies utilize molecular signatures to develop treatments targeted to specific cancer types or even individual tumors. A prime example is the use of the HER2 biomarker in breast cancer, which has led to the development of therapies like trastuzumab. Such advancements signify a move away from 'one-size-fits-all' treatments to more personalized strategies, enhancing treatment efficacy and reducing side effects. 

This evolution in therapy development necessitates a reimagined approach in drug development. Biomarker-driven strategies streamline the development process, exemplified by the accelerated approval of drugs like pembrolizumab. This precision not only speeds up regulatory processes but also increases the likelihood of successful outcomes. However, this approach raises questions around the availability of assays for biomarker identification and the need for new Companion Diagnostics (CDx), challenges that can be overcome through collaboration between pharmaceutical companies and diagnostic labs. 

Our white paper discusses the changing dynamics of drug and therapy development and the evolving role of diagnostic labs in this context. Diagnostic labs are now integral in the drug development process, advising on suitable clinical trial assays and CDx development. This collaborative spirit extends beyond therapy development to clinical implementation, ensuring therapies are quickly and efficiently integrated into patient care. 

We also emphasize the importance of diagnostic labs in ensuring accurate treatment allocation. This includes expediting test results and collaborating with healthcare providers to streamline the transition from diagnosis to treatment decision-making. For example, Quest Diagnostics is actively working with its pathology group, Ameripath, to optimize these processes. 

Finally, we highlight the vital role that precision medicine plays in modern oncology care and how diagnostic labs have moved from the background to become key strategic partners in drug development and patient care. This collaborative approach not only speeds up the development and implementation of new therapies but also ensures that these advancements reach patients swiftly and effectively. 

I invite you to download and read the full white paper for a comprehensive understanding of these significant advancements in oncology care and the transformative role of diagnostic labs in this journey. The future of cancer treatment is not just about the drugs we develop; it's also about how we diagnose, how quickly we can bring treatments to patients and how we can tailor these treatments to individual needs. This is the essence of precision medicine and it is a journey we are proud to be a part of. 

Download the white paper today!

As far as cancer treatments go, radiopharmaceuticals are conceptually one of the simplest — radioactive substances are very good at killing cancer cells, after all. And as targeting mechanisms improve, Big Pharma has taken a renewed interest in the area’s potential, driving more innovation at smaller companies developing radiopharmaceuticals of their own.

While the pharma industry may be seeing a radio-renaissance, the idea has been around since the years following World War II, said Jack Hoppin, CEO of the radiopharmaceutical company Ratio Therapeutics.

“It’s not a novel concept to put a radioisotope into patients,” Hoppin said, referring to the radioisotope iodine-131 that was first used in 1951 to treat thyroid conditions. 

Decades later in the early 2000s, GlaxoSmithKline’s Bexxar and Spectrum Pharmaceuticals’ Zevalin were both approved to treat lymphoma, but sales suffered due to logistical issues.

Beyond prolific diagnostic use for PET imaging and another radioisotope Xofigo from Bayer that was approved in 2013 for prostate cancer, two modern treatments brought therapeutic radiopharmaceuticals back into the spotlight, Hoppin said: Lutathera for neuroendocrine tumors and Pluvicto for prostate cancer, both acquired by Novartis in 2017 and 2018, respectively. Pluvicto in particular could become the first blockbuster drug in the space this year, according to reports. 

“There have been a couple other successes in the space, but those are the two driving forces that caught everyone’s eye,” Hoppin said. “When a buyer like Novartis steps in and starts building infrastructure, and oncologists are willing to prescribe and treat directly with these drugs, it builds momentum.”

Backed by another pharma giant, Bristol Myers Squibb, Ratio is still in early days with radiopharmaceuticals, also called radioligand therapies, as it seeks regulatory go-ahead for a phase 1 trial to treat soft tissue sarcoma, as well as several other therapeutic and diagnostic programs in preclinical stages.

“I think you’ll see these drugs evolve in the way that antibody-drug conjugates have — it took time to adopt and come to fruition, but we’re now in an era where companies are looking for fit-for-purpose molecules for radioligand therapy and the characteristics required to be successful,” Hoppin said.

Multi-disciplinary approach

One of the most important factors in therapeutic radiopharmaceuticals is finding the right balance between dosing and targeting to kill cancer cells without triggering harmful side effects.

To get that balance right requires more than just biology and chemistry, said Hoppin, who has a Ph.D. in mathematics. For example, understanding the way radioactive material — actinium-225 in Ratio’s case — populates a tumor and expanding the window of time that material is present is as much a math problem as it is biological.

“People in pharmaceutical sciences underestimate nuclear medicine, and people in nuclear medicine underestimate pharmaceutical sciences — we try to acknowledge that you’re only as good as the weakest disciplinarian within your group,” Hoppin said, adding that Ratio has medical, chemical, radiological, biological, pharmacological, mathematical, physical and dosimetric specialties all at once. “We’re a small, nerdy company just discovering and developing molecules with a goal of getting compounds for different targets into patients.”

Ratio uses actinium-225 with a combination of platforms for targeting and linking to ensure a calculated dose. From a mathematical modeling perspective, Hoppin believes small molecules like radiopharmaceuticals are ideal for treating solid tumors. 

And while advances in protein engineering or virology can lead to major biological breakthroughs that come in waves, he credits a steady accumulation of better biomarkers for growth in the therapeutic radiopharmaceutical space.

“There wasn’t a clear-cut smoking gun that changed the market, but more an evolution of medicinal chemistry and biomarker technology to image these agents faster and more quantitatively,” Hoppin said.

Building the market

Ratio is among a dozen or so small- to mid-sized startups exploring radiopharmaceuticals, and acquisitions by Big Pharma players have given rise to a thriving market for clinical-stage developers.

At the end of last year, Bristol Myers Squibb announced a $4.1 billion acquisition of RayzeBio, and that same week, Eli Lilly completed a $1.4 billion purchase of Point Biopharma. Both companies have radiopharmaceutical candidates in clinical trials and marked a sizable investment in the space compared with the decadeslong lull.

This year, AstraZeneca bought Fusion Pharmaceuticals for $2.4 billion, continuing the M&A trend. There were 86 deals in the radiopharmaceuticals space in the last five years, according to a Nature report, and the number of deals nearly tripled from 2021 to 2022, mostly for preclinical companies.

There are still challenges in the field, as Hoppin can attest, from manufacturing of radioactive materials to supply chain and storage. But the future looks bright.

“Some of these things can’t be instantly solved, but looking out a decade, there are going to be multiple approvals and really exciting times,” Hoppin said.

Big Pharma will need to pony up for some of its biggest price hikes. The industry expects invoices from the government later this year as a penalty for raising drug prices faster than the rate of inflation. 

Drug companies are required to pay inflation penalties to Medicare when prescription drug prices increase faster than the rate of inflation for certain drugs. The requirement is part of the Inflation Reduction Act, and the latest round of penalties announced in June includes 64 drugs, several of which come from Big Pharma.

The list of treatments doesn’t overlap with the first 10 drugs that are up for price negotiations with Medicare, which is a separate provision of the IRA. Those price adjustments are currently in negotiations and will become effective in 2026.

The inflation-related rebates are based on average sales price, and drug companies are required to pay Medicare the difference if the price rises faster than the inflation rate, equal to the amount of units sold to Medicare. The rebates are deposited into the Medicare Trust Fund, and people with the government-run insurance plan will see temporary savings on their coinsurance rates to make up the price difference. From July 1 through Sept. 30, people with Medicare will see savings as high as $4,593 per day depending on the drug, the CMS said. 

The rebate program began last year, when Medicare required payment for 46 drugs. The latest round includes several blockbuster drugs from Big Pharma. While pharma companies are also grappling with price negotiations, here are three cancer treatments on the rebate list that pharma giants will need to account for. 

Adcetris — Pfizer

Adcetris was Seagen’s top-selling drug when Pfizer acquired the pharma company for $43 billion late last year. Revenue reached $279 million during the second quarter of 2024, according to Pfizer’s earnings report this week, up from $257 million in the first quarter.

As a result of landing on the CMS’ inflation penalty list, the inflation-adjusted coinsurance percentage of Adcetris, an antibody-drug conjugate for Hodgkin lymphoma, will drop from 20% to 18.6%, giving recipients temporarily lower costs for themselves, the agency said.

Despite the penalties directed at Adcetris, Pfizer CEO Albert Bourla noted the IRA isn’t all bad news for the company thanks to a potential volume increase on vaccines related to cost-sharing with Medicare recipients. 

Abecma, Breyanzi —Bristol Myers Squibb

The CAR-T cell therapy Abecma hasn’t yet reached blockbuster status for Bristol Myers Squibb and partner 2seventy bio since it was approved in 2021 for multiple myeloma. The therapy reached $388 million in revenue in 2022, but revenue has since taken a dip with rising CAR-T competition, falling to $358 million in 2023. 

Still, Abecma could be due for growth, as 2seventy bio announced a new strategic path focused on commercialization at the start of the year that includes expanding the label.

Also on the penalty list is BMS’ Breyanzi, a CD19-directed CAR-T cell therapy approved for B-cell lymphoma. Revenue totaled $303 million in 2023, up from $182 million in 2022. The company snagged U.S. approval in follicular lymphoma and mantle cell lymphoma this year, and sales are expected to increase in the coming years. In the first six months of the year, Breyanzi revenue is up 52%. 

The inflation penalties are not the only government initiative set to impact BMS drug prices. The company is separately facing pressure from the IRA price negotiations with the blockbuster blood thinner Eliquis in the first wave of 10 drugs. Developed with Pfizer, Eliquis reached $12.2 billion in 2023 revenue, according to BMS’ end-of-year earnings. However, the company is still bullish on the drug’s short- and medium-term value now that price negotiations are likely set in stone, executives said.

Padcev —Pfizer, Astellas Pharma

The CMS called out the bladder cancer drug Padcev from Pfizer and Astellas Pharmaceuticals for an egregious price hike. The drug’s price has increased faster than the rate of inflation every quarter since the Part B rebate program went into effect. As a result, the CMS has adjusted the coinsurance rate since 2023 so Medicare recipients are paying lower amounts to account for the price hikes. 

“A beneficiary taking Padcev as part of their cancer treatment may have saved as much as $1,181 from April 1, 2023, through March 31, 2024, depending on their coverage and course of treatment,” the CMS said in a press release.

Along with Adcetris, Padcev was another drug Pfizer acquired in the Seagen deal to bolster its oncology portfolio. During the second quarter of 2024, revenue for Padcev reached $394 million, according to the company’s earnings report released this week. Revenue was better than forecast by analysts and contributed to Pfizer raising its full-year revenue guidance from $59.5 billion to $62.5 billion, Reuters reported. 

As a consumer company, 23andMe is well known in the public sphere for mail-in genetic test kits that provide a detailed family history. But alongside that business, the biotech is also developing drugs using its massive database of genomic information, getting closer to a cancer treatment of its own.

23andMe is building on the success of immunotherapies like Merck & Co.’s Keytruda and Bristol Myers Squibb’s Opdivo, which are checkpoint inhibitors that block a pathway between tumors and the immune system, allowing the body to fight back against cancer. And with a wealth of knowledge at their fingertips, researchers at 23andMe have uncovered new pathways that could have a similar effect and add to the arsenal of oncology drugs, said Dr. Jennifer Low, head of the company’s therapeutics department.

By identifying genetic variants from the world’s largest database, 23andMe found target biomarkers in the CD200 pathway that, when blocked with the treatment 23ME-00610, has shown preliminary clinical benefit in a mid-stage study of patients with neuroendocrine and ovarian cancer. As the first antibody to target this pathway, Low and her team hope this marks a foray into precision medicine that has been discussed in the industry for years.

And 23andMe needs a win. The company has been mired in controversy, from the ethics of using genetic information for research to a high-profile data breach. Last year, the therapeutics division had to cut jobs as biotech investment wanes and the company’s shares circle the drain.

But Low is optimistic about the company’s foothold in the drugmaking arena. Here, we spoke to the therapeutics head about the role genetic databases can play in discovering and developing new treatments for disease like cancer, how understanding demographics would help improve clinical trial diversity and the potential for collaboration with traditional pharma companies in the future.

This interview has been edited for brevity and style.

PHARMAVOICE: How has 23andMe’s huge customer database helped guide the company to the development of oncology checkpoint inhibitors?

DR. JENNIFER LOW: One of the biggest challenges across pharma is that we use animal models to try to understand human biology, but we’re very limited in terms of what will actually translate. Animal models don’t recapitulate what’s going on in people. And so the big advantage to the 23andMe database is that this is human data, human genetics — we have over 15 million genotyped individuals from our customer database, and this allows us to make statistical connections between genetics and what people experience in their biology. We ask about family history and disease, but we also ask them about a lot of other things, like, what is their susceptibility to toenail fungus? Or are they the kind of person who’s always getting attacked by mosquitoes? And this allows us to have subtlety around biology that you’re not going to get in a medical record.

That gives us a large amount of information so that we can also see subtle differences in immune function and how that connects with a propensity for developing cancer. Using that combination of information, we can draw insights into which parts of immune biology may be important for a person’s immune system to be able to see and attack cancer. And we can make tweaks to the drugs that we’re making to realign the immune system to no longer be blind to that cancer.

When you look at the success of immunotherapies like Keytruda, they are still limited by a patient’s genetics. How can 23andMe improve upon that to create what could be the next wave of checkpoint inhibitors?

Checkpoint inhibitors have been a massive advance. In the beginning, immune therapies like interferon or IL-2 were really hard for patients to take and would only offer a smaller chance of long-term survival. Then the PD-1 and PD-L1 immunotherapies brought [survival] up past 20%, which is phenomenal — but 70% to 80% of people still are not getting the long-term benefit. And it’s likely … that there are other checkpoints that are important. So our first program, the CD200R1 program, affects a different checkpoint independent of PD-1 and PD-L1. You need a lot of different options to get the right constellation of effects, and you need to understand more about the immune system you’re trying to activate. Because 23andMe has a much broader understanding of the variability of the immune system, we’re finding targets that allow us to look at many different ways to approach it. We’re really excited about the potential for these drugs.

23andMe has come into some ethical questions about addressing demographics in genetic research. How does the database help bring more diversity into clinical trials?

The FDA is very concerned about the lack of breadth that occurs in a lot of clinical trials, and they want to see that diversity because the American population is very diverse and they need to understand more broadly. With our experience in genetics and increased insights into the differences, the rest of the industry will realize how important it is to have that additional information as well. The U.S. is only 30% of the global market for most drugs, and so it’s really important to think about that.

With precision medicine becoming more advanced, biomarker expansion is critical. Where do you see 23andMe’s database fitting into that down the road?

We’ve been talking for ages about personalized medicine because, even when we have broad labels like lung or breast cancer, for any individual person, their tumor and immune systems greatly influence how their medications will work and what will eventually enable their body to gain control of a tumor. For oncology, we tend to focus on the tumor itself, but we already know that it’s much bigger than that. We’re trying to understand those subtle differences and understand biological processes. And so 23andMe is doing a lot of work to look at multigenic causes and multigenic risk around the propensity for developing disease. I see 23andMe as a critical contributor to how to think about these big problems, and any company that wants to understand some of these aspects would be great to partner with. That’s one mechanism by which our influence could be much, much broader.

What’s the biggest challenge for 23andMe moving forward in the therapeutics area?

This is a tough market right now for small biotechs, which is what we are. As a result, we’ve had to make tough decisions around prioritization and focus — we announced that we needed to scale back our activities and made a really tough decision to let go of a number of our employees within therapeutics. We would love to be able to do everything, but I do feel confident that the organization is leaner, meaner and ready to accomplish a lot in a very efficient way.

For well over a year, the FDA hasn’t granted any antibody-drug conjugate approval — the last one over the line was Immunogen’s Elahere for platinum-resistant ovarian cancer in November 2022. But the industry’s pipeline is set for more.

Over 80 ADC candidates are in phase 3 development, according to the healthcare management consulting and technology firm ZS.

In addition to treating a wide array of oncology targets — including breast, non-small cell lung, gastric and esophageal cancers — ADCs can be a less risky bet than other therapies. ZS estimates the probability of “technical and regulatory success” is 48% for ADCs currently in phase 3, compared to 41% for “oncology overall.”

This potential for patients and drugmakers has made ADCs one of the buzziest modalities in pharma and placed the technology at the heart of several big-ticket deals in recent years, including AbbVie’s $10 billion purchase of ImmunoGen and Pfizer’s $43 billion tie-up with Seagen.

While ADCs have already established ROI for many pharmas — ZS estimates global sales for the approved ADCs reached $7.5 billion in 2022 — there’s still a need to make them better. To boost outcomes and overcome lingering clinical challenges such as off-target toxicities, drugmakers are adjusting development strategies.

Some established leaders in the ADC space, such as Daiichi Sankyo, plan to test their drugs in combination with immunotherapy heavy-hitters like Merck & Co.’s Keytruda, while also working towards approvals in earlier lines of care.

Other developers are tinkering with the basic three components of ADCs — an antibody that hunts cancer cells, a cytotoxic payload that acts as a warhead and a linker molecule — to improve the technology. In a market that now includes most major players in pharma and a vast array of plucky upstarts, these emerging candidates have the potential to create longer lasting and less toxic therapies.

Here's how three rising companies in the ADC space are looking for an edge.

Genmab zeroes in on a novel linker tech

A long-time antibody specialist, Genmab is a natural fit for the ADC arena. In 2021, it snagged one if its first ADC wins when Tivdak, developed with Seagen, won an accelerated approval for metastatic cervical cancer. The ADC snagged a full nod in April based on phase 3 data showing it improved survival by 30% compared to chemo.

Genmab also deepened its commitment to developing ADCs this year through a $1.8 billion buyout of ProfoundBio. The deal will marry ProfoundBio’s ADC platform with Genmab’s antibody therapies and “suite of proprietary technology platforms.” The merger also pumped several assets into Genmab’s pipeline, including a phase 2 ADC called Rina-S.

Developed to treat ovarian cancer and other FRa-expressing tumors, the company believes its special sauce — a novel linker technology — will offer a favorable safety profile over rivals such as Elahere, which carries a boxed warning for numerous ocular toxicities, including some that are severe. 

“[Rina-S] is a second-generation ADC [with] a cleavable hydrophilic linker … this translates into none of the side effect profiles of the first ADCs,” Anthony Mancini, executive vice president and chief operating officer at Genmab, said. “With Rina-S, we’re not seeing ocular toxicities.”

As its ADC portfolio grows — the company has three candidates in the clinic including Rina-S — Mancini said Genmab is staking its claim in oncological women’s health.

“With Tivdak on the market for cervical cancer … we’re excited about Rina-S because these are two drugs in our target audience,” he said. “We think we can be a leader in gynecological cancer and differentiated in the market.”

Sutro Biopharma aims for multiple ADC breakthroughs

Sutro Biopharma’s lead asset luvelta could also become a competitor in the ovarian cancer landscape. In particular, the biotech aims to leverage the ADC in patients with “low to medium” levels of FRa expression, and won a fast track designation for the candidate, which is now in late-stage development for ovarian cancer, in 2021. 

But the company sees broad potential in indications including non-small cell lung cancer and other solid tumors. 

What sets Sutro’s approach apart from the rest of the field is that other ADCs use a “heterogenous mixture of molecules,” the company’s CEO, Bill Newell, said. 

“We started pioneering the notion that if you made a homogenous molecule, you could improve the medicines to be more beneficial to more patients and have less toxicity,” he said. “In the ADC field, that wasn’t possible when we started 13 years ago.” 

Sutro hasn’t indicated when it’s going to file for a luvelta approval, but if it hits the market, Newell said it’s targeting a patient pool of FRa-expressers in ovarian cancer that’s “more than double” that of Elahere.

And while it leads its own development for luvelta, the company has pulled together a string of partnerships for other pipeline hopefuls, including a $900 million deal with Ipsen to develop a preclinical ADC for solid tumors announced in April. 

The company also teamed up with Astellas Pharma in 2022 to advance immunostimulatory ADCs (iADCs), a potential breakthrough approach that Sutro said is “intended to deliver two different drugs directly to the tumor to not only kill tumor cells but also locally prime an immune response to the patient’s particular tumor cells.” 

Tubulis looks to payloads for a more durable ADC 

A spinoff born from two German academic institutions, Tubulis has set its sights on next-generation payloads.

The company has six assets in preclinical development for solid cancers and “one of the broadest platforms in the field right now,” according to chief scientific officer Jonas Helma-Smets.

Tubulis’ suite of platforms can “unlock novel payloads for the development of versatile and customizable ADCs,” the company said in a press release.

“We have a huge design space given by the technology in terms of drug-to-antibody ratio, different technologies to conjugate the antibody [and] we have novel technologies to explore other payloads,” he said.

Investors have been receptive to the idea. This spring, Tubulis raised $138.8 million to back pipeline development and “clinical proof of concept” for its two lead candidates.

As the company moves towards clinical trials, Helma-Smets said Tubulis’ technology could decrease the chances of off-target effects by “ensuring [it doesn’t] lose the payload,” while also creating a more durable treatment.  

“We’ve shown in preclinical animal models that we have a long-lasting effect in cancer-bearing mice, and that is a differentiating factor,” he said. “ADCs have done a good job of improving response rates, but we believe there’s still room for improvement. That durable response is what we hope to translate to the clinic.”

Pharma companies are on the edge of a looming patent cliff over the next several years, and generic competitors could topple sales of some of the industry’s best-selling drugs. For some Big Pharma companies, generics are already on the doorstep.

Bristol Myers Squibb could soon see some headwinds for its blockbuster leukemia drug Sprycel as the first generic is expected to hit the market in September.

Sprycel (dasatinib) is a kinase inhibitor that was approved in 2006 to treat chronic myeloid leukemia, a type of blood cancer that impacts 1 in 526 people in the U.S. The tablet has been a reliable blockbuster for BMS over the years, reaching $1.9 billion in sales in 2023, BMS reported in its latest quarterly update. Sales topped $2.1 billion in both 2022 and 2021.

BMS has faced several challenges to Sprycel’s patents, and filed a patent infringement lawsuit again Swedish biopharma company XSpray Pharma in 2022, as well as a handful of other companies that were challenging “two FDA Orange Book-listed monohydrate form patents expiring in 2025 and 2026,” the company said in a recent SEC filing.

BMS settled with XSpray last year, settling all pending litigation, but also paving the way for XSpray to launch a generic dasatinib as soon as Sept. 1, 2024. XSpray has previously billed itself as able to get around secondary patents before they expire thanks to its technology. The contested patents were not set to expire until Sept. 28, 2026. However, XSpray has a PDUFA date of July 31 for its “optimized version of dasatinib,” Dasynoc.

If Dasynoc is OK’d, it will join dozens of new generics approved across indications in 2024, including several cancer drugs. With this wave of generics, branded oncology treatments could see a price drop overall, according to IDP Analytics. 

There are more dasatinib generics in development from a handful of other pharma companies, including Biocon and Teva. 

What’s next for BMS

Amid the upcoming patent expirations and onslaught of generic competitors, BMS has kept its oncology pipeline warm with new candidates and also sought expansions for Sprycel — the FDA granted approval for Sprycel to treat pediatric patients with chronic CML in 2017

The pharma giant’s cancer drug Breyanzi, a one-time CAR-T cell therapy, won approval for large B-cell lymphoma in 2022, and the therapy has since seen expansions for patients with relapsed or refractory mantle cell lymphoma, as well as accelerated approval in May for those with chronic lymphocytic leukemia or small lymphocytic lymphoma. The FDA also granted accelerated approval of Breyanzi for follicular lymphoma the same month. However, BMS faces competition in the same therapy space from Gilead’s Yescarta.

Elsewhere in BMS’ pipeline are two candidates for acute myeloid leukemia in early clinical stages. AML is considered a hard-to-treat disease, and a drug developed by Celgene and picked up by BMS in 2019 when it acquired the company was approved in 2017 to treat the condition.

Right now is “singularly, the most exciting moment” in Daiichi Sankyo’s 100-year history, said Ken Keller, CEO and president of the company’s U.S. business and head of its global oncology unit.

Riding high from the success of the AstraZeneca-partnered blockbuster cancer medication Enhertu, the company in October announced a partnership with Merck & Co. valued up to $22 billion. And with potential new approvals coming this year, Daiichi is on track to become a cancer powerhouse ahead of its own schedule.

Born from a 2005 merger between two long-standing Japanese pharmas — Sankyo Co. and Daiichi Pharmaceutical Co. — the company has been “cardio-centric” for most of its history, Keller said. Now the second largest pharma in Japan, its diversified portfolio also includes vaccines, migraine meds and more.

But Daiichi trained its eyes on oncology in 2020 when it launched Enhertu for HER2-positive unresectable or metastatic breast cancer, vowing to become a “top 10 cancer pharma company” within a decade. 

“That was a big ambition coming from zero,” Keller said. “Here we are, five years later, and we’ve changed how cancer is treated.”

The company’s special sauce is a proprietary antibody-drug conjugate platform called DXd it used to develop six candidates for multiple cancers. Since an original nod in breast cancer, Enhertu has racked up approvals for several other HER2-related indications, including the first tumor-agnostic approval for an ADC, which the FDA granted in April. 

Daiichi and AstraZeneca, its development and commercialization partner for Enhertu, also recently announced positive topline results from a phase 3 trial in patients with lower levels of the HER2 protein. The results, which the companies said showed a “statistically significant and clinically meaningful benefit” in progression-free survival, could help move the ADC into earlier lines of care.

Meanwhile, the company has three key PDUFA dates within nine months. This June, the FDA will render a decision on a HER3 treatment for non-small cell lung cancer that is now a part of its three-drug collaboration with Merck. The agency is also slated to announce decisions for a TROP2-directed ADC Daiichi is developing with AstraZeneca — first in NSCLC this December and then for breast cancer in January 2025.

If the approvals are granted, Keller said Daiichi will be poised to hit “top 10 cancer company status” by fiscal year 2026. 

It’s got plenty of competition. With ADCs becoming one of pharma’s hottest commodities, Pfizer scooped up ADC specialist Seagen in a $43 billion acquisition last year. But Daiichi is slated to dominate the ADC market through 2029 with the highest level of sales, according to analysis by GlobalData.

Here, Keller discusses growth prospects for Enhertu and how ADCs could one day become curative treatments in cancer care. 

This interview has been edited for brevity and style.

PHARMAVOICE: Sales for Enhertu more than doubled last year from about $1.25 billion in 2022 to $2.5 billion. Tell me about the long-term prospects for the drug.

KEN KELLER: Today we’re looking at five indications that we’ve received. We announced a positive pivotal trial, which would be another indication [and] a pretty amazing potential indication in the HER2 low space. The study looked at using it to displace chemotherapy rather than after chemotherapy, and we also demonstrated efficacy in the ultra-low HER2 setting. 

When you look at breast cancer, HER2 positive is about 20% of cases, HER2 low is about 50%, and including ultra-low means we can help close to 90% of women with breast cancer. It would be the biggest drug ever in breast cancer. That gives you a sense of where the program is going. 

Enhertu has been massive for Daiichi, but is the company relying too heavily on this single drug for future growth?

Enhertu is the foundation of everything we’re doing. Today we’ve got the ADCs we’re developing with Merck and AstraZeneca, we have two other DXd treatments in the clinic and we are leveraging our leadership in ADCs. So, we’ve got second and third generations of treatments we’re working on right now.

We’ve got a decade of clear growth, and hopefully our technology continues to grow and improve.

Do you see any new, big partnerships on the horizon? 

It’s going to come down to the specific molecule or ADC we’re talking about. If we have a drug that we think has just a few indications, we can do that ourselves. If we have a drug that we think can be used across a dozen different cancers, that’s when we think about how we can develop it as fast as we can, and get it to as many patients as we can. 

I’ve been here about 10 years and was the first employee of the oncology unit. Back in 2015, we had one oncologist — today we have over 2,000 people in the oncology part of our business. We are much more capable today, but we know we have to be open to working with others.  

One of the biggest criticisms of emerging technologies in oncology is that pharma companies are making blockbusters out of drugs that only add months to patients’ lives. Do you have development efforts underway aimed at improving outcomes for ADCs?

This is what makes this DXd platform so unique. In our first indication [for Enhertu] we compared it to Kadcyle from Genentech, and we didn’t add months to survival — we added years. In second-line breast cancer, we added 28 months of progression-free survival compared to six.

When I look at starting an oncology franchise within a company, you couldn’t find a more profoundly beneficial drug. But two things are going to make a difference going forward.

We are going to move into early-stage disease and catch it earlier with a potent drug.

The second is moving into a combination setting with immuno-oncology treatments like Keytruda. We started in late-stage as a monotherapy, and as we move earlier and look at the power of ADCs and immuno-oncology, we think that could change things. 

In the earlier stage and in the adjuvant or near adjuvant setting, a cure is the goal.