The cliché of building an airplane while in flight might hold with today’s oncology market: new therapies are just on the horizon, while a host of issues around affordability, prescribing practices and reimbursement policies are shifting. Millions of patients are fighting their cancers—some with striking success—while hearing about hundreds of drugs in the development pipeline, and about the growing number of clinical trials that might enroll them. The other aeronautical metaphor that now applies to cancer—energizing the “cancer moonshot” of President Obama, and led by Vice President Joe Biden, heightens the excitement.
The one nagging worry in all this is how American society will be able to afford the therapies entering the market. One bright spot to that issue is the arrival, finally, of at least some biosimilars that promise to reduce the expense of some current therapies. The lower costs expected by the entrance of these drugs will help the affordability question, but the companies introducing these drugs have their own hill to climb to prove that the biosimilars will have the same, if not better, efficacy as the reference products (the originator drugs) they seem to replace.
Chemotherapy, radiation and surgery have been the staples in cancer care for over a century, but for most cancer patients, they have deferred what seems to be inevitable, and many of them bring devastating and costly side effects. In recent years, promising work in immuno-oncology (I-O) is encouraging new optimism.
The main problem with most existing therapies is that they attack healthy cells in the body as well as the cancerous ones; the side effects of gastrointestinal problems, weakened immune systems and the like are well known. These side effects are not only a burden for patients, but are partly to blame for the high cost of cancer care, as they often require additional medications, emergency room visits and hospitalizations.
Better knowledge of how the human body itself can attack cancer cells is leading to a series of new treatments, some already commercial, with many more in the pipeline. These include antibodies that function as checkpoint inhibitors, immune-modulating agents such as adoptive T-cell therapies, and so-called oncolytic viruses. The treatments are showing promise in targeting a variety of solid cancers (including breast, uterine and ovarian, gastrointestinal and colon, kidney and bladder, lung, metastatic melanoma, and more), as well as certain blood cancers, such as different types of leukemia, including chemotherapy-resistant acute lymphoblastic leukemia in children.
“The beauty of immune cells is that they have a high degree of specificity, are able to distinguish minute chemical alterations, have long memory (with immunity lasting for up to several decades after effective antigen priming), and can target the vulnerabilities of the tumor in real time,” says Eric Groves, MD, PhD and VP of the Center for Integrated Drug Development for Quintiles.
“Early work on many immuno-oncology agents have confirmed fewer toxic side effects, greater durability of treatment effect, less susceptibility to development of treatment resistance—improvements not seen with other therapeutic options,” adds Dana Evans, MD, medical affairs payer support for Genentech [Ed. note: Remarks by Evans reflect his personal view, not necessarily that of Genentech].
Today’s I-O efforts are generating so much enthusiasm thanks to a combination of factors, including greater disease stabilization and reduced systemic toxicity and side effects, and greater duration of therapy—with progression-free survival stretched from weeks to months or even years for many patients. As these new therapy options mature in the marketplace, time will tell as to whether the remission or “cure” lasts for the rest of patients’ lives, or attenuates over time.
“2015 was a remarkable year in the development of immuno-oncology as a foundational therapeutic in the cancer arsenal, and stakeholder adoption of I-O is no longer a question of ‘if,’ but ‘when,’” Bruce Feinberg, DO, VP and chief medical officer at Cardinal Health Specialty Solutions.
Important unanswered questions remain, however, as this new treatment paradigm continues to take shape. “Questions related to which patients will be eligible for I-O—in terms of types of cancer, in what stage and how long will treatment be required—and how I-O will further alter treatment paradigms and, as a result of those alterations, impact the global cost of care of the treated patient, will be critical to the value assessment process,” says Feinberg. He notes that traditional clinical research “seems ill-designed to address the many questions surrounding I-O value assessment,” and thus calls for “a rapid expansion of health economics and outcomes research in this nascent field.”
Checkpoint inhibitors, also called PD-1 agents, block signals from cancer cells that essentially inhibit the body’s inherent cancer-killing capabilities. Two checkpoint inhibitor PD-1s are already on the market—Opdivo (nivolumab) from Bristol-Myers Squibb and Keytruda (pembrolizumab) from Merck—and both are said to provide many improvements over Yervoy (ipilimumab), an early I-O therapy from Bristol-Myers Squibb that is already FDA-approved for the treatment of metastatic melanoma. Genentech’s atezolizumab is another new PD-1 checkpoint inhibitor that is working its way toward FDA approval.
“With four or five PD-1s in late-stage development, and three nearing commercialization now, the PD-1s are poised to become a major drug class,” says Ryan Million, partner at consultancy Trinity Partners. “There is huge investment going on, and an arms race underway to get there first, and major companies, such as Bristol-Myers Squibb and Merck are investing heavily in this area.”
“In metastatic melanoma, more than 50% of patients in one trial were put into long-term survival—from this radically lethal disease—so this shows the amazing promise of this new approach,” says Barry Brooks, MD, an oncologist and hematologist at Texas Oncology, and serves as vice chairman of the Pharmacy and Therapeutics Committee for the US Oncology Network. (US Oncology Network comprises independent, community-based oncology centers and is supported by McKesson Specialty Health). However, he notes that checkpoint agents, when used as a single agent, often develop resistance, so to be most successful, the checkpoint inhibitor PD-1s will likely be combined with other checkpoint inhibitors, with chemotherapy, with biologic agents, or with demethylating or hypomethylating agents—to exploit several different mechanisms of action in the fight against cancer. But any combination therapy will increase treatment costs, and add to the administrative and reimbursement complexity of that approach.
Michael Kolodziej, MD, FACP, national medical director for oncology solutions for Aetna, notes that “the possibility that combination therapy might be even more effective is tantalizing. Unfortunately, if you look at how the drugs are being tested and developed, it looks an awful lot like the old chemotherapy paradigm.” For instance, “If you look at the ongoing and proposed clinical trials for these agents, they look just like the development of traditional chemotherapy (i.e. Phase II, Phase III, all possible combinations of one immunotherapeutic with another, with targeted agents and with chemotherapy). This would seem to be a prime opportunity to use biomarkers to choose the right population. But unfortunately that is not what is happening right now.”
I-O technologies are considered to be among the most complicated treatment options that are being developed, so at least at the outset, many of these promising checkpoint inhibitors “could easily cost $300,000 per patient per year, and if the treatment requires two agents to be used together, it could cost upward of a half million dollars per patient per year,” says Brooks of US Oncology Network. “That’s just too much and we clearly have a problem.”
In another I-O approach, white blood cells known as T-cells are harvested from the patient, and re-engineered by exposing them to proteins that are made in abundance by tumor cells. Scientists then isolate and replicate those T-cells that were best able to recognize the tumor proteins, producing billions of enhanced immune system cells. Once infused back into the patient, these adoptive T-cells are able to seek out and destroy the cancerous cells more effectively.
Initial clinical trials using adoptive T-cell therapy have helped patients who had only been given months to live go into remission. “When you see it work, it is so amazing—the bone marrow just goes from being full of leukemia to being in remission, and very large tumors simply melt away,” said Stanley Riddell, immunotherapy researcher and oncologist with the Fred Hutchinson Cancer Research Center (Seattle, WA), in an online interview .
However, Riddell notes that T-cells have a fatal flaw in that they die quickly, so if a desired immune response is not sustained, the cancer eventually comes back. Riddell and his team have now focused on harvesting one particularly robust T-cell that has more of a capacity to survive.
Other I-O work is focused on exploiting so-called oncolytic viruses, which can be manipulated to preferentially infect and attack certain cancers, and then induce the patient’s immune system to attack the virus. Today, a variety of native and genetically modified viruses are being investigated for commercial development, with some in advanced trials already . In October 2015, FDA approved its first oncolytic virus therapy, Amgen’s Imlygic (talimogene laherparepvec), for the treatment of patients with melanoma lesions in the skin and lymph nodes. It is based on live, genetically modified herpes simplex I virus that is injected into the melanoma lesions.
Meanwhile, efforts are also underway to develop “cancer vaccines” that would be able to prevent that type of cancer for those who have a high risk for certain cancer types—before the disease develops. For example, a vaccine, currently in early-phase clinical trials, is being developed by the Fred Hutchinson/University of Washington Cancer Consortium, for women who are at risk of breast cancer relapse to prevent breast cancer. 
Similarly, Inovio Pharmaceuticals has developed an immunotherapy vaccine to treat cervical dysplasia (VGX-3100). Phase II data, which was published in The Lancet last year  that the DNA-based immunotherapy activates killer T-cells that then clear the neoplastic cervical lesions as well as the HPV virus. It is a first-in-class product for treating high-grade cervical neoplasia associated with the human papillomavirus (HPV). Phase III trials will get underway later this year. This development was recognized as the “Best Therapeutic Vaccine” by the World Vaccine Congress in March.
“In every other field of endeavor, when there are more products and more competition—the price goes down, but in oncology drugs, the prices just go up, they never go down, until there is generic competition,” says Brooks of US Oncology Network. “There’s tremendous promise for patients but right now I am very worried that we are going to end up in a place where the government just steps in and puts price controls in all of oncology—you run the risk of not only stifling competition but also innovation—so the entire machine would stop.” Calling it “financial suicide,” Brooks continues, “The drug-development industry needs to act to address the exorbitant prices that reduce access to all of the terrific scientific advances that are improving the capabilities of today’s life-saving medications.”
“Right now, the use of the newest I-O agents are not yet limited by biomarkers or companion diagnostics that aim to define designated sub-populations of patients, so this provides a great opportunity to treat a broad base of patients,” says Evans of Genentech. “However, there is tremendous interest in identifying specific genetic mutations and other biomarkers that will help to identify which patients are most likely to respond to these costly therapies.”
Parallel efforts could have implications for manufacturers pursuing biologic therapies for the same indication. “If two I-O therapies rely on the same MOA, and later, a biomarker is discovered or companion diagnostic test is pioneered by the maker of one, would both therapies be affected? At this point it’s unclear what FDA would do, so this will be an interesting development to watch in the coming years,” says Evans of Genentech.
Researchers who are working to understand which biomarkers are most relevant with I-O therapies and how to use them most effectively. However, researchers are also wary that “small populations make verification difficult,” says Groves of Quintiles. “If researchers cannot secure a large enough group of patients in the target subpopulation due to requirements for a novel screening or limited number of potential candidates, it can be difficult to accumulate enough data to validate results.”
Here come biosimilars
Biologic therapies have become a mainstay in oncology (and other indications) for many years. However, specialty medications tend to be particularly expensive, easily costing tens or hundreds of thousands of dollars per patient per year. Among the top 20 anticancer drugs only five are biologics—Avastin (bevacizumab), Rituxan (rituximab), Herceptin (trastuzumab), Erbitux (cetumixab) and Vectibix (panitumumab).
Just as the many small-molecule blockbuster drugs famously reached the “patent cliff” in the 2010–2014 time frame, the first wave of leading biologics are facing their own patent cliff in the near future. Specifically, by 2020, about 20 of the most widely used innovator biologic therapies will be facing patent expiry (although not all of them in oncology), says Jaclyn Bosco, PhD, MPH, director of epidemiology and outcomes research for Quintiles. “This will help to keep the momentum going over the next few years in terms of many new biosimilars being approved and entering the marketplace,” says US Oncology Network’s Brooks.
Today, there are 89 companies plus partners developing 204 biosimilar drugs in 456 development projects in cancer, according to a February report from ResearchandMarkets.com. The six primary branded monoclonal antibodies currently on the market enjoyed $22 billion/year in US sales alone. Of those, three used in oncology (Avastin, Herceptin and Rituxin) will lose their US patent protection in 2018–19, and this will create the first major patent cliff in biologics, says Ryan Million, partner at the Consultancy, Trinity Partners.
While it is not a direct anticancer agent, the first biosimilar to have received FDA approval in the US is already impacting oncology. Zarxio (filgrastim-sndz) from Sandoz/Novartis was approved in 2015, as a biosimilar version of Neupogen (filgrastim), Amgen’s bone marrow stimulant that is widely used to counter the effects of chemotherapy and radiotherapy for cancer patients.
“Neupogen’s market share had already experienced decline, as its long-acting version, Neulasta, has been dominating physician prescribing. It is still too soon to measure the impact Zarxio will have on the market,” says Cardinal Health’s Feinberg.
Meanwhile, the US patents for Neulasta (pegfilgrastim), a PEGylated form of filgrastim that is Amgen’s longer-acting version of Neupogen, ended in October 2015 and the patents will end in Europe in August 2017. Several companies, including Sandoz/Novartis, Apotex and Coherus are already pursuing biosimilar versions of pegfilgrastim. However, these biosimilars are “likely to face patent challenge that could delay their entry into the marketplace for a while,” says Brooks of US Oncology Network, because Amgen recently launched Neulasta Onpro Kit, a novel formulation of Neulasta that is sold with a disposable, auto-injector system, which allows the patient to receive the drug at home the day after chemotherapy.
In April, the second biosimilar drug was approved for use in the US. Celltrion received FDA approval for the monoclonal antibody infliximab, which will be marketed as a biosimilar alternative to Remicade (infliximab) from Johnson & Johnson/Merck; Hospira, Celltrion’s partner in the US, will market infliximab as Inflectra. While infliximab, an immunotherapy for rheumatoid arthritis, is not used during cancer care, many observers say that decisions made related to its commercialization and reimbursement strategy will provide important lessons for others working to bring biosimilars to market in the US.
Just as traditional, small-molecule generic drugs have now been widely accepted—after some initial resistance by many stakeholders—and have been proven to help reduce the cost of care in many therapeutic categories, industry observers are confident that biosimilars will be accepted and prescribed widely over time, following a similar trajectory. However, many observers note the price differentials and thus cost savings associated with biosimilars will not be as dramatic as those experienced with traditional small-molecule generics, due in part to the complex manufacturing processes required to synthesize biosimilars in living organisms. In general, biosimilars are expected to be priced 25–33% below their branded counterparts. While this price differential will certainly increase access for patients, “it won’t open the floodgates or generate quite the same dramatic savings we’ve seen with the small-molecule generics,” says Brooks.
Meanwhile, ongoing innovation is advancing so rapidly throughout oncology that some of the biosimilars—by the time they reach the market—may be viewed by oncologists as obsolete, in the face of newer innovative therapies (both biological and small-molecule) that provide improvements in clinical outcomes, cost, tolerability or administration routes,” says Genentech’s Evans.
The European playbook does not necessarily translate
“The European Medicines Agency pioneered the regulatory guidelines for biosimilars; thus Europe is way ahead of the US in terms of biosimilars—the EU has been approving biosimilars since 2006 and currently has 19–20 on the market, so there are plenty of lessons to be learned from EU experience to date,” notes Bosco of Quintiles. “We are just starting to see more articles being published to showcase the real-world experience with biosimilars there.”
European countries that have a national healthcare system typically have more controlled choices in terms of what drugs are available to be prescribed, so lower-cost biosimilars may be used more widely due to such drivers, she adds. By comparison, in the US, the decisionmaking process for what treatment any cancer patient receives is so highly fragmented, and depends on many different factors—the type of cancer, the stage and severity of the cancer at diagnosis, patient age, co-morbid conditions, treatment options, access (based on both clinical considerations and affordability.)
In addition to the inherent manufacturing complexity, nearly all biosimilars will require at least one head-to-head clinical trial to confirm similarity to the original biologic, and this creates a process that is more complex and costly than that required for standard small-molecule generics.
“While regulators tend to focus mainly on safety issues, physicians and patients are keenly interested in not only safety, but clinical effectiveness, and how the risks and benefits of one treatment compare to another (in terms of comparisons between the biosimilar and the originator product or with other therapy options in the class,” says Nancy Dreyer, PhD, MPH, global chief of scientific affairs, and SVP, real-world and late phase research, for Quintiles. “The onus is on the manufacturer to provide real-world evidence that would substantiate equivalence in a robust enough manner to satisfy physicians, patients and insurance providers.”
“Marketing efforts (to characterize one biosimilar versus another), distribution challenges, mechanisms for returns and adjustments, and sufficient real-world evidence to demonstrate efficacy, safety and interchangeability level will have to be reconciled,” says Brooks of US Oncology Network.
Meanwhile, non-harmonized naming conventions for biosimilars, and policies around interchangeability and automatic substitution among biosimilars, vary by country and by jurisdiction, adding further complexity that will impact the commercialization strategy for any company entering the space, adds Dreyer. “Such rules have implications for drug makers, too, by impacting pharmacovigilance reporting and the ability to track exactly which medication a patient has received during actual clinical practice.”
With all of these challenges facing any manufacturer, “there is a much higher barrier to entry for biosimilars,” says Million of Trinity Partners. “Ultimately, the need for higher capitalization and the ability to handle more risk will reduce the number of players in the biosimilars arena.” Established makers of innovator biologic therapies, such as Amgen, Sandoz and others, are expected to play a big role in biosimilars, thanks to their established footprint and experience in manufacturing and commercialization. Similarly, partnerships, acquisitions and strategic alliances between smaller biosimilars producers and major pharma companies (such as Pfizer and others), will be essential to support the biosimilars market, as it evolves in the US, he adds.
An abbreviated pathway, without head-to-head comparative studies for every indication (only the “most sensitive” ones), is available to biosimilars in the US and EU. While this may cut the time to market, it also generates questions for some stakeholders about how the therapy will perform when used under real-world conditions, says Bosco of Quintiles. “If there is scientific justification, such as a similar mechanism of action (MOA), a biosimilar company may receive approval through extrapolation for all indications that the originator product is approved for. However, some physicians believe that this raises concern with regard to safety and efficacy in those extrapolated indications.”
“In both clinical trials and in actual practice, there is still some hesitancy among prescribers, who may not want to prescribe them, and we’ve been working to explore their angst and hesitation,” says Brooks. “For instance, uptake of Sandoz’s Zarxio is strong now, but it did not happen without a lot of conversation with oncologists, many of whom have a strong, unstated hesitation to embracing biosimilars.”
“Payers themselves may also experiment with, and implement, various mechanisms to promote greater use of biosimilars,” adds James H. Jackson, PharmD, MPH, and VP, global health economics and outcomes research, at Xcenda. “These include differential physician payments based on biosimilar-utilization targets, reliance on pathways that promote less expensive options, and potentially, episode-based contracting structures that will ultimately promote increased use of less expensive therapies.”
Meanwhile, Jackson notes that to receive the most favorable coverage from payers, “manufacturers of biosimilars must work to educate all stakeholders—including payers, physicians, pharmacists, hospital employees, coding/billing staff and patients—on the value of biosimilars, emphasizing both clinical safety and efficacy, and financial impact on patients and overall healthcare costs.”
“As manufacturers explore how to successfully bring biosimilars on to the market, certain strategies will be critical for supporting providers and patients,” says Ana Stojanovska, VP, reimbursement and policy insights, Xcenda. Of particular importance for biosimilars in oncology—where oncology practices so often use a buy-and-bill mode to purchase and stockpile drug inventories onsite—will be a strong focus on strategy and support programs to help practitioners work through the complex insurance verification, billing, coding and prior authorization issues that will only become more complicated as more biosimilars come to market. This will require increased deployment of highly trained, reimbursement-support specialists in the field. “Providers may be unwilling to prescribe biosimilars if they have concerns around payer coverage, and further confusion may arise if future biosimilars may be approved for only some but not all of the reference product’s indications,” she says.
“Current CMS coding policy for physician-administered products places all biosimilars for a reference product into a single billing code, while the innovator or reference product retains its own individual billing code,” explains Stojanovska. “From a payment standpoint, this means that as more biosimilars come to the marketplace, they will be reimbursed based on a shared average sales price (ASP) for all biosimilars (plus 6% ASP of the reference product).”
Some are concerned that this shared ASP could result in an unpredictable and volatile drug pricing environment for biosimilars, which could heavily impact the economics of the oncology practice. “In such an environment, some providers could perceive the reference product as being more predictable and less cumbersome from an administrative and logistical perspective, and choose to utilize reference products despite the availability of lower-priced biosimilars,” Stojanovska continues. Today, she says there are a number of advocacy efforts underway that are targeted at improving the current CMS coding policy for biosimilars.
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