The Same, But Different: Biosimilars May Rival Name-Brand Cancer Treatments

What’s new about the recently approved medication Zarxio? Nothing — and everything.

Zarxio (filgrastim-sndz) is an injectable medication that produces a vital effect; it stimulates bone marrow, increases white blood cell production and thus helps patients taking chemotherapy for breast or other cancers to fight off infection. It is also a breakthrough cancer medication for a very unusual reason: There’s absolutely nothing new about what Zarxio does or how it does it.

Zarxio mimics an older treatment called Neupogen (filgrastim), but unlike generic versions of typical name-brand drugs, it’s not 100 percent identical to Neupogen. That’s because Neupogen isn’t a traditional medicine that can be synthesized in any properly equipped lab or factory. It’s a genetically modified strain of E. coli bacteria that comes from a particular culture owned by a particular company. Zarxio is a different strain of modified E. coli — one that can still be distinguished from the original even though it has undergone such similar modifications that it also produces human granulocyte colony-stimulating factor and performs like Neupogen in trials.

Zarxio, therefore, is a breakthrough because it acts the same as Neupogen without actually being the same. Zarxio was the first so-called “biosimilar” approved for sale in the U.S., and it’s still the only such medication used in cancer treatment, but that’s probably about to change. Many of the most important cancer medications developed in the past 20 years are monoclonal antibodies that are just losing patent protection. Like Neupogen, they are complicated biological drugs that are developed in ways that cannot be copied precisely, so would-be competitors have created biosimilar rivals that are nearly ready for use. The difficulty of reproducing medications that are harvested rather than synthesized has led the U.S. Food and Drug Administration (FDA) to require more proof of safety and efficacy from biosimilars than generics. The generic approval process typically requires nothing more than chemical analysis. The biosimilar approval process requires most candidates to undergo chemical analysis and trials in both animals and humans.

Still, many companies are spending the money to develop and test biosimilar cancer medications. Amgen has already filed for permission to sell a biosimilar of Avastin (bevacizumab), an antibody drug that disables blood vessels needed to support a tumor and is approved for use in metastatic HER2-negative breast cancer in Europe and several other cancer types, including some gynecologic diseases, as well as some lung, colon and brain cancers. Both Amgen and Mylan have completed what they believe to be the last trials needed to receive approval for two different biosimilars of Herceptin (trastuzumab), another antibody that treats HER2-positive breast cancer. Novartis believes it has finished testing a biosimilar to Rituxan (rituximab), which is used to treat non-Hodgkin lymphomas. And a smaller company called Sorrento Therapeutics has announced results of phase 3 trials on a biosimilar of Erbitux (cetuximab), which treats squamous cell carcinoma of the head and neck, as well as certain colorectal cancers.

Evidence from Europe, which implemented a comparable biosimilar approval process a decade ago, suggests the FDA’s rules will ensure American patients that biosimilars are both as safe and as effective as the treatments they imitate. That said, neither the biosimilar trial process nor any biosimilar’s brief time on any market here in America provides the sort of overwhelming performance data that’s available for original medications.

How much will doctors and patients trust an approval process that deems biosimilars as effective as originals against all tumor types for which they’re approved, after comparing them against just one tumor type in trials?

One expert who’s very comfortable with the idea is Francisco J. Esteva, M.D., Ph.D., director of the Perlmutter Cancer Center at NYU Langone Medical Center.

“At this point, the process of developing a biosimilar is not as exact a science as the process of developing a generic drug, but the companies that are developing them tend to be very large and very reputable, and the approval process is rigorous,” Esteva says. “I would feel comfortable using any approved biosimilar from a well-established company, and patients should feel comfortable, too. If it hadn’t shown itself to be equivalent, the FDA wouldn’t have approved it.”

Another important question is what the introduction of biosimilars will do to the cost of treatment. When biosimilars are approved by the FDA, it is expected that they will be covered by health insurers. But once that happens, will insurers continue to pay more for original treatments?

Biosimilars are anticipated to cost significantly less than original treatments. Optimistic observers think that a combination of good policy and good luck could eventually reduce the prices of very expensive treatments by more than half. Even skeptics believe that biosimilar competition will not only end yearly price hikes but also force price cuts that exceed 20 percent. Of course, there are unresolved questions about how this will work. For instance, if there is only one biosimilar for a drug, will that represent enough competition to drive prices down significantly? Will drug companies fight to keep prices up for their brand-name drugs by increasing their advertising and promotional efforts?

UP AND COMING

Traditional medications dispensed via pills are now known as small-molecule medications, and for good reason. A small number of atoms, arranged in a relatively simple shape, produce the active ingredient. They tend to be pretty easy to make, pretty easy to store and pretty easy to compare in the laboratory.

Everything about a biologic medication like a monoclonal antibody is more complex. They can easily have 1,000 times as many component parts, which makes it hard to compare the structure of any two molecules. They are fragile living things, which makes it impossible (with current technology) to put them in a pill and store them anywhere for months. Most importantly, they are grown, rather than made. Antibodies from unrelated cultures could no more be structurally identical than grapes from different vines. Indeed, because cells make errors when they reproduce themselves, today’s name-brand antibodies are somewhat different than their ancestors that were approved by the FDA. They are, to some degree, biosimilars of themselves. All that said, experience shows that it’s possible to overcome these challenges and copy biologic treatments in every way that matters.

The FDA approved Zarxio in March 2015, thanks largely to a pair of head-to-head trials with Neupogen — one in 174 healthy volunteers, the other in 388 patients with breast cancer. Side effects were comparable in both trials and efficacy on white cell counts and infection rates was comparable in the breast cancer trial. (Although the efficacy trials were only done in patients with breast cancer, the FDA approved Zarxio for all five indications that Neupogen had earned with separate trials.)

Studies comparing the outcomes of American patients who use Zarxio and Neupogen have yet to appear, but there is extensive real-world data for Zarxio use from other nations. The medication was approved in 2009 in the European Union, where researchers have followed more than 3,800 people who take the drug and found no signs that it performs differently than Neupogen.

There’s no real-world data yet for any other biosimilar designed for patients who have cancer (or any biosimilar designed to treat actual cancer), but Amgen has released data on trials that compare the original medications to its versions of Avastin and Herceptin. Indeed, more than a year has passed since the company reported that its Avastin biosimilar (known as ABP-215 until the marketing department names it) shrank tumors as effectively as the original in patients with non-small cell lung cancer; 642 participated and were randomized to either ABP-215 or Avastin. Amgen believes this one trial will lead the FDA to approve ABP-215 for all seven cancers on Avastin’s list of indications: breast cancer, colorectal cancer, glioblastoma, non-small cell lung cancer, ovarian cancer, cervical cancer and renal cell carcinoma.

At least one other company hopes to have an FDA-approved Avastin biosimilar by the time that drug loses its U.S. patent protection in 2019. Samsung Bioepis announced in April that it had launched a phase 3 trial for its own candidate, which is also unnamed.

As for Amgen’s Herceptin biosimilar, ABP-980, top-line data from a trial in 725 patients with earlystage breast cancer expressing high levels of HER2 (human epidermal growth factor receptor 2) indicate that the experimental product is certainly not inferior, and is possibly superior, to the original.

Another Herceptin biosimilar, this one from Mylan, has also completed a phase 3 trial designed to win it FDA approval. Investigators randomized approximately 450 women with untreated metastatic HER2- positive breast cancer to a taxane chemotherapy and either Herceptin or MYL-1401O.

“Our efficacy endpoint was overall response rates at 24 weeks in the intent-to-treat population, and those rates were almost identical in the two trial arms,” said lead investigator Hope S. Rugo, M.D., director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco. “Safety was also identical between the two arms … This study demonstrated equivalency based upon regulatory criteria in both the United States and Europe.”

Another product that Amgen has in the works is a biosimilar of Rituxan, which targets the immune system’s B cells by binding to the protein CD20. (It is used to treat diseases characterized by overactive, malfunctioning or malignant B cells.) However, development of Amgen’s product is significantly behind development efforts at Novartis, which has already asked the European Medicines Agency (EMA) to approve its Rituxan biosimilar on the strength of clinical trials in 173 patients with rheumatoid arthritis and 629 patients with follicular lymphoma.

Some trial data is also available for an unnamed biosimilar of Erbitux, which binds to epidermal growth factor receptor (EGFR) and thus disrupts growth of EGFR-expressing metastatic colorectal cancer that is free from KRAS mutations. STI—001 from Sorrento Therapeutics has yet to undergo head-to-head head comparisons, but, used in conjunction with the chemotherapy irinotecan and compared against irinotecan alone in a phase 3 trial, it did produce results comparable to Erbitux in a trial in 501 patients with colorectal carcinoma.

LESSONS FROM EUROPE

The American biosimilar market lags considerably behind the market in Europe. To date, the FDA has approved only four products: Zarxio; a Remicade (infliximab) biosimilar called Inflectra, which treats patients with Crohn’s disease, colitis, rheumatoid arthritis and other autoimmune conditions; a Humira (adalimumab) biosimilar called Amjevita, which treats a similar list of conditions; and a Lantus (insulin glargine) biosimilar called Basaglar, for diabetes. The EMA, which has a similar approval process but began reviewing biosimilars long before the FDA, has approved 23 biosimilars, including nine Neupogen biosimilars.

All those biosimilars have been monitored by their manufacturers, the EMA, national health systems and independent researchers. Many of these studies have been quite large — the Danish government decided to save money last year by switching nearly every infliximab user from the original Remicade to a biosimilar called Remsima — but none of them have reported underperformance by an approved biosimilar.

The European experience also provides considerably more data about the potential cost savings associated with biosimilar medications. Unfortunately, it does not tell a simple story. Unlike generic drugs, which consistently reduce prices by more than half and often reduce them by more than 75 percent, biosimilars often cost only slightly less than the medications they mimic. Zarxio reportedly cost just 15 percent less than Neupogen when it hit U.S. markets.

Prices in Europe indicate that many factors influence biosimilar pricing, the most important being the number of approved biosimilars for each medication and the ease of substituting the cheapest product for the original drug. In Germany, which has made it easy to shop among many versions of a particular medication, Neupogen biosimilars cost 27 percent less than the original once did. Analysts from IMS Health believe that smart policies could help the U.S. attain similar-sized discounts on a wide variety of medications.

If technological improvements make it easier for companies to reliably simulate biological medications (or make it easier for regulators to evaluate biosimilars without costly trials), prices would likely drop further still. What’s more, most people would probably be comfortable prescribing or taking biosimilars.

Generic drugs seemed a bit scary to many people at first, but almost everyone is comfortable with them now. They currently account for nearly 80 percent of all the medications consumed in the U.S., and they save the system millions of dollars per day.

Until doctors and patients become that comfortable with biosimilars, however, they may be able to avoid using them. Although the FDA can deem a biosimilar fully interchangeable with the original — and in so doing allow pharmacies to substitute biosimilars for name brands at will — none of the biosimilars approved so far have been deemed fully interchangeable.

“A patient can ask about, and a health care professional can prescribe, a biosimilar product by using its proprietary name (e.g., Zarxio) or its nonproprietary name (e.g., filgrastim-sndz), just like any other prescription product,” FDA Spokeswoman Sandy Walsh said in a press release. “A health care professional should write the specific name of the product intended to be prescribed (e.g., Zarxio or filgrastim-sndz for the biosimilar or Neupogen or filgrastim for the reference product).”

Pharmacies in most states will have to fill the prescription as written.