Christina Mattina

A research poster presented by at the Academy of Managed Care Pharmacy Annual Meeting, held March 27-30 in Denver, Colorado, explored the effectiveness and safety outcomes of the branded and biosimilar versions of filgrastim in a real-world comparative study.

Sandoz, the maker of a biosimilar version of filgrastim-sndz sold as Zarxio, has been locked in 

 with Amgen, manufacturer of the branded filgrastim sold as Neupogen, for almost 2 years. A Supreme Court decision on the “patent dance” fight is expected by this June, but in the meantime, researchers have continued to investigate whether the drugs are clinically equivalent.

In randomized trial settings, filgrastim-sndz has demonstrated a high degree of similarity to the reference drug with no clinically meaningful differences in effectiveness. The drugs are granulocyte-colony stimulating factors (G-CSFs), which work to prevent chemotherapy-induced febrile neutropenia by imitating natural proteins that spur neutrophil production in the bone marrow. Febrile neutropenia was defined as hospitalization with a diagnosis of infection and/or neutropenia, within 14 days post-index (broad definition). The narrow definition was hospitalization with a diagnosis of infection and neutropenia within 14 days post-index.

Although randomized trials have demonstrated equivalent outcomes sufficient for FDA approval, a group of researchers from Humana decided to investigate the real-world effectiveness and safety outcomes of filgrastim and filgrastim-sndz, as well as pegfilgrastim, which is another G-CSF sold as Neulasta by Amgen. The researchers used administrative claims data from the Humana Research Database of around 19 million patients enrolled in commercial or Medicare plans.

Beneficiaries with medical and pharmacy coverage were included in the study if they had a claim for a G-CSF during the study period and had received chemotherapy within 6 days prior to the G-CSF claim. The research outcomes were the incidence of neutropenia, using both the broad and the narrow definitions, and the incidence of adverse events, defined as a claim for spleen rupture, acute respiratory syndrome, serious allergic reaction, capillary leak syndrome, thrombocytopenia, leukocytosis, cutaneous vasculitis, or bone and muscle ache.

The researchers determined that filgrastim and filgrastim-sndz had less than a 1% difference in the incidence of febrile neutropenia, using both the broad and narrow definitions. This small difference in incidence combined with a confidence interval that crossed 0 indicated statistical equivalence. The incidence of adverse drug events, however, was higher among the patients with claims for filgrastim-sndz (5.9% vs 3.4%).

In a separate analysis comparing filgrastim to pegfilgrastim, which has greater bioavailability, the researchers found that the only measure for which the 2 drugs were equivalent was the narrower definition of febrile neutropenia, which required the presence of both infection and neutropenia—patients taking pegfilgrastim had significantly higher rates of adverse medication events (5.8% vs 3.4%) and febrile neutropenia when defined broadly as infection and/or neutropenia (6.8% vs 3.4%).

The study authors concluded that this real-world evidence does not necessarily support equivalence between branded filgrastim and the biosimilar or the newer pegfilgrastim. They acknowledged, however, that the study group sizes were imbalanced and they could not control for differences in cancer type or chemotherapy exposure, which could have accounted for some of the variability in outcomes.

“The study findings should be interpreted in context given that chemotherapy regimens vary based on patient and cancer type/stage,” the poster explained.

The researchers also indicated that they could not include tbo-filgrastim, sold by Teva as Granix, in the statistical comparison due to low sample sizes in the claims database. Tbo-filgrastim’s approval predated the initiation of the FDA’s biosimilar approval pathway, so it is not technically considered a biosimilar, but it has demonstrated comparable safety, efficacy, and pharmacokinetic activity to the branded version of filgrastim.  

Douglas AG, Schwab P, Lane D, Kennedy K, Slabaugh L, Bowe A. A comparison of brand and biosimilar granulocyte-colony stimulating factors for prophylaxix of chemotherapy-induced febrile neutropenia. Presented at the AMCP Managed Care & Specialty Pharmacy Annual Meeting 2017, Denver Colordao. 

Articles

New Research Compares Effectiveness, Safety of Branded and Biosimilar Filgrastim

following the approval of filgrastim-sndz (Zarxio), a biosimilar product developed by Sandoz. Amgen, which markets the reference drug filgrastim (Neupogen), now claims that Sandoz did not provide sufficient information about the biosimilar, Zarxio. Here's a 

Infographic: A Guide to Briefs in the Amgen vs Sandoz Supreme Court Case

According to budget projections, filgrastim biosimilars could save health insurers millions of dollars each year as they seize more market share from the branded drug, Neupogen, a granulocyte colony-stimulating factor (G-CSF).

 by Susan Gabriel, director of global health economics and outcomes research for Teva Pharmaceuticals, at the American Society of Hematology’s 2016 meeting. It assessed the potential monetary impact on payers of increased use of filgrastim-sndz, sold by Sandoz as Xarxio, and tbo-filgrastim, sold by Teva as Granix.

Tbo-filgrastim is not technically regarded as a biosimilar, as it preceded the development of the FDA’s biosimilars approval pathway, but its Biologics License Application was approved after it demonstrated comparable safety, efficacy, and pharmacokinetic activity to Neupogen.

Analysts ran a model, which assumed that tbo-filgrastim would take 5% of the market share over a 1-year period and filgrastim-sndz would take 2%, resulting in a total 7% loss of market share for filgrastim. They calculated the annual drug cost per patient based on a regimen of 6 cycles of 10 days each. Their estimates for the yearly per-patient costs in both medical benefits and pharmacy benefits are as follows:

Tbo-filgrastim: $11,904 to $19,047 in medical benefit; $16,961 to $27,199 in pharmacy benefit

Filgrastim-sndz: $15,418 to $24,669 in medical benefit; $16,216 to $26,015 in pharmacy benefit

Filgrastim: $15,573 to $24,917 in medical benefit; $18,034 to $30,663 in pharmacy benefit

Overall, the use of short-acting G-CSFs for 1 million members would cost a health plan $177.1 million annually under the current scenario and $175.2 million in the future scenario, representing a yearly saving of almost $2 million. The model was sensitive to changes in the proportion of patients whose G-CSF drugs are administered by their healthcare providers, and to fluctuations in the average price per dose of filgrastim.

G-CSFs like filgrastim are used to fight neutropenia in patients receiving chemotherapy, as they work similar to the body’s proteins that signal to the bone marrow to produce more neutrophils. Neutropenia is a common and serious complication for many cancer patients, as it can result in severe infections and even death.

Due to the high price tag of the branded drug, payers, clinicians, and patients alike are looking to biosimilars as a potentially less expensive solution.

“Based on these assumptions, a million-member health plan could save almost $2 million per year by switching over to tbo-filgrastim as opposed to filgrastim or filgrastim-sndz,” Gabriel concluded. “However, as with any budget impact model, estimated results based on future product market share should be interpreted cautiously.”

Payer Cost Savings From Filgrastim Biosimilars Could Reach $2 Million Annually 

Currently, 29 US states and Puerto Rico have passed laws allowing pharmacists to substitute biosimilars in place of a name-brand biologic drug. However, not all biosimilars laws are created alike: some require patients to be notified of the substitution, and some dictate that any substitutions must be for the lowest-cost drug.

To learn more about biosimilars legislation and which state could be next to pass such a law, see the 

Infographic: Biosimilar Substitution Laws By State

The approval of Scott Gottlieb, MD, as FDA Commissioner would place a staunch advocate for biosimilar development at the head of the drug approval agency. Gottlieb’s past writings and actions signal his support for speeding up the pipeline for “robust pharmaceutical innovation.”

After a whirlwind of rumors on March 10, President Donald Trump confirmed that he would nominate Gottlieb to lead the FDA. Gottlieb, who had widely been considered the frontrunner for the position, is a less radical choice than other names that had been hypothesized for the post, but if confirmed he could have a transformative impact on the drug approval process, including the pathway for biosimilars.

 Gottlieb favors a more rapid pace of drug approvals, but without discarding current safety and efficacy regulations. He has also advocated for greater transparency during the approval process, saying that the FDA should publicly release the complete response letters it sends when it rejects a drug application, instead of keeping them under wraps as they are now.

Perhaps the biggest clue into Gottlieb’s stance on biosimilar regulation comes from a 

 with Gillian Woollett, MA, DPhil, in 2013, where they discussed how policy compromises can balance innovation and value, adding that “biopharmaceutical innovation is increasingly dependent on a functional regulatory path for quality biosimilars.”

Specifically, he praised the European Medicine Agency for its “abridged regulatory process that creates genuine savings,” while the FDA had yet to “make key regulatory decisions” regarding interchangeability, bioequivalence, and labelling indications. Biosimilars’ promise of innovation, he cautioned, “will be put at risk if policy makers start to implement blunt measures to restrict the pricing and access to these drugs by policies that reduce the market-based incentives that have attracted capital into these endeavors.”

Gottlieb’s support for biosimilars dates back even before the FDA implemented the Biologics Price Competition and Innovation Act in 2010. He penned an 

article for the American Enterprise Institute

 in 2008 that envisioned how an abbreviated regulatory pathway for biosimilars could produce cost savings and expand access to treatment. He recommended using the European Union’s biosimilar approval process as “a model for anticipating and resolving the scientific and policy issues related to biosimilars in the U.S.”

Gottlieb has worn many hats in the pharmaceutical and medical industries, but his most relevant experience was his role as deputy FDA commissioner of medical and scientific affairs under President George W. Bush. After serving as a practicing physician, he also currently works as a clinical assistant professor at New York University, is a resident fellow at the American Enterprise Institute, a 

 contributor, and a health information technology adviser for HHS. He will have to give up these posts if the Senate confirms his nomination to lead the FDA, which appears likely.

Dr Scott Gottlieb, Trump's FDA Pick, a Consistent Supporter of Biosimilar Innovation 

German pharmaceutical company Merck KGaA has confirmed that it is far along in talks to sell off its biosimilars unit, which has not yet brought any drugs to the market.

Rumors began swirling in October, amid reports that Merck was seeking a buyer for its biosimilars unit. Chief executive Stefan Oschmann 

 at a press conference today, saying that Merck is in “deep talks” to sell off the division. He did not reveal the identity of the buyer or the selling price of the unit, but its worth is estimated at around $1 billion.

The prospective buyer to gain the division has not yet put a product on the market, but has built solid foundations for eventually becoming competitive. According to Merck’s website, the biosimilar portfolio is focused on therapies for cancers and inflammatory disorders. Last year, it began a phase 3 study of its proposed adalimumab biosimilar to compete with the branded drug, Humira, made by AbbVie. The trial results have not yet been released.

In 2015, Humira cost an average of $27,665 per year after discounts, an increase of almost 50% from its cost 3 years prior. Due to these high prices, it has become a popular target for drug companies hoping to market a less expensive biosimilar to patients with chronic plaque psoriasis. This opportunity means that a number of Merck’s competitors have already gotten a head start on developing a biosimilar for adalimumab.

Amgen’s Amjevita is the only adalimumab biosimilar to be approved by the FDA, but its launch has been delayed by legal roadblocks from AbbVie. 

 from phase 3 trials that showed its adalimumab biosimilar achieved the endpoints for demonstrating efficacy. 

 successful bioequivalence trial results in an announcement the week before.

, Merck began collaborating with India-based Dr. Reddy’s in 2012 to develop a host of potential biosimilars, including ones for adalimumab, rituximab (sold as Rituxan by Roche), and pegfilgrastim (sold as Neulasta by Amgen). The FDA has not yet approved biosimilars for the latter 2 drugs, although its European 

counterpart granted authorization to Celltrion’s

 rituximab biosimilar, Truxima, this February. Mylan and Biocon’s pegfilgrastim biosimilar application is 

 the increasingly crowded biosimilar market, it will likely concentrate its development efforts on multiple sclerosis to capitalize on the success of its interferon beta-1a injection, sold as Rebif. 

Merck KGaA Close to Selling Biosimilars Division to Undisclosed Buyer 

At the American Academy of Dermatology Annual Meeting, 

 that its proposed biosimilar adalimumab has met its primary endpoint for demonstrating efficacy in clinical trials.

The phase 3 study results found that the proposed biosimilar, GP2017, was in fact slightly more effective than the reference drug, AbbVie’s Humira. The primary endpoint was the proportion of participants with moderate to severe chronic plaque psoriasis who saw a 75% improvement in symptoms, as measured by the Psoriasis Area and Severity Index. After 16 weeks of treatment, 67% of those receiving the biosimilar achieved this benchmark, as did 65% of those on Humira. 

At the end of the first 17-week study period, GP2017 had demonstrated favorable results for safety and immunogenicity, as the occurrence of adverse events and antibody reactions were similar to those observed in patients receiving the reference drug. Any adverse events were consistent with those listed in Humira’s safety profile.

Executives of Sandoz, a subsidiary of Novartis, heralded the trial data as an exciting step towards expanded access to treatment for patients with chronic plaque psoriasis.

"Currently, it is estimated that as few as five percent of eligible psoriasis patients get the biologics they need," said Mark Levick, MD, PhD, global head of development in biopharmaceuticals at Sandoz. "We are pleased the data reinforce the potential of our biosimilar adalimumab, if approved, to be another treatment option for moderate-to-severe chronic plaque psoriasis and other inflammatory diseases."

Sandoz plans to file its application for GP2017’s approval with both the European Medicines Agency and the FDA this year. The FDA filing was originally intended for the last quarter of 2016, but was pushed back due to concerns about the timing of regulatory inspections in conjunction with manufacturing facility upgrades, 

. Chief medical officer Vasant Narasimhan denied that the delay was due to any unfavorable clinical data for the proposed biosimilar.

GP2017 will be racing against another competitor, Coherus’s CHS-1420, as it travels through the development and approval pipeline. Less than a week ago, 

 that its proposed adalimumab biosimilar achieved pharmacokinetic (PK) equivalence with the reference drug in clinical trials and had demonstrated comparable safety and tolerability profiles.

The president and CEO of Coherus, Danny Lanfear, said that the drug maker is confident it can “similarly complete future PK studies with modified formulations, anticipated to commence later in 2017.” He did not specify a timeline for submitting a regulatory application.

There is currently just 1 FDA-approved biosimilar for autoimmune drug adalimumab, Amgen’s Amjevita, but its launch has been held up by patent lawsuits from AbbVie. One analysis in 2015 reported that a yearlong course of AbbVie’s Humira cost an average of $27,665 after discounts, an increase of almost 50% from its cost 3 years prior.

Sandoz Releases Efficacy Data for Its Humira Biosimilar

 that its proposed adalimumab (Humira) biosimilar met the primary endpoints in a bioequivalence study, which signifies an important step towards approval.

The drug, currently referred to as CHS-1420, achieved the necessary criteria for clinical pharmacokinetic (PK) similarity to the reference drug in a randomized, double-blind study. It assessed bioavailability after administration of a 40 mg injection using 3 metrics: maximum serum concentration, area under the time-concentration curve from first to last time point measured, and area under the time-concentration curve from first time point extrapolated to infinity.

This early-stage study, conducted in healthy subjects, also found that CHS-1420 was well-tolerated and did not find any safety differences between the biosimilar and the branded drug. In the announcement, Coherus executives expressed optimism about the study findings and the future of the potential biosimilar.

“Positive results from this study are an essential global regulatory requirement to demonstrate PK bioequivalence on multiple prespecified primary PK endpoints between CHS-1420 and Humira,” said Barbara Finck, MD, chief medical officer of Coherus. “We are pleased to have achieved results which we believe represent a significant reduction in development program risk.”

“This is our second successful CHS-1420 PK study,” added Denny Lanfear, president and CEO of Coherus. “Our ability to achieve these results gives us confidence that we can similarly complete future PK studies with modified formulations, anticipated to commence later in 2017.”

Coherus has 2 other biosimilar products under development, for etanercept (Enbrel) and pegfilgrastim (Neulasta). The company has already filed a Biologics Licens Application in the United States and Europe for the pegfilgrastim biosimilar, while the etanercept biosimilar is in phase 3 studies. 

Adalimumab is used to treat autoimmune diseases like rheumatoid arthritis, Crohn’s disease, and some kinds of psoriasis. Since the patent on Humira expired in 2016, the FDA has approved 1 adalimumab biosimilar, Amjevita, made by Amgen. Its entrance into the market has been delayed by patent lawsuits brought by AbbVie, which manufactures Humira.

Coherus is not the only drug maker jumping into the fray of adalimumab biosimilars. Sandoz, a subsidiary of Novartis, has been developing its own candidate, but 

 with the FDA. Executives said that the delay was unrelated to the drug’s clinical performance; instead, the application was postponed so the company could have time to upgrade its manufacturing facilities before an inspection would be required.

Bioequivalence Endpoints Successfully Met for Humira Biosimilar, Coherus Announces

A recent report predicts that the market for biosimilar drugs to treat diabetes will grow rapidly in the coming years, fueled by impending patent expiries and the rising costs incurred by diabetes patients.

According to the American Diabetes Association (ADA), the total costs of the disease reached $245 billion in 2012, representing both direct medical costs and reduced productivity. Over 29 million Americans have diabetes—a number that grows by about 1.4 million per year&mdash;and in 2013 they paid an estimated $1922 of their $14,999 average annual healthcare costs out of pocket.

Looking at these factors, it is clear why drug developers and patients alike are excited about the prospect of biosimilar drugs to treat diabetes. According to a 

, biosimilar insulin has the “potential to reduce diabetes treatment costs, increase accessibility of insulin treatment, and expand the number of insulin brands.”

In late 2015, the FDA approved Basaglar, an analog of insulin glargine, which was produced by Eli Lilly and Boehringer Ingelheim. It could not technically be approved as a biosimilar product because “no insulin glargine products are currently licensed under the Public Health Service Act, so there is no ‘reference product’ for a proposed biosimilar product,” according to 

Still, Basaglar underwent rigorous testing similar to the processes of the biosimilar approval pathway, as the application had to demonstrate that Basaglar was not only safe and effective, but was also sufficiently similar to the branded drug, Lantus. The approval of the new drug was accelerated by the inclusion of safety and effectiveness data from when the FDA approved Lantus.

Other insulin glargine analogs, including one by Samsung Bioepis and Merck, are currently under review by the FDA, and some are available in the overseas market. The report also predicts that biosimilars will be developed for insulin aspart and insulin lispro when their patents expire. Prior 

 that insulin glargine biosimilars could produce savings of up to 15%, but with the introduction of additional competitors, the price will likely drop further.

The report notes that some drug makers may face challenges in getting insulin biosimilars on the market due to the “stringent regulatory requirements” in the United States. However, it predicted that the allure of selling a more affordable biosimilar alternative to the growing population of diabetes patients will outweigh most companies’ hesitancies about the drug development process.

ADA and other organizations are looking forward to increased biosimilar availability, citing their potential to lower prices and expand access.

“We are excited for the availability of more biosimilar insulins for people with diabetes, with the recent approval of insulin glargine and the ongoing development of aspart and lispro,” said William T. Cefalu, MD, chief scientific, medical, and mission officer of the ADA. “Availability of biosimilars could increase access to analog insulins, which provide more tailored insulin treatment, and improve health outcomes for the nearly 6 million Americans with diabetes who rely on insulin.”

Cefalu emphasized that the promise of biosimilars can only be fulfilled if they are priced substantially lower than brand-name drugs, which can be a difficult endeavor considering their high development costs.

“With regards to cost, the impact of biosimilars is currently unclear. A key challenge to pricing of biosimilars is the production process—it is expensive to produce insulin, and the FDA will only approve a biosimilar product if it has the same mechanism of action, route of administration, dosage form, and strength as the reference product,” Cefalu explained.

“What we saw with the introduction of insulin glargine (Basaglar) in January was a savings of approximately 15% off of the list price of the brand-name insulin glargine. We are hopeful for insulin to be accessible and affordable for all who need insulin.”

Diabetes Drugs Could Be Next Frontier of Biosimilar Development

Celltrion’s Truxima, a biosimilar of rituximab, has been granted approval from the European Medicines Agency (EMA) for its use in several cancers and autoimmune disorders. The drug has already been approved in Korea, and Celltrion plans to submit an application to the FDA this year.

 announcing the approval, Truxima is the first biosimilar monoclonal antibody approved as an oncology therapy. It has been indicated for the treatment of non-Hodgkin’s lymphoma and chronic lymphocytic leukemia, as well as autoimmune disorders (rheumatoid arthritis and granulomatosis with polyangiitis and microscopic polyangiitis).  

 that gave the application the green light for the subsequent marketing authorization. It did so after reviewing data on safety, efficacy, immunogenicity, pharmacodynamics, and pharmacokinetics that demonstrated convincing similarity between Truxima and the reference rituximab, sold by Roche as MabThera. The Celltrion press release declared that these “trials were conducted in over 600 patients and include data up to 104 weeks.”

Truxima is manufactured in Korea, where Celltrion is based. In November, when Korea’s Ministry of Food and Drug Safety approved Truxima, 

 about the drug’s chances of success with the EMA, as its application was then underway, and eventually with the FDA. The company has not yet announced an FDA application, which it said would be submitted sometime in early 2017.

Mundipharma has distribution rights in 7 European countries, and plans to have Truxima on the market starting in the second quarter of 2017. Teva and Celltrion have already formed a $160 million partnership that will allow Teva to sell Truxima in the United States upon its approval by the FDA, according to a 

Celltrion’s manufacturing facilities are undergoing expansion in hopes of boosting production capacity to 310,000 liters by 2021, reflecting its enthusiasm about the potential for biosimilars to disrupt the market and expand access due to their lower price. The press release quoted projections from László Gulácsi, a Hungarian professor and consultant, who said that savings could reach €570 million across the 28 EU countries over a 3-year period, allowing 49,000 new patients to receive the treatment.

"For healthcare systems burdened with high-cost oncology treatments, we are pleased to provide an option that has the potential to offer significant savings whilst ensuring patients retain access to high-quality and effective treatments,” said Celltrion chairman Jung-Jin Seo at a meeting in Paris, according to the press release.