Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

Real-world studies demonstrating comparable safety for trastuzumab biosimilars vs the originator (Herceptin) were presented at the ASCO 2021 Annual Meeting. 

Investigators in Poland said a study of patients with human epidermal growth factor receptor 2–positive (HER2+) breast cancer who switched to the trastuzumab biosimilar Kanjinti yielded safety outcomes comparable to those for Herceptin.

“The 12-month follow-up treatment with Kanjinti [demonstrated] an acceptable cardiac safety profile. In cases where there was a switch from Herceptin to Kanjinti or Kanjinti combined with pertuzumab, the safety profile was similar to that previously reported in other studies,” investigators said.

Clinicians have been cautious about switching patients to trastuzumab biosimilars because of the paucity of real-world data for these agents, hence the value of conducting this study, investigators said in the abstract presented at 

The observational retrospective study evaluated Kanjinti therapy in patients (N = 195) with HER2+

breast cancer between July 2018 and January 2020.

Investigators said 34 patients received carboplatin, docetaxel pertuzumab, and the trastuzumab biosimilar in the neoadjuvant setting; 99 received Kanjinti as monotherapy or in combination with other cytostatic drugs in the neoadjuvant or adjuvant settings; and 62 received docetaxel, pertuzumab, and the trastuzumab biosimilar in the metastatic setting.

In this population, pertuzumab was used in conjunction with the trastuzumab biosimilar in 49% of patients (32%, first line of palliative treatment; 17%, neoadjuvant settings); 65% of patients with metastatic breast cancer switched to the biosimilar form of trastuzumab; and 37% of patients with early breast cancer switched. “Switching was done at a median of the fourth cycle.”

Investigators said 6 patients experienced a decline in left ventricular ejection faction and no other trastuzumab-related adverse events (AEs) occurred.

In a second real-world trastuzumab biosimilar (Zedora; Mylan/Biocon) Brazilian study, predominantly evaluating patients with HER2+ breast cancer, AEs for Zedora were comparable to those associated with Herceptin.

“The risk benefit remains consistent with the reference safety information and no new safety signals were detected,” investigators wrote. 

Zedora is marketed in the United States under the brand name Ogivri and was 

Investigators evaluated 74 AE reports from 73 female patients with

HER2+ breast cancer and 1 male patient with gastric adenocarcinoma. Among 656 AEs identified in the reports, 588 (89.63%) were nonserious (413 expected, 175 unexpected) and 68 (10.37%) were serious (51 expected, 17 unexpected)

Among the 17 serious unexpected AEs, 13 were not related to trastuzumab therapy and 4 were related to therapy, investigators said. Among the 175 nonserious unexpected AEs, 56 were unrelated to therapy vs 119 related.

The most common AEs, according to system organ classification, were 111 (16.92%) general disorders/administration site conditions, 98 (14.93%) gastrointestinal disorders, and 88 (13.41%) nervous system disorders.

Those included diarrhea (4.11%), fatigue (3.66%), nausea (3.35%), weight decrease (2.74%), and infusion reactions (2.59%).

“The AEs noted in patients with breast cancer and gastric cancer treated with biosimilar trastuzumab were consistent with the known safety profile of trastuzumab,” investigators said. Earlier findings from the study were reported at ASCO annual meetings in 2019 and 2020.

1. Jagiello-Gruszfeld AI, Lemanska I, Brewczynska E, et al. Trastuzumab biosimilar (Kanjinti) in breast cancer patients: one-center retrospective observational study. Presented at: ASCO 2021: June 3-7, 2021. Abstract e13015.

2. Monteiro da Silva A, Watanabe TTWO, Honda E, Yamaguchi J. Biosimilar trastuzumab active post marketing surveillance real world 2020 data update: results from a patient support program for patients under treatment with the first biosimilar trastuzumab approved in Brazil. Presented at: ASCO 2021: June 3-7, 2021. Abstract e14504.

Articles

Real-world evidence from Poland and Brazil confirms comparable safety for the trastuzumab biosimilars Kanjinti and Zedora in the breast and gastrointestinal cancer settings.

Safety Findings Are Reported for Trastuzumab Biosimilars

Amneal Pharmaceuticals said the FDA is reviewing its 

(BLA) for a proposed bevacizumab biosimilar (Alymsys).

The product candidate references Avastin and was developed in collaboration with mAbxience of Spain. Amneal, of Bridgewater, New Jersey, said the FDA expects to complete the BLA review in the second quarter of 2022.

Amneal is also developing biosimilars for filgrastim and pegfilgrastim, referencing Neupogen and Neulasta, respectively.

Bevacizumab is a vascular endothelial growth factor inhibitor used in the treatment of metastatic colorectal cancer as well as other cancers. Amneal is seeking an indication for colorectal cancer and intends to seek approvals for other indications too, although once a biosimilar is approved for 1 indication of an originator biologic, health care practitioners are free to use it for other indications.

The company noted that bevacizumab sales in the United States were $2.8 billion for the year ended April 2021. Two existing bevacizumab biosimilars, Mvasi and Zirabev, were launched in July 2019 and December 2019, respectively.

Xcenda Releases Report on Originator Pricing

The first biosimilar in the United States was approved 6 years ago, and since that time, biosimilar competition has succeeded, on average, in averting 

 on originator drugs for which biosimilars are available, according to the Biosimilars Forum and Xcenda, a division of Amerisource Bergen. 

The findings were based on the 2-year average sales price (ASP) trends for the originator biologic products over the 2 years prior to the introduction of the respective biosimilars. Xcenda said that without the presence of biosimilar competition, prices for the originator drugs would have climbed 56% on average.

The price increase estimates are not based on actual price increases by the reference product companies, nor is it certain that the companies would have increased their prices at all or to the extent that Xcenda projected. There are currently 20 biosimilars on the market referencing 7 originator drugs.

Despite the downward pricing pressure on reference drugs, making biologics more affordable for patients, “uptake still remains slow,” the report said of biosimilar use. “The US market needs bipartisan policy solutions to break down barriers to continued access.”

According to the report, the ASP for Remicade (infliximab) would have been 150% higher (

); Neulasta (pegfilgrastim), 100% higher (

); epogen and Procrit (epoetin alfa), 60% higher; and Avastin (bevacizumab), Herceptin (trastuzumab), and Neupogen (filgrastim), 13% to 26% higher.

Although the price increase estimates are based only on the assumption that reference companies would have raised their prices, there is evidence that reference product companies are fairly consistent about raising prices of their biologics year by year.

Members of the House Committee on Oversight and Reform in a recent 

 noted the steep and frequent price increases for adalimumab (Humira) and etanercept (Enbrel) over 19 years by AbbVie and Amgen, respectively.

Amgen used to be a member of the Biosimilars Forum but had a 

 with the group in which both sides accused each other of failure to properly support biosimilars in the marketplace.

Similar concerns about pricing were raised this month by the attorney general of Mississippi, who 

 against the big 3 insulin makers, Eli Lilly, Novo Nordisk, and Sanofi, contending that their pricing increases are needless, excessive, and depriving hundreds of thousands of patients of affordable medicine.

For a column on the price projections by representatives of the Biosimilars Forum and Xcenda, 

Magellan Rx Management Touts Biosimilar Savings It Achieved

The pharmacy benefit manager (PBM) Magellan Rx Management said that over a 2-year period it achieved $40 million in 

 for 5 health plans that were early adopters of biosimilars in oncology.

“We have been tracking the emergence of biosimilars and started to deliver biosimilar-first solutions as early as 2016,” said Steve Cutts, PharmD, senior vice president and general manager of specialty drugs.

The program encouraged the use of 3 biosimilars in oncology. From the third quarter of 2019 through the third quarter of 2020, use of these biosimilars grew to 69% vs 31% for the originator products, which initially represented 99% of usage (

). According to Magellan Rx, these biosimilars may offer savings of up to 40% from reference products.

Magellan Rx did not identify the oncology biosimilars used in this program. In a statement issued prior to the start of the program, the PBM said it anticipated 

 to be $5 million to $8 million per 1 million covered lives.

Amneal Pharmaceuticals develops its biosimilar pipeline with mAbxience, Xcenda estimates biosimilar effect on originator pricing, and Magellan Rx Management touts oncology biosimilars savings.

News Roundup: Amneal's Bevacizumab Biosimilar, Originator Pricing Impact, and More

Reykjavik, Iceland–based company Alvotech believes it has obtained the data it needs to convince the FDA to award an “interchangeable” designation for its high-concentration, citrate-free biosimilar candidate (AVT02) for adalimumab.

AVT02 (100 mg/mL) is one of the key drugs in Alvotech’s drug pipeline. Being citrate free, it causes less pain upon injection and has potentially greater acceptance by patients and health care practitioners. The originator company (AbbVie) has already captured significant market share in the United States and Europe with the high-concentration version of adalimumab it introduced in 2018.

The interchangeability designation would constitute an additional differentiator for AVT02. This would allow pharmacists to fill prescriptions with the biosimilar without first having to obtain authorization from a prescribing physician.

Obtaining an interchangeable designation requires a successful switching study demonstrating that no significant clinical differences or risks in safety and efficacy arose despite multiple switches between the biosimilar candidate and the reference product.

On June 15, Alvotech reported a major milestone in the switching study (N = 568) for AVT02. In the first phase of the study, all patients received Humira. In the just-completed second phase, 1 cohort of patients continued to receive Humira and a second cohort switched between AVT02 and Humira. Alvotech reported that it has finished the second phase.

Completion of the second phase, at week 28 of the study, enables Alvotech to collect final data for primary outcome measures of the study. The study, AVT02-GL0302, is evaluating the pharmacokinetics (PK), safety, efficacy, and immunogenicity of AVT02.

The completion of the comparative treatment phase of the switching study is a key milestone in our program for our AVT02 interchangeable biosimilar candidate. Achieving interchangeability in the United States is a cornerstone in our development strategy and consistent with our commitment to patients

“The completion of the comparative treatment phase of the switching study is a key milestone in our program for our AVT02 interchangeable biosimilar candidate. Achieving interchangeability in the United States is a cornerstone in our development strategy and consistent with our commitment to patients,” Mark Levick, CEO of Alvotech, said in a 

Top-line results for the switching study are expected to be reported later this year, the company said. Still to come is the third, open-label phase in which all patients receive AVT02.

Alvotech has applied in the United States and the European Union for approval of AVT02. The company anticipates an FDA decision on the US biologics license application for this product in September 2021 and a European Medicines Agency decision in the fourth quarter of 2021.

In the event of product approvals, however, the exact timing of a market launch will depend on the outcome of litigation between Alvotech and the originator company, AbbVie. The 2 companies have gone to court over the validity of patents governing Humira and whether Alvotech fairly and honestly obtained its technical knowledge of adalimumab production.

Alvotech states that it is the only biosimilar developer so far to seek an interchangeable designation for high-concentration adalimumab. However, it is not the only biosimilar developer to seek an interchangeable designation for an adalimumab formulation.

 from VOLTAIRE-3, a phase 3 randomized study comparing PK for Cyltezo (40 mg/0.8 mL) and the respective adalimumab formulation from AbbVie. Cyltezo was approved in August 2017 and is scheduled for launch in 2023, according to an out-of-court settlement between AbbVie and Boehringer Ingelheim.

Boehringer Ingelheim stated that it was the first, to its knowledge, to report findings that it anticipated would meet FDA requirements for an interchangeable designation—any type of interchangeable biosimilar, not just an adalimumab interchangeable. The FDA has 

Getting to the stage where clinical data on interchangeability are reportable to the FDA is a key milestone in Alvotech’s bid to get its high-concentration adalimumab biosimilar approved and on the market. 

Alvotech Achieves Milestone in Bid to Capture Adalimumab Share

The regulatory pathway for biosimilar approvals was saved from deletion today when the Supreme Court ruled that plaintiffs had no standing to challenge the constitutionality of the Affordable Care Act (ACA), which embodies the Biologics Price Competition and Innovation Act (BPCIA; Title VII) that allows the licensure of biologic products as biosimilars.

The decision (7-2) by the nation’s highest court was not unexpected, although without the certainty of a ruling the biosimilars pathway was never fully in the clear. 

“Biosimilar applications and approvals are continuing to increase as companies and FDA are becoming more familiar with the pathway, and it would have been unfortunate had the biosimilar approval process become a collateral casualty of a constitutional challenge,” said Kevin Nelson, a partner in the intellectual property practice at Schiff Hardin.

The ruling also was applauded by the Biosimilars Forum, an association of biosimilar developers. “Upholding this law means that millions of patients will continue to have access to biosimilars—lower-cost options for life-saving brand name biologic therapies both now and in the future,” the group said in a statement.

Plaintiffs had challenged the constitutionality of the individual mandate portion of the ACA, which requires that participants either obtain health insurance or pay a penalty. Plaintiffs contended that although Congress reduced the penalty to zero dollars, the mandate effectively undermined the constitutionality of the entire ACA. A lower court ruled the mandate was unconstitutional but left it to the Supreme Court to decide whether other provisions of the ACA, including the BPCIA, also should be struck down or were “severable,” meaning they could be preserved.

The plaintiffs were found to have “no standing” in the case, meaning they could not demonstrate that the individual mandate had caused them harm. 

By rejecting the case as lacking standing, the court sidestepped the need to evaluate the issue of severability, noted Ha Kung Wong, an intellectual property attorney with Venable. "This makes it more difficult to bring further constitutional challenges to the ACA in the courts. What this shows us, since this is the third time the Supreme Court has found a way to uphold the ACA, is that this is not an issue that they believe should be addressed in the courts, but, rather, in legislation. 

"The ACA isn't perfect," Wong said, "but this holding perhaps allows us all to refocus on finding ways to improve the ACA to better provide necessary health coverage for Americans." 

Legal experts argued prior to the Supreme Court ruling that the intent of Congress in creating the BPCIA was not that it should hinge on the survivability of components of the ACA. Instead, they argued, the BPCIA was created specifically to ensure that lower-cost competitive alternative biologics should be available to the American public to protect their access to vital, affordable medicines.

To date there have been 29 biosimilar approvals in the United States and 21 of those products have reached the market. Biosimilars, a distant cousin to generic medicines, although much more complex and made from living organisms as opposed to static chemical compounds, are certified as being as safe and efficacious as the originator biologics they reference.

Critics contend that BPCIA upgrades or other fixes are needed to make it easier for biosimilars to reach the marketplace. Heavy litigation, lengthy periods of originator product exclusivity, and  lack of clarity on which patents apply to originator biologics are some of the burdens that biosimilar developers must face.

With the debate over the ACA settled for now, “Congress should go forward with improving the biosimilar pathway to increase confidence and uptake in biosimilars and to provide incentives for companies in seeking to manufacture lower-cost biosimilar products,” Nelson said.

A technicality—inability to demonstrate harm—frustrated plaintiffs whose case threatened to sink not just the Affordable Care Act but also the Biosimilars Price Competition and Innovation Act (BPCIA), the pathway for biosimilars approvals.

Supreme Court Ruling Leaves BPCIA Intact

Citing the cost burden of ever-rising insulin prices on the people of Mississippi, state Attorney General Lynn Fitch has filed suit against major producers and pharmacy benefit managers (PBMs) that produce and distribute insulin, alleging they are running a massive “insulin pricing scheme” designed to gouge patients and payers and leverage higher and higher profits in the absence of strong competition.

“Diabetes is an epidemic in Mississippi,” Fitch says in the complaint filed with the Hinds County Chancery Court in Jackson. Over 400,000 people, or 13.6%, of the Mississippi state population is living with diabetes and 750,000 more are prediabetics with high blood sugar levels that put them at risk of becoming diabetics. To treat diabetics, the state shells out $3.5 billion per year, which Fitch says represents 1 in 4 health dollars spent.

With so many dependent on insulin for good health and survival, they are highly vulnerable to price increases for popular insulin products that have well exceeded 1000% over the past 10 years, Fitch says. Many in the state skip insulin treatments or go without, at risk of severe health problems or death, she contends.

Her lawsuit is not the first attempting to liberate insulin from the near monopolistic conditions that make such price increases possible. In recent years, insulin makers have been hit by racketeering allegations and at least 1 class action suit by patients with diabetes contending they have been gouged by drugmakers.

Using alternate means to lower prices, lawmakers and regulators in the United States have attempted to foster more insulin competition. In 2020, insulin product approvals were moved under the 

Biologics Price Competition and Innovation Act

It is possible that as early as this year, Semglee, a product previously approved as a follow-on copy of Sanofi’s Lantus-brand long-acting insulin, could be approved as a biosimilar under the BPCIA, which would boost its profile and, potentially, its marketing reach in the United States.

However, there is debate whether the BPCIA pathway will lead to robust insulin competition and bring down the price scaffolding erected by the big 3—Sanofi, Novo Nordisk, and Eli Lilly—which dominate the market.

Because the PBMs base the price they charge for the at-issue diabetes medications on the manufacturer’s price, the more the manufacturers inflate their prices, the more money the PBMs make.

In a recent discussion at The Festival of Biologics, expert panelists contended the barriers are high for would-be insulin producers to establish themselves in the United States. Although a simple biologic, insulin is difficult to produce with consistent quality in high volumes, and smaller producers would be 

 to find the resources to do this, they said.

Without large-scale production by competing producers, it’s possible the high prices for insulin products will continue unabated.

The Mississippi suit names insulin producers Eli Lilly, Novo Nordisk, and Sanofi as defendants, along with PBMs CVS Caremark, Express Scripts, and OptumRx. The activity of PBMs is so intertwined with insulin manufacturers that it cannot be said that PBMs do not profit from the extremely high prices of insulin or the price increases, Fitch contends.

 Allegations that Caremark plays any role in determining the prices charged by manufacturers for their products are false, and we intend to vigorously defend against this baseless suit.

“Manufacturer defendants artificially and willingly raise their prices, and then pay a significant portion of that price back to the PBMs” in categories of payments that are disguised to not appear like complementary price increase payments, Fitch alleges. “Manufacturer defendants are able to make these secret manufacturer payments to buy preferred formulary position, which significantly increases their revenue, without sacrificing their profit margins.”

The Center for Biosimilars® reached out for comment to a number of defendants listed in the suit, not all of whom responded by press deadline.

Novo Nordisk said the allegations are false. “We are aware of the complaint and disagree with the allegations made against the company. We are vigorously defending ourselves in these matters,” the company said. “We have a longstanding commitment to supporting patients’ access to our medicines.” Novo Nordisk said that due to the litigation it could not comment further.

CVS’ response to the suit contended the allegations “are built on a false premise and completely without merit.” CVS placed the blame for high insulin prices on pharmaceutical companies. “Nothing in our agreements prevents drug manufacturers from lowering the prices of their insulin products, and we would welcome such an action. Allegations that Caremark plays any role in determining the prices charged by manufacturers for their products are false, and we intend to vigorously defend against this baseless suit.”

Fitch in her suit described the practice of competing insulin producers increasing prices by almost the same increments at almost the same time, resulting in a staircase effect where there is little price differential from 1 product to the next. This compels health care consumers to pay almost the same price for insulin whether they buy it from producer A or producer B and whether they bought it in 2012 or 2020.

Prices of the comparable long-acting insulin products Lantus SoloStar (Sanofi) and Levemir FlexPen (Novo Nordisk) both were roughly $200 by average wholesale price in 2009 and in the $500 to $550 range in 2020, according to the suit.

A similar pricing effect was noted for the adalimumab and etanercept originator products (Humira and Enbrel, respectively), for which 

 have climbed from the $13,590 level in 2003 to $77,590 by 2021, according to a May 2021 report issued by members of the House Committee on Oversight and Reform. The report made similar allegations about pricing behavior by originator companies and called for a Federal Trade Commission antitrust investigation into AbbVie.

The Mississippi suit demands $10,000 in civil penalties "for each purchase of an at-issue" diabetes medication. 

The Mississippi attorney general takes on major insulin producers and pharmacy benefit managers in a suit alleging a massive pricing scheme to gouge patients and payers. 

Mississippi Seeks Restitution for High Insulin Prices

European Union countries are ahead of the United States in introducing biosimilars, and they rely on competitive bidding systems known as tenders to ensure that biosimilars or lowest-cost biologics get used in the clinic. But there is much variability in the way tenders are applied throughout health systems in the European Union, and the playing field isn’t always level for biosimilar manufacturers, according to a new study.

Questions exist around the effective organization and application of tender procedures and significant variation exists in the organization of such tenders across European member states, regions and purchasing groups.

“Signals emerged across the board that some of the current tender approaches might negatively affect market dynamics for off-patent biologicals and biosimilars,” authors of the report said.

Tenders may be structured so that they favor the incumbent supplier—often the originator brand manufacturer—and purchasers may restrict tender awards to a single manufacturer, as opposed to a subset of competing producers, thereby driving others out of the market, they said.

“While price-driven single tender winners generally translate into welcomed large initial savings for health care systems, these might decrease supplier plurality in the market,” the authors wrote.

Tender awards may focus too heavily on achieving deep and immediate reductions in the cost of the relevant biologic and overlook better structuring that might lead to more reliable market sustainability, authors of the study said.

“The focus on generating short-term savings and the existence of originator-favoring tender practices were identified as elements that may limit timely competition from and market opportunity for biosimilar suppliers,” they wrote.

They surveyed hospital pharmacists and purchasers (N = 60) in the European union about their thoughts about and experiences with the tender process. Authors said 47 completed the survey. They also conducted interviews with purchasers and suppliers (N = 28).

Shelf life, stability before and after reconstitution

Reconstitution time, efficient use, handling 

Supply logistics, urgent delivery modalities, packing and storage locations

Customer support, returns policy, product expiration

Home delivery, nurse service, therapeutic drug monitoring support

Product administration (ease of use, injection pain)

Patient services (education, online portals, device training, adherence support)

In the European Union, public and nonpublic hospitals and clinics are encouraged to organize tenders to obtain lowest-cost biologics, but there are factors beyond price that also should be considered in tender awards, authors of the study said. Product or service differentiation, such as application devices and education or user support, can add value to a provider deal.

Relying on these broader criteria can also stimulate suppliers to innovate and “sustainably compete on value-adding criteria,” the authors said.

However, 46% of the survey and interview respondents indicated that tenders they are familiar with generally go to a single winner, and just 9% indicated that tenders are routinely structured to achieve multiple winning suppliers. 

According to the study, 20% of tender contracts are based solely on the price of the biologics, 38% predominantly on price, 19% on price and other criteria equally, and 19% mostly on nonprice criteria.

Many factors that go into award decisions were listed. However, 29% of respondents said emergency delivery and 24/7 reachability of the supplier are important considerations, and 22% said they award based on efficacy and safety data that are issued post regulatory approval decisions.

Ensuring enough players are supplying biosimilars or originator product in the market requires that sufficient volume of demand exists, the authors said. Without enough demand for the underlying biologic, slim volumes allotted to individual suppliers may result in only shallow price discounts, they said.

In smaller countries or in small health care systems, single tender winner deals may still be the best option. In England, regions are divided so that manufacturers get a slice of the overall market, and this still allows for multiple supplier participants.

Prompt and efficient tenders were recommended because unnecessary delays in opening tenders and making awards could discourage participants, the authors said. Some suspicion was expressed by participants in the survey that there are deliberate delays in implementing new tenders, solely to “extend the originator’s market exclusivity artificially.”

In Italy, regional authorities are required to reopen supply agreements 60 days within the launch of a biosimilar, although the authors said this can be problematic if fresh rounds of bidding are opened for each new biosimilar. They also recommended that tender durations last from 12 months to 2 years—neither too frequent nor too seldom—which they said not only would encourage biosimilar manufacturers but also protect patients from too-frequent medication switches.

Presently, tenders are often organized on a single-winner basis, in which the total tendered volume is awarded to 1 supplier. A single-winner tender design generally leads to significant discounts, certainly if the product volume is significant such as in national single-winner tenders.

The study acknowledged that switching patients to biosimilars carries an initial cost, often in terms of additional clinic or hospital visits; however, the authors wrote that these costs are generally offset by the greater savings achievable from biosimilars. “Most purchasers argue that the cost of switching is marginal compared to the savings that are generally generated in a tender and will, as such, not play a decisive role in tender decisions.”

“Steep price erosion” attributed to tender contests demonstrates that companies are “willing to fiercely compete on price due to important advantages” associated with being first to market, participants said. The winning supplier is left in the position of being able to gather real-world data on the use of its biologic, which in turn can be used as a selling point. Further, the deeper the initial discount and the higher the cost of switching patients, the less encouraged purchasers will be to reopen tenders later on for another round of bids.

Barbier L, Simoens S, Soontjens C, et al. Off-patent biologicals and biosimilars tendering in Europe—a proposal towards more sustainable practices. 

The “winner-takes-all” tender process for biosimilar procurement in the European Union runs the risk of driving competitors out of the market, authors of a new survey contend. 

Survey: European Union Needs to Fine-tune Its Biosimilars Procurement 

Same-day vs next-day administration of pegfilgrastim as prophylaxis against febrile neutropenia (FN) in patients undergoing myelosuppressive chemotherapy (CTX) shows promise despite preexisting concerns this may increase the incidence of FN, investigators reported in studies of patients with lung and breast cancer presented at the ASCO 2021 Annual Meeting.

With the savings biosimilars afford and in a country emerging from the COVID-19 pandemic, same-day treatment appears to make economic and practical sense, they said.

Findings from a retrospective study at the University of Arizona suggest that for patients with lung cancer, same day treatment with pegfilgrastim “provides a unique opportunity for cancer care without concerns for FN,” investigators wrote.

Guidelines suggest that pegfilgrastim be administered 24 hours after myelosuppressive chemotherapy (CTX), and data from previous studies had not clarified the utility of same-day vs next-day pegfilgrastim use for this class of patients, they said.

They included 114 patients who met the inclusion criteria; 76% (n = 87) of patients had non–small cell lung cancer and 24% (27) had small cell lung cancer. Of those, 52% had stage III/IV cancer and 63% had ECOG status of 0 to 1.

Study authors said 72% of patients had mild FN risk, mean standard deviation absolute neutrophil count at baseline was 5.68, and 384 CTX cycles were received in total.

One patient developed FN after the first cycle of CTX of irinotecan and, across all cycles, 5 patients developed 6 FN episodes.

Two of those patients were on carboplatin etoposide, 1 was on cisplatin etoposide, and 1 on vinorelbine. For the patient who experienced 2 episodes of FN, these occcured following a switch from pemetrexed to irinotecan CTX.

Vraney J, AlRawashdh N, Choi B, Abraham I, McBride A. An institutional evaluation of the safety and efficacy of same-day administration of pegfilgrastim in patients receiving chemotherapy for lung cancer. Presented at: ASCO 2021: June 3-7, 2021. Abstract e18591

In patients with breast cancer, pegfilgrastim biosimilar (Udenyca) administered as prophylaxis for FN on the same day as CTX appears to be safe and effective, investigators wrote. “Previous literature has indicated that pegfilgrastim administration prior to 24 hours post chemotherapy may result in a deepened and prolonged neutropenia due to the increase in circulating granulocytes exposed to chemotherapy.”

Oncologists at Inova Schar Cancer Institute in Fairfax, Virginia, conducted a retrospective chart review of 55 patients treated by 4 medical oncologists in the center’s breast cancer group. They said 16.4% of patients experienced grade 3/4 FN and 10.9% (n = 6) were hospitalized. There were no grade 5 events and FN was not the cause of therapy discontinuation for any of the patients. “Of note, there were no cases of COVID-19 among the 9 patients who had an episode of FN.”

They said 94.5% (n = 52) of patients included in the study received treatment with curative intent and 5.5% (n = 3) had metastatic disease in subsequent lines of therapy.

“Same day pegfilgrastim-cbqv appears to be a safe and effective option in the primary and secondary prophylaxis of FN with myelosuppressive standard of care chemotherapy used in breast cancer treatment,” they concluded.

They cautioned that their study was confined to a relatively small sample of patients and a young age group (median age, 49.1).

“This opens the door to further re-evaluation of same day [Udenyca] administration in other patient populations. In a postpandemic treatment world, this slight change in practice has the potential to reduce patient financial toxicity associated with multiple medical visits, provide an alternative to on-body injector formulations, and ensure treatment adherence,” they said.

Leiva M, Pennisi A, Kiernan Harnden K, Rizzo PC, Mauro LA. The feasibility of same day pegfilgrastim-cbqv administration in breast cancer patients receiving myelosuppressive chemotherapy regimens at a northern Virginia cancer center. Presented at: ASCO 2021: June 3-7, 2021. Abstract e18687

Same-day pegfilgrastim to combat febrile neutropenia in conjunction with myelosuppressive chemotherapy (CTX) is safe, investigators conclude. 

Investigators: Same-Day Pegfilgrastim Is Safe and Effective in Patients Receiving CTX for Breast, Lung Cancer

Celltrion Healthcare reported positive findings from a European Union real-world 

 comparing the company’s rituximab biosimilar (CT-P10, Truxima) with the reference product (Rituxan) in patients with diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma (NHL). Results were reported at the European Hematology Association 2021 Virtual Congress.

Celltrion also released real-world data demonstrating comparable safety and effectiveness of CT-P10 rapid infusion.

CT-P10 treatment data were collected during a 30-month observation period. Primary end points included overall survival (OS) and progression-free survival (PFS), and secondary end points included safety profile and CT-P10 treatment pathways.

At the 30-month point, OS was 74% (95% CI, 69.2%-79.1%) and PFS was 67% (95% CI, 61.3%-72.1%) among patients (N = 382) undergoing first-line treatment with CT-P10.

Among enrollees, a complete response (CR) was observed in 82% (n = 312); partial response (PR), 12% (n = 46); no response or stable disease 4% (n = 16); and progressive disease, 2% (n = 8).

CT-P10 tolerability also was reported to be comparable to the reference product. The investigators said 90% (n = 351) of patients reported 1 or more adverse events (AEs), 65% (n = 253) experienced a grade 3 or higher event, and 28% of AEs were reported as “definitely, probably, or possibly related to CT-P10.”

“This is the first multicountry retrospective postapproval study to investigate the effectiveness and safety of CT-P10 treatment in patients with DLBCL in a real-world setting across Europe,” said Mark Bishton, MD, consultant hematologist and a clinical associate professor at the University of Nottingham, School of Medicine, England.

The European Medicines Agency approved CT-P10 for treatment of rheumatoid arthritis and certain blood cancers, including NHL, in 2017. DLBCL accounts for an estimated 30% to 40% of NHL incidence.

“The response rates, survival rates and overall safety profile for CT-P10 appear consistent with those reported for reference rituximab, which could support the use of CT-P10 in combination with chemotherapy as a therapeutic option for DLBCL,” authors of the study wrote.

Discussing the second study, the investigators said rapid infusion of CT-P10 was generally well tolerated, with 10% (n = 20; 95% CI, 6%-15%) of patients experiencing infusion-related reactions (IRRs).

“We are encouraged by the results of the study, as CT-P10 has demonstrated a similar IRR rate to reference rituximab,” said HoUng Kim, PhD, head of the Medical and Marketing Division of Celltrion.

The investigators said most IRRs were grade 1/2 (96%), and the most common of these were fatigue (35%), nausea (30%), and vomiting (15%). Patients achieving CRs and PRs over 6 months of observation were 74% and 22%, respectively.

“The recommended protocol for rituximab infusion in Europe is a slow initial infusion rate with a gradual upward titration. Rapid infusion is often used in subsequent infusions for patients who had no serious complications related to the first infusion,” Kim said.

Postmarketing retrospective studies of the rituximab biosimilar (CT-P10, Truxima) demonstrated comparable safety and efficacy for treatment of diffuse large B-cell lymphoma (DLBCL).

Celltrion Reports Positive Real-World Findings for Truxima in DLBCL

The patent system in the United States differs markedly from that in the European Union, where biosimilar developers can challenge patents with far greater ease and less expense, according to a 

The report explains how US patenting laws enable originator companies to build almost impenetrable walls of patents to protect their drugs from competition.

The reality is that the PTO is an imperfect arbiter of intellectual property, and originators are able to capitalize on this, leaving biosimilar manufacturers—and consumers—to bear the burden.

In the United States, originator biologics companies may file unlimited numbers of patent applications on biologics, although many that are approved do not stand the test of scrutiny, which calls into question the rigorousness of the US Patent and Trademark Office’s (PTO) review process, according to the report’s authors, Alex Brill and Christy Robinson.

Brill founded Matrix and previously served as policy director and chief economist for the House Committee on Ways and Means. Robinson is a public policy analyst formerly with American Enterprise Institute.

It may be years following a patent award that a biosimilar developer or any other party may be able to bring a legal challenge or request for an inter partes review (IPR), which is a patent review trial before the US PTO.

European regulators grant far fewer patents to originator companies than the United States, and they allow almost immediate challenges of patents once awarded, according to the Matrix report.

Nothing prevents an originator company from filing scores of patent applications for a single product, and in fact, they do.

For the 8 top-selling biologics in the United States, the least number of patents obtained for any individual biologic was 41 (Enbrel, etanercept), Matrix said, citing I-MAK data. The most was over 130, for AbbVie’s adalimumab product (Humira).

“Originators have a strong incentive to amass as many patents as possible on reference biologics with high asset value. They also have ample opportunity to accumulate patents,” according to Matrix.

Originator companies in the United States may obtain multiple “families” of patents for a single product, effectively extending product exclusivity for years beyond the original protection granted by the FDA (

In the United States, the cost of a biologics IPR can reach $1 million, according to Matrix. Conversely, it may cost an originator company as little as $25,000 to apply for and maintain a single patent. Such lopsidedness makes it far more advantageous for originator companies to apply for multiple patents than for biosimilar developers to attempt to fight them.

In the United States, a biosimilar developer may have to wait years before it can demonstrate the “legal standing” necessary to challenge a patent. In the European Union, even a third party can bring a patent challenge, and much sooner (

There is “no statutory prohibition” on creating a patent thicket to obstruct biosimilar competition in the United States, the Matrix report notes. Years after the primary patent family is created, the manufacturer may still be busy creating patent families for antibody composition, product formulations, dosing regimens, routes of administration, and manufacturing processes.

Bristol Myers Squibb already has 38 patent families (or groups of patents) for nivolumab (Opdivo; FDA approval 2014), and patent applications for 30 of these families “were filed after Opdivo entered the US market.”

“This is not to say that patent examiners [in the United States] are individually to blame for the rise of patent thickets, but the reality is that the PTO is an imperfect arbiter of intellectual property, and originators are able to capitalize on this, leaving biosimilar manufacturers—and consumers—to bear the burden,” the report states.

The report recommends expanding the resources of the PTO and creating higher standards for patent issuance.

“Broadly, what will help ease the problem of patent thickets will be reforms at the PTO that promote better patents and IPRs, antigaming policies that deter anticompetitive patent practices by originators, and reasonable limits on the number of patents that can be asserted against biosimilar competitors,” the report states.

There’s another deleterious effect of US patent laws, the report’s authors said. “Drug manufacturers are at legal risk if they manufacture or stockpile biosimilars for commercial launch in the United States before patents expire or patent litigation is resolved.”

Biosimilar manufacturers may find it more advantageous to manufacture outside the United States, costing the United States manufacturing jobs and revenue.

The European Union in 2019 allowed the production and stockpiling of biosimilar and generic medicines before “supplementary” patent expiration. “Establishing an exception policy in the United States like the one the European Union recently instituted would reduce some [but not all] of the barriers to manufacturing biosimilars in the United States,” the report said.

 series on patents and biosimilars, read this 

 from Axinn about the limitations of the Purple Book patent listings.

The European Union makes it far more difficult to obtain patents on biologics, reducing the likelihood of patent “thickets” that stifle competition, the Matrix Global Advisors report states.