Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

In an update on the possibility of an interchangeable designation for its insulin glargine biosimilar candidate (Semglee), Biocon of Bengaluru, India, said in 

 this week that an “end of July 2021” FDA decision is possible.

The much-anticipated interchangeable designation could potentially be the first awarded for a biosimilar, which is a copy biologic that has no clinically meaningful differences from the originator, or reference, product. The interchangeable designation would allow pharmacists to substitute the insulin product for the reference product (Lantus) without the express authorization of the prescribing physician.

In August 2020, Biocon Biologics and Mylan (now Viatris), launched Semglee on the US market but did not have biosimilar or interchangeable status for it because it wasn’t approved under the biosimilar pathway in the Biologics Price Competition and Innovation Act (BPCIA). They have since sought biosimilar and interchangeable status for this product. Biocon Biologics is a subsidiary of Biocon.

Potentially, these designations would help to build acceptance and use of this product in the medical community, leading to increased revenues and, if the product helps to lower the cost of insulin, broader access to this medicine for patients who currently have difficulty paying for it.

“The regulatory process for the grant of ‘interchangeability’ designation to our [glargine; Semglee] is progressing under the 351(k) pathway in the United States,” Biocon said. Biologics license applications for biosimilar and interchangeable status must be submitted under the 351(k) pathway of the Public Health Service Act, which encompasses the BPCIA.

In addition, Biocon has submitted an application to the FDA for a biosimilar form of insulin aspart. Whereas glargine is a “long-acting” insulin, aspart takes effect in the body with rapidity and is considered “short-acting.”

The company said there are no pending requirements from the FDA for technical or clinical information about the aspart biosimilar candidate and the FDA has scheduled a “pre-approval inspection” of Biocon’s manufacturing facility in Malasia, where the insulin aspart would be manufactured. That inspection would occur in the final business quarter of this year, Biocon said.

Total revenue was up for the year just ended but total profits were down at Biocon. The company said biosimilar revenues have grown and highlighted those as a growth driver.

Biocon Biologics reported $102 million in revenues for the quarter just ended, up from $93 million in the comparable year-ago quarter, representing a 10% increase. These figures include biosimilar revenues predominantly, but also sales of novel biologics marketed in India. Biocon's net profit for the just-ended quarter was $11.3 million vs $20 million a year earlier, down 44%. Generics income for the company was down 22%. 

The company attributed the decline in profits partly to losses associated with 

, a start-up novel drug development subsidiary based in Boston, Massachusetts; as well as COVID-19–related operational challenges for the company’s facilities in Bengaluru and Hyderabad, which produce key ingredients for drugs, known as active pharmaceutical ingredients, or APIs.

“Globally, we see a strong demand for biosimilars and generic drugs, given the growing emphasis on affordable drug pricing,” company officials said in their earnings statement.

Read about expert opinion on the potential for competition in the insulin market 

Articles

Biocon reports on its revenues from biosimilars and the FDA status of its insulin glargine product.

Biocon Updates on Semglee Interchangeable Status

Pfizer and Johnson & Johnson have privately settled long-running litigation over alleged anticompetitive practices in the infliximab market. Pfizer had accused J&J of contracting with payers and providers to restrict the use of Pfizer’s infliximab biosimilar (Inflectra), which was launched in 2016, in favor of J&J’s originator product, Remicade.

Infliximab is an immunosuppressor for the treatment of rheumatoid arthritis, ankylosing spondylitis, Crohn disease, and ulcerative colitis, among other conditions. Remicade was first approved in 1998.

Commenting on the litigation, Pfizer said parties to the case had “agreed to resolve and dismiss all claims.” Terms of the settlement were not disclosed.

Pfizer said it will continue to sell Inflectra in the US marketplace. The company said it “has begun to see progress in the overall biosimilars marketplace in the United States. However, changes in policy at a government level and acceptance of biosimilars among key stakeholders are critical to deliver more meaningful uptake so patients and the healthcare system at-large can benefit from the cost savings these medicines may deliver.”

Pfizer filed suit against J&J in 2017 alleging that anticompetitive practices by J&J were preventing providers and patients from using Inflectra even though it was available for an average selling price of 10% less than Remicade.

Pfizer alleged that insurers originally showed no coverage preference for Remicade and allowed doctors to use Inflectra freely, but then 

 after J&J began threatening to withhold rebates unless payers agreed to “biosimilar-exclusion” contracts.

Remicade payer contracts allegedly were written to deny reimbursement for Inflectra unless Remicade was proven ineffective for patients.

Pfizer maintained that this not only caused a reluctance among doctors to stock Inflectra in their pharmacies but also caused some to avoid treating Medicare and Medicare patients with Inflectra, for which coverage was available.

For its part, J&J countered that Pfizer's own sales practices were to blame for lackluster Inflectra sales and that it could have structured its sales contracts more effectively to achieve better performance. J&J responded that Remicade was a well established product and that patients and providers were still unfamiliar with biosimilars and consequently leery of them. It was also contended that Pfizer had not established that Inflectra was available at a lower cost than Remicade, given the sum total of pricing incentives offered by J&J. 

The case put a spotlight on the use of "bundlied contracts," or the manufacturer practice of tying promotional deals for one pharmaceutical product to use of another. These lucrative deals have led to "anemic" biosimilar competition, according to former FDA Commissioner Scott Gottlieb.

In releasing the agency's 2018 Biosimilars Action Plan, Gottlieb contended that "rebating schemes" and patent "thickets" created by originator pharmaceutical companies were "purely designed to deter the entry of approved biosimilars."

Pfizer at the time contended that the biosimilars approval pathway under the Biologics Price Competition and Innovation Act (BPCIA) had been subverted.

“Congress enacted the BPCIA to improve patient access to more affordable treatment options and to foster meaningful price competition for biologic products,” said a Pfizer official. “J&J’s behavior runs counter to the spirit of this law and to US antitrust laws.

In June 2019 the Federal Trade Commission 

Johnson & Johnson in connection with whether its Remicade practices were in violation of antitrust laws. And in June 2018, retail pharmacy companies Walgreen and Kroger filed an antitrust complaint alleging that J&J’s contracting strategies for Remicade were restricting free trade.

Since the launch of Inflectra, 3 other infliximab biosimilars have been approved in the United States and 2 of them have launched, Renflexis (Samsung Bioepis/Merck) and Avsola (Amgen). Infliximab biosimilars have achieved the 

 of all biosimilars currently available in the United States: a 23% share of the infliximab market, according to Amgen.

At press deadline, J&J had not responded to a request for comment on the antitrust settlement. 

Without disclosing terms, Pfizer said it has settled with Johnson & Johnson (J&J) over a long-running dispute in which J&J was alleged to have blocked payers from covering Inflectra.

Pfizer Resolves Antitrust Lawsuit With J&J Over Remicade

Shanghai Henlius Biotech said the first patient has been dosed in a clinical trial for its bevacizumab biosimilar cancidate HLX04-O for the treatment of wet age-related macular degeneration (wAMD).

In the single-arm phase 1 trial, Henlius planned to 

 a maximum of 12 patients with wAMD, with the primary end points being safety and tolerability of HLX04-O.

A secondary end point is the pharmacokinetics (PK) of HLX04-O following intravitreal (directly into the eye) injection. Previous clinical studies have evaluated nonclinical pharmacodynamics, safety, pharmacology, toxicities, PK, immunogenicity, and local irritation of vitreous injection of this biosimilar candidate. These have provided evidence of the safety and effectiveness of HLX04-O, Henlius said in a 

Bevacizumab inhibits excessive vascular growth caused by overproduction of vascular endothelial growth factor (VEGF). VEGF production increases when tissues are getting insufficient oxygen (hypoxia). Growth of additional blood vessels may be beneficial in heart muscle or in an infant but can be harmful in the eye.

“Age-related macular degeneration (AMD) is one of the leading causes of visual impairment and blindness in the elderly worldwide,” Henlius stated, noting market potential and unmet need for treatments such as bevacizumab. “According to the World Health Organization, about 30 million people have suffered from AMD globally, and about half a million people go blind due to AMD each year.”

Anti-VEGF drugs are being employed as first-line therapy for wAMD, the company said. Henlius, Essex Bio-Investment, and Zhuhai Essex in October 2020 entered into an agreement to conduct clinical trials of HLX04-O in the United States, Australia, China, and the European Union and use those findings as the basis for regulatory approval applications in a broader slate of countries and regions.

“HLX04-O has the potential to be one of the first bevacizumabs approved for ophthalmic diseases, benefiting more patients with eye diseases worldwide,” the company said.

Republic of Korea and Japanese companies Dong-A ST and Meiji Seika Pharma, respectively, have signed a deal for the marketing of a ustekinumab (Stelara) biosimilar they have been developing since 2013. The biosimilar candidate (DMB-3115) is undergoing phase 3 clinical trials in Poland, Estonia, Latvia, and the United States, according to 

. Additional trials are slated for rollout in more EU countries.

Stelara controls inflammation and is used in the treatment of psoriasis, psoriatic arthritis, Crohn disease, and ulcerative colitis. The Johnson & Johnson drug had revenues of $7.7 billion in 2020, up from $6.4 billion the previous year. US sales last year were close to $1.6 billion.

, manufacturing of the drug would be conducted by DMBio, and Accord Healthcare, a UK-based subsidiary of Intas Pharma (India), would handle regulatory filings and marketing in the European Union and the United States.

Shanghai Henlius Biotech initiates a trial for patients with macular degeneration while Dong-A ST and Meiji Seika Pharma agree on a distribution plan for a ustekinumab biosimilar candidate. 

Henlius Initiates a Trial of Bevacizumab Candidate in Ophthalmology

Has a Chinese company come up with an improvement on infliximab, the immunosuppressive drug used to treat rheumatoid arthritis, Crohn disease, and ulcerative colitis, among other conditions?

Mabpharm, of Taizhou, and its commercialization partner Sorrento Therapeutics, of California, said China’s National Medical Products Administration has granted Mabpharm 

 to market a “biobetter” (CMAB008) for infliximab in China.

Biobetters are drugs that have similar structure and properties to an innovator product but are enhanced or modified to produce better outcomes. In a statement, Sorrento said the antibody biobetter was developed with Chinese hamster ovary cells, vs mouse cells for infliximab, and “has demonstrated a better safety profile…while maintaining [infliximab’s] efficacy profile.”

Sorrento has been granted rights to commercialize the product outside China and said it would now approach regulators in the United States and Europe for guidance on filing for marketing approval.

In the United States and the European Union, in addition to the originator product, Remicade (Janssen), there are several infliximab biosimilars on the mark

t, including Renflexis (Merck, Samsung Bioepis), Avsola (Amgen), and Inflectra (Celltrion, Pfizer). 

The arrival of a biobetter could shake up demand for the originator product and its biosimilars, and this highlights one of the challenges for biosimilar makers.

By the time biosimilars come on the market, an originator company has enjoyed a long run of profits, presumably more than compensating for research and development expense, but this may not be the case for biosimilar companies.

Biosimilar developers may invest as much as $200 million in development of a biosimilar and could immediately face competition from other biosimilars, costly litigation from originator companies, and heavy pressure to reduce prices.

Avsola, for example, launched in the United States just a year ago, in July 2020. Inflectra and Renflexis launched in the United States in 2016 and 2017, respectively, and their makers have enjoyed a longer run of sales revenue.

However, in the United States infliximab biosimilars have been among the slowest of biosimilars to take off. They commanded just 23% of the market for infliximab by the close of the first quarter of 2021, according to Amgen.

Competition and pricing pressures have also battered the returns on these products for drug makers. Infliximab biosimilar average sales prices (ASPs) have declined roughly 45% since these biosimilars were first introduced in the United States, whereas the ASP for Remicade has experienced a drop of greater than 40%, according to 

Remicade notched revenues of $3.7 billion in 2020, down from $4.4 billion the previous year, according to a Johnson & Johnson earnings 

. Sorrento estimated that total 2020 infliximab sales, including biosimilars, were $4.2 billion.

In the rapidly changing field of oncology, where the pace of treatment advances is high, the business risks are more acute. For this reason, pharmaceutical companies may adopt a cautious stance toward developing biosimilars for use in oncology.

Infliximab is an anti–tumor necrosis factor (TNF) antibody that targets inflammation characteristic of arthritic and gastrointestinal disorders. “It is usually prescribed when other medicines or treatments have failed,” which makes it an important treatment of last resort, Sorrento noted in its statement.

Sorrento said the Mabpharm biobetter has not only an improved safety profile but also lower immunogenicity compared with infliximab. “The Chinese approval covers 6 different indications, including adult ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis, adult and childhood Crohn disease, fistula Crohn disease, and psoriasis,” the company said.

Sorrento was described as a clinical stage, antibody-centric biopharmaceutical company geared toward developing therapies for cancer and COVID-19.

Mabpharm describes itself as a biopharmaceutical company with a focus on development and production of new drugs and biosimilars for cancer and autoimmune diseases.

Mabpharm has multiple monoclonal antibody drugs (both biobetter and biosimilar candidates) in development, including versions of omalizumab (asthma), cetuximab (colorectal cancer), trastuzumab (breast, metastatic gastric cancer), and nivolumab (non–small cell lung and hepatocellular cancers).

China has approved a product for rheumatoid arthritis and Crohn disease that Mabpharm and Sorrento Therapteutics say is an improvement on infliximab.

Mabpharm Raises the Stakes in Infliximab Market With a "Biobetter" Approval

Analyses of multiple switches between biosimilars and originator forms of infliximab were presented at the European Crohn’s and Colitis Organization annual meeting  (ECCO’21).

Switching Between Remicade and Biosimilars

Patients with inflammatory bowel disease (IBD) who switched multiple times between biosimilar forms of infliximab and the originator product (Remicade) demonstrated no unusual patterns in efficacy, safety, or immunogenicity, investigators reported at ECCO’21.

Investigators sought to elucidate outcomes of significance among patients who switched from biosimilars to the reference product and switched multiple times between biosimilars. “As the access to biosimilars at competitive prices increases, it is necessary to evaluate multiple switches to provide data on their interchangeability,” they wrote.

In this retrospective cohort study (N = 26), investigators evaluated clinical disease activity, biochemical markers, infliximab trough (lowest concentration) levels, and anti-infliximab antibody levels both before and after switching.

The study enrolled patients with Crohn disease (n = 22) and ulcerative colitis (n = 4). Most patients were between 17 and 42 years of age, had ileocolonic disease, and an inflammatory phenotype (nonstricturing/nonpenetrating, structuring, or penetrating). Investigators said 44% of patients had perianal disease and half had pancolitis.

They said 51% of patients had prior resection surgery and 27% were on combination therapy when they first switched among infliximab products. Nine patients (35%) switched 3 times.

Investigators said there was no significant difference in the percentage of patients in clinical remission and no significant differences in laboratory markers such as C-reactive protein (an inflammation marker), hemoglobin (anemia marker), or albumin (protein deficiency marker) were noted before or after multiswitching.

Mean drug trough levels were not significantly different and no patients developed antidrug antibodies, had infusion-related adverse events, or lost response leading to drug discontinuation. Investigators said drug persistence was 100%.

Investigators found that patients who switched from one infliximab biosimilar to another experienced an increase in drug trough levels following the switch, although there was no effect on clinical and biochemical disease activity.

In a poster presentation at ECCO’21, researchers concluded that switching infliximab biosimilars in IBD “appears safe in the short term with respect to maintaining drug pharmacokinetic (PK) profile and disease control whether switching for the first or second time.”

The advent of anti–tumor necrosis factor (TNF) biosimilars, which reduce inflammation, has enabled switching from originator products and cost savings in IBD without loss of disease control. In this study, investigators set out to understand the significance of a switch between biosimilars.

They reported on a prospective study (N = 221) of patients who switched from Remsima to Flixabi, both infliximab biosimilars, produced by Celltrion and Samsung Bioepis, respectively. Outcomes were compared for patients who switched up to 2 times.

Patients were stable on infliximab at baseline, and 79% (n = 174) were on concomitant immunomodulators. Investigators said roughly half of patients (n = 112) had a PK analysis done before and after switching.

Investigators observed a baseline median trough level of 4.5 µg/mL (2.9-6.3) prior to switching and 5.1 µg/mL (3.4-7.0; 

Clinical scores, including for C-reactive protein, trough infliximab levels, and clinical disease activity, were similar before and after switching, and no new anti-infliximab antibodies were observed.

Investigators said 107 patients (48%) switched infliximab biosimilars for the second time, and of those, PK analysis was performed for 51. Investigators said the post-switch increase in median drug trough levels was similar between patients who switched for the first (4.7 vs 6.1 µg/mL, 

They said there was no change in clinical disease activity or C-reactive protein in either group. Further, the use of concomitant immunomodulators and patient disease classification had no bearing on changes in infliximab levels, although these findings were not statistically significant (

1. Nascimento C, Revés J, Morão B, et al. Outcomes of multiswitching from original infliximab to biosimilars in patients with inflammatory bowel disease. Presented at: ECCO’21 Congress; July 2-3 and 8-10, 2021. Poster P555.

2. Luber R, O’Neill R, Singh S, Arkir Z, Irving P. Switching infliximab biosimilar: no adverse impact on inflammatory bowel disease control or drug levels with the first or second switch. Presented at: ECCO’21 Congress; July 2-3 and 8-10, 2021. Poster P485.

Pharmacokinetic, safety, and efficacy findings for patients with inflammatory bowel disease (IBD) were presented at the European Crohn's and Colitis Organization's annual meeting. 

Investigators Report Findings on Infliximab Switching in IBD

The COVID-19 pandemic has exposed weakness in the US health care system on multiple levels, including drug supply discontinuity, poor access to health care, and health care system financial stress.

These problems can be solved with greater advance preparation and collaboration among stakeholders, and biosimilars have a role to play, too, said a panel of experts convened this week by Amgen Biosimilars, a division of Amgen.

The discussion on health care resiliency and sustainability included Cecelia Calhoun, MD, MSPH, MBA, assistant professor of medicine and assistant professor of pediatrics at Yale Cancer Center and Smilow Cancer Hospital, where she directs the Adolescent-Young Adult Sickle Cell Program; Allison Arwady, MD, MPH, commissioner of the Chicago Department of Public Health; and Michelle McMurry-Heath, MD, PhD, president and CEO of the Biotechnology Innovation Organization. 

They were joined by Ian Thompson, MBA, senior vice president and general manager of US General Medicine for Amgen.

In underserved communities, many are unused to access to health care, so despite the availability of COVID-19 vaccines, many have not stepped forward to receive this potentially lifesaving treatment, Arwady said.

“They’re too used to being shut out. We need to rethink ways of delivering care,” she said.

Calhoun said the public health safety net is not stretched evenly across the landscape. “We need to acknowledge gaps in health care before we can address them. That includes understanding how we interact with communities,” she said.

She and others in the discussion noted that chronic diseases have often been poorly treated during the pandemic because of lack of continuity in care. This has led to a higher risk of mortality, especially among those with sickle cell disease, whom Calhoun treats, but also among those with asymptomatic conditions, such as high blood pressure. 

“We have to make sure communities of color and vulnerable communities are involved every step of the way,” McMurry-Heath said.

Residents of disadvantaged communities have been unable to socially distance as effectively as those in more affluent communities. Their jobs may not have given them the opportunity to work remotely, and their housing conditions may be crowded. It may not have been possible for them to stock up on groceries and cut down on trips to stores, Arwady said.

“People have to decide between earning a living or adhering to guidelines, and we’re not out of the pandemic yet,” Calhoun said.

The panelists said lessons to be learned from the pandemic include planning ahead for rapid response and developing interconnected systems among communities and health networks, to ensure treatments and preventive measures are applied where needed.

“We have to involve minority communities from the beginning about how we address infection,” McMurry-Heath said.

Thompson said biosimilars, low-cost alternatives to originator drugs, can play a role in building up resilience of health care systems and improving access to care. “The pandemic highlighted the need for health care resilience and innovation,” he said.

He noted a report that Amgen is working on that he said demonstrates that biosimilars are helping to improve the competitiveness of markets and bring down costs of medicine. A preview of that report, expected to be released later this year, can be found 

COVID-19 exposed a lot of holes in the public health safety net. An Amgen panel focused on ways to extend the reach of US medicine to make it more inclusive.

Panel: Build Health Care System Resilience With Biosimilars

Just days after Bio-Thera announced initiation of a phase 3 study of patients receiving a candidate ustekinumab biosimilar, Samsung Bioepis said that it, too, has begun a phase 3 clinical trial for its own biosimilar version of this agent.

The reference ustekinumab product is Stelara, which commands a $5 billion market among patients with autoimmune diseases. Samsung’s trial will evaluate SB17 in patients with moderate-to-severe plaque psoriasis in a randomized, double-blind, multicenter analysis.

In the United States, Stelara is indicated for the treatment of moderate-to-severe plaque psoriasis, active psoriatic arthritis, moderate-to-severe Crohn disease, and moderate-to-severe ulcerative colitis. The drug was first approved in 2009 and potentially could see the end of US patent protection in 2023.

If SB17 is approved for plaque psoriasis, physicians in the United States could extrapolate its use for other indications of the reference product.

Samsung Bioepis said it aims to enroll 464 patients in the 

 and randomize them 1:1 to either SB17 or the reference product via subcutaneous injection. At week 28, all patients on Stelara will be randomized to continue on Stelara or transition to SB17. A final assessment will be performed at week 52. The study’s estimated primary completion date is June 2022.

For more about Bio-Thera’s ustekinumab biosimilar development program, click 

Samsung Bioepis launches a potential pivotal trial for its SB17 ustekinumab biosimilar candidate. 

Samsung Bioepis Initiates Phase 3 Ustekinumab Trial

Was a cannibalization scheme at work in Amgen’s 

 for the Onpro wearable pegfilgrastim injector? In a cannibalization ploy, the manufacturer will draw sales away from an existing product to support growth of revenues for a follow-on product.

In this case, Amgen’s advertising claims made the Onpro pegfilgrastim injector seem superior in efficacy to its longstanding Neulasta prefilled syringe (PFS). In a warning to Amgen recently, the FDA said the evidence supporting this claim was weak, and the agency raised concerns that the advertising would weaken public faith in pegfilgrastim biosimilars, all of which are in a PFS.

“If Amgen believes that the way to go is to cannibalize its Neulasta PFS for the Neulasta Onpro device with an analysis subjected to many potential biases, I don’t think that they’ll get much of a hearing from the pharmacy and therapeutics [P&T] committees,” said Ivo Abraham, PhD, a professor in the Department of Pharmacy Practice at the University of Arizona, who has conducted multiple studies into the value of pegfilgrastim in the cancer care supportive setting. P&T committees are the clinical groups that make decisions about which drugs to use in medical institutions.

Pegfilgrastim is a long-acting granulocyte colony stimulating factor (GCSF) used to spur the growth of neutrophils and ward off the development of febrile neutropenia (FN) in patients receiving chemotherapy.

In advertising for the Onpro, Amgen relied upon data that described a 31% higher incidence of  FN among patients using PFS vs Onpro forms of pegfilgrastim application. As the FDA pointed out, that was actually the difference between 2 very low proportions of patients who experienced FN and the finding was not statistically significant, meaning no reliable medical inference could be made from it.

 evaluated for possible reduction in FN incidence between the Onpro and PFS pegfilgrastim, which also found no statistical significance. The incidence of FN in the initial cycle of chemotherapy was 1.01% for Onpro vs 1.48% for PFS (

 = .336). In all chemotherapy cycles, FN incidence was 0.91% for Onpro vs 1.22% for PFS (

The FDA found other problems with the Amgen study, saying there was strong potential for bias in selection of patients and a failure to define the sensitivity of the data sources.

The Onpro proved its worth to Amgen during the pandemic as it allowed patients undergoing chemotherapy to receive their follow-up pegfilgrastim injections at home. PFS biosimilars currently hold a 35% market share of the pegfilgrastim market, but the Onpro still retained a 54% share of the total market at the end of the first quarter of 2021. Overall sales of Neulasta, meanwhile, had declined 21% for the year ended March 31, 2021, according to Amgen.

However, the dynamics of the pegfilgrastim market are changing and it may become difficult for Onpro to maintain its dominance. Pegfilgrastim is a long-acting agent that is administered once per chemotherapy cycle at a cost of around $6200 per injection. There is evidence that payers are sometimes preferring to use filgrastim, another GCSF that is administered daily at a lower cost of around $360 per injection. Further, the number of filgrastim injections in a 

 averaged around 5, which means that comparatively speaking, filgrastim can be administered for far less than pegfilgrastim.

Another trend has to do with the administration of PFS. It is beginning to appear that pegfilgrastim can be safely administered on the same day as chemotherapy, obviating the need for home-based or follow-up injections, Abraham noted.

 of patients with lymphoma receiving CHOP chemotherapy (cyclophosphamide/hydroxydaunorubicin/vincristine [Oncovin], prednisone), investigators concluded pegfilgrastim (Udenyca) can be safely administered on the same day as the CHOP chemotherapy.

“This study from the University of Arizona Cancer Center showed that administration of pegfilgrastim on the same day as chemotherapy is a safe, effective method of preventing FN in patients who receive standard-of-care chemotherapy to treat lymphoma,” investigators concluded.

“While the pegfilgrastim label implies that this growth factor should not be injected before the 24-hour to 72-hour time window, there is growing evidence, some from controlled trials—including a set sponsored by Amgen—and more from noncontrolled studies, that same-day administration may be a safe and effective alternative during treatment with chemotherapy. In addition, there is initial evidence that eflapegastrim, a novel GCSF, administered the same day as chemotherapy may be safe and effective,” Abraham said.

When the Onpro fails, the patient may not have received any or all of the necessary prophylaxis, and therefore may be at higher risk of chemotherapy-induced FN and its many consequences, including hospitalization or death.

And lastly, whether there is a lower incidence of FN with the Onpro vs PFS pegfilgrastim, studies have shown 

 with the Onpro ranging from 1.7% to 6.9%, meaning that these proportions of patients enrolled in trials failed to receive appropriate dosing of pegfilgrastim from the Onpro.

“When the device fails, the patient may not have received any or all of the necessary prophylaxis, and therefore may be at higher risk of chemotherapy-induced FN and its many consequences, including hospitalization or death,” Abraham said.

In Abraham's opinion, Amgen has transformed supportive oncology care through the development of Neupogen (filgrastim) and Neulasta, but it’s time for Amgen to develop new and more effective products, using its significant pharmaceutical resource base, and allow competition and market dynamics to take over the pegfilgrastim market and make this agent more affordable and more widely available.

“Amgen’s growth factor innovation has given clinicians effective means of combating the effects of myelosuppressive chemotherapy, enabling better and more sustained chemotherapy. Just as much, it has decreased patient suffering and has improved clinical outcomes and quality of life.

“But there is also the much-needed patent system: It helped Amgen develop and market growth factors with the protection afforded by the patent system. That protection has ended and biosimilar competition for market share is now a global reality,” he said.

Amgen's advertising appeared to push doctors and patients away from the prefilled syringe version of its pegfilgrastim (Neulasta) product, which may have a better sales future than the Onpro.

How Risky Was Amgen's Onpro Advertising? 

Ustekinumab (Stelara) is a blockbuster drug for the treatment of Crohn disease, ulcerative colitis, and psoriatic arthritis that brought in $5.24 billion in revenues for Janssen Pharmaceuticals in 2020, up from $4.35 billion in 2019. There are many contenders in the global race to produce the first biosimilar for this product, and progress reports are now routine.

This week, Bio-Thera Solutions of Guangzhou, China, said it has dosed the first patient in a 

 of a biosimilar candidate for ustekinumab (BAT2206). Phase 3 trials, if successful, typically precede a regulatory filing for marketing approval.

Bio-Thera is a commercial-stage pharmaceutical company—it has 1 product in circulation, an adalimumab biosimilar (Qletli), which became available on the Chinese market in January 2020. Besides BAT2206, Bio-Thera has several biosimilar candidates in clinical stages of development, including BAT1806, a tocilizumab biosimilar candidate, and BAT2506, a golimumab biosimilar candidate.

Tocilizumab (Actemra) is used in the treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, systemic sclerosis–associated interstitial lung disease, and giant cell arthritis. Bio-Thera said its tocilizumab candidate has successfully completed a global phase 3 clinical trial.

Golimumab (Simponi) is used in the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis. BAT1806 and BAT2506 have each entered the phase 3 trial stage, according to Bio-Thera.

Bio-Thera’s ustekinumab candidate is undergoing evaluation in a multicenter, randomized, double-blind, controlled study (N = 472) comparing the efficacy and safety of BAT2206 with the reference product in patients with moderate-to-severe psoriatic arthritis.

Ustekinumab works by suppressing the action of cytokines interleukin (IL)-12 and IL-23, which facilitate immune cell signaling and in disorders that involve an overstimulated immune system response. “IL-12 and IL-23 have been implicated as important contributors to the chronic inflammation that is a hallmark of Crohn disease and ulcerative colitis, among many other autoimmune diseases,” Bio-Thera said in its statement.

Also, the company has a bevacizumab biosimilar candidate that has completed phase 3 clinical trial development. In April, Bio-Thera reported it has entered a commercialization agreement with Biogen for the distribution of the tocilizumab biosimilar candidate in countries outside the China region.

Other companies in the ustekinumab biosimilar development race include NeuClone of Sydney, Australia (NeuLara), Samsung Bioepis (SB17), Formycon and Bioeq (FYB202), Amgen (ABP 654), Meiji Seika (DMB-3115), and Celltrion (CT-P43).

Bio-Thera's BAT2206 ustekinumab candidate is in contention with multiple other proposed biosimilars to Janssen's Stelara. 

Bio-Thera Moves Ustekinumab Candidate Into Phase 3 Trial

After receiving complaints through its Bad Ad Program, the FDA has issued a 

 to Amgen to discontinue what it says are misleading claims about its Onpro pegfilgrastim wearable injector kit.

The FDA says a banner advertisement used by Amgen falsely claimed that the Onpro is more successful at reducing the incidence of febrile neutropenia (FN) than the prefilled syringe (PFS) form of administering pegfilgrastim.

The FDA said the study upon which Amgen based that claim was not geared to provide a reliable comparison of FN incidence between patient populations using Onpro vs PFS. The FDA also contends that the wording of the advertisement could create the false impression that biosimilar forms of pegfilgrastim, all of which are in PFS form, are inferior to Amgen’s wearable injector kit.

“These violations are concerning from a public health perspective because this promotional communication’s misleading claims could cause health care providers to conclude that Neulasta delivered via the Onpro on-body injector is more effective than Neulasta delivered via PFS or that it is more effective than FDA-licensed biosimilar pegfilgrastim products, which are only delivered via PFS,” the FDA wrote in an “untitled letter.”

In terms of severity, an untitled letter from the FDA is 1 step below a "warning letter," but still is intended to point out noncompliance with regulatory standards.

For its part, Amgen has indicated an intention to work with the FDA to resolve the issue. In a statement, it touted the demonstrated efficacy of Neulasta, but did not directly address the advertising message the FDA has objected to. 

“There is a robust body of clinical and real-world evidence that demonstrates that when used every cycle, Neulasta significantly reduced the incidence of febrile neutropenia (FN) as well as FN-related events, including FN-related hospitalization and the use of anti-infective drugs in patients undergoing chemotherapy,” Amgen said in a statement to The Center for Biosimilars

The study cited is inadequately designed and precludes the drawing of conclusions regarding the comparative risk of FN in patients taking Amgen’s pegfilgrastim products depending on delivery method. It likewise does not support conclusions about any other FDA-licensed pegfilgrastim products.

The company noted it has a $2-billion stake in biosimilars, implying that running them down would not be to its benefit.

Amgen said the FDA's concerns relate to a banner ad directed at health care providers about a "real-world evidence" study for Neulasta used in both the Onpro and PFS study arms. 

The FDA contends the ad did not make sufficiently clear that Neulasta, Amgen’s originator product, was also used in the PFS arm, and so merely using the nonproprietary name pegfilgrastim could tarnish biosimilars by association.

The FDA also takes issue with the following claims used in the advertisement:

“In a real world study with nearly 11,000 patients, pegfilgrastim PFS resulted in a significantly higher risk of FN vs Onpro.”

"Across all cycles of chemotherapy, the incidence of FN associated with prefilled syringe (PFS) was 1.7% (n = 455) vs 1.3% (n = 126) for Neulasta Onpro.”

“With PFS, FN incidence increased by 31% vs Onpro.”

The FDA contends that “multiple limitations” of the retrospective study used to justify these assertions makes such assertions very unsound.

The FDA also contends Amgen cannot fairly state that the alleged higher risk of FN with PFS reached the level of statistical significance. “Accordingly, reporting a 

 value for the claims and presentations in…the banner is misleading,” the agency wrote.

It said the algorithm chosen to select study participants relied on diagnosis codes for neutropenia and fever or infection and no information was provided to the FDA's Office of Prescription Drug Promotion about the sensitivity or positive predictive value of the algorithm or diagnostic codes. 

“The use of an unvalidated algorithm with unknown performance characteristics is a significant limitation because of the potential for misclassification of patients at the onset of the study,” the FDA wrote.

The FDA also noted the purported 31% increase in incidence of FN was based on the difference between small proportions of patients who experienced FN in the PFS vs on-body injector groups (1.7% vs 1.3%, respectively). “It cannot be ruled out that selection bias is entirely responsible for the observed risk difference,” the FDA wrote.

Amgen was given 15 days to respond to the FDA with its reasoning and any supporting information to justify the advertising claims it has made.

The FDA noted the potential that Amgen had made similar claims in other advertisements and asked for corrections. The advertisment provided for story illustration can be found 

In a statement, the Biosimilars Forum, which is a trade association of biosimilars companies, applauded the FDA's warning notice. 

"Misinformation about the safety and efficacy of biosimilars emanating from market-leading brand-name drug companies is rampant," the group wrote. "The Biosimilars Forum has consistently engaged with the FDA and Federal Trade Commission (FTC) on this issue since day one, including calling on both agencies to take aggressive actions."

“Spreading false claims and misinformation harms patients and is a barrier to access to safe, effective and lower-cost biosimilars,” said Meaghan R. Smith, executive director of the Biosimilars Forum.

An advertisement for the Onpro wearable pegfilgrastim injector kit has the potential to undermine sales of biosimilars, the FDA stated in a warning letter.  