Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

The FDA has approved an insulin glargine (Semglee) under the generic 505(b)(2) New Drug Application pathway, and the drug automatically is deemed a biologic under section 351(a) of the Public Health Service Act of the Biologics Price Competition and Innovation Act (BPCIA), based on a policy enacted March 23, 2020. The drug references Sanofi’s Lantus.

Mylan and Biocon Biologics, which co-developed the agent, said they intend to seek “interchangeable” status for it, meaning pharmacists could fill prescriptions with Semglee without consulting the prescribing physician.

Semglee is approved in vial and and prefilled pen applications to control high blood sugar in adults with type 2 diabetes and adult and pediatric patients with type 1 diabetes. “Semglee has an identical amino acid sequence to Sanofi’s Lantus and is approved for the same indications,” Mylan and Biocon said in a 

"This approval is an important milestone, first and foremost for the millions of patients living with diabetes in the United States as we seek to expand their access to insulin through more affordable treatment options,” said Mylan CEO Heather Bresch. “It's also another milestone for Mylan as we continue to leverage our scientific, commercial, manufacturing and regulatory expertise to benefit patients, and as we enhance our portfolio with increasingly complex and higher value-chain products, like insulin.”

“We look forward to making this product available to patients in the United States as soon as possible," Mylan President 

Mylan and Biocon said the product remains “at risk” of further litigation.

“Favorable judgments on all remaining patent claims asserted by Sanofi against Mylan's insulin glargine products have been obtained. Although Sanofi may seek certain appeals of those judgments, Mylan is confident they will not affect commercialization plans,” the companies said in the statement.

Lantus revenue for the 12 months ending April 30, 2020, was roughly $6 billion, according to Mylan and Biocon.

 Semglee in Australia. The country has allowed the product to be substituted at the pharmacy level without consulting with the prescribing physician.

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In gaining FDA approval, the insulin glargine product Semglee receives automatic status as a biologic under the Biologics Price Competition and Innovation Act (BPCIA), although it was approved as a 505(b)(2) product under the Food Drug and Cosmetic Act. Semglee becomes the first insulin glargine under the 351(a) pathway.

Semglee Insulin Gains Automatic Approval under BPCIA

 uptake in England found huge missed savings over a 4-year period starting with the reference product’s loss of exclusivity in 2014.

The study, published in the current issue of 

, said the savings generated from biosimilar use totaled just $1.1 million and the missed savings amounted to $32.1 million, “indicating that only 3.42% of the potential savings were achieved.”

Investigators also noted a large variation in uptake of insulin glargine biosimilars across Clinical Commissioning Groups (CCGs), which serve to facilitate health care services between patients, physicians, and community groups.

Insulin glargine market shares between these groups ranged from 0% to 53.3% in December 2018, according to the study.

“These results may encourage decision makers in England to promote the use of best-value treatments in primary care and to reevaluate variation across CCGs,” authors of the study wrote.

To conduct the study, investigators collected information on all insulin glargine products prescribed by general practitioners up through December 2018. They then calculated total costs of insulin glargine and uptake rates of biosimilars.

They estimated what it would have cost to have filled all of the prescriptions with the reference product versus the actual cost of biosimilar and reference insulin glargine. The missed savings amount was based on what it would have cost to supply all of the patients with biosimilar forms of the drug.

Investigators described the study as the first to analyze adoption rates for insulin glargine biosimilars in the primary care environment in England and calculate the savings achieved and missed. The reference product that formed the basis for the study was Lantus.

Agirrezabal I, Sánchez-Iriso E, Mandar K, Cabasés JM. Real-world budget impact of the adoption of insulin glargine biosimilars in primary care in England (2015—2018). 

. 2020;43(6):dc192395. doi:10.2337/dc19-2395

Investigators said the English health care system has realized only a sliver of the potential savings potential from biosimilar insulin glargine and that uptake is widely uneven across health care centers.

England Missed Out on Biosimilar Insulin Glargine Savings, Study Says

The overall response rate (ORR) was 88% in an interim analysis study of a Sandoz rituximab biosimilar evaluated in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with CD20-positive diffuse large B-cell lymphoma (DLBCL), according to data presented at EHA20 Virtual, the 25th European Hematology Association (EHA) Congress.

The international REFLECT trial was the first prospective postapproval study to evaluate a rituximab biosimilar in this context. The study employed Sandoz’s rituximab biosimilar Rixathon (SDZ-RTX), which is approved in Europe, Japan, Australia, and Switzerland, among more than 20 countries and regions, for all indications of reference rituximab.

The efficacy and safety data presented this month at EHA20 Virtual confirmed 

from REFLECT released in 2019 at meetings of the American Society of Clinical Oncology and EHA, investigators said.

The primary end point was complete response (CR) and secondary end points were overall response and progression-free survival at 24 months, safety, and quality of life. Of the patients enrolled (N = 170), 38% completed the first 12 months of observation, 41% were ongoing, and 21% discontinued by the data cutoff (8% discontinued because of progressive disease).

At the end of treatment, CR was 57% and partial response was 31%. Investigators said 61% and 29% reported enlarged lymph nodes and disease-related pain, respectively.

They said 32% of patients had nodal lesions >15 mm. Most had an Eastern Cooperative Oncology Group functional performance score of 0 (35%) or 1 (46%), and for 70%, the Karnofsky performance scale score for functional impairment was ≥70%.

Early-stage (I-IIB) disease, low-to-intermediate disease risk (International Prognostic Index 0-2), and known DLBCL symptoms were reported for 55%, 50%, and 30% of patients, respectively.

Treatment-related adverse events (AEs) were reported for 28% of patients, and the rates of serious AEs and treatment-related serious AEs were 37% and 7%, respectively. Investigators said 2.5% of patients died on treatment.

The most common AEs were organ related (83%), general disorders and administration site conditions (40%), blood and lymphatic system disorders (38%), gastrointestinal (33%), and nervous system (32%). Among these, 21% experienced fatigue; 24%, anemia; 12%, nausea; and 15%, polyneuropathy.

Investigators concluded their findings reconfirm the safety and efficacy profile for this treatment combination in patients with DLBCL treated in a real-world setting. No new safety concerns were observed.

Welslau M, Marschner N, Otremba B, Topaly J, Bittencourt da Silva L. REFLECT real-world evidence: non-interventional, prospective study update on the efficacy and safety of Sandoz biosimilar rituximab for the treatment of diffuse large b-cell lymphoma (DLBCL). Presented at: EHA25 Virtual; June 11-21, 2020. Poster EP1245. library.ehaweb.org/eha/2020/eha25th/293734

Investigators reported an 88% overall response rate for a Sandoz rituximab biosimilar in combination with chemotherapy in patients with CD20-positive diffuse large B-cell lymphoma.

Sandoz R-CHOP Combination Confirms Findings in REFLECT

 Pfizer’s pegfilgrastim biosimilar Nyvepria for use in lowering the incidence of infection as manifested by febrile neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs.

There are 3 pegfilgrastim products already on the US market that also reference Amgen’s Neulasta. Those include Ziextenzo, Udenyca, and Fulphila.

Pfizer intends to launch Nyvepria on the US market later this year. No specific date was provided.

“The FDA approval of Nyvepria is a positive step that could both enable cost savings and increase access to an important treatment option,” said Andy Schmeltz, global president of Pfizer Oncology, in a 

“Chemotherapy-induced febrile neutropenia is a relatively common and severe [adverse] effect of some cancer treatments that could cause significant complications and can result in the alteration of treatment regimens,” said Ali McBride, PharmD, MS, BCPS, BCOP, immediate past president of the Association of Community Cancer Centers. “The FDA approval of Nyvepria provides clinicians with an additional long-acting treatment option that can help prevent infections in patients undergoing myelosuppressive chemotherapy.”

Pfizer now has 6 FDA-approved oncology biosimilars, 3 of which are indicated for supportive care for patients with cancer. Its total US-approved biosimilar portfolio, including the cancer agents, includes 9 biosimilars.

in the United States so far in 2020. The company brought a rituximab biosimilar (Ruxience) to market earlier this year, along with a trastuzumab (Trazimera).

The FDA has approved Pfizer’s pegfilgrastim biosimilar Nyvepria for use in lowering the incidence of infection as manifested by febrile neutropenia.

FDA Approves Pfizer Pegfilgrastim Biosimilar Nyvepria

A retrospective study of patients with anemia in myelofibrosis (MF) treated with biosimilar erythropoiesis-stimulating agents (ESAs) demonstrated this to be an effective and well-tolerated option, according to data to be presented at the EHA20 Virtual, the 25th European Hematology Association Congress.

Investigators said ESAs are used to manage anemia in hematological malignancies, but scarce evidence exists for the use of these agents in the treatment of MF, and available results are divergent: Response rates range from 23% to 69%, according to the abstract presented at EHA25 Virtual. Until this study, there were no data on the use of biosimilar ESAs in this setting, investigators said.

The Italian study enrolled patients (N = 40) with MF who received biosimilar ESA (B-ESA) for at least 1 month to treat anemia (hemoglobin [Hb] ≤10 g/dL). B-ESA was given off label with patient consent.

Investigators reported anemia response (AR), without significant toxicities, and concluded that patients who achieved AR demonstrated a significant survival advantage compared with those who had no response (NR).

They also concluded that transfusion dependency at baseline was a negative predictor for AR, suggesting that outcomes could be improved via earlier B-ESA treatment in patients with MF.

AR included complete and partial responses (CR and PR, respectively). PR was defined as a transfusion decrease of more than 50% or sustained Hb increase between 1 and 2 g/dL.

The study included slightly more male than female patients and 21 patients with primary MF and 19 with secondary MF. Median age at baseline was 73 years. At start of treatment, 17.5% of patients were at high risk and 70% and 12.5% of patients at intermediate-2 and intermediate-1 risk MF, respectively.

Patients began treatment with B-ESA at a median of 8.5 months from MF diagnosis, and the median dose of B-ESA was 40,000 U/week subcutaneously. Investigators said 29 patents (72.5%) received B-ESA before, at start of, or during ruxolitinib treatment.

The median Hb level at baseline was 9.2 g/dL (range, 8.2-10.0), and just 3 patients were transfusion dependent.

Investigators said 34 patients (85%) achieved an AR, with 28 CR (70%), 6 PR (15%), and 6 NR (15%). The median time to response was 1.7 months, and median B-ESA exposure time was 12.4 months. Six patients (17%) lost response to therapy after a median 12.9 months.

“The only significant predictor of poor response rate was transfusion dependency at baseline (Fisher’s exact test, 

Inzoli E, Pugliese N, Renso R, et al. Use of biosimilar erythropoiesis stimulating agents for anemia in myelofibrosis: a multicenter real-life experience on 40 patients. Presented at: EHA25 Virtual; June 11-21, 2020. Abstract EP1119. library.ehaweb.org/eha/2020/eha25th/293608/elena.inzoli.use.of.biosimilar.erythropoiesis.stimulanting.agents.for.anemia.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Asearch%3Dbiosimilar

Investigators produced what they described as the first evidence supporting the use of biosimilar erythropoiesis-stimulating agents (ESAs) in patients with myelofibrosis-related anemia.

Biosimilar ESA Is Effective in Myelofibrosis Anemia

An extension study of a trastuzumab biosimilar (SB3, Ontruzant) versus reference trastuzumab (TRZ) supports a hypothesis that a downward "drift" in antibody-dependent cell-mediated cytotoxicity (ADCC) contributed to lower event-free survival (EFS) and overall survival (OS), according to data 

at ASCO20 Virtual, the annual meeting of the American Society of Clinical Oncology.

The study, an extension of a phase 3 trial, assessed long-term cardiac safety and efficacy in patients with HER2-positive early or locally advanced breast cancer treated with biosimilar or TRZ.

 (N = 875), 13 were classified as having a drift in ADCC activity, and the remainder were considered to have ADCC activity in the normal range. Investigators in this study had previously observed that ADCC appears to correlate with EFS.

“ADCC is thought to be an important contributor to the efficacy of trastuzumab, and amplification of ADCC activity could be a promising area of research,” the investigators noted in the October 2019 report.

In the extension study, 367 patients were enrolled from the main study after completing neoadjuvant-adjuvant therapy, 187 on the SB3 arm and 181 on 1 of 2 reference product arms: nondrifted TRZ (n = 55) and drifted TRZ (n = 126).

The investigators reported that the incidence of asymptomatic significant left ventricular ejection fraction (LVEF) decrease was comparable between the biosimilar and TRZ groups. “All of the patients recovered with LVEF above 50%.” There were no instances of congestive heart failure, cardiac death, or other significant cardiac conditions during the follow-up.  

Further, there was no statistically significant difference in EFS or OS between SB3 and TRZ. The 4-year EFS rates for SB3 and TRZ were 83.4% and 80.7% (HR, 0.77; 95% CI, 0.47-1.27), respectively; and the 4-year OS rates were 94.4% and 89.6% (HR, 0.53; 95% CI, 0.24-1.16).

With regard to EFS between SB3 and nondrifted TRZ, an ad-hoc analysis revealed no difference (HR, 1.60; 95% CI, 0.58-4.40; 

 = .362). There also was no difference in OS between SB3 and nondrafted TRZ (HR, 0.97; 95% CI, 0.11-8.50; 

However, between drifted TRZ and nondrifted TRZ, differences were observed for EFS (HR, 5.50; 95% CI, 1.81-16.65; 

 = .003) and OS (HR, 15.35; 95% CI, 1.78-132.69; 

The Investigators concluded that “comparable long-term cardiac safety and survival at the 4-year follow-up supports biosimilarity between SB3 and TRZ,” but “ad-hoc analysis results by ADCC status suggest a possible correlation between ADCC and clinical efficacy,” meriting further study.

For further biosimilars coverage of ASCO20 Virtual, click 

Downward “drift” in batches of reference trastuzumab shed more light on the importance of antibody-dependent cell-mediated cytotoxicity on survival, investigators reported at ASCO20 Virtual, the annual meeting of the American Society of Clinical Oncology.
 

Batch Variation in Trastuzumab Study Affects Outcomes

In an attempt to bring biosimilars to more people, especially those in lower income countries, the World Health Organization (WHO) has certified, or “prequalified,” its second biosimilar for the treatment of cancer.

The WHO gave the nod to a rituximab biosimilar (Truxima) produced by Celltrion. The WHO prequalification program provides for full assessment of clinical and other data related to the development of biosimilars or an abbreviated pathway for prequalification that is based upon prior acceptance by a “stringent” regulatory authority, such as the FDA.

The prequalification of the Celltrion biosimilar marks the second such action since the WHO’s pilot biosimilar program was launched in 2017.

In November 2019, the WHO prequalified Samsung Bioepis’ breast cancer trastuzumab biosimilar Ontruzant, which references Herceptin.

The WHO pilot program for cancer biosimilars is aimed in particular at trastuzumab and rituximab products, and the agency has invited other manufacturers of these agents to apply for prequalification through the dual pathway program.

These agents can cost in the tens of thousands of dollars annually for oncology treatment, and so the discounts offered for biosimilars can make a huge difference for patient access, the WHO maintains.

“As with all biologic medicines, the complex development and manufacturing process for rituximab have meant high treatment costs. Therefore, access to affordable versions of this effective essential medicine in nations with fewer resources and less advanced infrastructure remains limited,” the WHO said in a 

Rituximab is used in the treatment of diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and follicular lymphoma. The WHO noted it has “significantly improved therapeutic responses and remains a fundamental component of treatment regimens” for the treatment of cancer.

In the United States, Truxima was launched in November 2019 at a 10% discount to the rituximab biosimilar, which is marketed as Rituxan in the United States and MabThera in the European Union.

In 2017, the Celltrion version of rituximab became the first biosimilar for the treatment of oncology to be approved in the European Union.

It is regulator-approved in both the United States and the European Union for the treatment of non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with poly-angiitis, and microscopic polyangiitis.

The WHO also offers prequalification for numerous other medicines. “Many low-income countries also use WHO’s lists of prequalified products to guide their selection of medicines, vaccines and technologies for national procurement,” the WHO said in a 

Rituximab is a monoclonal antibody (mAb) that binds to CD20 on the surface of B-cells, and subsequently mediates the destruction of cancer cells. Trastuzumab is a mAb that is specifically used to treat HER2-positive breast cancer, a particularly aggressive form of cancer that is often successfully treated with trastuzumab.

As part of pilot program designed to improve access to cheaper medications in oncology, a rituximab biosimilar from Celltrion has been approved for use by the World Health Organization (WHO).

WHO Clears Celltrion Rituximab for Use

Coronavirus disease 2019 (COVID-19) put a crimp in just about everything, including the FDA’s new drug and biosimilars review activities. In so doing, the pandemic helped make the case for an FDA project to upgrade its system for assessing workplace capacity and setting user fees required from manufacturers that make drug application submissions.

“Our staff is currently in a primarily telework environment,” the agency said in a recent 

 that described the strain on its resources caused by COVID-19 and expressed uncertainty about the FDA’s ability to continue drug application reviews on schedule.

“At this time, the New Drug Program, the Generic Drug Program, and the Biologics and Biosimilars Programs are continuing to meet key review program user fee performance goals, approve applications, and communicate with applicants. With many staff working on COVID-19 activities, it is possible that we will not be able to sustain our current level of performance indefinitely,” the agency said.

Just as COVID-19 hit, the agency had embarked on an effort to revise its methodology for determining resource and capacity needs for its human drug and biosimilar biologic review programs under the Prescription Drug User Fee Act (PDUFA) and Biosimilar User Fee Act (BsUFA).  

A previous problem with these programs was that unanticipated increases in workload did not result in comparable increases in user fees collected from manufacturers who submitted review applications for new drug products, leaving the FDA with a funding shortfall.

“In other words, the agency would have more work while fee revenue remains fixed and would not be able to afford hiring the additional staff required to maintain review timeline performance,” the FDA wrote in an April 2020 

 explaining its decision to develop a new workload—user fee calculation methodology.

In 2003, a workload adjustment plan was introduced for the PDUFA program, and it allowed for adjustments based on long-term changes in the volume of regulatory submissions; however, it has been revised multiple times owing to the complexities of regulatory submissions, and studies conducted in the hopes of fine-tuning this methodology have been considered “suboptimal,” the agency said.

No such adjustment methodology was adopted for BsUFA, and in its current initiative, the FDA seeks to incorporate private sector analysis and feedback into what it believes is a more efficient plan.

 commissioned by the FDA, management consulting firm Booz Allen Hamilton has given the new workload capacity tool a thumbs-up, stating that it “comprehensively includes workload submission types in a manner that will likely forecast resource demands close to real-world figures” and is also scalable as FDA resource needs evolve or increase.

A considerable amount of money is collected from user fee programs at the FDA. For example, the base PDUFA target 

for 2020 is slightly more than $1 billion, and the base target 

Booze Allen has also recommended the FDA consider creating prediction intervals (a range with upper and lower limits) for its resource demand forecasts to address future uncertainties in its estimates. The firm said the FDA should consider making its forecast models more interpretable to build public trust in its methods and suggested that it find a way, within the model, to account for work that is not directly related to drug application submissions, “such as postmarket safety and some subsets of policy and guidance development.”

The firm also recommended that the FDA make further refinements by evaluating the accuracy of user fee adjustments made in previous years, develop business scenarios to model workplace needs, and closely evaluate its ability to enlarge the agency workforce to accommodate needs.

During the month-long public comment period that closed in May, the FDA received just 1 comment, from the trade organization Pharmaceutical Research and Manufacturers of America (PhRMA). The group expressed 

 with the findings and recommendations from Booze Hamilton but called for reassurance that the resources requested by the FDA would be used for the purposes intended.

“If the [capacity planning adjustment] provides additional resources due to increases in workload for specific functions, PhRMA believes there should be an effective allocation of agency staff and resources to meet those needs,” PhRMA said in its comment. The group asked for clarification on how resource needs are determined and follow-up reports explaining how resources were allocated to those needs.

The group also requested that the FDA improve transparency on how much is being spent on overlapping needs by different departments within the agency that may be funded by multiple user fee programs. “The FDA should include a comprehensive and aggregate accounting of the cross-cutting activities and how each funding source contributes to the effort,” the group said.

Even before the pandemic, the FDA was having trouble estimating its resource needs for biosimilar application reviews. An ongoing process may fix that.
 

FDA Reevaluates User Fees for Biosimilar Reviews

The Oncology Care Model (OCM) has served as a proving ground for the value of biosimilars, as various studies presented at this year’s American Society of Clinical Oncology meeting 

The model of value-based care established through CMS’ Center for Medicare and Medicaid Innovation (CMMI) was intended to terminate next year and be replaced. It’s now among a number of models that CMS has decided to extend owing to the disruption caused by the coronavirus disease 2019 (COVID-19) pandemic. The OCM will now extend 1 additional year, until mid-2022.

A key feature of the model was that practices would share the upside financial gain that CMS received from savings achieved by the model. Eventually, they also would have to share the financial downside (ie, negative savings) as they learned how to manage the model's complex requirements.

As part of the COVID-19 arrangements, the 175 practices enrolled in the model will have the option to forgo the upside and downside risks associated with performance reporting periods during the pandemic. Practices have seen reduced flow of patients, and the practice of oncology has been made more complicated by the need to ensure the safety of clinicians and patients. Clinical trial activities also have been disrupted.

As one of the concessions offered by CMS for practices that choose not to forgo the upside or downside risk, episodes of care affected by COVID-19 will not be factored into their performance evaluations.

“When it comes to a pandemic of the proportion we’re now experiencing, as part of ensuring that value-based payments are sustainable, the models must be adjustable to address the uniqueness of the current situation,” CMS Administrator Seema Verma said in a 

Recognizing that oncology practices are struggling with the pandemic, the Center for Medicare and Medicaid Innovation has eased some performance requirements.
 

Timeline Is Extended for Practices Struggling With COVID-19

A recent settlement over patent challenges will enable Amgen to bring its biosimilar for eculizumab to market March 1, 2025, giving originator company Alexion breathing space to bolster its revenue base by developing sales of a follow-on product.

Alexion announced in a May 29, 2020, Securities and Exchange Commission filing that it has 

 3 inter partes patent challenges initiated by Amgen, which seeks to gain a share of the nearly $4 billion in yearly revenue generated by Alexion’s eculizumab (Soliris) product for paroxysmal nocturnal hemoglobinuria (PNH), an ultra-rare disease.

PNH is a rare blood disease characterized by the breakup of red blood cells due to the absence of a protein that protects the cells against the immune system. Alexion’s Soliris costs about $500,000 per patient, per year, making it one of the most costly medicines.

It is also by far the highest revenue-generating agent in Alexion’s drug portfolio. In 2019 the drug generated $3.95 billion in sales, which made up the majority of Alexion’s $4.99 billion 2019 revenue haul.

A follow-on product Alexion has developed for PNH is ravulizumab (Ultomiris) has shown marginally better efficacy and is rapidly growing in sales as Alexion works to convert Soliris patients and generate loyalty to the replacement product.

 in the first quarter of 2020 alone, as opposed to $338.9 million in all of 2019.

A key selling point from the consumer perspective is that Ultomiris requires intravenous administration every 8 weeks as opposed to every 2 with Soliris, which reduces the number of doses needed per year to 6 from 26.

Although Alexion has sought to move its Soliris PNH patients over to Ultomiris to defend against loss of eculizumab market share to biosimilars, Soliris’ sales have continued to rise, thanks in part to the addition of new indications, for generalised myasthenia gravis and neuromyelitis optica spectrum disorder, also both rare diseases. Soliris generated $1 billion in net sales in the first quarter of 2020, up from $962 million in the comparable year-ago quarter.

The settlement reached on the patent challenges before the Patent Trial and Appeal Board of the US Patent and Trademark Office grants Amgen a nonexclusive, royalty-free license to manufacture and market biosimilar eculizumab in the United States.

Amgen’s eculizumab biosimilar candidate is ABP 959, and phase 1 trial findings supporting pharmacokinetic and pharmacodynamic equivalence were 

A randomized, double-blind, controlled phase 3 study of ABP 959 is 

 in patients with PNH to compare the biosimilar candidate with the reference product on basis of efficacy and safety.

Roche, Novartis, and Akari have previously initiated development of other potential competitors to eculizumab.

In a settlement announced via a Securities and Exchange Commission filing, Alexion said it had settled with Amgen over eculizumab patent disputes, allowing Amgen to bring a competing biosimilar to market in 2025.