Biosimilars Update

New Data Support Using Tbo-Filgrastim in Pediatric Patients

Kelly Davio

In research presented at the 59th American Society of Hematology Annual (ASH) Meeting and Exposition in Atlanta, Georgia, Noah Federman, MD, evaluated the safety and e cacy of subcutaneous tbo- lgrastim (Granix) in pediatric patients undergoing chemotherapy for solid tumors.¹

Chemotherapy-induced neutropenia, a common adverse event (AE), can limit optimal dosing and treatment. Tbo- filgrastim, a nonglycosylated recombinant methionyl human granulocyte colony stimulating growth factor (G-CSF), is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies who are receiving myelosuppressive anticancer therapy associated with clinically signi cant incidence of febrile neutropenia. Tbo- filgrastim is not technically a biosimilar of filgrastim (Neupogen); it was approved prior to the establishment of a biosimilar approval pathway in the United States.² However, the 2 drugs do not differ significantly in terms of pharmacokinetic (PK) parameters, safety, or efficacy.

This phase 2, multicenter, open-label study investigated the safety, tolerability, PK, pharmacodynamics, efficacy, and immunogenicity of tbo- filgrastim in patients aged 1 month to 16 years who had solid tumors without bone marrow involvement and had received at least 1 cycle of myelosuppressive chemotherapy.

Patients (n = 50) were given a subcutaneous dose of tbo-filgrastim at 5mcg per kilogram of body weight once daily. Tbo-filgrastim administration was started at approximately 24 hours after the end of the last chemotherapy treatment, and daily dosing continued until the expected neutrophil nadir has passed and neutrophil count had recovered, but not for more than 14 days.

The most common cancers for which the 2 infants (aged 1 month to 2 years), 30 children (2 to 12 years), and 18 adolescents (12 to 16 years) were being treated were rhabdomyosarcoma (14%), neuroblastoma (14%), Ewing tumors (12%), and osteosarcoma (12%). The mean number of doses of tbo- filgrastim administered was 9.2 in children and 7.3 in adolescents. One infant patient received 12 doses and the other, 14.

Serious treatment emergent AEs were reported in 24% of patients, with febrile neutropenia (12%), anemia (8%), thrombocytopenia (8%), increased alanine aminotransferase (6%), and increased aspartate aminotransferase (6%) being the most commonly reported. Nine patients experienced treatment-related AEs, most commonly musculoskeletal and connective tissue disorders (8%) of grade 1 severity. Two patients had increases in liver function enzymes that the investigator considered to be related to tbo- filgrastim and chemotherapy; no clinical symptoms were observed in these events, and both resolved by the end of the study. No deaths or study withdrawal occurred during the study period.

PK parameters of exposure were comparable between age groups. The incidence of severe neutropenia was 52%, with a mean duration of 1.8 days. The incidence of febrile neutropenia was 26%. Immunogenicity assessments found that none of the patients had developed anti-drug antibodies to tbo-filgrastim.

The researchers concluded that a daily dose of tbo- filgrastim at 5 mcg per kg of body weight administered to pediatric patients with solid tumors without bone marrow involvement demonstrated a safety profile consistent with that of adult patients, and no immunogenic response was observed in this population.

“We are very excited to present the results of the first study of tbo- filgrastim in children,” Federman told The Center for Biosimilars® in an e-mail. “As we all know, chemotherapy-induced neutropenia is a common complication from chemotherapy [that] may lead to prolonged hospitalization, increased morbidity, and limitation of optimal dosing of chemotherapy and treatment of cancer....G-CSF, while standard of care, is quite expensive, and there is a need for additional agents to expand access.”

References:

1. Federman N, Dragomir MD, Kizyma Z, et al. A phase 2, international, multicenter, prospective clinical trial of sub- cutaneous tbo- filgrastim in pediatric patients with solid tumors undergoing chemotherapy. Abstract presented at: 59th Annual Meeting & Exposition of the American Society of Hematology; December 9-12, 2017; Atlanta, GA. Abstract 2271. ash.confex.com/ash/2017/webprogram/Paper106027.html.

2. Pappas AL, Hanna S. TBO- lgrastim (Granix). Pharmacy Times. March 1, 2014. pharmacytimes.com/publications/ health-system-edition/2014/march2014/tbo- lgrastim-granix. Accessed December 8, 2017.

Study Results Show Low Incidence of Immunogenicity With Tbo-Filgrastim

Kelly Davio

Neutropenia, a primary cause of delays, interruptions, and dose reduction to chemotherapy, can compromise both patient survival and complete response rates. Granulocyte colony-stimulating factors (G-CSFs), including tbo- filgrastim (Granix), can reduce the incidence, duration, and severity of febrile neutropenia in patients receiving chemotherapy. However, serious immune reactions can be caused by drugs like tbo- filgrastim (a follow-on filgrastim product approved before the United States instituted a regulatory pathway for the approval of biosimilar products under the Biologics Price Competition and Innovation Act).

The production of antidrug antibodies (ADAs) can have negative consequences for patients, including such reactions as anaphylaxis, reduced efficacy, and neutralization of endogenous counterparts by cross-reactive neutralizing antibodies. A new study, conducted by Linglong Zou, PhD, and colleagues, evaluates the immunogenicity of tbo- filgrastim in patients receiving chemotherapy for solid and hematologic malignancies.¹ The data were presented at the 59th American Society of Hematology Annual Meeting and Exposition in Atlanta, Georgia.

Zou and his team collected blood samples during 3 different phase 3 clinical studies that compared the efficacy and safety of tbo-filgrastim with filgrastim and/or placebo, administered 1 day after chemotherapy for a duration of 5 to 14 days. The team implemented a 3-tier approach— screening, confirmation, and a titer assay—to evaluate binding ADAs for tbo- filgrastim using a validated homogeneous enzyme-linked immunosorbent assay. Neutralizing activity was assessed for confirmed-positive ADA test samples using a validated cell-based proliferation assay. Clinical measures were examined for all patients who had confirmed ADAs to assess a possible correlation between ADAs and the potential clinical impact of immunogenicity.

In total, 436 patients diagnosed with cancer who had received tbo- filgrastim were assessed for immunogenicity of the follow-on filgrastim product. These patients had breast cancer (n = 213), lung cancer (n = 160), or non-Hodgkin’s lymphoma (n = 63).

Only 3 patients with breast cancer developed ADAs at a low titer, and none of the samples showed cross-reactivity to endogenous G-CSF or neutralizing antibody activity. Three patients with lung cancer developed ADAs at a low titer, but none of the ADA-positive samples cross-reacted with endogenous G-CSF, and 1 predose sample showed neutralizing antibody activity in cycle 1 prior to tbo- filgrastim treatment. Among the patients with non-Hodgkin’s lymphoma, 1 developed ADAs at a titer too low to be determined. No cross-reactivity or neutralizing antibody activity was associated with this patient’s blood sample. Overall, immunogenicity incidence was 1.6% among all the patients tested, and none of those with positive ADA samples showed evidence of hypersensitivity, anaphylaxis, or a loss of treatment efficacy.

The researchers concluded that the incidence of immunogenicity or treatment-emergent ADAs in patients who were receiving chemotherapy and tbo- filgrastim was low across the 3 cancer populations tested and all positive samples had low-titer ADAs. None of the positive samples had cross-reactive ADAs to endogenous G-CSF, and none of the patients who had positive ADA samples had clinically relevant immunogenicity-related symptoms during the study period.

References:

2 Studies Highlight Biosimilar G-CSFs

1. Zou L, Buchner A, Field J, Barash S, Liu P. Immunogenicity assessment of tbo- filgrastim in cancer patients receiving chemotherapy. Abstract presented at: 59th Annual Meeting and Exposition of the American Society of Hematology; December 9-12, 2017; Atlanta, GA. Abstract 2274. ash.confex.com/ash/2017/webprogram/ Paper99985.html.Samantha DiGrande

Biosimilar Filgrastim Saves Costs

Two studies presented at the 59th American Society of Hematology Annual Meeting and Exposition in Atlanta, Georgia, highlight biosimilar granulocyte-colony stimulating factor (G-CSF) therapies.The savings generated by using biosimilars can be reallocated to provide other treatments, including expensive and recently approved novel therapies, according to study results presented by Sanjeev Balu, PhD. The study examines expanded access to the drug obinutuzumab (Gazyva) made possible on a budget-neutral basis through savings obtained from using biosimilar filgrastim-sndz (Zarxio).¹

The investigators estimated the potential costs saved by converting febrile neutropenia prophylaxis from reference filgrastim (Neupogen) or pegfilgrastim (Neulasta) to the biosimilar filgrastim, and then simulated a hypothetical reallocation of those savings to therapeutic care with obinutuzumab (a humanized anti-CD20 monoclonal antibody approved in 2016 for relapsed or refractory follicular lymphoma).

Assuming therapeutic similarity of filgrastim, pegfilgrastim, and biosimilar filgrastim, a simulation analysis was performed using the average selling price cost for 1 patient for 1 chemotherapy cycle with 5, 7, 11, and 14 days of prophylaxis. This study was performed with a 20,000-patient panel.

Per-cycle cost savings from utilizing biosimilar filgrastim over filgrastim was estimated at $327 (5-day prophylaxis), $457 (7-day), $719 (11-day), and $915 (14-day). For 20,000 patients, conversion from filgrastim to biosimilar filgrastim was estimated to yield savings of $6,540,000 (5-day prophylaxis); $9,156,000 (7-day); $14,388,000 (11-day); and $18,312,000 (14-day). The savings would provide expanded access to obinutuzumab treatment to 60, 85, 133, and 169 patients, respectively.

Conversion-related savings relative to pegfilgrastim decline as daily injections increase. For 20,000 patients, conversion from pegfilgrastim to the biosimilar filgrastim would yield savings of $55,893,600 (5-day prophylaxis); $47,177,600 (7-day), $29,745,600 (11-day); and $16,671,600 (14-day), the authors found. This would expand access to obinutuzumab treatment to 516, 435, 275, and 154 patients, respectively.

Cinfa Biotech's Pegfilgrastim Candidate Has Similar PD, Immunogenicity to Neulasta

The results show that converting from reference filgrastim and pegfilgrastim to biosimilar filgrastim yields significant savings, especially when converting from pegfilgrastim. Conversion to biosimilar growth factors for prophylaxis of febrile neutropenia in large payer panels can create substantial savings that enable more patients with hematological malignancies to be treated without additional cost to payers, according to the authors.Cinfa Biotech’s proposed pegfilgrastim biosimilar, B12019, has similar pharmacodynamics (PD) and immunogenicity to the reference Neulasta, according to a research team led by Karsten Roth, PhD.²

B12019 is being developed as a biosimilar to Neulasta, a long-acting form of recombinant human granulocyte-colony stimulating factor (G-CSF) filgrastim for the prevention of chemotherapy-induced neutropenia. Cinfa’s clinical development program, based on scientific advice from the European Medicines Agency, consists of 2 clinical studies conducted to confirm the biosimilarity to the European Union—authorized reference product as established by analytical, functional, and preclinical data. This study investigates the immunogenicity and pharmacodynamic comparability of the biosimilar and reference at a dose of 3 mg.

The 3-mg dose was selected because, compared with clinical dose of 3 mg, it is more sensitive for detecting potential differences in PD between the biosimilar and the reference. This study was designed as a multiple-dose, randomized, double-blind, 3-period, 2-sequence cross-over study in 96 healthy individuals.

A hierarchical antidrug-antibody (ADA) test strategy with highly sensitive screening assay followed by 4 parallel epitope-specific, confirmatory assays was established. Primary study end points were area under the effect curve (AUEC0-last) of the absolute neutrophil count for PD after crossover and the ADA rate for immunogenicity after repeat dosing.

The number of ADA-positive subjects was very low for both the B12019 and Neulasta groups. No imbalance was observed between either drug after repeat doses. Neither anti- filgrastim nor neutralizing antibodies were detected for B12019 or Neulasta. The model-based PD comparison included 82 subjects; comparability was demonstrated, and there were no clinically meaningful differences observed in the safety profile for B12019 and Neulasta.

This study of the prospective biosimilar to the reference pegfilgrastim confirmed PD comparability with the reference product at a sensitive dose of 3 mg, and the researchers concluded that the study confirmed biosimilarity of the proposed biosimilar to the reference.

References:

1. McBride A, Campbell K, Bikkina M, MacDonald K, Abraham I, Balu S. Expanded access to obinutuzumab from cost- savings generated by biosimilar lgrastim-sndz in the prophylaxis of chemotherapy-induced (febrile) neutropenia: US simulation study. Presented at: 59th Annual Meeting and Exposition of the American Society of Hematology; December 9-12, 2017; Atlanta, GA. Abstract 3380. ash.confex.com/ash/2017/webprogram/Paper105737.html.

Presenters Share New Data on Rituximab Biosimilars Approved in European Union, Argentina

2. Roth K, Wessels H, Hoe er J, Jankowsky R. Comparability of pharmacodynamics and immunogenicity of B12019, a proposed peg lgrastim biosimilar to Neulasta. Presented at the American Society of Hematology 59th Annual Meeting and Exposition 2017, December 9-12, 2017; Atlanta, GA. Abstract 1002. ash.confex.com/ash/2017/webprogram/ Paper100922.html.Samantha DiGrande

Although no rituximab biosimilars have been approved in the United States to date, experience with rituximab therapies approved in other regulatory areas adds to the body of evidence concerning these products’ safety and efficacy.

European Union-Approved Biosimilar Safe for Rapid Infusion

Raakhee Shah, MPharm, and colleagues presented study results demonstrating that patients can be switched from reference rituximab (MabThera) to biosimilar rituximab (Truxima) without reverting to slower infusion rates.¹

Rituximab is a monoclonal antibody approved in the European Union and United States to treat non-Hodgkin’s lymphoma and chronic lymphocytic leukemia, as well as other indications, and can be associated with infusion- related reactions (IRRs). The incidence is greatest with the first infusion and decreases significantly with subsequent infusions.

To reduce the risk of IRRs, manufacturers recommend that the first dose be gradually increased every 30 minutes in increments of 50 mg per hour to a maximum rate of 400 mg per hour. For subsequent infusions, the dose is gradually increased every 30 minutes in increments of 100 mg per hour, known as standard subsequent rate infusion. That means a typical rituximab infusion can take 4 to 6 hours.

If the first infusion is well tolerated, it has become common practice to administer subsequent doses as a “rapid infusion” over 90 minutes, with 20% of the dose given over the first 30 minutes and the remaining 80% over the following 60 minutes.

This study aimed to assess the safety of rapid infusion of biosimilar rituximab by reviewing infusion-related adverse events (AEs) that fall into 3 categories:

• Patients switching from the reference product, MabThera, to the biosimilar (n = 78)
• Patients with previous exposure to the reference product but who received their last dose over 6 months prior (n = 6)
• Rituximab-naive patients (n = 58)

In total, 142 patients received the biosimilar between May 22 and July 26, 2017. Infusion-related AEs were noted from nursing infusion records and graded using Common Terminology Criteria for Adverse Events, version 4.03.

Patients who had been receiving the reference product as a rapid infusion continued at this rate with the biosimilar. Those who had received just 1 prior dose of the reference product at the standard first-dose infusion rate got their first dose of the biosimilar as a rapid infusion.

Patients who had not received the reference product for over 6 months or were rituximab-naive received their first dose at the standard first-dose infusion rate. If that was well tolerated, subsequent doses were given as rapid infusion. All patients received premedication with acetaminophen and an antihistamine.

The study results showed that the rapid infusion of the biosimilar was well tolerated in all 3 groups. In addition, patients who switched from the reference safely received their first dose of the biosimilar as a rapid infusion. One patient who switched from the reference developed tachycardia during the first dose of the biosimilar at a rapid infusion rate; however, this patient was able to receive subsequent doses of the biosimilar with an added glucocorticoid pre- medication without further IRRs.

Grade 2 or 3 IRRs were observed with 8 first-rate infusions (12%), and 4 patients received further doses of the biosimilar. They received their next doses at the standard subsequent infusion rate with glucocorticoid premedication without incident, and 2 of the patients received further doses at a rapid infusion rate without an IRR.

These results—the first reported postmarketing experience of rapid infusion of biosimilar rituximab—showed that patients can be safely switched from the reference product to rituximab biosimilar without reverting to slower infusion rates. The authors said they hope that these findings will facilitate the introduction of the biosimilar at centers prescribing rituximab without adversely affecting use of resources or the patient experience.

Argentine- Approved Novex Has Similar Safety Profile to MabThera

Gustavo Milone, MD, and his team presented a study that investigates the postmarketing trends of Novex, a biosimilar rituximab approved in Argentina for the same indications as the reference product (MabThera, Rituxan).² Postmarketing surveillance data from the first national pharmacovigilance plan for a biosimilar monoclonal antibody show that, in terms of tolerability, this biosimilar has a similar safety profile to that of the reference product.

To determine deviations from expected frequencies of adverse events (AEs), a prospective treatment registry was implemented from the start of the biosimilar’s commercialization on November 26, 2014, with data reported until June 30, 2017. Physicians—180 in total— tracked age, gender, indication, dose, dose frequency, and date of treatment initiation and nalization for each patient receiving the biosimilar.

The study comprised the records of 525 patients who had at least 1 follow-up. Most were female (52%), the mean age was 63.3 years (range, 10-90), and most received the biosimilar rituximab for hematological disease (91.2% of cases). The treatment duration ranged from 154 to 309 days, with the number of treatment cycles varying from 1 to 12. Individual Case Safety Reports were collected from 24 patients with 29 AEs. The most frequently reported were acute infusion-related reaction (14), arrhythmia (3), pneumonia (2), and stroke (2).

The researchers noted that 41 treatments with rituximab were initiated before the product launched and, assuming treatment began with MabThera, imply switching to the biosimilar from the reference.

Researchers investigating data from the postmarketing surveillance found a similar incidence of AEs after the use of rituximab biosimilar compared with the published data of the reference product. Thus, in terms of tolerability, the biosimilar and its reference have similar safety profiles.

References:

1. Shah R, Cheesman S, Ardeshna K, et al. Evaluation of the safety and tolerability of rapid infusion of biosimilar rituximab Truxima—the University College London hospitals (UCLH) experience. Abstract presented at: 59th Annual Meeting and Exposition of the American Society of Hematology; December 9-12, 2017; Atlanta, GA. Abstract 3387. ash. confex.com/ash/2017/webprogram/Paper107375.html.

2. Milone G, Penna M, Fernandez F, et al. Post-marketing surveillance with a biosimilar of rituximab (Novex) in Argentina. Abstract presented at: 59th Annual Meeting and Exposition of the American Society of Hematology; December 9-12, 2017; Atlanta, GA. Abstract 2131. ash.confex.com/ash/2017/webprogram/Paper102866.html.

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