August 2015 FAQs

How will fusion technology for factor concentrates change prophylaxis strategies in the management of hemophilia A and B?

Background

In the past few years, developments have occurred in treatment and prophylaxis strategies for bleeding in patients with hemophilia. Evidence has shifted management of patients with hemophilia from a strategy of administering coagulation factors to treat episodic bleeding on-demand, to administering coagulation factors prophylactically, reducing the need for on-demand treatment. When initiated early, prophylactic strategies have been shown to reduce bleeds and prevent joint damage related to bleeds.^1,2 The most recent systematic review on the use of factor concentrates for prevention of bleeding in people with hemophilia A or B confirmed that prophylaxis significantly reduces bleeding and joint damage compared to on-demand treatment of bleeding in children.³ The findings do not apply to use of prophylaxis in patients who already have joint damage, however.

The 2013 World Federation of Hemophilia guidelines recommend the intravenous infusion of factor concentrates as prophylaxis, and they provide a review of multiple strategies that may be used.⁴Prophylaxis aims to maintain plasma concentrations of factor levels at or above 1%, but may still be useful even if this level is not achieved. Continuous prophylaxis can be primary (regular treatment is initiated in the absence of joint disease and before the second large joint bleed and before the age of 3 years); secondary (regular treatment is initiated after 2 more large joint bleeds and before the onset of joint disease); or tertiary (regular treatment is initiated after the onset of joint disease). The objective of primary and secondary prophylaxis is to prevent joint disease before it starts (although patients receiving secondary prophylaxis are at greater risk for developing joint disease), whereas the objective for tertiary prophylaxis is to slow progression of joint disease and maintain joint mobility.⁵Intermittent prophylaxis may also be used in order to stop the bleeding cycle when patients experience repetitive bleeding episodes.⁴ Treatment is given periodically as needed but for no more than 45 weeks per year. For example, short-term prophylaxis for 4 to 8 weeks is recommended for patients who have multiple repeat bleeding episodes. As for dosing, a commonly used strategy is the Malmo protocol, where 25 to 50 IU/kg of factor are administered 3 times per week for hemophilia A and twice a week for hemophilia B. The Utrecht protocol is the same schedule but uses lower dosing: 15 to 30 IU/kg 3 times a week for hemophilia A and twice a week for hemophilia B. Prophylaxis can be further categorized as “full dose” or “low dose.”⁶ The guidelines emphasize that prophylaxis should be tailored to the individual, with consideration for availability of factor concentrates, venous access, age, and bleeding phenotype.⁴

However, prophylaxis of bleeding and bleeding complications in hemophilia is not without its limitations. Inhibitor development is a main concern with factor use.⁷ Inhibitors are neutralizing antibodies that decrease a person’s hemostatic response to factor concentrates. ^4,7 An inhibitor titer of ≥0.6 Bethesda units (BU)/mL is considered clinically significant, and once inhibitor titers reach >5 BU/mL, bypassing agents, such as recombinant factor VIIa and activated prothrombin complex concentrates, usually have to be used. Development of inhibitors is most common in hemophilia A, affecting up to 33% of those who have severe disease. Inhibitor development occurs in <5% of patients with hemophilia B.⁴ Risk for development of inhibitors increases with increased exposure days, as well as with higher intensity of treatment, so frequent infusions for prophylaxis and treatment may lead to inhibitor development.

Because of their short half-lives, the factor concentrates have to be administered multiple times per week for prophylaxis.⁶ The pharmacokinetics vary among individuals, but generally, the half-life for factor VIII (FVIII) is between 8 and 12 hours, and the half-life for factor IX (FIX) is between 18 and 24 hours. More pharmacokinetic variability exists for FVIII because it complexes with von Willebrand factor, which has a shorter half-life.⁸ The frequent administrations often necessitate placement of central venous access devices.⁶ This comes with risk for infection and thromboses. The infusions can be painful and disruptive to a family’s schedule. The cost of factor products is also a major deterrent to care, and is the reason that prophylaxis is not feasible in some parts of the world.

One of the most recent developments in the management of hemophilia is the addition of an Fc fusion protein to the coagulation factor concentrates.^6,8 This technology is similar to that of conjugating agents/drugs to polyethylene glycol (PEG) (e.g., pegfilgrastim) or fusing to albumin (e.g., albiglutide). These technologies allow for extension of the agents’ half-lives. Examples of drugs that utilize Fc fusion technology are etanercept and romiplostin.⁶  The first factor concentrates manufactured with Fc fusion technology approved by the Food and Drug Administration were recombinant factor IX (rFIXFc; Alprolix) in March 2014 and recombinant factor VIII (rFVIIIFc; Eloctate) in June 2014.^9,10 The Fc fusion technology utilizes the Fc domain of immunoglobulin G to form fusions with cytokines, growth factors, and now factor concentrates, including FVIII and FIX. This complex interacts with the neonatal Fc receptor (FcRn), which is expressed in endothelial cells in the vasculature, as well as epithelial cells in the intestine, lung, and kidneys.^6,8 This interaction protects the complex from endosomal/lysosomal degradation, and the moiety to which the Fc fusion protein is attached (such as the factor concentrate) is recycled back into circulation. Fc fusion-mediated recycling allows for extended half-lives of the factor concentrates.

Pharmacokinetics and clinical efficacy

The major phase 3 trials that led to the approval of rFVIIIFc and rFIXFc are the A-LONG and B-LONG trials, which assessed the products in patients ≥12 years with severe hemophilia A and B, respectively.^11,12 Both trials assessed pharmacokinetics, a primary efficacy endpoint of annualized bleeding rates (ABR), and development of inhibitors. The open-label, partially randomized A-LONG study had 3 arms: individualized prophylaxis, weekly prophylaxis, and on-demand treatment, as described in Table 1.¹¹ Eighty-seven patients were on prophylaxis prior to this study, of which 87% were receiving prophylactic injections ≥3 times a week. Median duration of treatment ranged from 28 to 32 weeks, depending on group. A subset of patients also had pharmacokinetic comparisons to a rFVIII product. Investigators found that the terminal half-life of rFVIIIFc was extended by a significant amount in comparison to rFVIII: 19.0 vs 12.4 hours, respectively; p<0.001. The median ABR was reduced by 92% in the individualized prophylaxis group in comparison with on-demand treatment (p<0.001) and it was reduced by 76% in the weekly prophylaxis group in comparison with on-demand treatment (p<0.001). Inhibitors were not detected in any of the patients. The treatment was well-tolerated and 6.1% of adverse events were deemed to be related to rFVIIIFc. The authors concluded that rFVIIIFc allows for decreased prophylaxis dosing of 1 to 2 times weekly, with excellent control of bleeding, and that the Fc fusion protein did not interfere with efficacy of the factor and was not associated with immunogenicity.

The B-LONG trial on rFIXFc had 4 treatment groups: weekly dose-adjusted prophylaxis, interval-adjusted prophylaxis, on-demand treatment, and perioperative management (Table 1).¹² Similar to the A-LONG study, 80% of patients who were receiving prophylaxis prior to enrollment reported receiving ≥2 injections per week. The median duration of the study varied for groups 1, 2, and 3, ranging from 40 to 58 weeks. A pharmacokinetic analysis showed that rFIXFc had a significantly prolonged half-life in comparison with rFIX: 82.1 hours vs 33.8 hours, respectively; p<0.001). The ABR was significantly reduced in the weekly prophylaxis group by 83% compared with the on-demand group, and by 87% in the interval-adjusted prophylaxis group compared with the on-demand group (p<0.001 for both comparisons). Twenty-three percent of patients in the weekly prophylaxis group and 43.3% of patients in the interval-adjust prophylaxis group did not experience any bleeding during the trial. Inhibitors were not detected in any patients, and the most common adverse events were nasopharyngitis, influenza, arthralgia, upper respiratory tract infection, headache, and hypertension.

Recently, an open-label phase 3 study of safety, efficacy, and pharmacokinetics of rFVIIIFc in children ≤12 years of age with hemophilia A was completed (KIDS A-LONG).¹³ The study was noncomparative, with a single prophylactic treatment arm consisting of twice-weekly rFVIIIFc. None of the 71 children enrolled developed inhibitors. The half-life of rFVIIIFc was prolonged in comparison to rFVIII, although not to the same extent as in an adult population. For children <6 years of age, the half-life was 12.67 hours and for children 6 to <12 years, the half-life was 14.88 hours. Approximately 46% of patients did not experience a bleeding event. Overall, the median ABR was decreased with rFVIIIFc use as compared to FVIII when used as prophylaxis prior to study enrollment. Also, dosing frequency with rFVIIIFc was decreased by 74% in comparison to their previous FVIII dosing.

The KIDS B-LONG on rFVIXFc in children ≤12 years of age with hemophilia B is nearing completion and results are expected to be published in the near future.¹⁴ A long-term extension study of KIDS B-LONG, B-YOND, is also planned to assess long-term safety and efficacy of rFIXFc.⁸

Conclusion

Prolonging the half-life of factors for hemophilia A and B through Fc fusion proteins may help reduce some of the complications of prophylaxis. Fewer administrations are needed with these long-acting factors, decreasing the prophylaxis exposure days to factor concentrates, as well as the days of treatment since bleeding events are reduced as well with this strategy. This potentially could lead to a decreased risk for development of inhibitors. The need for central venous access may be reduced since infusions are given less frequently, which would decrease the risk for infection. Interruptions to daily life for children and parents would also lessen. Patients who choose to be treated on-demand may elect to switch to a prophylaxis strategy knowing they would not need to receive as many weekly infusions with the long-acting factor concentrates. Because these agents are new, studies have yet to be conducted to elucidate their cost-effectiveness in comparison to factor concentrates without the Fc fusion protein. Overall, the prolongation of the factor half-lives has proven to be an important advancement in the management of patients with hemophilia A and B.

References

1. Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357(6):535-544.
2. Gringeri A, Lundin B, von Mackensen S, Mantovani L, Mannucci PM; ESPRIT Study Group. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Thromb Haemost. 2011;9(4):700-710.
3. Iorio A, Marchesini E, Marcucci M, Stobart K, Chan AK. Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B. Cochrane Database Syst Rev. 2011;(9):CD003429. doi: 10.1002/14651858.CD003429.pub4.
4. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al; Treatment guidelines working group on behalf of the World Federation of Hemophilia. Haemophilia. 2013;19(1):e1-e47. doi: 10.1111/j.1365-2516.2012.02909.x.
5. Oldenburg J. Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens. Blood. 2015;125(13):2038-2044.
6. Carcao M. Changing paradigm of prophylaxis with longer acting factor concentrates. Haemophilia. 2014;20(suppl 4):99-105.
7. Kempton CL, Meeks SL. Toward optimal therapy for inhibitors in hemophilia. Blood. 2014;124(23):3365-3372.
8. Mancuso ME, Mannucci PM. Fc-fusion technology and recombinant FVIII and FIX in the management of the hemophilias. Drug Des Devel Ther. 2014;8:365-371. doi: 10.2147/DDDT.S47312.
9. Eloctate [package insert]. Cambridge, MA: Biogen Idec Inc; 2014.
10. Alprolix [package insert]. Cambridge, MA: Biogen Idec Inc; 2014.
11. Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 2014;123(3):317-325.
12. Powell JS, Pasi J, Ragni MV, et al. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N Engl J Med. 2013;369(24):2313-2323.
13. Young G, Mahlangu J, Kulkarni R, et al. Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A. J Thromb Haemost. 2015;13(6):967-977.
14. Fischer K, Kulkarni R, Nolan B, et al. Safety, efficacy and pharmacokinetics of recombinant factor IX Fc fusion protein in children with haemophilia B (KIDS B-LONG). Paper presented at: International Society on Thrombosis and Haemostasis 2015 Congress; June 2015; Toronto, ON, Canada. Abstract LB009.

August 2015

The information presented is current as of July 2015. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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How should allergic reactions to local anesthetics be managed?

Introduction

Local anesthetics are widely used, with therapeutic applications including local anesthesia for dental, ocular and dermatologic procedures; regional, spinal, or intravenous anesthesia for surgery; epidural anesthesia for labor and delivery; and chronic pain. Due to their ubiquitous presence in clinical practice, allergy to these agents presents several therapeutic challenges. In addition to acute management of allergic reactions, clinicians must determine which local anesthetic patients can safely receive in the future, if any. This article summarizes current evidence and recommendations for the management of local anesthetic allergy.

Characterization of local anesthetic allergy

There are 4 types of allergic reactions based on antigen-antibody immune responses.¹ Type 1 reactions involve the production of IgE antibodies to the offending substance upon first exposure; anaphylactic, life-threatening symptoms occur after the second exposure. Type 2 reactions are cytotoxic, with the formation of IgG or IgM antibodies directed against antigens on native cells. Type 3 reactions involve antigen-antibody complexes that deposit in blood vessel walls and cause vascular and connective tissue damage. Type 4 reactions are characterized by cellular immunity rather than antibody formation, with T-cell sensitization after first exposure to the offending substance and lymphokine-mediated inflammatory reactions after the second exposure.

Allergic reactions to local anesthetics are limited to Type 1 and 4 reactions; Type 2 and 3 reactions have not been reported with these agents.¹  Type 4 reactions are most common. Although more severe, Type 1 allergic reactions are rare.² According to a recent literature review of published observational studies and case reports, the prevalence of confirmed IgE-mediated allergy to local anesthetics is 0.97%.³

Currently available local anesthetics fall into 2 general categories based on the chemical structure of the intermediate chain linkage between the lipophilic aromatic and hydrophilic amine portions of the local anesthetic molecule: amides and esters.¹ Local anesthetics with an ester linkage (ie, benzocaine, chloroprocaine, cocaine, procaine, tetracaine) may be more likely to result in allergic reactions since the para-aminobenzoic acid (PABA) metabolite of ester anesthetics has been associated with allergy. However, allergic reactions to amide agents (ie, bupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine) have also been reported. In fact, one literature review found that 75% of confirmed IgE-mediated allergic reactions to local anesthetics were to amide agents.³

In addition to the local anesthetic agent itself and its metabolite(s), excipients in the product’s formulation can induce allergic reactions.¹ Methylparaben, a common preservative in multidose local anesthetic vials, is metabolized to PABA. Antioxidant compounds such as sodium bisulfite or metabisulfite, which are commonly found in epinephrine-containing solutions, have also been associated with allergic reactions. The presence of these excipients may account for some reports of cross-sensitivity between amide and ester local anesthetics.³ However, allergic reactions have occurred after exposure to preservative-free products as well.

Diagnostic considerations

Further testing and investigation of a suspected local anesthetic allergy should only occur if there is a high clinical suspicion that the local anesthetic was responsible for the adverse reaction. In most cases, adverse reactions to local anesthetics are not IgE-mediated.² Local anesthetics are often administered concurrently with other medications and as part of surgical or other procedures, so the presence of confounding factors should be considered when assessing the adverse reaction. Suspected local anesthetic allergies may actually be due to vasovagal or autonomic responses to procedural trauma, anxiety, unintended effects of systemically absorbed epinephrine, or allergy to a different substance (eg, latex, antibiotics).^2,3 Therefore, a thorough history of the reaction should be obtained, including the local anesthetic name, amount administered, preservative in the formulation, time elapsed, duration of the reaction, specific reaction symptoms, and the presence of confounding factors.¹

There are several methods for testing/diagnosis of local anesthetic allergy. These include patch testing, skin prick testing, intradermal injection, subcutaneous injection, and laboratory testing.^1,4  Type 4 allergic cutaneous reactions are generally evaluated with patch testing, which involves the topical application of several patches containing varying concentrations of preservative-free local anesthetics.^1,2 Patches containing methylparaben and sulfites are also applied. The skin under the patches is assessed for inflammation after 48 hours. Patch testing can help determine the agent that is least likely to elicit a future response, but false positive results have occurred so findings should be interpreted cautiously.

Suspected Type 1 allergic reactions are assessed with skin prick testing and incremental challenge techniques.^1,2 The purpose of these tests is to rule out the possibility of an IgE-mediated reaction.² In prick testing, a small amount of local anesthetic is placed topically and pricked into the skin with a needle.¹ After 10 to 20 minutes, any wheal and flare reaction is evaluated and compared to a histamine control. A positive reaction consists of a wheal that is at least half the size of the wheal produced by the histamine control, and at least 3 mm larger than a negative saline control.⁴ Skin prick testing is fairly easy and safe and may be the only test needed to evaluate the allergy.³ Several local anesthetics are tested, including the offending agent and agents from both the amide and ester classes. Preservatives may also be tested.

If skin prick results are indeterminate or if further testing is needed, then incremental challenge tests can be performed.¹ Incremental challenge tests involve serial dilutions of individual local anesthetic agents, preservatives, and positive and negative controls, followed by examination of the injection site for erythema, urticaria, and swelling. Injections are given periodically until there is a lack of reaction to an undiluted local anesthetic or a positive reaction occurs. Numerous incremental challenge protocols have been described in the literature and the choice of protocol is left to the discretion of the clinician.³Subcutaneous incremental challenge is generally preferred due to disadvantages of intradermal challenge, which include waning levels of IgE antibodies and decreased potential for a positive reaction with a longer duration of time since the reaction, the potential for false-positive results (8% to 15%), a low probability of detecting IgE reactions, and procedure-related pain.^1-3 Incremental challenge testing carries a risk of a Type 1 allergic reaction occurring, so it should be performed in a hospital with adequate access to emergency life support.^1,3 Some authors have suggested use of shorter challenge protocols to minimize the risk of Type 1 allergic reactions.³

Laboratory tests have been used to evaluate medication-related allergy but their overall usefulness for local anesthetic allergy is unclear. Measurement of serial serum concentrations of mast cell tryptase measured immediately after a suspected reaction to the anesthetic agent are endorsed by British Society of Allergy and Clinical Immunology guidelines as a measure of mast cell activation.^3,4 However, there is no consensus for the cutoff point that should be used to indicate that an allergic reaction has occurred, especially if baseline tryptase levels are unknown. There is little data about tryptase concentrations in published reports of local anesthetic allergy.³ Normal tryptase levels do not rule out an anaphylactic reaction.⁴ Histamine levels could also be measured within the first hour after the reaction but do not distinguish between IgE-mediated and non-IgE mediated reactions. Other tests, like IgE assays and basophil activation tests, are available but there is little clinical data regarding their use in evaluating local anesthetic allergy.

Using diagnostic findings to select safe alternatives

The ultimate goal of diagnostic testing in patients with a history of local anesthetic allergy is to identify alternative local anesthetics that can be given safely in the future.³ Patients with an allergy to bisulfite preservatives can probably receive preservative-free local anesthetics without future reaction.¹ Allergies to methylparaben likely indicate an allergy to PABA, so patients should avoid both methylparaben-preserved products and ester-containing local anesthetics. Confirmed IgE-mediated reactions to an ester- or amide-containing agent should preclude use of all other agents in the same structural group, but agents from the other group may be safe if testing did not reveal any evidence of cross-sensitivity. In practice, cross-sensitivity between ester and amide agents has been rarely reported and is usually attributed to preservatives, but one case of confirmed IgE-mediated reactions to both classes has been published.^1,3,5 If an allergy to both classes of local anesthetics is confirmed, alternative anesthetic options should be considered such as general anesthesia or topical diphenhydramine.^1,5

Conclusion

Suspected allergic reactions to local anesthetics are rarely true IgE-mediated reactions. The results of diagnostic tests in patients with a suspected local anesthetic allergy can help identify alternative agents that can be used safely in the future. Agents from both the amide and ester classes, along with methylparaben and bisulfite preservatives, should be included in the testing process to facilitate identification of the true allergenic substance and the safest alternative agents.

References

1. Eggleston ST, Lush LW. Understanding allergic reactions to local anesthetics. Ann Pharmacother. 1996;30(7-8):851-857.
2. Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105(4):259-273.
3. Bhole MV, Manson AL, Seneviratne SL, Misbah SA. IgE-mediated allergy to local anaesthetics: separating fact from perception: a UK perspective. Br J Anaesth. 2012;108(6):903-911.
4. Volcheck GW, Mertes PM. Local and general anesthetics immediate hypersensitivity reactions. Immunol Allergy Clin North Am. 2014;34(3);525-546.
5. Stahl M, Gome R, Waibel K. Allergy to local anesthetics: specific IgE demonstration to both amides and esters in a single patient. Ann Allergy Asthma Immunol. 2012;108(1):63-64.

August 2015

The information presented is current as of June 5, 2015. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What is the efficacy and safety evidence for Zarxio (filgrastim-sndz), the first biosimilar approved in the United States?

Background

Filgrastim is a granulocyte colony-stimulating factor (G-CSF) first approved in the United States in 1991 as Neupogen, marketed by Amgen, Inc.¹ It is a therapeutic protein biologic created by recombinant DNA technology; its main action is to stimulate and activate neutrophils.² In clinical practice it is used to prevent and treat neutropenia in oncology patients as well as to mobilize hematopoietic stem cells for transplantation. Because of the complex nature, proteins such as filgrastim are not easily reproduced, and as such, generic products cannot be approved through the typical Food and Drug Administration (FDA) approval process. However, the FDA has recently created a new approval pathway for biosimilar drugs.

According to the FDA, a biosimilar product is a biological product that is approved based on a showing that it is highly similar to an FDA-approved biological product, known as a reference product, and has no clinically meaningful differences in terms of safety and effectiveness from the reference product.³ A biosimilar may be interchangeable with the reference product if it meets additional requirements, allowing it to be substituted by a pharmacist without clearance of the prescriber.⁴ These requirements were put in place under the Biologics Price Competition and Innovation Act, which is part of the Affordable Care Act, created in 2010. For additional information on the status of biosimilars in the United States, see: http://dig.pharm.uic.edu/faq/2014/Nov/faq1.aspx.

The first US biosimilar, Zarxio (filgrastim-sndz) was FDA-approved on March 6, 2015 by Sandoz, a division of Novartis.¹ It is approved as a biosimilar to Neupogen, its reference product; however, it is not interchangeable.⁴ The placeholder name filgrastim-sndz will be used until the FDA releases guidance on how biosimilar products will be named in relation to the reference product. Zarxio was FDA approved for the same indications as Neupogen, which include:^2,4

• Reducing the incidence of infection in patients with nonmyeloid malignancies treated with myelosuppressive anti-cancer therapeutic regimens associated with a significant risk of myelosuppression and fever
• Reducing the time to neutrophil recovery in acute myeloid leukemia (AML) patients receiving induction and consolidation chemotherapy regimens
• Reducing the duration of neutropenia in patients with nonmyeloid malignancies receiving myeloablative chemotherapy prior to bone marrow transplantation (BMT)
• Mobilizing autologous hematopoietic progenitor cells into peripheral blood for leukapheresis
• Reducing the incidence and duration of neutropenia and its complications in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia

Clinical trials

Zarxio was approved as a biosimilar to Neupogen based on an array of data including structural similarities, animal data, human pharmacokinetic and pharmacodynamics studies, and human clinical efficacy and safety data.³

The structure and function of Zarxio, along with its physiological response, were compared with Neupogen to determine biosimilarity.⁵ The protein amino acid sequence, purity, 3-dimensional structure, receptor binding, potency, and protein content of Zarxio were evaluated. Analytical comparisons were conducted with numerous batches of the drug, and the results of these comparisons confirmed that Zarxio and Neupogen are highly similar and are expected to produce identical therapeutic effects in human clinical studies. The product stability of Zarxio was also tested for similarity to Neupogen and no appreciable differences in the products were found when stored at recommended temperatures.

Clinical pharmacokinetic and pharmacodynamic (PK/PD) studies, along with safety and efficacy studies, were completed in order to demonstrate no clinically meaningful differences between Zarxio and Neupogen.⁵ One pivotal PK/PD equivalence study, along with 4 additional supportive studies, comparing Zarxio to the European-approved Neupogen (which is considered identical to the US product) were conducted. A total of 174 healthy volunteers were evaluated and the main markers assessed were absolute neutrophil count (ANC) and CD34+ cell counts, which are considered surrogate markers for effectiveness of G-CSF products. The pivotal PK/PD study was a randomized, double-blind, crossover study conducted in 28 healthy volunteers administered a single 10 mcg/kg dose of Zarxio or Neupogen.^5,6 Blood samples were obtained prior to and up to 336 hours post-dose to evaluate pharmacokinetics, ANC, and CD34+ cell counts. Results showed equivalent serum concentrations (the 90% confidence intervals [CIs] were within 80% and 125%), ANC response, and CD34+ cell response between products. The studies concluded that single-dose administration of Zarxio was bioequivalent to Neupogen.

A pivotal phase 3, randomized, double-blind, non-inferiority study was conducted comparing the efficacy and safety of Zarxio to Neupogen in 218 breast cancer patients receiving adjuvant TAC (docetaxel, doxorubicin, and cyclophosphamide) chemotherapy.^5,7 Patients received either Zarxio or Neupogen 5 mcg/kg subcutaneously starting on Day 2 of the chemotherapy cycle until ANC recovered to 10 x 10⁹/L after the nadir, or up to a maximum of 14 days, whichever occurred first. The primary efficacy endpoint was the duration of severe neutropenia during cycle 1 of chemotherapy. The noninferiority margin was defined as -1 day in the duration of severe neutropenia during Cycle 1 (i.e., the largest acceptable difference between treatments was 1 day of severe neutropenia). The study found that Zarxio was non-inferior to Neupogen with a mean duration of severe neutropenia of 1.17 days with Zarxio and 1.20 days with Neupogen (mean difference 0.04 days, lower limit of 97.5% CI -0.26 days). They also concluded similar rates of febrile neutropenia, mean ANC, time to ANC recovery in Cycle 1, and incidence of infection. Safety data from this study reported the most common adverse events to be alopecia, nausea, asthenia, fatigue, and bone pain, with similar frequency between the 2 groups.

Zarzio – the European experience

Zarzio, the brand name of filgrastim-sndz marketed in Europe, has been approved in Europe as a biosimilar to Neupogen since 2009.⁸ A pooled analysis of 5 studies examining the post-marketing use of Zarzio for prevention of chemotherapy-induced neutropenia in cancer patients was conducted. A total of 1,302 patients were included in the analysis, with the majority of patients having breast cancer (42%). The analysis assessed the incidence of febrile neutropenia and severe (grade 4) neutropenia in patients who received Zarzio as primary or secondary prophylaxis. Overall, 2.2% (n=29) of patients experienced an episode of febrile neutropenia and 8.5% (n=104) of patients experienced (grade 4) neutropenia. Patients who received Zarzio as secondary prophylaxis were more like to have febrile neutropenia or severe neutropenia than patients who received Zarzio as primary prophylaxis. The analysis concluded that the incidence reported in this study was comparable to observed rates in previous studies with filgrastim, and shows that Zarzio is effective for the prevention of chemotherapy-induced neutropenia.

Because Zarzio was not studied in stem cell donors prior to its approval, the World Marrow Donor Association in 2008 recommended against using biosimilar Zarzio outside of clinical trials for healthy stem cell donors until efficacy and safety data were established in this population.⁹ However, data regarding the safety and efficacy in this population continue to accumulate. A recent review of studies assessed the use of biosimilar G-CSF for stem cell mobilization in 904 healthy donors for allogeneic stem cell transplantation as well as patients with malignancy undergoing autologous stem cell transplantation.¹⁰ A total of 384 of these patients received Zarzio in 12 separate studies. The included studies looked at outcomes relating to stem cell mobilization and yield, drug toxicity, and post-transplantation engraftment outcomes. Patients typically received 5 to 10 mcg/kg/day of Zarzio, which varied among studies. Results showed that biosimilar filgrastim produced comparable stem cell mobilization with similar drug side effects. Engraftment after transplantation was similar to studies conducted previously with Neupogen. The authors concluded that biosimilar filgrastim could be used safely and effectively for mobilization of stem cells for transplantation.

Zarxio availability in the United States

It is not yet known when Zarxio will be available for clinical use in the United States. A current lawsuit filed by Amgen is underway, preventing Novartis from selling Zarxio.¹¹ The lawsuit states Novartis did not provide full disclosure of product information and committed patent infringement. A hearing was scheduled on June 3, 2015; however, no final decision was made at that time.  The outcomes of the case will be crucial in determining future development of biosimilars in the United States.

Conclusion

In summary, Zarxio is the first approved biosimilar in the United States.² Based on clinical data, the efficacy and safety of Zarxio are comparable to Neupogen. It is not yet known what Zarxio’s place in therapy will be across all approved indications. Similar to the European experience, US organizations may require additional clinical studies prior to recommending the new agent. Although not yet available, it is expected that Zarxio will cost up to 35% less than Neupogen, with additional cost savings into the future.¹² This will be a major consideration for institutions when choosing a filgrastim product. In addition, it is important to note that Zarxio has not been approved as interchangeable with Neupogen, and education to healthcare providers will be needed to clarify prescribing practices.

References

1. Drugs @ FDA. FDA approved drug products. U.S. Food and Drug Administration website. http://www.accessdata.fda.gov/scripts/cder/drugsatfda. Accessed June 10, 2015.
2. Neupogen [package insert]. Thousand Oaks, CA: Amgen, Inc; 2015.
3. Biosimilars. U.S. Food and Drug Administration website. http://www.fda.gov/Drugs/ DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/default.htm.  Accessed June 10, 2015.
4. FDA approves first biosimilar product Zarxio. FDA news release. U.S. Food and Drug Administration website. http://www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm436648.htm. Published March 6, 2015. Accessed June 10, 2015.
5. Zarxio (filgrastim). FDA oncologic drugs advisory committee meeting. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM428782.pdf.  Accessed June 30, 2015.
6. Sӧrgel F, Schwebig A, Holzmann J, Praasch S, Singh P, Kinzig M. Comparability of biosimilar filgrastim with originator filgrastim: protein characterization, pharmacodynamics, and pharmacokinetics. Biodrugs. 2015;29(2):123-131.
7. Phase III study comparing the efficacy and safety of EP2006 and filgrastim (PIONEER). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT01519700. Published January 13, 2012. Updated April 14, 2015. Accessed June 10, 2015.
8. Gascón P, Tesch H, Verpoort K. Clinical experience with Zarzio in Europe: what have we learned? Support Care Cancer. 2013;21(10):2925-2932.
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Prepared by:
Kelly Burke, PharmD
PGY1 Pharmacy Practice Resident
College of Pharmacy
University of Illinois at Chicago

August 2015

The information presented is current as of June 10, 2015. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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