Pegylated version (pegfilgrastim) Neulasta® is the more commonly prescribed agent, with a significantly longer half-life than its predecessor and is the preferred in patients receiving cancer chemotherapy.
Although filgrastim-sndz (Zarxio®) was launched for use as a supportive care treatment about 1 year ago, the pegylated version (pegfilgrastim) Neulasta® is, by far, the more commonly prescribed agent. This agent has a significantly longer half-life than its predecessor and is the preferred agent in patients receiving cancer chemotherapy.
Pegfilgrastim is one of the most costly prescribed oncology drugs in the US market based on cost and utilization. Even though the patent expired in October 2015 in the US there is no approved biosimilar in the US and even in Europe as of October 2016. This may be because of the difficulty in changing the filgrastim’s structure to increase the half-life.
The originator product Neulasta is indicated for decreasing the incidence of infection in the presence of febrile neutropenia, in patients with nom-myeloid tumors receiving chemotherapy associated with febrile neutropenia, and for increasing survival in patients receiving myelosuppressive doses of radiation.
The type of studies required by the US Food and Drug Administration (FDA) to approve a pegfilgrastim biosimilar to treat chemotherapy-induced neutropenia is expected to be similar to those submitted by Sandoz for Zarxio. Those studies focused on nonclinical investigations (i.e., mechanism of action, manufacturing, analytical similarity [structure and biologic activity, receptor binding, protein binding, stability], immunogenicity, animal pharmacology and toxicology, and bioavailability), and clinical studies. In the case of Zarxio, Sandoz conducted 4 clinical studies in healthy subjects and one in patients with cancer, which confirmed the pharmacokinetic attributes of the product and the increase in absolute neutrophil count (ANC). According to FDA staffers preparing the briefing documents on Zarxio “a study in healthy volunteers is considered to be more sensitive in evaluating similarity between products because the population is likely to produce less PK variability compared with that in patients with potentially confounding factors such as underlying disease and concomitant medications.”
An Array of Biosimilar Candidates
Currently, 5 drug makers are actively involved conducting clinical trials for pegfilgrastim products (Table): (1) Apotex/Apobiologix (drug name not known), (2) Coherus BioSciences (CHS-1701, (3) Mylan/Biocon (MYL-1401H), (4) Pfizer (HSP-130), and (5) Sandoz (LA-EP2006). A Korean company, Dong A, registered a trial with clinicaltrials.gov however, no study sites were in the US and their website does not indicate that they have plans to file for approval in the US, even though their product is approved in Korea. Teva had submitted their product for approval to the FDA; however, they withdrew their application in 2013 even after they had resolved litigation with Amgen and had agreed to wait until at least November 2013 to launch their product after FDA approval.
launch their product after FDA approval.
Table: Pegfilgrastim Products in Development
Phase I Trials Complete
Completed May 2013
Filed for approval in US in November 2015, but FDA issued a complete response letter; Filed for approval in the EMA in Feb 2016
*Not actively being developed.
Information updates are not available about this product. The FDA accepted the filing under the 351(k) abbreviated approval pathway for the biosimilar in December of 2014. In September 2016, the District Court for the Southern District of Florida ruled that Apotex’s product does not infringe on Amgen’s patent; however, Apotex must give Amgen 180 days’ notice of their intent to market the product after they receive FDA approval. Since the FDA accepted the application 23 months ago, it must be assumed that a complete response letter has been issued by FDA (these are not made public by the agency, and the manufacturers do not always disclose this fact). If this agent is approved by the FDA, it will be marketed by Apotex’s US subsidiary Apobiologix.
Coherus Biosciences CHS 1701
The immunogenicity of CHS-1701 was tested in a study of 303 healthy subjects. Patients were enrolled in a double-blind, randomized, 2—period, parallel-arm study. They received 2 sequential subcutaneous doses (6 mg) of CHS-1701 or the Neulasta. The researchers did not detect any neutralizing antibodies with either product; the percent difference in anti-drug antibody response was within the prespecified criteria for a biosimilar. The side-effect profiles were not clinically meaningful.
A study comprising 122 healthy subjects assessed pharmacokinetic (PK) and pharmacodynamics parameters as well as safety. The study compared CHS-1701 and the originator product in a 3-sequence, 3-period crossover design that was single blinded. Results for absolute neutrophil count and PK parameters were within the prespecified margins of 80% to 125%, demonstrating that it is a biosimilar to Neulasta. The safety profiles of the products were similar; serious adverse events or study discontinuations were not seen with either product(http://investors.coherus.com/phoenix.zhtml?c=253655&p=irol-newsArticle&ID=2184363).
Coherus Biosciences submitted its 351(k) biologic license application for CHS-1701 to the FDA on August 9, 2016.
MYL-1401H was tested in a controlled, double-blinded, randomized phase III trial of individuals with newly diagnosed stage 2/3 breast cancer who were eligible to receive docetaxel, doxorubicin, and cyclophosphamide every 3 weeks for 6 cycles. The 194 enrolled patients received either the biosimilar or the European-licensed version of Neulasta at a dose of 6 mg/0.6 mg subcutaneously on day of 2 of each chemotherapy cycle. The primary endpoint was the duration of severe neutropenia (ANA < 0.5 x 109/L) in the first chemotherapy cycle. Equivalence was defined as being if the confidence interval of the least squares means difference between the duration of severe neutropenia (DSN) fell within the range -1 to +1 days.
The trial revealed a mean DSN of 1.2 for both products, and a least squares means difference that met the prespecified criteria for equivalence. Other end points were also similar (e.g., the frequency of grade 3-4 neutropenia, time to ANC nadir, and duration of post nadir recovery). Additionally, patients in both groups reported bone pain as the most frequently reported treatment-emergent adverse event.
A randomized, double-blind, 3-period, 3-treatment, crossover study was conducted in healthy volunteers, comparing compared the PK and PD of MYL-1401H, EU-Neulasta, and US-Neulasta. The 208 study participants received a 2-mg subcutaneous dose for each phase of the study. All of the PK and PD results were within the predefined equivalence criteria. There were no notable differences in tolerability or safety between the biosimilar and the European- and US-licensed versions of Neulasta.
The EMA accepted the product for review in July 2016.
At this time, MYL-1401H has not been submitted for review by the US FDA.
A comparison trial in 308 patients with early-stage breast cancer patients receiving adjuvant or neoadjuvant myelosuppressive chemotherapy were randomized to receive 6-mg doses of either LA-EP2006 or Neulasta. The patients received docetaxel, doxorubicin, and cyclophosphamide on day 1 followed by LA-EP2006 or the reference product subcutaneously on day 2 of each cycle for at least 6 cycles of therapy. The mean DSN during cycle 1 was the primary end point. Secondary end points included time to ANC recovery, number of days of fever, frequency of infections, mortality from infection, and number of episodes of febrile neutropenia by cycle. Safety was also assessed during the trial.
The mean DSN was 1.4 days for the study drug and 1.2 days for the originator product, which was deemed to be equivalent, based on a predefined definition of equivalence for DSN being a difference of less than 1 day. Results for all secondary efficacy end points were also considered equivalent. Researchers found similar safety profiles for the study drug and Neulasta. The most common treatment-emergent adverse events were related to musculoskeletal category system organ class (16.1% vs 13.7%, respectively). No treatment-related antibody binding or neutralizing antibodies were detected in either treatment group.
Sandoz filed a 351(k) biosimilar application for the biosimilar November 15, 2015. In July 2016, Sandoz communicated that a complete response letter had been received from the FDA, and that they were working with the agency to address questions(https://www.novartis.com/news/media-releases/novartis-delivered-solid-q2-despite-full-quarter-us-gleevec-generic-impact). It is not yet known when Sandoz will respond to the FDA’s concerns or resubmit their application.
Although 3 biosimilars have been submitted to the FDA by different manufacturers, it seems that Sandoz and Apotex have lost the time advantage to Coherus Biosciences, which may be the next in line for a FDA review.
Payers, prescribers, and patients will no doubt benefit from access to a new pegfilgrastim biosimilar in the near future. With the principal patents expired, a manufacturer that obtains approval will be able to market their product as soon as the 180-day notification period expires.