Type: Development

The testing and approval pathway for ABP 980 provides a model of accelerated development programs for novel, safe, and efficacious biosimilars.

There is increasing interest in biosimilars as alternatives to their originator reference product (RP), given their potential to improve patient access to important biological treatments. ABP 980 is a biosimilar of trastuzumab (Herceptin). Like trastuzumab, ABP 980 exerts its therapeutic effects by targeting cancer cells that overexpress the HER2 receptor, including those of the breast and stomach. ABP 980 is approved in the EU, USA, and Japan for the same indications, dosages, and route of administration as trastuzumab RP.

During development, ABP 980 underwent comprehensive analytical characterisation using state-of-the-art techniques. These assessments demonstrated ABP 980 has highly similar structural and functional attributes to trastuzumab RP, with only minor differences that are not expected to alter its biological activity or clinical performance. Phase I pharmacology studies conducted in healthy subjects confirmed ABP 980 has equivalent pharmacokinetics properties relative to trastuzumab RP.

Clinical similarity was evaluated in the LILAC study in women with HER2+ early breast cancer – who were deemed a sensitive patient population. The primary endpoint, pathologic complete response, was noted in 48% of patients treated with ABP 980 and 41% of those receiving trastuzumab RP – demonstrating noninferiority between the two groups. The trial confirmed clinical similarity between ABP 980 and trastuzumab RP. Safety and immunogenicity of the two test products were also similar. On the basis that the drug’s mechanism of action – inhibition of HER2-mediated proliferation – is the same for different cancer cells, the totality of evidence for ABP 980 supported scientific justification for extrapolation across all approved indications for trastuzumab RP. ABP 980 provides an additional treatment option for patients with breast and gastric cancers.

Key takeaway

The biosimilar, ABP 980, shows similar structural and functional attributes, as well as demonstrating clinical non-inferiority in a clinical trial, when compared to its trastuzumab RP. This provides an additional treatment for breast and gastric cancer therapy, and therefore improving patient access.

Given the high cost and sharply increased use of biologics in recent years, the approval pathway for biosimilars echoes a phenomenon first introduced for generic drugs 40 years ago

Since the simplest forms of biologics (blood products and vaccines) entered the US market in the 1970s, followed by recombinant human insulin in 1982, and the first FDA-approved monoclonal antibody in 1997, biologics have transformed the treatment of serious medical conditions, but have also sharply increased the overall healthcare cost curve.

In 2009, the Biologic Price Competition and Innovation (BPCI) Act was passed to create an avenue for abbreviated FDA licensure pathways for biosimilars, and thereby enable developers to bring them to market at the lowest viable cost. The first biosimilar, filgrastim-sndz, was approved in the USA in 2015 and was quickly followed by many more approvals of biosimilars for an array of medical conditions.

Biosimilars are manufactured following reverse-engineering – by starting with the final therapeutic protein and working the synthesis steps backwards. Like all biologics, biosimilars are created in living systems (cell lines), and therefore are not exact copies of their reference product, although they are required to have the same amino acid sequence. During the development and approval process, their small molecular differences must be demonstrated not to impact efficacy and safety (i.e. not to be ‘clinically meaningful’). Because of this, the approval pathway for biosimilars is largely focused on analytical studies of their physical characteristics relative to the originator product, albeit supplemented with clinical evaluation.

Biosimilars are not granted patent exclusivity – several biosimilar versions of the same reference product may be available to purchase. For example, there are six FDA-approved biosimilars of trastuzumab. As more of these products enter the market, there will be increasing need for healthcare providers to gain trust in their efficacy and safety. With ever-rising healthcare costs and biologics occupying the most expensive drug category, the advent of high-value biosimilars may serve as a release valve to otherwise unsustainable markets. Healthcare professionals need to stay committed to evaluating biosimilar evidence to make these treatment options available.

Key takeaway

Biosimilars are not granted exclusivity on approval and there may be several biosimilars for a single biologic. Healthcare providers need to gain trust in the efficacy and safety of each biosimilar that is marketed; although greater numbers of high-value biosimilars will help reduce overall healthcare costs.

The extensive preclinical and clinical testing program for CT-P6 demonstrates this biosimilar is as safe and effective as reference trastuzumab, and its clinical use could considerably reduce financial toxicity without compromising care.

The development of trastuzumab monoclonal antibody in the 1990s was a milestone in targeted therapy that has dramatically improved progression-free and overall survival rate in patients with breast cancer overexpressing the HER2 receptor (which account for 15% of all breast cancer diagnoses).

The success of trastuzumab opened the floodgates for a new generation of targeted therapies for both early-stage and metastatic breast cancer and other solid tumours – although at a huge financial burden. Biosimilars were developed in response to this problem. CT-P6 (trastuzumab-pkrb, Herzuma) is a trastuzumab biosimilar currently approved in the EU, Japan, South Korea, Australia, and USA. Like all biosimilars, CT-P6 underwent rigorous testing during pre-approval stage. In head-to-head comparisons CT-P6 demonstrated equivalent pharmacokinetics parameters, adverse events profile, immunogenicity level and anti-cancer efficacy compared with reference trastuzumab. Clinical trials have been conducted in women with stage I–IIIa operable HER2-positive breast cancer. These trials revealed that neoadjuvant CT-P6 added to chemotherapy does not elicit a significantly different pathologic complete response rate to the same treatment approach using the reference, trastuzumab.

In all, the totality of evidence for CT-P6 supports its biosimilarity to the reference, trastuzumab. CT-P6 can be safely used in patients with HER2-positive breast cancer and other malignancies where indicated. Rapid integration of economically favourable biosimilars such as CT-P6 promises to improve access to essential medicines and help alleviate overburdened healthcare systems.

Key takeaway

The development of the trastuzumab biologic dramatically improved outcomes for a large proportion of HER2-overexpression breast-cancer patients, although the financial burden has been high. The trastuzumab biosimilar, CT-P6, shows comparable pharmacokinetic parameters and anti-cancer efficacy compared to the reference biologic, and with lower associated costs, makes it economically favourable to healthcare providers.

Abstract published: August 2021

Several efforts have been introduced to improve access to biosimilars and deliver cost savings to healthcare systems. This review considers some of these recent initiatives.

Biosimilar use is set to increase significantly in cancer patients requiring supportive care; however, several challenges to implementing biosimilars into clinical practice remain.

Epoetin-α is an erythropoeisis-stimulating agent (ESA) that improves haemoglobin levels in patients receiving chemotherapy and reduces their need for blood transfusions. Since the first epoetin-a biosimilar was launched in Europe in 2007, many short- and long-acting biosimilar versions of this drug have been made available worldwide, with apparently similar degrees of efficacy. The introduction of biosimilar ESAs and consequent cost reductions for these drugs in the UK led the National Institute for Health and Care Excellence (NICE) to review its stance on their cost-effectiveness and subsequently to approve them for reimbursement on the NHS, in 2014. Similarly, there is now acceptance and expanded use of biosimilar versions of filgrastim across Europe and the USA.

Despite the known advantages of adopting biosimilars into oncology practice, there is a lack of confidence among prescribers. Areas where healthcare professionals report having knowledge gaps include the biosimilars approval processes, pharmacovigilance, and concepts of extrapolation and interchangeability. Patients, caregivers and the general public also may not accept biosimilars, therefore good-quality education resources for HCPs and patients alike have been made available by a number of bodies including professional societies and government organizations, along with continued gathering and dissemination of pharmacovigilance and pharmacoeconomics data.

Differences in the way biosimilars are commissioned and reimbursed can also influence uptake. Healthcare policies that incentivize competition and sustainable pricing, such as value-based care schemes, ensure manufacturers continue to invest in the biosimilars market. The UK Cancer Vanguard project provides a good example of an initiative to speed up biosimilar uptake – in this case, rituximab. This project, which included stakeholder engagement and teaching materials, financial incentives and targets for implementation, was rewarded with biosimilar infliximab achieving 90% market share within 12 months.

Clearly, to enhance access to biosimilars in supportive care, several existing barriers should be addressed. These include increased standardization of regulation, commissioning and reimbursement, better product availability and not least, clearer understanding of the broad usefulness of biosimilars.

Key takeaway

Prescribers and patients often lack knowledge about biosimilars, thus lowering their acceptance in clinical care. There are knowledge gaps in several areas (e.g., approval processes, pharmacovigilance, and extrapolation and interchangeability) which need to be addressed before take-up increases. Healthcare policies incentivising competition and sustainable pricing ensure manufacturers continue to invest in the biosimilars market.