Isha Bangia, PharmD, MBA, is a manager of US market access at Certara Evidence & Access. She received her PharmD from Rutgers University and an MBA from Johns Hopkins University. Her current responsibilities include optimizing product value stories and working with customers to improve access across the US healthcare system. Her experience includes practicing pharmacy, payer market research, and pharma strategy and analytics. Her work has covered many therapeutic areas, including biosimilars, oncology, diabetes, vaccines, and rare diseases.

Isha Bangia, PharmD, MBA

Product differentiation is a critical component of product strategy, especially for biologics and biosimilars, as drug competition across therapeutic categories continues to increase. For disease types with multiple competing brands of a single type of medicine, there are sometimes opportunities for manufacturers to demonstrate value beyond clinical parameters.

Drug delivery systems such as devices, technologies, and formulations—which may offer faster or slower medicine release—have become key value differentiators that manufacturers continue to invest in. The attractiveness of these devices may improve physician and patient acceptance, leading to improved revenues and market share; and the ease and convenience of devices 

 patient adherence and satisfaction. Further, patient comfort with a device may lead to brand loyalty, regardless of whether cheaper options (generics, biosimilars) are available.

Also important for manufacturers, delivery systems may serve as a patent protection strategy and thwart biosimilar competition. A prominent example of this is the success of Amgen’s Neulasta Onpro, a wearable pegfilgrastim injector kit that reduces the number of office visits patients need to make.

In 2015, Amgen’s blockbuster Neulasta (pegfilgrastim), an oncology supportive care agent, lost exclusivity and became subject to biosimilar competition. Since then, 4 pegfilgrastim biosimilars have been approved in the United States—Fulphila (Mylan), Udenyca (Coherus), Ziextenzo (Sandoz), and Nyvepria (Pfizer)–of which 3 have launched. By 2019 these biosimilars had captured less than 25% of the 

, but indications were that Neulasta would not be able to continue dominating this market.

In just the second quarter of 2020, Neulasta sales decreased 28% due to biosimilar competition. Despite this decline in sales for the originator product, Amgen has retained a sizeable share of the pegfilgrastim market due to the Neulasta Onpro, which the 

As a delivery system, the Neulasta Onpro wearable injector enables patients to go home after chemotherapy and receive an automatic follow-up pegfilgrastim injection the next day. The convenience of this device, particularly for patients who have to travel many miles for chemotherapy treatment or could not easily schedule visits as the COVID-19 outbreak spread, has given Amgen a tremendous competitive advantage in the pegiflgrastim market. By midyear 2020, the Onpro held a 58% share of 

 patients to the Onpro kit as a part of its product life cycle extension strategy and defense against biosimilars. Consequently, Amgen has maintained a sizeable market share while limiting the uptake of biosimilars. There is no biosimilar delivery device comparable to the Neulasta Onpro, and pegfilgrastim biosimilars cannot be used with the Onpro. This means that, purely from the convenience aspect, physicians and patients may be discouraged from using a biosimilar pegfilgrastim, even if biosimilars are preferred from the payer side. Further, although Neulasta’s patent exclusivity ended in 2015, Neulasta Onpro is still patent protected.

Interestingly, the original Neupogen product was itself a 

. Whereas filgrastim (Neupogen, Amgen) must be injected daily for up to 2 weeks, Neulasta can be administered once every 3 weeks as a single, fixed dose during the patient’s chemotherapy cycle.

Outside of Neulasta Onpro, manufacturers have employed other delivery systems to extend product life and avoid biosimilar competition. In 2017 Amgen launched an auto-injector for etanercept (Enbrel Mini) that was designed to reduce the pain of patient-administered injections. Further, AbbVie, owner of the adalimumab reference brand (Humira), which stands to lose exclusivity in the United States in 2023 to multiple biosimilar competitors, has a longstanding partnership with Unilife to use a system that allows patients to synchronize auto-injector products with their smartphones.

On the formulation side, in an effort to stall sales erosion to biosimilars for the trastuzumab originator Herceptin, Roche/Genentech 

 a subcutaneous delivery system (Herceptin Hycleta), which was approved by the FDA in early 2019.

Manufacturers have often used drug delivery systems to ward off competition following loss of exclusivity. With small molecular entities, this was seen with the introduction of extended or delayed-release products that would limit generic uptake. Now, such is the case with biologics. The number of drug-device combination patents, in general, 

 in recent years, marking the upward trend to differentiate and capture market share through delivery systems. Investigators reported that drug products with an associated patented delivery device rose from 3% in 2000 to 10% in 2016.

The number of strategic partnerships in the biologics space has increased as well, such as in the insulin and immunology categories, all of which demonstrates that developing and patenting convenient delivery systems (devices, formulations) that drive patient compliance and improve outcomes are embraced among manufacturers as 

life cycle management strategies against biosimilar competition.

Articles

Amgen's Onpro autoinjector device for pegfilgrastim is a stunning example of how product differentiation via drug delivery devices can protect market share in the biologics market.

Contributor: Drug Delivery Devices Help Originator Companies Retain Market Share

The introduction of biosimilars brought hope for more affordable treatments and expanded access to high cost medications. The key value driver of biosimilars, well before the launch of the first biosimilar, a filgrastim product (Zarxio), has been a lower price compared with reference biologics.

As early as 2012, it was predicted that biosimilars would lead to $13 billion in savings to the US healthcare system over 10 years. Payers expected biosimilars to come in at discounts of 30% to 40%, and they anticipated larger cost savings for starting new patients on biosimilars versus switching patients from a reference product to a biosimilar (21%-30% cost savings). Over time, however, payers lowered expectations around biosimilar pricing and anticipated discounts of just 10% to 20% from reference biologics.

Thus far, the biosimilars commercially available in the United States span 3 main therapeutic classes: oncology supportive care, immunology, and oncology. Biosimilar prices are estimated to be 10% to 37% cheaper than originator products.

 Discount levels between each class of biosimilars vary, likely attributable to the differing competitive landscapes and indication characteristics (eg, supportive therapy vs oncology agents).

Zarxio (Sandoz), which launched in the United States in 2015, is available at an 18% discount to reference filgrastim (Neupogen). Comparatively, the second US filgrastim biosimilar to launch, Nivestym, arrived at a larger discount of 37%.

 There are currently 3 pegfilgrastim biosimilars with discounts above 30%. The newest of these, Ziextenzo (Sandoz), has the largest biosimilar discount seen across all categories, at 37%.

 On average the pegfilgrastim class of biosimilars has the largest discounts seen across biosimilar agents.

Patent obstacles have largely prevented the entry of immunology biosimilars. The infliximab products Inflectra (Pfizer/Celltrion) and Renflexis (Merck/Samsung Bioepis) are the 2 launched biosimilars for reference product Remicade, available at 19% and 35% discounts, respectively.

 Unlike Europe, the United States has yet to see significant competition, discounts, or savings from immunology biosimilars.

Biosimilars for adalimumab (Humira) are not expected until 2023, and etanercept biosimilars to Enbrel are even further out. In the third quarter of 2019, AbbVie 

a 33.5% decline in Humira revenue as a result of biosimilar competition in the European Union.

Some countries are seeing vast cost-savings from switching from reference adalimumab to biosimilars; Denmark, for example, has seen savings of 82.8% by making this switch. It is uncertain, however, if the United States will be able to see similar savings, or any at all. Although there are still 3 years to market entry of an adalimumab biosimilar, AbbVie has 

a citrate-free Humira and its follow-on product, risankizumab (Skyrizi).

As patients transition to these, adalimumab biosimilars may not have as large a market to capture upon entry and, subsequently, may not provide deep discounts leading to greater savings.

Oncology biosimilars are the most recent market entries. There are biosimilars available for trastuzumab (Herceptin), rituximab (Rituxan), and bevacizumab (Avastin). The discount levels for oncology biosimilars range from approximately 10% to 25%.

Trastuzumab biosimilars are about 10% to 15% cheaper than the reference product, with Kanjinti (Amgen/Allergan) and Ogivri (Mylan/Biocon) the cheapest at 15% lower. The trastuzumab biosimilar Herzuma (Celltrion/Teva) has a 10% discount to Herceptin and Trazimera (Pfizer) is available at 22% below the reference.

For the rituximab reference product (Rituxan) there are 2 biosimilars available, Truxima (Celltrion/Teva) and Ruxience (Pfizer), with discounts of 9% and 24%, respectively. The wholesale acquisition cost (WAC) of the bevacizumab reference product (Avastin) reaches up to $12,000 per month. The bevacizumab biosimilar Zirabev (Pfizer) was launched at a 23% discount to Avastin’s WAC and Mvasi (Amgen/Allergan) at 15% less.

Although biosimilar savings have been discussed with regard to lower discounts compared with reference product WAC prices, it is critical to note that, in practice, payers will look to the net price rather than the WAC cost. It is possible that payers may have bigger rebates, exclusive contracts, and altogether a lower net price associated with a reference product than for a biosimilar offered at a lower WAC. Such pricing strategies from developers are partly why originator products, such as Remicade, have fared well against biosimilar competition.

Howell P. How much cheaper will biosimilars be? 

. March 2, 2012. fiercepharma.com/pharma/how-much-cheaper-will-biosimilars-be. Accessed May 21, 2020.

Hernandez  I, Good  CB, Shrank  WH, Gellad  WF.  Trends in Medicaid prices, market share, and spending on long-acting insulins, 2006-2018.

Chase L. A guide to biosimilar prices: how much they cost and how you can save. GoodRx. April 14, 2020. 

goodrx.com/blog/biosimilars-prices-how-much-they-cost-how-to-save/. Accessed May 23, 2020.

Brennan Z. US biosimilar launches about to turn a corner. 

. December 10, 2019. //endpts.com/us-biosimilar-launches-about-to-turn-a-corner/.  Accessed May 23, 2020.

Biosimilar discounts to reference products have improved over time, but they are deeper in some categories than others.
 

Biosimilar Discounts Vary by Category 

 of the 26 FDA approved biosimilars have come to market in the United States. The 12 launched products have experienced challenges with uptake, at first largely attributed to the uncertainty around biosimilars. Now 5 years since the introduction of the first biosimilar, Zarxio (filgrastim), uptake remains a challenge for a multitude of reasons, including payer support, stakeholder education, and patent dances. To date, 3 main classes of biosimilars have emerged in the United States. There are some key similarities and differences across these categories that have impacted utilization and continue to do so.

Colony-stimulating factors (CSFs) were the 

 biosimilar entrants in the US market. In total, there are 3 biosimilars for reference pegfilgrastim (Neulasta) and 2 for the originator filgrastim (Neupogen). Zarxio, a CSF, became the first biosimilar on the US market when it launched in September 2015. To date, it has a market share of roughly 50%. Biosimilars to Neulasta are increasing in share, such as 

 (pegfilgrastim-cbqv), which has captured a roughly 20.5% market share since launching in January 2019.

In terms of gaining market share, the oncology supportive care biosimilars have fared well compared with other classes. Fewer market barriers have allowed for more entrants. Clinically, these products are 

 therapies resulting in a quick therapeutic effect, such as an increase in red or white blood cells. As a result, stakeholders have generally been accepting of these agents. Payers such as Prime Therapeutics have preferred biosimilar CSFs over reference products, and healthcare professionals are prescribing them, leading to improved market share.

The immunology class has seen the most approvals with 5 adalimumab, 4 infliximab, and 2 etanercept biosimilars. However, only 2 infliximab biosimilars are available in the United States. Inflectra (infliximab) was the first infliximab biosimilar to launch in this market, followed by Renflexis (infliximab); together, these have captured only an estimated 12% of the total infliximab market share, which is far 

Market penetration in immunology has been challenging for biosimilars due to many factors. For one, this class is one of the most competitive across the board, with many agents including anti-TNFs and anti-interleukins. Biosimilars face competition from reference products, other anti-inflammatories, and even biosimilars.

Biosimilar launches have experienced delays due to litigation challenges. Reference adalimumab (Humira) has an extensive patent library and, therefore, biosimilar launches are delayed until 2023.

Etanercept biosimilars face similar barriers and may not be expected until 2029.

Compared with CSFs, immunology biosimilars have seen less stakeholder acceptance. The indications of rheumatology, inflammatory bowel diseases (IBD), and psoriasis are chronic conditions requiring long-term treatment. Patients and prescribers are hesitant around the efficacy of biosimilars, as a response to treatment (eg, remission) is not immediate. Further there is a concern about switching stable patients from a reference biologic to a biosimilar due to immunogenicity, even though many real-world data from Europe, including findings from the NOR-SWITCH study, generally show similar efficacy and safety without an increase in immunogenicity.

Another key challenge for prescribers has been indication extrapolation. Biosimilars do not undergo robust clinical studies for all approved indications, and prescribers may be less accepting of biosimilars in these indications due to a 

Although payers generally favor biosimilars due to the potential for cost savings, biosimilars have failed to fully integrate in immunology. Aggressive contracting by reference manufacturers, such as Johnson & Johnson has done for 

 (infliximab), has limited biosimilar uptake. However, the payer push for biosimilars has improved in some cases; United Healthcare Medicare Advantage now prefers the infliximab biosimilars Inflectra and Renflexis.

Biosimilars in oncology are the latest entrants, with 8 product launches since 2019. Although barriers to uptake remain, the experience of biosimilars in immunology does not directly translate here. Since launch, oncology biosimilars have been able to capture a sizeable market share. For example, Amgen’s oncology biosimilars, Mvasi (bevacizumab) and Kanjinti (trastuzumab) have 

 a 15% and 17% market share for trastuzumab and bevacizumab, respectively. Payers  such as United Healthcare have also started including oncology biosimilars to formularies. United Healthcare is accelerating utilization.

There remain concerns around indication extrapolation. For instance, clinical trials to demonstrate biosimilarity for rituximab biosimilars were conducted in rheumatoid arthritis rather than oncology, leading to an 

 of oncology data. As rituximab bevacizumab and trastuzumab are approved across many indications, therapeutic response data take time as key oncology end points focus on survival; as a result, prescribers may hesitate to extrapolate findings across indications. The absence of oncology-relevant data also means there is a lack of immunogenicity data, which has been a mainstay concern around biosimilars.

Thus far we have seen 3 key classes of biosimilars emerge, each with a different commercial trajectory. The CSF biosimilars have had a growing market share over the years with relatively good acceptance by healthcare stakeholders. On the other hand, biosimilars have seen limited market penetration in immunology, although it is the largest market. Perhaps the sluggishness of acceptance and utilization will change once biosimilars for adalimumab enter and as more real-world data are generated from Europe around tumor necrosis factor inhibitors. The oncology class of biosimilars has seen success in early days of product launches, which signifies an accelerating US market.

Biosimilar manufacturers should continue to educate and generate real-world data on biosimilars, especially in challenging categories such as immunology. This, alongside a greater payer shift toward biosimilars, continues to prime the US market for biosimilar uptake.

 
Oncology supportive care, oncology, and immunology biosimilars make up the 3 main classes of biosimilars that have emerged on the US market. However, rates of uptake are vastly different owing to a variety of factors.

Isha Bangia, PharmD, MBA

Contributor: Drug Delivery Devices Help Originator Companies Retain Market Share

Biosimilar Discounts Vary by Category

Biosimilar Uptake Varies by Class of Agent