Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

As it inches closer to encountering biosimilar competition in the United States, AbbVie continues to see US sales of its adalimumab (Humira) originator product increase.

Over the past year, the company has battled with biosimilar competition to this arthritis product on the European market and has seen steepdeclines in revenue there. Whether the European situation for adalimumab is a representation of what is to come in the United States in 2023, when Humira loses market exclusivity, remains to be seen.

Meanwhile, 2 Humira follow-on products appear to be gaining ground. AbbVie anticipates these will absorb a share of the adalimumab market, in the face of biosimilar competition.

Further, biosimilar competition for AbbVie may take on an added dimension if Mylan and Revance team up to develop an onabotulinumtoxinA (Botox) biosimilar. AbbVie will acquire the original Botox product when it closes on the pending Allergan acquisition.

In the United states, Humira net revenues were $3.7 billion for AbbVie in the 

, up 13.7% from the year-ago quarter. Outside the United States, however, Humira net revenues were $1 billion, down 14.9%, also from the year-ago quarter and a drop that the company blamed on biosimilar competition.

At least 9 biosimilar adalimumab products are lined up to enter the US market in 2023, so these are important final years of dominance for Humira, which entered the US market in 2003.

 for Humira were $14.9 billion, up 8.6% from 2018. But 2019 also saw heavy biosimilar competition in Europe eroding market share for Humira, which outside the United States earned $4.3 billion, down 31.1% compared with 2018.

In Europe, adalimumab lost patent protection in 2018, and at least 6 adalimumab biosimilars have been approved for marketing there. The road to market entry for these products has not been without pitfalls.

In the Netherlands, AbbVie was so desperate to fend off competition that it slashed prices of Humira by up to 89%, according to the 

. This reportedly caused biosimilar competitors of the product to reconsider entering the market at all.

However, 2019 year-end results for Humira show that biosimilar competitors in Europe have attained a very sizeable share of the market that continues to increase.

As the halcyon days for Humira’s US dominance near an end, AbbVie continues to see impressive results for 2 follow-on products that it hopes will cushion the blow from biosimilar competition against its blockbuster product.

Skyrizi (risankizumab), which treats psoriasis,was launched in May of 2019 and quickly began racking up the sales. The product netted global revenues of $355 million for theyear. Rheumatoid arthritis pill Rinvoq (upadacitinib) launched in August 2019 and had net revenues of $47 million through December 2019.

AbbVie predictstotal 2020 sales of $1.7 billion for those 2 drugs, and based on first-quarter 2020 results, that may not be an unrealistic assumption. Skyrizi netted sales of $300 million in the just-ended quarter, and Rinvoq took in $86 million. “Skyrizi global revenues of $300 million were…significantly above expectations,” said Richard A. Gonzalez, chairman of the board and chief executive officer of AbbVie. “Rinvoq is also performing at a very high level in the [rheumatoid arthritis] segment.”

 in late 2018 that it was negotiating with Revance to jointly bring a Botox biosimilar to market. There are no patent restrictions on the originator product, although its formulation is a trade secret.

Mylan has not been able to reach a final decision on whether to move forward with the partnership, and in a statement released on May 1, 2020, Revance said that although an April 30, 2020, decision deadline had come and gone, the two had decided to continue discussing the potential for a deal. “Revance will issue an update on the path forward for the program once Mylan’s decision has been reached,” the company said in a 

Revance has a Botox-like product of its own, Daxi (daxibotulinumtoxinA), but plans to bring this to market may be contingent on the outcome of the Mylan negotiations. The company 

 in February that the FDA had accepted its application for approval of the product.

Articles

After 17 years on the US market, Humira (adalimumab) proves it can still generate high sales, but competition from biosimilars is growing.

Humira Sales Grow as Competition Heats Up

If a pharmaceutical company receives a patent long after competitor versions of its drug have come to market, can that company still bring a suit for lost profits and patent infringement? Amgen is trying to do just that.

 against Hospira and Pfizer over a patent involved in the manufacture of a filgrastim biosimilar to Neupogen, Amgen’s reference product.

The biosimilar in question, Nivestym, received FDA approval in July of 2018 and went on market in October of that year. The patent under dispute (No. 10,577,392) was issued on March 3, 2020.

Amgen said the patent concerns methods of purifying proteins used in the manufacture of the biological product, contending, “Before the expiration of the patent,” Hospira, acting “in concert” with Pfizer, sought regulatory approval for the biosimilar under the abbreviated Biologics License Application (BLA) pathway in the Biologics Price Competition and Innovation Act.

Nivestym was approved by the FDA for all 

 of the reference product, among them lowering the incidence of infection, caused by febrile neutropenia, in patients with nonmyeloid malignancies receiving chemotherapy. Neupogen stimulates the production of a known as neutrophils, a type of white blood cell that fight the infection.

Amgen contends that by September 24, 2018, Hospira and Pfizer were importing the biosimilar into the United States and making it available for sale. The company wants to recoup profits that it claims would otherwise have been made on the sale of Neupogen had there been no infringement as alleged.

Price erosion was partly responsible for those alleged lost profits, Amgen contens, citing a 2018 

 Pfizer made to The Center for Biosimilars

 that Nivestym would be offered at a wholesale price 30.3% lower than that of reference filgrastim and 20.3% lower than that of Zarxio, a filgrastim biosimilar produced by Sandoz.

Amgen said in its court filing that it has had to battle obtain a full copy of the BLA from Hospira. Initially, Hospira provided 10,000 pages worth of material, but upon checking the cross-referencing, Amgen noticed that much of the document was missing. Hospira eventually produced an additional 70,000 pages, claiming that the extra pages were “inadvertently” not included with the original paperwork, Amgen contends.

Amgen, which is seeking a jury trial, initially contended that as many as 6 patents could be subject to a claim of infringement by Hospira. In subsequent negotiations, that number was whittled down to just 1 patent, covering the purification process for reference filgrastim. This patent remains under litigation in Delaware.  

Trying to carve back its market share for Neupogen, its filgrastim originator product, Amgen is hoping product exclusivity can be backdated.

Amgen Claims Infringement of a Patent That Didn't Exist

Biosimilar earnings climbed by the double digits for Biogen and Pfizer during the first quarter of 2020. Pfizer has introduced multiple biosimilars in recent months, although it also anticipates that biosimilar competition will erode its earnings base significantly.

Biogen has extended its commercialization agreements for biosimilars and said sales of biosimilars to treat coronavirus disease 2019 (COVID-19) improved the earnings picture in the first quarter of 2020.

 that its biosimilar revenues climbed to $288 million in the first quarter, up 63%. That breaks down to $167 million in the US market and $122 million internationally.

The company attributed much of the increase to steady growth of sales in the United States, particularly for its epoetin alfa biosimilar Retacrit, which references Amgen’s Epogen. Retacrit’s US market first-quarter revenues were up 363%, the company said.

Pfizer said its infliximab biosimilar Inflectra, which it markets under an agreement with Celltrion, saw US sales increase 46% to $84 million, driven by higher demand but also affected by product price declines. Worldwide sales of the product were $158 million, up 14%.

therapeutic monoclonal antibody oncology biosimilars. It put a rituximab product on the US market, Ruxience. That was in January. In February the company launched Trazimera, a trastuzumab product. In December 2019, Pfizer launched the bevacizumab biosimilar Zirabev.

“We are encouraged by our initial engagements with payers and providers, where we have not seen the negative impact of exclusionary contracting by the innovator companies that we had seen with the Inflectra launch,” company chairman and chief executive officer Albert Bourla said about the launches in an 

 that the European Commission had approved its rituximab monoclonal antibody, Ruxience, for the treatment of non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, and other disorders.

It wasn’t all rosy for Pfizer on the biosimilar front. The company said its sales of reference etanercept Enbrel were hit hard by biosimilar competition in European markets, Brazil, and Japan. Sales were off 21% for the quarter.

In providing guidance for investors for the full year 2020, Pfizer warned of an anticipated $2.4 billion “negative revenue impact” due to recent and expected generic and biosimilar competition for products that have recently lost or will soon lose patent protection.

Biogen reported biosimilars earnings of $219 million for the first quarter, up 25% compared with the year-ago comparable quarter, an increase of $44 million. The company said its anti—tumor necrosis factor (TNF) biosimilars have been used to combat COVID-19 and it attributed $15 million of its first-quarter earnings to this.

The company estimated that its biosimilar business in Europe led to a savings of roughly $2 billion for the healthcare systems. Biogen said it has 215,000 patients using its biosimilars in Europe. The company does not yet market any biosimilars in the United States.

Biogen has a commercialization agreement with Samsung Bioepis to market the Republic of Korea—based company’s 3 anti-TNF biosimilars: Flixabi, Imraldi, and Benepali.

The infliximab biosimilar Flixabi saw revenues reach $24 million in the first quarter of 2020, up from $15 million in the first quarter of 2019. The adalumumab biosimilar Imraldi achieved first-quarter 2020 revenues of $62 million, up nearly 100% from $36 million in the year-ago quarter. The rheumatoid arthritis biosimilar Benepali was the top performer, achieving first-quarter revenues of $133 million, up from $124 million in the year-ago quarter.

Benepali is the overall top-selling biosimilar to reference Enbrel in the EU5 markets, which include France, Germany, Italy, Spain, and the United Kingdom, Biogen said.

In late 2019, Biogen notched a commercialization agreement with Samsung Bioepis for SB11, a ranibizumab biosimilar referencing Novartis’ Lucentis, and the aflibercept biosimilar SB15, referencing Eylea, by Regeneron. Both products are for age-related macular degeneration. These 2 reference products had a global 

 of almost $11 billion in 2018, according to Biogen.

The company has strong expectations for its biosimilars business, although it continues to represent a small portion of its overall revenues. Total first-quarter revenues for Biogen were $3.5 billion, up 1% from the year-ago quarter.

Pfizer is battling biosimilar competition as its brands lose exclusivity but it is fighting fire with fire, launching multiple biosimilars of its own. Biogen has extended its commercialization agreements for biosimilars and said its earnings picture improved in the first quarter of 2020.

Pfizer Says Biosimilar Competition Cuts Both Ways

Timing is important in biosimilars as in everything else. Genentech found this out last year when it missed a key opportunity to block a trastuzumab biosimilar from coming to market.

This error in timing may have implications for how litigants in biosimilar disputes map out their strategies and initiate court proceedings in the coming years under the Biologics Price Competition and Innovation Act (BPCIA), Ted Mathias, a patent law attorney with Axinn, Veltrop & Harkrider of Hartford, Connecticut, said.

Under the BPCIA, patent litigants enter a period of discovery known as the patent dance, during which they exchange key information about biosimilars that a company wants to bring to market and the patents that the originator company asserts may be transgressed by the biosimilar. Also under the act, the companies must resolve these issues as part of the business of clearing a biosimilar for marketing.

The patent dance may stretch over many months, and it is punctuated somewhere in the middle by the filing of a notice of commercial marketing by the biosimilar applicant, which customarily has been followed by a preliminary injunction filing by the originator company. The preliminary injunction, if accepted by the court, preserves the status quo, meaning the biosimilar could not come to market until patent issues are resolved.

In the case of Genentech, the company waited too long to file the preliminary injunction motion after Amgen served a commercial marketing notice for its trastuzumab biosimilar (Kanjinti). Amgen filed the notice in May 2018, but Genentech did not file the injunction motion until July 10, 2019, a month after Amgen got its FDA approval for Kanjinti. Usually, such a motion would have been filed before the FDA approval.

“That was the principal reason the district court denied Genentech’s motion for a preliminary injunction,” Mathias said in a presentation at the recent World Biosimilar Congress USA 2020 at the Festival of Biologics USA in San Diego, California.

 its trastuzumab product “at risk” of litigation, but it became the first trastuzumab biosimilar on the US market and began to carve into the $2.9 billion US market for Herceptin, the reference product.

It has not been uncommon for originators to wait before filing a preliminary injunction motion. The type of patent information exchanged after such a motion represents a second line of defense against a biosimilar applicant.

During this phase, the originator company can assert any remaining patents that were not litigated during the first phase, prior to the notice of commercial marketing.

“What was happening was that the originators were receiving early notices of commercial marketing but holding off on seeking preliminary injunctions until FDA approval drew closer. Genentech actually waited too long to seek preliminary injunction. It knew by April 2019 that Amgen was planning to launch in July 2019, but it waited until almost a month after Amgen got approval in June 2019 before filing for the preliminary injunction,” Mathias said.

Knowing how the court ruling went for Genentech, originator companies are liable to start filing these motions much earlier in the process, which could serve the interests of biosimilar companies, Mathias said.

If the preliminary injunction comes earlier in the patent dance, the biosimilar company gets the benefit of more information sooner that may expose vulnerabilities in the originator company’s legal position. “Some applicants may welcome that early preliminary injunction motion. They’re likely to see the originator’s best arguments right away and be able to assess the weaknesses in their own position,” Mathias said.

In addition, some biosimilar applicants may not be expecting an FDA decision on their application for many months. With an early preliminary injunction motion, they could take their time about entering the litigation process until they know better how the FDA is likely to respond. This would spread out the cost of litigation and allow a biosimilar developer to assess the strength of its FDA application for biosimilar approval before committing to a potentially costly fight over the preliminary injunction.

 “So, we can expect some changes and, specifically, some more varied approaches to litigation based on what we saw last year with trastuzumab,” Mathias said.

 the lower court ruling by the US District Court for the District of Delaware on the preliminary injunction. In early March, the US Court of Appeals for the Federal Circuit upheld the lower court’s ruling.

In the meantime, the underlying patent litigation involving Kanjinti continues, and 4 other 

 biosimilars have come to market, all of them within the past 5 months.

Taking an abundance of time to file a motion to block Kanjinti from coming to market, Genentech unwittingly may have tipped the scales in favor of biosimilar applicants.
 

Genentech's Misfire on Kanjinti Creates Opening

For a company with global ambitions for a trastuzumab biosimilar candidate, it’s important to meet international standards for manufacturing and quality control, and Henlius Biotech of Shanghai, China, said a successful EU inspection of its Xuhui Facility has provided that level of certification.

Henlius has multinational agreements to market the biosimilar HLX02, which is currently awaiting authorization for marketing from the European Medicines Agency. That application was filed in June 2019.

The company is poised to put its commercialization plans for HLX02 into high gear. “Henlius has reached strategic cooperation agreements with Accord, Cipla, Mabxience, and Jacobson Medical for the commercialization of HLX02 in over 80 countries and regions around the world,” the company said.

Accord has been granted exclusive rights to sell HLX02 in Europe, the Middle East, North Africa, and the Commonwealth of Independent States (Eurasian post-Soviet Union states).

It was, in fact, Accord’s marketing application for HLX02 that was 

 with the EMA last June. Henlius said HLX02 has the potential to become the first biosimilar developed in China to be approved in the European Union.  

In a release, the company said its Xuhui Facility has received EU Good Manufacturing Practice (GMP) approvals, based on on-site inspection, which certify that it complies with manufacturing standards.

It’s a huge and important milestone, the company said, because the EU GMP stamp of approval represents “one of the most authoritative and rigorous inspections globally.”

The EU GMP inspection is recognized by nearly 30 EU member states and the inspection results also may be shared with other countries that have signed Mutual Recognition Agreements with the European Union. These countries include the United States and Canada.

“Therefore, the EU GMP Certificate is considered a passport for drugs to be launched in international markets and has significant global impact,” Henlius said in the 

HLX02 is a biosimilar developed and manufactured by Henlius for the treatment of HER2-positive early-stage breast cancer, HER2-positive metastatic breast cancer, and HER2-positive metastatic gastric cancer.

In a November presentation at the European Society for Medical Oncology Asia Congress 2019, the company 

 that the biosimilar met its primary end point of best overall response rate at week 24 in a phase 3 trial of the drug in patients with breast cancer.

Henlius was founded in 2010 and has established 3 research and development facilities in Shanghai, Taipei, and California. The company is focused on developing biologics for oncology and autoimmune diseases.

In February 2019, the company's first product, HLX01, a rituximab injectable biosimilar, was approved by the China National Medical Products Administration (NMPA) and became the first biosimilar launched in China.

Henlius said a new drug application for HLX02 filed with the NMPA has been assigned to the priority review list and the agent is expected to be launched in China this year.

“We will make every effort to accelerate the global commercialization progress of HLX02, hoping to benefit more patients and to represent China in the 'World Cup' to compete with the world's top bio-pharmaceutical companies from Europe, the United States, South Korea,” and other regions, Scott Liu, cofounder and chief executive of Henlius, said.

Henlius Biotech said its manufacturing facility has met European standards for production of its trastuzumab biosimilar candidate, which the company said is "a passport" for potential commericialization across the globe.

Henlius Manufacturing Plant Gains European Stamp of Approval

Patients who do online searching for medical information about biosimilars are liable to have exacerbated concerns about switching to biosimilars, according to a New Zealand 

 that examined patient attitudes toward these agents. The study examined patients with rheumatic conditions.

The findings also indicated that women are more likely to have concerns about switching from originator drugs to biosimilars.  

There was a positive correlation between adverse events experiences from the bio-originator and adverse events anticipated from the biosimilar (

There was a positive association between perceptions of bio-originator safety and the expectation that biosimilars are unsafe (

There was a significant negative association between the perceived effectiveness of the current bio-originator and a preference for a biosimilar medicine (

Recognizing that many patients have difficulty accepting biosimilars and are unwilling to switch to them, investigators set out to explore demographic and psychological characteristics associated with safety perceptions and switching concerns.

Investigators surveyed 96 patients taking originator biologics for rheumatic conditions (rheumatoid arthritis, 65%).

The survey was completed in an Auckland, New Zealand rheumatology service. Patients were predominantly female (69%) and 54 years of age on average. They were also predominantly New Zealand European (67%). The most common bio-originator therapy was rituximab (35%).

According to the findings, negative perceptions about biosimilars were associated with being female, having had only a short-term experience with a bio-originator, illness beliefs, a habit of searching for information online, high perceived sensitivity to medicines, and negative beliefs about medicines.

Patients who research medical information online are likely to be more concerned about switching from originator products to biosimilars, according to the study.

However, investigators warned that online searching for medical information by patients “can lead to Internet users accessing nonfactual information and can influence their perceptions toward unbranded medicines, particularly as information shared online often does not align with best practice guidelines.”

They said that directing patients toward reliable information after discussions about switching may help to reduce these concerns.

Further, patients who have strong emotional responses to their condition are likely to have higher concerns about switching to biosimilars. Patients with arthritis tend to have these strong emotional responses to their condition, investigators said. Another factor that influences patients’ perceptions of biosimilar safety and adverse event profiles is the experience they have with the originator products.

“This finding is consistent with recent studies that have demonstrated that [patients with] rheumatology who have effective bio-originator treatments or are satisfied with their treatment are hesitant to change, due to fearing new [adverse events],” the authors said.

Even among patients who said they expected a biosimilar to have similar safety and adverse event profiles to a bio-originator, fears and uncertainty may persist and influence treatment preferences, the authors said.

For this reason, clinicians should try to reassure patients who have had unfavorable experiences with bio-originators. “By assessing patients’ preferences for branded medicines, healthcare professionals can provide educational interventions to address misconceptions toward medicines.”

 of biosimilars may derive from beliefs that biosimilars are substandard in quality, safety, and efficacy to bio-originators. These can induce nocebo responses, in which the patient’s negative attitude toward the therapy worsens the outcome. Nocebo responses contribute to intentional nonadherence and wasted resources, investigators wrote.

A New Zealand study of patients with rheumatic conditions suggests that providers need to be mindful of patient attitudes toward biosimilars to prevent biased therapy choices and poor outcomes.
 

New Zealand Study Reveals Importance of Patient Attitudes Toward Biosimilars

The United States market for biosimilars doesn’t always get the respect it deserves, especially when it’s compared with Europe, which has at least a 10-year lead on biosimilar introduction. But for one company that’s moving into this space, there are undeniable advantages to the US market.

Samsung Bioepis in a partnership with Merck is 

its own trastuzumab product, Ontruzant, and conditions for biosimilar uptake in the United States have been improving lately, said Sang-Jin Pak, MD, executive vice president of Samsung Bioepis’ Commercial Division, in an interview with The Center for Biosimilars®.

“If you look at the latest launches, especially in oncology, they actually are quite successful,” he said. “The uptake is steep, and we see that, among both payers and providers and also patients, the acceptance level is increasing significantly, and so we remain very optimistic for the US market.”

The introduction of Ontruzant marks the fifth trastuzumab biosimilar introduced since 2019, but also the third trastuzumab biosimilar introduced just this year, the other recent entrants being from Pfizer and a partnership of Celltrion and Teva. Samsung Bioepis is based in the Republic of Korea.

It may seem like the market has grown very crowded very quickly, and also highly competitive, but the time proximity for all of these launches is so narrow that sales opportunity is still robust, Pak said.

“We believe there is enough room in the market for us to grow, and there’s enough unmet patient need for this life-saving medicine, so we believe we have an important role to play here in the US market,” he said.

Ontruzant was cleared for marketing by the FDA in January of 2019, and with the first competitor to reference Herceptin jumping into the market in July 2019, and the fourth biosimilar trastuzumab arriving in March 2020, there was undeniable pressure on Samsung Bioepis and Merck to get rolling with their commercialization plan as well, but this was a preplanned launch that was not accelerated by any competitor action, Pak said.

Nor did coronavirus disease 2019 (COVID-19) influence the schedule, he said, although, “obviously, COVID-19 is an exceptional time.”

In the United States, Merck is handling the commercialization end of the launch. For that reason, Pak could not speak to the strategy that would be employed to get the product out to providers and patients. But remote access will be part of that effort, as sales representatives across the pharmaceutical industry have been grounded by COVID-19 and forced to utilize other means of getting the product message out, he said.

“In the time of this lockdown, none of the pharma companies can actually do face-to-face meetings. I think all of them have resorted, more or less, to remote technologies. But I cannot comment if this is going to be the case after COVID-19,” Pak said.

COVID-19 has been a well-placed wrench in the works of many engines of commerce, but Samsung Bioepis believes it will be able to fully support the commercialization of its trastuzumab biosimilar. “We’re very proud of our supply continuity because we have a dual-sourcing strategy, and we believe we have enough inventory in order to ensure continued supply, even in times of COVID-19,” Pak said.

Samsung Bioepis has indicated that it intends to market traszuzumab at a 15% discount to Herceptin. With 6 trastuzumabs on the market, including the reference product, The Center for Biosimilars® asked Pak whether the diversity of offerings would make it difficult to sustain an 85%-to-reference price level.

“It’s obviously hard to predict how this will go, but our experience in Europe has shown that with more competition there is also more price competition; so, yes, my expectation would be that prices will go down over time,” he said.

Samsung Bioepis already has 1 biosimilar on the US market—the infliximab product Renflexis. The company also has a bevacizumab biosimilar planned for the United States. The application for that product was accepted by the FDA in November 2019 and a decision is anticipated by the fourth quarter of 2020.

The company aims to bring an adalimumab biosimilar to market. That launch, against AbbVie’s blockbuster Humira, is expected to occur in 2023, at which time as many as 9 adalimumab biosimilars could 

the market. Five of those, including Samsung Bioepis’ Hadlima, have received FDA approval.

An additional product is Eticovo, an etanercept biosimilar to Amgen’s Enbrel. Eticovo got its approval in April 2019, but the launch date is up in the air. “Eticovo is still not decided yet, and I cannot comment further because there’s some legal action ongoing with another etanercept biosimilar (Erelzi, Sandoz) that we are closely monitoring,” Pak said.

Samsung Bioepis was founded in 2012 as a joint venture between Samsung Biologics and Biogen.  Biogen is handling commercialization of the Samsung Bioepis’ biosimilars in Europe. It’s an exciting time for the company, Pak said.

“This is the first oncology biosimilar for us, together with our commercialization partner Merck, in the United States, and we believe that we have really, through process innovation and our quality management, developed and manufactured a high quality biosimilar which will help patients gain access to this medicine,” he said.

Samsung Bioepis isn't flinching on its trastuzumab biosimilar launch schedule, COVID-19 and 4 other biosimilar competitors notwithstanding, said Sang-Jin Pak, MD, executive vice president of the company's Commercial Division.

Samsung Bioepis Sees Wide Open Market for Its Trastuzumab

Exclusionary strategies, the practice of leaving drugs off formulary to save money and direct patients to more clinically effective therapies, are on the rise, and biosimilars can be structured into these programs to make them effective, said Jeenal Patel, PharmD, BCGP, a formulary manager for WellDyne, who spoke this week at the AMCP eLearning Days virtual 

, which replaced the annual meeting of the Academy of Managed Care Pharmacy.

Higher utilization and higher unit costs of specialty drugs continue to drive overall spending upward in the US market, and these rising costs “put pressure on patients, employers, and providers,” Patel said. WellDyne is a pharmacy benefit manager (PBM) based in Lakeland, Florida.

The year 2018 saw 5.8 billion 30-day equivalent specialty medication prescriptions dispensed, representing a 2.7% increase from 2017, Patel said. “This was primarily driven by new therapies and expanded indications for existing products.”

Specialty medications represent 2.2% of total drug prescription volume, Patel said. Use of this class of drugs has increased at twice the rate of other drugs. “This percentage may seem small, but specialty drugs contribute to a large, large portion of drug spend,” she said.

More specialty medications can be expected to debut, as “manufacturer pipelines remain robust,” which suggests that costs will push higher, she said.

These trends are pushing payers toward strategies such as formulary exclusion to control costs, Patel said.

Some of the main tactics employed include prior authorization, quantity limits, multi-tier plan design, and step therapy. They help payers to mitigate waste and focus on efficacious, safe, and cost-saving alternatives, she said.

Exclusions Are a Stronger “Deterrent”

are gaining popularity as a means of managing the type and cost of medications used. “Many times when you have an excluded or not-covered product, it’s perceived to be a stronger deterrent to usage, versus to having the product placed on a higher tier, or controlled by prior authorization or step therapy,” Patel said.

Cosmetic and fertility drugs are examples of drugs that are often placed on exclusion lists, she said. About three-fourths of 273 employers surveyed in a report used formulary exclusions, compound exclusions (nonallowed drug ingredients), or prescription exclusions, Patel said. “So, very much, it’s a common practice in formulary management today.”

Even in the specialty arena, we’re starting to see limited drugs available on formulary for narrow therapeutic areas and unique oncology indications, for example. We’re seeing decreased redundancy across the board in broader categories, such as psoriasis and arthritis,” Patel said.

The risk of exclusion can have downward effect on pricing, as it encourages drug discounting for better formulary placement. “It can also encourage manufacturers to demonstrate the value of their products, while payers are focused on trying to balance costs,” she said.  

Patel said signs point to rapid growth of the use of exclusions in the future, although she cautioned that these should be utilized to promote use of the most effective drugs while saving money and reducing waste. She also said that exclusions should not be allowed to disrupt ongoing patient therapy.

PBMs are finding exclusions “one of the more attractive ways to lower costs” and develop a more competitive pricing landscape, she said.

Exclusions may apply to drugs with “hyperinflationary” tendencies, or what Patel termed “egregious year-over-year price increases.” Other agents that find themselves on the outside of formulary lists and looking in are “me-too” drugs that have different ingredients but no added clinical value, high-cost brands for which there are generic alternatives, high-cost generics, and “nonessential drugs,” which have not been approved by the FDA.

“There are a lot of opportunities out there when it comes to more granular management of these drugs,” Patel said, noting that huge cost savings are possible by looking for alternatives to high-priced, low-value products.

One tactic is to delay formulary placement for new drugs to market. This allows time to review the clinical evidence for or against a particular product. It also provides some buffer against aggressive launch promotion by manufacturers. And it enables the creation of benefit design programs that incorporate product rebates, for example, thereby allowing for better cost strategies, Patel said. These product placement delays typically do not include drugs for rare or orphan diseases.

For a strategy for reversing the increasing costs of drugs, Patel suggested a 3-part strategy: Identify the high-cost drugs that can be replaced with lower-cost alternatives; eliminate excessive utilization by employing formulary exclusion, prior authorization, and step therapy; and substitute higher-value agents via a patient engagement program.

“We have to get better,” she said. “We have to identify and substitute with clinically appropriate, lower-cost alternatives that drive the same therapeutic outcomes, and that’s going to be a combination of monitoring the robust pipeline for new generic launches, or looking to see if there are biosimilars to help promote lower cost.”

That’s not to say that exclusionary strategies don’t sometimes lead to higher-cost medications. Patel cited evidence that relatively ineffective diabetes medication on formulary led to an increase in overall costs partly because providers and patients were shifting to higher-cost medications.

Challenges of implementing exclusion practices include patient dissatisfaction with therapy changes and disruption to clinical progress, such as loss of disease control, impact on adherence, or inappropriate changes that increase total costs of care. Providers may complain and there may be a rise in appeals of prior authorization denials, Patel said.

Jeenal Patel, PharmD, BCGP, a formulary manager for WellDyne, said pharmacy benefit managers (PBMs) and employers are increasingly turning to formulary exclusions to control the rising cost of drugs.
 

WellDyne Executive Says Formulary Exclusions Are on the Rise

The year 2020 has already seen 4 biosimilar launches in the United States, and those could be augmented by several more, although the coronavirus disease 2019 (COVID-19) pandemic has introduced a wild card to the mix, said presenters at the American Academy of Managed Care Pharmacy eLearning Days 

But the pipeline from 2021 to 2025 is stocked with at least 5 approved biosimilars to adalimumab, and potentially 4 others, all of which could conceivably launch in 2023, and 14 other potential biosmilar products, which could make the next several years a very active growth time for the US biosimilar space, the presenters said.

The pace of clinical trials has also been affected, and with regard to approvals, the FDA’s most recent notice has been that there will be no “near-term” affect on these, said Leslie Fish, RPh, PharmD, who co-presented with Jeffrey Casberg, MS, RPh, in the session, "Drug Pipeline: Traditional Pharmaceuticals and Bisoimilars." Both are experts on the pharmaceutical pipeline with IPD Analytics.

 caused by COVID-19 in 2020 could lead to a slew of backlogged approvals or launches in 2021, Fish said.

A lot of companies have stated that they are going to slow their existing studies or hold up new studies of various agents, because they’re now working on COVID-19 therapies or vaccines, she added.

There could be multiple biosimilar agents reaching the market in the oncology space for the remainder of 2020, Fish and Casberg said. One of those drugs is HSP-130, a pegfilgrastim biosimilar that Hospira and Pfizer intend to launch against Amgen’s Neulasta originator drug. However, HSP-130, expected to launch this June, would join other biosimilars already on the market, including Ziextenzo, Udenyca, and Fulphila.

An additional drug in this class is Rolontis (eflapegrastim). The FDA accepted the application for this investigational granulocyte-colony stimulating factor analogue in December of 2019. Rolontis is under development by Hanmi Pharma and Spectrum and is targeted for an October launch.

Another biosimilar that could debut this year is a bevacizumab copy (SB8) that Samsung Bioepis and Merck hope to bring to the US market in September, according to Casberg and Fish. There are 2 bevacizumab biosimilars on the market currently, Mvasi and Zirabev, which were introduced last year. The reference product is Avastin.

There is one other bevacizumab biosimilar candidate, Bmab-100, which is under development by Biocon. This also has the potential to augment the number of biosimilar bevacizumabs available to providers, Fish said.

Lastly in the oncology class of emerging biosimilars is a rituximab biosimilar, ABP 798, the product of an Amgen/Allergan partnership, with a debut scheduled for somewhere in the fourth quarter of this year. It would go up against 2 biosimilars already launched: Truxima by Celltrion and Ruxience by Pfizer. The reference product is Rituxan by Biogen and Genentech.

“With this many biosimilars on the market, and available, there will be a decrease in costs. This decrease in cost will be seen in increasing rebates and better contracting in both the branded and biosimilar space,” Fish said.

Casberg said that eyes have been following the attempts by Sandoz to bring an etanercept biosimilar (Erelzi) to market. That issue was held up in court over patent litigation with originator manufacturer Amgen. “We’d been waiting for an Amgen versus Sandoz decision for quite a while. Turns out, Amgen prevailed, and we likely will not see an Enbrel biosimilar until 2029,” Casberg said. “There is still 1 pending court case that could change that, but odds are in favor of Amgen keeping protection for Enbrel through 2028/2029.”

There are 2 infliximab biosimilars on the market currently, Inflectra and Renflexis, and a third, Avsola (Amgen) will likely launched this year, Casberg said. Avsola was approved in December of 2019. “There are a couple other biosimilar infliximabs coming down the road,” he said. “Those won’t be available for another year or more.”

Hopes for an adalimumab biosimilar to AbbVie’s blockbuster Humira product had been on hold owing to patent litigation. Much of that legal activity has subsided, Casberg said, resulting in individual patent settlements with 9 potential competitors, each with an agreement to launch at some point in 2023. “So, 2023 will be a big year for biosimilar Humira,” he said. Of the 9 products for which settlements have been hammered out, 5 are approved by the FDA.

From 2021 to 2025, up to 14 additional biosimilars could be launched. These include biosimilars for ranibizumab, aflibercept, eculizumab, ustekinumab, cetuximab, omalizumab, botulinum toxin, natalizumab, abatacept, certolizumab pegol, darbepoetin alpha, golimumab, palivizumab, and ado-trastuzumab emtansine, Casberg said.

“There are quite a few bigger products in the works in coming years,” he said.

Novel drug approvals by the FDA have been on the uptick in recent years, Casberg noted. There were 48 last year and a record 59 in 2018. “This year with COVID-19, we’ll have to see if that impacts approvals,” he added.

thus far in 2020, 3 trastuzumab biosimilars have reached the market: Ontruzant, Herzuma, and Trazimera. Also, Pfizer launched its rituximab biosimilar, Ruxience, in January. The FDA has approved 26 biosimilars thus far, and of those,17 have been launched.

Many additional biosimilars could be on the market by 2025, said presenters at the Academy of Managed Care Pharmacy eLearning Days virtual meeting.
 

AMCP Presenters Predict 4 More Biosimilar Launches in 2020

A Swedish company is racing against the coronavirus disease 2019 (COVID-19) to complete clinical trials of its ranibizumab 

Xbrane said its candidate for age-related macular degeneration needs to complete enrollment in the Xplore trial by the end of the third quarter of 2020 to meet its target date for a regulatory filings.

The biosimilar would carve out market share from Novartis’ blockbuster drug Lucentis, which loses its patent exclusivity in the United States this year and in Europe in 2022. Lucentis earned slightly $2 billion outside the US market in 2019.

COVID-19 has been wreaking havoc on clinical trials, forcing modifications to accommodate for patients’ inability to get to clinics and to prevent COVID-19 infections from compromising trial outcomes. However, Xbrane said that due to the locations of its 

 operations and the progress it has made so far, it is “on track” toward approval of Xlucane ahead of the European expiration of Lucentis’ patent in 2022.

“Xbrane is supporting the clinics to take all measures possible to ensure patient safety in relation to visit,” the company said in a 

Xplore Has Recruited 61% of its Target Population

The Xplore trial has recruited 355 (61%) of 580 planned patients so far, and some of these have been brought aboard in just the past month. However, the company predicted that COVID-19 will cause a reduced recruitment rate. Until recently, Xbrane had been bringing patients onto the trial at the rate of 60 to 80 per month.

“Since the situation changes so rapidly any forecasting of recruitment rates in the coming months becomes challenging,” the company said.

Xbrane has agreements with the European Medicines Agency and the FDA to submit marketing authorization applications (Biologics License Application in the United States) when the last patient enrolled has reached month 6 in the treatment schedule.

The company said that although it is racing against the spread of COVID-19, it is putting patient and clinician safety first. “Xbrane will ensure the safety of Xplore study participants as well as the integrity of study data during the COVID-19 pandemic by following recommendations set by the EMA and the FDA,” the company said.

Meantime, the company also intends to continue treatment for all patients currently enrolled in the study.

Macular degeneration if not treated leads to significant vision impairment; the worst case scenario is blindness. So, despite the risk of trial results being compromised by COVID-19, the company feels the Xplore trial must continue if possible.

Nonurban Trial Locations May Be Beneficial

“Participation in Xplore does not lead to significantly more visits to a clinic than if the patients would receive standard treatment outside of a clinical trial,” Xbrane said.

One advantage to running this trial is that over 50% of the participating clinics are private eye clinics located independently from general hospitals and so the threat of COVID-19 infection is lower in theory, Xbrane said in its release.

Approximately 42% of enrolled patients are based in Eastern Europe, 20% in India, 10% in Israel, 6% in Russia and Ukraine, 14% in the United States, and 8% in Spain.

Xbrane’s headquarters is in Solna, just outside of Stockholm, and the company has research and development facilities in Sweden and in Italy. The company describes itself as a biosimilar development company that looks to exploit niche markets.

A Swedish company that wants to bring a ranibizumab biosimilar to market said it may finish trial enrollment despite the pandemic.