Tag: Inflectra

A Health System Biosimilar Survey’s Implications

When asked about potential cost savings with the infliximab biosimilar, nearly one-quarter of health system respondents did not believe that it represented a cost savings opportunity for their organization, according to a newly published survey in the Journal of Managed Care and Specialty Pharmacy.

Conducted by Premier, Inc., a group purchasing organization, 57 US health systems responded to its questionnaire in April and May 2017 (before the launch of Merck/Samsung Bioepis’ Renflexis® biosimilar). All of the health systems currently used infliximab at their facilities.

The greatest barrier to adoption cited by the health systems was the reimbursement from payers (28%), with actual cost of the biosimilar being a lesser concern (10%). According to the survey, about one-third of the respondents had had communications by that time with payers regarding the latter’s approach to biosimilar coverage.

Interestingly, 62% of those systems represented by the survey respondents had not reviewed Pfizer’s Inflectra® in their Pharmacy and Therapeutics Committees. In large part, thiBR&R Logo Transparent1.5-21-2017s was a continuation of a “wait-and-see” approach, particularly in view of the relatively small discounts offered by Pfizer. Others responded that they were awaiting Merck’s entry into the marketplace, to review both biosimilars at the same time.

“For sites of care that approved formulary addition of the infliximab biosimilar, implementation strategies ranged from full product conversion to ‘new patients’ only,” wrote the author, Sonia T. Oskouei, PharmD, Director of Pharmacy Program Development-Biosimilars at Premier. “Some sites added it to their formularies as a preferred product but only when payer coverage supported it.”

Seventy-six percent of respondents perceived that there was a cost savings opportunity for biosimilars compared with the reference product. What are the expectations of the remaining health system executives? If they don’t believe biosimilars do not save the system money, why not?

The Week in Biosimilar News

You know it’s been a pretty desperate week in the biosimilar blogosphere when twitter feeds relate back to articles published in January, rehashes of the US Supreme Court decision in June, or yet another estimate of the savings potentially ascribed to biosimilar use (based on erroneous assumptions). However, there were a few significant tidbits announced last week that are worth reviewing.

First, Biocon announced that the decision to approve its trastuzumab biosimilar (with partner Mylan) has been delayed by the Food and Drug Administration (FDA) 3 months (until December 3, 2017). According to Biocon, this delay was required so that the FDA could “review some of the clarificatory information submitted as part of the application review process.” Clarificatory? Really? Maybe the extra time was needed to translate the application itself.

Second, a survey of 103 US gastroenterologists raised a couple of questions as to how well information about Inflectra®, the biosimilar to Remicade®, is sinking in on the practice level. According to a press release from Spherix Global Insights, cross-category prescribing may be interfering with the uptake of the biosimilar. They state, “not only is the decline [in Remicade prescriptions] attributed to the adoption of infliximab biosimilars, but use of Humira® has also significantly increased, potentially indicating that more ulcerative colitis patients are being placed on Humira to avoid insurance mandates for infliximab biosimilar use.” This limited survey found that more than one-third of gastroenterologists “agree that if a pharmacy or managed care plan advises them to use Inflectra over Remicade, that they are more likely to choose a different TNF-inhibitor altogether.” This is a weird finding, perhaps indicating nothing more than spite for the health plan’s benefit design. Clearly, if the physicians fully considered the evidence, they would be less likely to prescribe in this way. Admittedly, as notable numbers of managed care organizations have not actually mandated Inflectra use at this point in time, we would have to wait to see if this opinion is validated in actual practice.

Finally, Sanofi announced that it had received tentative approval on a follow-on biologic form of insulin lispro (the originator product was Lilly’s Humalog®). Patent issues will have to be resolved before Sanofi can receive final approval and bring this product to the market. The insulin biosimilars are not regulated under the Biologics Price Competition and Innovation Act, but rather under the Hatch–Waxman Act—the application was filed as a 505(b)2 rather than a 351(k) variety. They are transitional products, which will considered under the newer regulations after March 23, 2020. We will detail these lesser-known transitional drug categories in a future post.

Inflectra Sales Lagging for Pfizer in Second Quarter

Pfizer announced some disappointing results for the second quarter in its quest to advance a foothold in the biosimilar market. The second-quarter results hinted at more difficulties to come for the Inflectra® brand, with the most recent launch of Merck’s Renflexis®.

Amid somewhat positive signs with group purchasing organizations, which supply hospitals and health systems, commercial health plans have lagged in covering the product. On the earnings call, John Young, Pfizer’s Group President for Pfizer Essential Health, said that in the second quarter, “our Inflectra share was 2.3% of the overall infliximab volume,” including both patients who had not used infliximab before and those who switched to Inflectra. The total US revenue for the quarter was only $23 million. In Europe, sales were $94 million—better but not yet gaining the penetration of other biosimilars in the EU.

The 15% discounting strategy may have limited uptake by US health plans and insurers to date, but Janssen’s actions to defend marketshare have no doubt been effective. Pfizer’s most recent price drop, coinciding roughly with the launch of Merck’s (and Samsung Bioepis’) infliximab biosimilar, will likely muddy this picture in the near term.

Overall, Pfizer’s revenue decreased by 2% (to $12.9 billion) compared with the second quarter of 2016. This is not terrible, considering that its European revenues from Enbrel® (etanercept) continue to be under siege from biosimilars, dropping 20% compared with Q2 2016.

Pfizer’s pipeline remains robust, however, with 8 biosimilars in the works, including 4 in phase 3 trials. Its epoetin alfa product Retacrit® had been rejected by the Food and Drug Administration (FDA) because of potential manufacturing concerns. The second-quarter financial report did not update its progress in discussions with FDA.

What Happens When Switching Among Biosimilars?

Late last year, I wrote about a biosimilar challenge that could be on the horizon. With the approval of the second infliximab biosimilar (infliximab-abda by Samsung Bioepis), that horizon is a lot closer. However, we are no closer to understanding how to address the issue.

When Renflexis™ is launched in October (it is unknown whether the US Supreme Court ruling that wiped away the 180-day postapproval waiting period will affect this), 3 noninterchangeable versions of infliximab will be available. Based on patient turnover in health plans, the following scenario will soon occur.

 

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Image Copyright 2017 by Lee Fogel

Mr. Jones, a 39-year-old man with Crohn’s disease, works for a large self-funded employer. He has been taking Remicade®, the reference product, for some time. In January 2018, his employer decides to change its plan offerings. His new health plan does not cover Remicade, favoring Inflectra® (infliximab-dyyb) instead. He could seek a medical exception to continue on Remicade, but his new plan actually offers considerable incentives to switch, including significantly lower cost sharing. After discussing the situation with his doctor, he makes the change, and experiences much the same clinical results. In 2019, his employer makes another change in plan. And this plan covers Renflexis on the specialty tier but has Remicade available on the higher-cost nonpreferred specialty tier. He and his physician are unsure of the best move.

Keep in mind that it would be rare and probably makes little sense for a health plan to cover both biosimilars and the reference product. At some point, the plan will seek a contract that leverages marketshare. In the scenario above, at what point does the patient unduly risk the development of neutralizing or antidrug antibodies?

No data have been published on switches among 3 biosimilar products. These agents are not designated as interchangeable—though Pfizer’s Inflectra may be closest to it based on its NOR-SWITCH investigations; therefore, no one is truly confident of what might or might not occur with regard to efficacy or safety. I suspect it may be some time before switches among reference product, biosimilar A, biosimilar B, or even biosimilar C may be considered routine.

Patients receiving biologic products for serious chronic diseases may also be subject to case/care management. This is not a clean transition when changing health plans. The situation described above will likely happen in the near future with infliximab and possibly adalimumab (once the patent litigation is cleared). It would be a good idea for health plans and insurers to start reviewing their options now to ensure both patient safety and cost-effective decision making.

Savvy Move or Illegal Anticompetitive Action?

Merck, which markets Remicade® in Europe, may have stepped over an anticompetitive line when Pfizer’s Inflectra® biosimilar was first made available, according to the U.K.’s Competition and Markets Authority. In the US, however, this activity would be considered routine. Certainly, nothing prevents this action and it would be fully expected, in terms of net costs.

According the UK’s Competition and Markets Authority, Merck took unfair advantage of “dominant position through a discount scheme for Remicade that was likely to restrict competition” from the biosimilar infliximab when it was launched in 2015. In this scheme, the drugmaker “unfairly” discounted the product to customers who remained loyal to the product.

Is this really different than offering rebates for preferred positioning? Anecdotal reports in the US indicate that Janssen Biotech, which markets the originator agent in North America, has taken similar action with rebates against Inflectra® (infliximab-dyyb). In fact, Amgen did the same to ward off competition from Zarxio® (filgrastim-sndz). In their cases, they did not discount the wholesale acquisition cost (WAC) to meet the biosimilars’ but simply increased the rebate to yield an equivalent net cost.

This action may be more attractive because it may have fewer implications for “best pricing” discounts required by Medicaid and other payers. Certainly, the maker of the originator product can cut their WAC costs if they desired; at the biosimilars’ modest 15% discounts, this would simply roll pricing back to 2015 levels.

In other news…A case report has been published from New York City, in which a patient switching from the reference infliximab agent to the biosimilar version experienced papulosquamous lesions a few days after the change in medication. Skin biopsy revealed the existence of a lichenoid eruption. This adverse event has not been cited previously in the literature with the reference agent Inflectra®. The direct cause of the drug reaction is unknown but further monitoring is warranted, according to the authors.

On June 2, the European Medicines Agency accepted Sandoz’s application for biosimilar infliximab and adalimumab. Sandoz has not filed a 351(k) application with the US Food and Drug Administration for either product.

No Clear Winner on Supreme Court’s Biosimilar Hearing Day

Despite the fact that the arguments at Wednesday’s Supreme Court wrestling match on the patent dance and 180-day notification issue went into overtime, there was no clear winner discernable in Amgen v. Sandoz.

Some observers believe that the Supreme Court justices were more comfortable with Amgen’s arguments, but the justices admitted that there was little clarity in trying to interpret the ambiguous language of the Biologics Price Competition and Innovation Act. Justice Stephen Breyer stated his unfamiliarity with the technical aspects of the field and expressed concern about ruling on these issues.

Indeed, it is possible that the Court will not issue any ruling, since the case specifically arose around Sandoz’s launch of Zarxio®. Sandoz waited out the 180-day notification period before launching the product, which could prompt the justices to decide that the question is moot, avoiding the larger question of whether it should be enforced for future biosimilar launches.

Judicial experts and industry watchers will be pouring over the comments and questions from the justices for some time, until a final ruling is released (thought to be in July).

In other news… US sales of Janssen’s Remicade® slipped 2.4% to $1.18 billion, in the first full quarter following the launch of its biosimilar competitor, Pfizer’s Inflectra®. This does not necessarily reflect lost marketshare but Janssen’s concessions in matching the price of Inflectra to retain its preferred positioning. With a new competitor looming later this year (Renflexis™), Remicade’s earnings slide is expected to accelerate.

Amgen’s Enbrel® is also facing a less-rosy future, as the product’s sales in the anti-TNF category has begun to slip, independent of any active biosimilar competition. However, competition in the rheumatoid arthritis and psoriasis categories from other products, especially interleukin inhibitors, has been stiff. First quarter 2017 sales of Enbrel in the US dropped 15% to $1.18 billion. Sandoz’s biosimilar etanercept, though approved by the FDA and beyond the 180-day notification period, has not yet launched due to patent litigation questions.

FDA Approves Second Infliximab Biosimilar

On April 21, 2017, the US Food and Drug Administration (FDA) gave its nod to a new biosimilar version of infliximab, and will compete against the originator product Remicade®. Manufactured by Samsung Bioepis, it will be marketed by Merck in the US as Renflexis™.

The new agent, the first approved from Samsung Bioepis, will have to elbow its way to marketshare alongside Pfizer’s Inflectra®, which was launched late in 2016. The nonproprietary name of the new agent is infliximab-abda, in keeping with FDA’s 4-letter suffix policy.

Renflexis was approved for the full slate of indications of the other infliximab agents, including Crohn’s disease, ulcerative colitis, rheumatoid arthritis, psoriasis, psoriatic arthritis, and ankylosing spondylitis.

This biosimilar approval was the first by FDA without the formal meeting of its advisory committees. The agency had first indicated that it would not require advisory committee meetings for biosimilar products in September 2016, when an FDA official   stated that “the first biosimilar for each reference product will have an advisory committee, but there will not be hearings for any others ‘unless there’s a specific issue to discuss.’”

This version of infliximab was approved in 2016 by the European Medicines Agency as Flixabi, and this agent is marketed by Biogen. Biogen is a partner with Samsung in Samsung Bioepis.

The manufacturing and licensing partners have indicated that they intend to market Renflexis at the end of its 180-day notification period, in November. However, assuming patient litigation is ongoing, the launch may have to be at-risk, as was Pfizer’s launch of Inflectra, to avoid additional delays in commercialization.

Biosimilar Immunogenicity, Antibodies, and Extrapolation

Based on the clinical studies to date, most clinicians and policy makers would be surprised if a biosimilar did not yield the same patient efficacy outcomes as the originator biologic. We’ve become accustomed to seeing these equivalent results. However, one of the greatest concerns of physicians and patients in biosimilar development has been the potential safety of the biosimilar when it replaces an originator product.

This concern is largely driven by the type of immunogenetic response the biosimilar molecule might elicit. What is the likelihood that it will result in the production of neutralizing antibodies, which would affect the clinical effectiveness of the product? The appearance of antidrug antibodies could theoretically cause serious immunogenic reactions, beyond just injection-site reactions, including anaphylaxis. Years of experience gained in the US and Europe with the first generation of approved biosimilars (filgrastim, epoetin, etc) have demonstrated that these concerns are unfounded. The question is just beginning to be addressed for the first biosimilar monoclonal antibodies approved by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA). Clinical studies of patients who received Inflectra®, Amjevita®, or Erelzi® showed that immunogenicity was not significantly different between these and the originator products. However, their use for other approved autoimmune disorders (i.e., extrapolation) seem to concern those clinicians expressing discomfort with biosimilar prescribing. Usually, studies of the biosimilar do not address ankylosing spondylitis if the principal clinical studies involved rheumatoid arthritis. This is why the FDA weighs so heavily the importance of analyzing the equivalence of a compound’s structure and characterization. Even these characterizations do not necessarily predict the risk of immunogenicity in practice.

According to the FDA, a head-to-head study in treatment-naïve patients is the most sensitive way to detect potential immunogenicity differences. The FDA believes, however, that a single crossover design, in a subgroup of patients, from originator to biosimilar agent, should help quantify the immunogenicity risk. Critical measurements include the formation of antibodies (measurement of their concentrations or titers), how quickly they develop and how long they persist, and their implications for pharmacokinetics and clinical sequelae. Additionally, researchers should monitor for the neutralization by antibodies of the drug’s activity.

An interesting question that could be raised is whether the immunogenicity of the product varies in patients with different autoimmune disorders (e.g., Crohn’s disease vs. rheumatoid arthritis). Although this has not been extensively studied, the use to date of Inflectra®, for instance, in its various indications, has not revealed a significant problem.

The key is that biosimilars in clinical trials and in experience have not elicited immunogenicity responses that are significantly or clinically different than those of the originator. Comprehensive efforts at tracking and surveillance postmarketing will either put these concerns to rest or raise red flags, rather quickly.

Budgeting the Impact of Inflectra and a Possible Clinical Benefit for Amjevita

Although the biosimilar marketplace is fairly stagnant at the moment, there was plenty of action at this week’s annual meeting of the Academy of Managed Care Pharmacy held in Denver, March 27–30.

Calculating the Breakeven Point for a Health System

A poster presentation from the University of Pittsburgh School of Pharmacy discussed the budget impact of adding biosimilar infliximab (Inflectra®) to the formulary of a model health system.

In this presentation, the researchers assumed the health system had 1,000 patients taking infliximab; of these, 400 were new prescription starts for the biosimilar’s rheumatology and gastroenterological indications, and the rest were receiving maintenance therapy on the originator product Remicade®. The model assumed 3 levels of discounting on Remicade: 10%, 15%, and 20%. They assumed that 60% of patients with a gastrointestinal indication would start on Remicade, and 40% of new start patients would be given Inflectra. At a new start and maintenance price of $20,430 for the biosimilar, they calculate a breakeven point of 15% discount for Remicade to keep only the originator on formulary.

If they assumed that the biosimilar was given not only to new starts but also to 50% of patients initially receiving Remicade , the breakeven discounting point for keeping Remicade only on the formulary becomes far greater. This model is somewhat conservative, because it assumes no further discounting by Pfizer for its biosimilar product. However, it also does not consider additional levels of rebating by Janssen Biotech.

A Biosimilar’s Noneconomic Benefit?

Although biosimilar manufacturers are constrained in the respect that their product has to not only mirror the structure and clinical effect of the originator biologic, it also cannot be produced in a more convenient form of administration (autoinjector vs. vial/syringe). The expectation is that the biosimilar will not be superior in any way to the originator. In a second poster presentation, Amgen researchers disputed this assertion with their biosimilar version of adalimumab. According to their findings, Amjevita® was associated with less injection-site pain compared with Humira®, based on pain scores given by clinical trial patients with moderate to severe rheumatoid arthritis. They found that pain site scores (based on a 100-mm visual analogue scale) were significantly lower at each 4-week office visit for the biosimilar.

The researchers theorize that the reason for the benefit may be the different excipients used in the biosimilar versus the originator drug.

Large European Society Lends Its Support to Switching

In a recent statement published in the Journal of Crohn’s and Colitis, the European Crohn’s and Colitis Organization (ECCO) announced its support for switching from an originator product to a biosimilar in patients with inflammatory bowel disease  (IBD).

In its position statement, ECCO asserts that switching from the originator to a biosimilar in patients with IBD is acceptable if it is in line with national recommendations and has been discussed among the physician, nurse, pharmacist, and patient. This view, which represents a change from ECCO’s previous position, is based on the clinical experience gained from investigational studies and postmarketing trials using the biosimilar version of infliximab.

Lead author and President Elect of ECCO, Silvio Danese, MD, said, “Findings from the 2015 ECCO survey of IBD specialists found that around 80% of specialists are either totally confident, very confident or confident enough in using biosimilars, which is a huge change compared to 39% when a similar survey was conducted back in 2013.”

As for all biologics, traceability should be based on a robust pharmacovigilance system. The authors also noted that several postmarketing studies are ongoing or near publication, which lends further support to the improved confidence in the safety and efficacy of the biosimilar (Celltrion’s Remsima®, which is marketed in the US as Inflectra®).

This marks a significant shift in attitude from the previous ECCO position paper, which advised that switching from an established biologic to a biosimilar was inappropriate and called for more data on the safety and benefit of biosimilars in general.

Dr. Danese and his colleagues concluded, “there have been no reports so far that switching from the reference to the biosimilar infliximab [Remsima] has caused problems, in either adult or pediatric IBD patients. On the contrary, an increasing number of publications have shown that there are no safety or efficacy concerns about switching.”