Even Today, Patients and Payers Hold the Key to Biosimilar Uptake Success

Reading the white paper co-published March 19 by the US-based Biosimilars Forum and UK-based Medicines for Europe highlighted for me the importance of an essential roadblock to increased biosimilar uptake in the US.

The white paper outlined structural market changes needed in the US to gain comparable conversion of marketshare in the European market. Without a doubt, barrier number 1 is the patent thicket erected by biologic makers and the resulting patent litigation. This causes barrier number 2: the signing of licensing arrangements that prevent biosimilar makers from entering the market at the earliest possible date.

However, this still doesn’t address the lack of biosimilar uptake for infliximab: Inflectra® has been available for use since 2016. Whereas I placed considerable blame for this on Pfizer, which underestimated payers’ reaction to its initial discount on Inflectra. Today, I place more of the responsibility on the health plans and insurers for lacking the backbone needed to ensure a vibrant biosimilar market for infliximab. The health system can gain the greatest savings by converting to biosimilar infliximab compared with any currently launched biosimilar. With that in mind, let’s consider these agents.

According to the white paper, “Full buy-in is needed from payers to sustain a competitive market that values the most cost-effective medicines. This includes proactive incentivizing of biosimilar prescriptions, educating stakeholders on the promise of biosimilars, and requiring commercial insurers to provide access to biosimilars.”

I will take this one step further. Patients need to act on their desire for less-expensive alternatives at the physician’s office. Two things must occur to produce this result: (1) the provision of more accurate, less misleading information to patients relating the quality of biosimilars and their clinical efficacy and safety, and (2) financial incentives for patients to specifically request biosimilars.

There is no question that patients are often confused by the contradictory information they receive on biosimilars. This harkens back to generic–branded drug battles of decades ago. Without accurate education, patients will not reliably consider a biosimilar alternative to products like Remicade® . Much has been published on this issue already, and several biologic makers have been castigated about their contributions to misinformation. This must intensify if the second “pull-through” for biosimilar uptake is to be successful.

Any American patient who has faced high cost sharing or deductibles has considered ways to lower his or her costs. That includes making the decision to not refill their prescription or take their medications as directed. Infliximab is only available today as an office-based infusion, but should a subcutaneous version be approved, this, too, would be more directly in the patient’s hands.

The only way this will occur is if patients are given an appropriate choice by their health plans and insurers: lower cost sharing for biosimilars. This is accomplished easily, through the creation of a specialty biosimilar tier (or assignment of biosimilar agents on a fixed cost, tier 3–type payment). With the reference product strictly on tier 4 or 5 (co-insurance tiers with high dollar maximums), this would be the practical step to move the needle. For Medicare Part D beneficiaries, this could be as high as 33% co-insurance.

With the exception of very few payers, this has not occurred for Inflectra. It did occur for Zarxio®, as early as 2017, but it is not used for a chronic medication. When patients begin asking for lower-cost alternatives and payers provide cost-sharing structures that favor biosimilar use, Inflectra or Renflexis® uptake will begin to increase. That means payers foregoing short-term rebate revenue for longer-term cost savings. But one cannot occur without the other.

Pfizer Gets FDA’s Green Light on Its Filgrastim Biosimilar

Pfizer's Biosimilar Filgrastim
FILE PHOTO – The Pfizer logo is seen at their world headquarters in Manhattan, New York, U.S., August 1, 2016. REUTERS/Andrew Kelly/File Photo

On July 20, the US Food and Drug Administration (FDA) approved the second biosimilar version of filgrastim. Pfizer’s filgrastim biosimilar is named Nivestym™ (filgrastim-aafi).

The originator product, Amgen’s Neupogen®, has steep competition from two other products (Sandoz’s Zarxio® [filgrastim-sndz] and Teva’s Granix® (tbo-filgrastim]). Granix was approved as a follow-on biologic, before the biosimilar pathway was implemented.

The FDA granted Nivestym the following indications:

  • To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever.
  • For reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML).
  • To reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation (BMT).
  • For the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.
  • For chronic administration to reduce the incidence and duration of sequelae of severe neutropenia (e.g., fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.

Although a launch date was not announced for Pfizer’s filgrastim biosimilar, the company’s press release stated that “Nivestym is expected to be available in the US at a significant discount to the current wholesale acquisition cost (WAC) of Neupogen.”

Rather than competing aggressively for the filgrastim market, Amgen seems to be focusing its efforts on its pegfilgrastim brand, a longer-lasting version. Specifically, it is seeking to move its utilization to the Onpro formulation of Neulasta®. The first biosimilar to pegfilgrastim was approved in June (Mylan and Biocon’s Fulphila™).

Plans Use Step Therapy to Encourage Utilization of Remicade Over Biosimilars

Health plans and insurers are not yet turning to biosimilar infliximab as a preferred therapy, according to Gillian Woollett, DPhil, MA, of Avalere. Her new report surveyed publicly available policy about health plans across the nation. The principal finding was that step therapy was commonly used  to encourage use of the originator product.

In fact, just one health plan (representing 1% of the 172 million lives covered in this study) supported the use of either Inflectra® or Renflexis® over the reference product Remicade® through step therapy. One plan (2% of the covered lives) allowed the use of either the originator product or Inflectra as a first step.

Gillian Woollett of Avalere on step therapy and biosimilars
Gillian Woollett

Four of the 18 plans with publicly available information did not utilize step-therapy rules for any forms of infliximab. However, “10 of the 18 plans (55% of plans, 52% of covered lives) require the use of [Remicade] first, alone or in combination with another DMARD,” stated Dr. Woollett in the report. A total of 81% of the covered lives from these 18 plans were subject to step therapies limiting access to one infliximab product or the other.

On its face, this type of step policy makes a bit of sense. Step therapies are often used alone or part of prior authorization mechanisms to make sure patients try more cost-effective agents first. In rheumatoid arthritis, that may comprise use of nonbiologic drugs before proceeding to a TNF inhibitor and then to another biologic in patients with rheumatoid arthritis. However, there is no proven benefit (or even logic) to offering a biosimilar infliximab after failing Remicade, or vice versa. If there was a significant clinically relevant difference in immunogenicity, this could be an issue, but this also has not been seen in practice. It makes more sense to try another anti-TNF or perhaps even move to an interleukin inhibitor—something with a different (or slightly different) mode of action.

A policy such as this can confuse the issue for patients, whose knowledge of biosimilars seems tenuous, and even providers, some of whom have little experience prescribing them, particularly because of payers’ Remicade-first policies.

The Avalere report provides some support for how payers are arresting utilization of biosimilar infliximab in favor of the originator infliximab product.

Dr. Woollett paints a very different picture for subcutaneously administered filgrastim products. Forty-nine percent of the covered lives (five large plans) had policies favoring Zarxio®, whereas 27% of covered lives were encouraged to use Neupogen® first.  For these 18 plans, five (28% of plans, 49% of covered lives) demonstrate a preference for the biosimilar, filgrastim-sndz. Five (28% of plans, 27% of covered lives) demonstrate a preference for the reference filgrastim. Eight plans (44% of plans, 24% of covered lives) do not indicate a preference through formulary design. A further 24% were not subject to any preference.

Sandoz’s Pegfilgrastim Biosimilar Under New Review at EMA

On October 27, Sandoz announced that the European Medicines Agency has accepted its re-application for review of its biosimilar version of Neulasta® as supportive treatment in patients receiving cytotoxic chemotherapy.

PrintSandoz’s attempt to bring its biosimilar pegfilgrastim to the market was stalled in the US in Q2 2016, when the FDA issued a complete response letter. It had withdrawn its application to the European Medicines Agency in January 2017. However, the new application seems to be bolstered by additional data, according to reports.

Sandoz is expecting to reapply to the FDA in 2019, according to its website.

As noted too often in this space, the journey to approval for a pegfilgrastim biosimilar has been marked by failure and setbacks. However, as shown in the Figure from the MarketRealist, revenues for Neulasta are considerably larger than that for its nonpegylated progenitor, Neulasta (filgrastim). This is a powerful impetus for potential biosimilar manufacturers to succeed. At close to $5 billion in annual revenues, there is little reason to think that a biosimilar pegfilgrastim will not be approved eventually.

Market Realist.png

Source: The Market Realist.

In other news… AbbVie expects its Humira sales to jump to $21 billion by 2020 from $16 billion today, evidently bolstered by its successful defense of its patents against Amgen.

Evidence to Support Zarxio Use Presented at AMCP

Two posters presented at the Academy of Managed Care Pharmacy bolstered the case for moving away from the use of the originator filgrastim product Neupogen®.

In a study from Magellan Rx Management, Scottsdale, AZ, the researchers grouped both Zarxio® and Granixzarxio® together as alternatives to the originator filgrastim in the granulocyte-colony-stimulating factor (G-CSF) category as supportive oncological care. They studied the effect of a step edit, requiring the use of either Zarxio or Granix first, and its effect on utilization trends and cost savings among 2.7 million covered lives.

The step edit was implemented in October 2016 and the results for the fourth quarter of 2016 were compared with utilization and cost data from the first three quarters of that year. In terms of utilization, the marketshare of Neupogen dropped from 18% in early 2016 to only 2% by the third quarter of 2017. As expected, the drop in utilization occurred just after the step edit was introduced a year ago. The combined marketshare of Granix and Zarxio jumped from 9% to 21% over that time, but the dominant player in the G-CSF space, Neulasta® (pegfilgrastim), maintained utilization, rising from 73% to 77%. Over the one-year period since the step edit was introduced, the authors calculated a cost savings of $662,278; the cost savings in the quarter after the policy change was $106,980, or approximately 8% of the total spent for the G-CSF category.

The authors noted that the cost savings were calculated using wholesale acquisition cost (WAC) not average sales price (ASP), and manufacturer discounts or rebates were not considered in the estimates.

The second poster, sponsored by Sandoz, was a retrospective claims analysis of the incidence of febrile neutropenia in patients receiving chemotherapy who were treated with Zarxio or Neupogen. This study covered 13 months of claims (from Optum) from 162 patients taking Zarxio compared with 3,297 receiving Neupogen. The groups did not differ significantly in terms of demographics, insurance, or tumor type.

The researchers found that the incidence of neutropenia (in addition to fever and/or infection) was nonsignificantly greater in those receiving the biosimilar compared with the reference product (2.3% vs. 1.7%, respectively).

Rituximab and Filgrastim Biosimilars Being Reviewed by FDA

Today, Sandoz announced the acceptance by the Food and Drug Administration of its application for a biosimilar rituximab. This biosimilar was approved by the European Medicines Agency in June 2017.

The manufacturer included a phase 3 trial of the agent to treat follicular lymphoma, one of two Hodgkin’s lymphomas for which the originator product is approved to treat. Its pharmacokinetic and pharmacodynamics studies were conducted in patients with rheumatoid arthritis, another major indication.

fdaThis marks the second rituximab biosimilar to be submitted to the FDA; Celltrion’s application for its Truxima™ brand was submitted in June. Sandoz’s Zarxio® has been marketed since 2015, and Erelzi® (etanercept-szzs) was approved in August 2016 but is not yet marketed.

In addition, Adello Biologic announced that their 351(k) application for a new biosimilar filgrastim was sent to FDA on September 11. No FDA decision date was announced, but assuming a smooth ride through the process, a decision may be expected around the third quarter of 2018.

This is Adello’s first biosimilar brought to FDA application. According to its website, Adello is currently in clinical trials with a pegfilgrastim biosimilar, with preclinical development on a version of adalimumab.

Coverage Uptake: Zarxio® Covered by 94% of Employer-Sponsored Plans

An analysis released by Avalere on July 11 showed that coverage of biosimilar filgrastim is the rule, not the exception, by employer-sponsored plans.

Avalere surveyed medical or pharmacy executives from 45 health plans and insurers, representing 183 million lives, about coverage for their commercial products. They found that 94% had placed Zarxio (filgrastim-sndz) on formulary. Forty-two percent of the plans responding to this online survey indicated that Zarxio was a preferred brand. This is on par with the competitors (Granix®, Neupogen®, and Neulasta®), one of which is preferred for 45% of the plans surveyed.

In the report, titled “Policy 360: Biosimilars—US Payer Perspective,” Avalere found that coverage in these same employer-sponsored plans for Inflectra® (infliximab-dyyb) was trailing, with 42% covering the biosimilar but only 7% listing it as preferred on their 2017 formularies. Pfizer has only been available for 7 months, so these numbers are expected to rise over time.

Unsurprisingly, health plans ranked relative cost as the number 1 factor in coverage decision making for biosimilars (95%), followed by efficacy (80%), safety (73%), and existing contracts (53%).

In other news: Mylan and its partner Biocon hit a stumbling block to approval of its trastuzumab biosimilar in Europe (application filed in 2016). French inspectors cited Biocon’s manufacturing facility in Bangalore, India, for a number of violations that need to be corrected before the partners can receive authorization to market from the Europeans Medicines Agency. An inspection of the facility, conducted in March, also revealed problems that could affect the production of Mylan and Biocon’s pegfilgrastim biosimilar. The companies had filed for Food and Drug Administration approval of both products, with trastuzumab being reviewed by the Oncology Advisory Committee on July 13. It is not known whether a potential US-licensed version of the drug will be produced at the same Bangalore plant.

Biosimilar News Bytes to Wrap up 2016

A Shrug of the Shoulders on Savings Payers are becoming increasingly pessimistic that they will be seeing substantial savings with biosimilar products in the near term. The results of several market research projects we’ve conducted point to payers’ assumption that the 15% discounts seen today with Inflectra® and Zarxio® introductions will be mimicked by manufacturers of new biosimilar and follow-on products (assuming they cross the FDA approval and patent litigation barrier). Risking these introductions, the payers assume that makers of the originator products will simply match the offer, enabling the payer to take the path of least resistance and stick with the originator. But this means that the predicted tens of billions in savings to be gained by the biosimilar introductions will remain a mirage, at least until several competitors enter the market for the same originator.

Trastuzumab Biosimilar Data Published The Mylan and Momenta partnership announced that the phase 3 trial data on its biosimilar version of trastuzumab, previously announced at major medical meetings this year, has been published in the Journal of the American Medical Association. The HERITAGE study confirmed the safety and efficacy of MYL-1401O.

Final Guidance Released by FDA The Food and Drug Administration finalized and released its guidance “Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product,” which describes how biosimilar products may be listed as “not similar,” “similar,” “highly similar,” and “highly similar with fingerprint-like similarity.” The latter, it is assumed, will be used as a basis for considering interchangeability designations. The guidance is a belated tool to assist drug makers with proving pharmacologically the similarity of their molecule to the originator.

Are 2 Biosimilars to the Same Originator Product Biosimilar to Each Other?

In Europe, several manufacturers are marketing approved biosimilars to the same originator product. In fact, 7 manufacturers compete for the biosimilar filgrastim market, 5 biosimilar versions of epoetin are sold, and 3 biosimilars of infliximab seek marketshare from Remicade®. In the US, this situation is not a reality yet. It will be one day, however, and it raises a couple of important questions.

We know that the biosimilars are not exactly the same structurally as the originator products, but how similar may they be to each other? In other words, at some point, payers will prefer one biosimilar version of filgrastim over another one, as some do currently with Zarxio® versus Neupogen®. We can assume that with 3 filgrastim biosimilars sold in the US, payers will seek to leverage 1 against the others and make it their preferred or only available form of filgrastim available. However, is another manufacturer’s version of filgrastim biosimilar to Zarxio? We can also assume that the new manufacturer’s product has received US Food and Drug Administration approval through testing for comparability only with the originator product—not against Zarxio. How about compared with Teva’s product tbo-filgrastim (a follow-on biologic, not a biosimilar according to the regulatory and statutory rules)?

What does this mean for switching products, much less interchangeability? Is one biosimilar interchangeable with another? Based on what we know about the FDA, the answer is likely no, as the agency seems to be having difficulty devising interchangeability guidelines for a biosimilar and its originator product.

Why is this important? Consider the patient with Crohn’s disease in 2019 who changes health plans. The patient was receiving biosimilar A, and the new plan covers only biosimilar B. Maybe he or she needs to enroll in a new plan in 2020, and the reverse is true. Regardless of whether we like it, that patient may be unintentionally providing real-world evidence of interchangeability.

Prevention of Febrile Neutropenia Even More Important in Elderly Cancer Patients

A primary indication for the granulocyte colony-stimulating factors (GCSFs) like filgrastim and pegfilgrastim is to prevent the incidence of cancer chemotherapy–induced febrile neutropenia, a serious complication of toxic oncologic treatments. Elderly patients are at higher risk for febrile neutropenia.

One less-frequently discussed issue associated with the use of GCSF treatment is the possibility for under- and over-prophylaxis. Apparently, under current protocols, it is not so simple to ensure that a patient with cancer who is at risk for neutropenia is receiving the right dose or duration of GCSF therapy, or initiated at the appropriate time. In a previous European study zarxio(https://www.ncbi.nlm.nih.gov/pubmed/26306517), 17% of patients were found to be undertreated with filgrastim and 26% of patients were overtreated, meaning just 57% of patients taking this therapy were receiving appropriate prophylaxis. A study evaluating European experience with Sandoz’s and Hexal AG’s biosimilar filgrastim (marketed today as Zarzio® in the EU, Zarxio® in the US) focused specifically on whether elderly patients with cancer were given correct prophylaxis.

The MONITOR-GCSF study involved patients from 12 European countries. This most recent analysis (http://dx.doi.org/10.1016/j.jgo.2016.09.006) stratified patients by age (< 65 yr and ≥ 65 yr). A total of 598 patients (41%) were in the older age group. Patients were considered eligible if they had mid- to late-stage breast, ovarian, bladder, or lung cancer; prostate cancer; diffuse large B-cell lymphoma, or multiple myeloma. The researchers assessed when patients began filgrastim therapy (covering up to 6 cycles of chemotherapy), its appropriateness based on EORTC protocols, and its relationship to the primary outcomes: grade 4 chemotherapy-induced febrile neutropenia or any febrile neutropenia episodes, and the need for hospitalization as a result.

In the evaluable patient population, 95% were prescribed the standard dose of chemotherapy appropriate to their tumor diagnosis. However, the study did not report the percentage of patients who completed the intended number of cycles. Similar proportions of patients were receiving primary or secondary prophylaxis in each group (e.g., primary prophylaxis, 70% in the older group, 74% in the younger group). The researchers determined that elderly patients were more likely to be under-prophylacted (26% of the elderly patients, 11% of younger patients) and less likely to be over-prophylacted (11% vs. 37%, respectively). Sixty-three percent and 52%, respectively, were considered to have received correct prophylaxis. The most common independent predictors of poor neutropenia outcomes were the use of antibiotic prophylaxis, lower performance status scores, and the occurrence of chemotherapy-induced neutropenia (any grade) in a previous cycle of therapy.

The researchers acknowledge that age 65 may not be the best definition of “elderly patients” in the current environment, but they did not assess subgroups of older patients (i.e., > 70 or > 75 yr). Interestingly, one of the determinants of positive outcomes was the incidence of over-prophylaxis. The authors suggest that prospective randomized studies should be undertaken to consider the implications of this finding. For elderly patients specifically, the presence of cardiovascular or liver disease, secondary prophylaxis, and under-prophylaxis were linked with poor neutropenia outcomes.