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.

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.

Is the Biologic Me-too Era Different?

We may have crossed a threshold in biopharmaceutical manufacturing some time ago and not even realized it. This paradigm mimics in several ways the decades of introductions and marketing of conventional (nonspecialty) drugs. Unfortunately, it could mean additional barriers to success for biosimilar manufacturers.

Payers (maybe less so the drug makers) recognize that the launch of brands that follow the first-in-its-class may not offer additional value, especially if priced at a premium. Often, these new agents were promoted as having a longer half-life, having fewer side effects, or simply were more effective than the class prototype. And in many cases, this proved correct. In other instances, the new drug was simply a different molecule with similar efficacy and safety. Payers referred to them as “me-too” agents, because they didn’t seem to offer advantages over the prototype. The phrase “me-too” connotes “no additional value.” In these cases, differentiating their value can be quite a challenge for the manufacturer, clinician, and payer alike. It is easy to see the economic and marketing importance of being the first to launch.Biosimilar concept art.5-15-2017

In migraine, for example, Imitrex® (sumatriptan) was approved in 1992, the first drug of the triptan class, to abort early-stage migraine attacks. Many other triptan agents followed, including Amerge (naratriptan), Axert (almotriptan), Frova (frovatriptan), Maxalt (rizatriptan), Relpax (eletriptan), and Zomig (zolmitriptan). The manufacturers of these other products did not intend necessarily to launch products that were third or fourth to the market. Imitrex had the advantage of being first approved as well as being available both in injectable and oral forms.

The development of agents like this may well occur concurrently; it is sometimes more a matter of timing and luck as to which one completes the clinical trials first and obtains FDA approval (without any hiccups). One may be just completing phase 1 as the other enters phase 3. On the other hand, some are developed well after the first launch. When these me-too agents hit the market, it is up to their manufacturers to figure out how to obtain preferred positioning. Other well-known examples include the statins for hypercholesterolemia, DPP-4s for diabetes, angiotensin-receptor blockers for hypertension, oral contraceptives, respiratory inhalants for asthma, and well, the list can go on ad nauseam.

With a great number of biologic agents on the market today, are several considered me-too agents? It is much more difficult to stick this label on a group of biologics because of several factors. For instance, their approved indications can be quite broad (e.g., anti-TNFs) and some members of the individual classes can only be received via infusion versus self-injection. The other consideration is that their effectiveness for all approved indications may not quite be the same (e.g., Enbrel® vs. Humira® for rheumatoid arthritis [RA] or for psoriasis). The frequency of administration can vary as well. Their mechanism of action may also be somewhat different (e.g., interleukin-17 vs. interleukin 12/23 inhibitors vs. interleukin 23 inhibitors).

Yet the number of members in the anti-TNF category and the burgeoning interleukin category does raise the question as to whether the clinical value of each biologic is substantially different. For some indications, like RA, the answer is that they are more similar than different. Remicade® was the first anti-TNF inhibitor approved, but the initial approval was for Crohn’s disease and only as an infusion (the RA indication came later). Enbrel, the first member of the class to be approved for RA, was launched as a self-injectable. Humira was approved at the end of 2002 for RA, and its other indications followed later.

Unlike other conventional me-too drug categories, the biologics have produced multiple blockbusters. Perhaps being early to market was more important than being first to launch. The anti-TNFs introduced later, like Cimzia® and Simponi®, have largely battled for remaining marketshare.

In the biologic category, the biosimilars Inflectra®, AmjevitaTM, ErelziTM, and RenflexisTM (when the latter 3 are launched)‑may even be considered me-too brands without substantial discounts and without interchangeable designations. Many payers already consider the approved biosimilars as new brands, because they are not inexpensive or interchangeable. If the me-too label sticks, their struggle up the value mountain could be steep indeed.

ICER: Current Biologics for Rheumatoid Arthritis Well off the Mark for Cost Effectiveness

The Institute for Clinical Effectiveness and Research (ICER) released its report on biologic treatment of rheumatoid arthritis on April 10th, and it wasn’t pretty. The group, which assesses the value of therapies based on effectiveness and cost, found that none of the available immunomodulators approach the cost-effectiveness threshold of $100,000 to $150,000 per quality-adjusted life-year (QALY).

Of course, the price of this drug class plays a large role in ICER’s calculation, utilizing a discounted wholesale acquisition cost (WAC) that reflected rebates and discounts. The base WAC was the price obtained from the February 2017 Red Book. Although this figure may not be accurate for individual payers, the conclusion of the study was that Humira® would have to be sold at roughly half its quoted $40,415 annual cost to reach an acceptable level of cost effectiveness. At the current net price used and when used as monotherapy, its cost per QALY was $232,644. AbbVie’s Humira adalimumab originator took the brunt of the heat in the study, because it was considered the most costly anti-TNF inhibitor. However, even Janssen’s Remicade® (infliximab), the least expensive anti-TNF inhibitor cited (at $28,906 per year), was not deemed cost effective, at $202,824 per QALY.

Of any biologic used to treat rheumatoid arthritis, Genentech’s interleukin-6 inhibitor Actemra® (tocilizumab, subcutaneous injection) was deemed to have the best monotherapy cost per QALY, at $168,660.

One issue for the immunomodulator class is that a major component of the calculation‑the number of QALYs over the time horizon (the lifetime of the patient‑was closely bunched. They ranged from 12.95 for adalimumab to 13.35 for tocilizumab IV, compared with 10.75 for conventional DMARDs. These figures were slightly lower when the immunomodulators were added onto conventional DMARD therapy (although drug costs were somewhat lower).

Although the calculation did not consider the real issues of dose escalation for certain medications, a sensitivity analysis showed that virtually under all scenarios, the biologic drugs failed to meet the ICER threshold for cost effectiveness. However, it should be pointed out that ICER’s evidence of efficacy was based on patients achieving a fairly low standard: 20% improvement in American College of Rheumatology scores. Therefore, the actual cost to treat patients to a higher standard of improvement should be greater.

The evaluation was done by the New England Comparative Effectiveness Public Advisory Council, an ICER group. According to ICER’s value-based benchmark prices for these targeted immunotherapies, WAC discounts must be slashed from 29% (for tocilizumab subcutaneous) to 55% (for adalimumab) to reach the $150,000 cost per QALY level. In other words, for a biosimilar of Humira to be deemed cost effective by today’s reckoning, it would have to require a WAC discount (or net cost through rebating) of 55% below that of February’s Humira pricing.

This magnitude of reduction in net costs would effectively bend the specialty cost curve in the US. However, without several biosimilar competitors for the same drug, this is unlikely for the monoclonal antibodies. Cost reductions of 50% or more have been seen in certain European countries for first-generation biosimilars, but this would represent an alarming “race to the bottom” for US manufacturers and might dissuade future biosimilar development.