Jackie Syrop

Traditional pharmacologic approaches to the treatment of rheumatoid arthritis (RA) have relied on combinations of nonsteroidal anti-inflammatory drugs, analgesics, glucocorticoids such as prednisone), and disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, and are still widely used in RA patients. DMARDs not only control RA symptoms, they may also slow progression of the disease, lessen the severity of existing joint damage, and induce remission.

A better understanding of the inflammatory disease processes behind RA and other chronic health conditions led to the discovery of a class of DMARDs known as biologics, which have changed the lives of many RA patients, especially patients whose arthritis does not respond to traditional DMARDs. Biologics are genetically engineered drugs derived from human genes that target specific inflammatory cells, cellular interactions, and cytokines that mediate RA-related tissue damage. Biologics have been shown to help slow progression of RA where other treatments have failed.

Similar to the traditional small-molecule drugs, biologics can be associated with side effects. A common side effect of biologics is irritation and redness at the injection or infusion site. In addition, because biologics suppress components of the immune system that drive the inflammatory process behind RA, these medications come with risks associated with modulating the immune system. For example, patients taking biologics have increased risk of infections, and biologics can cause the reactivation of latent tuberculosis (TB); so TB skin tests are needed prior to beginning biologic therapy. There are other precautions that patients taking RA biologics should engage in, for example, not receiving live vaccines and stopping the biologic medication if they have a fever or infection of any kind. Pregnant women should take biologics only if deemed clearly necessary because the effects on a developing fetus are unknown. Biologics require regular monitoring and follow up by physicians, along with related lab work, tests, and examinations.

Biologics are also more expensive than traditional RA treatments. While most health insurance companies cover biologic therapies for RA, some may require patients try less costly treatments first. Additionally, drug makers offer payment assistance for biologic RA treatments for patients who have no insurance or inadequate coverage.

When one biologic doesn’t successfully control RA, or side effects become an issue, physicians may prescribe a different biologic from the same class. Biologics can be the sole medication used or be part of a combination approach using biologics and non-biologic medications (dual-DMARD therapy). Biologics are administered by infusion or injection (with the exception of tofacitinib [Xeljanz], which is taken orally).

The first biologic approved for treatment of RA was etanercept (Enbrel, the first tumor necrosis factor [TNF]-antagonist), which was approved by the FDA in 1998. Other biologics have since been approved and marketed for RA:

Adalimumab-atto (Amjevita, a biosimilar* to Humira)

Interleukin [IL]-1 inhibitor anakinra (Kineret)

T-cell co-stimulation blocker abatacept (Orencia)

B-cell-depleting agent rituximab (Rituxan; Mabthera)

Janus kinase inhibitor tofacitinib (Xeljanz).

Curtis JR, Singh JA. Use of biologics in rheumatoid arthritis: current and emerging paradigms of care. 

. 2011;33(6):679-707. doi: 10.1016/j.clinthera.2011.05.044.

Biologics for rheumatoid arthritis treatment. 

http://www.webmd.com/rheumatoid-arthritis/guide/biologics#1

Articles

Treating Rheumatoid Arthritis With Biologic Medications: A Quick Take

 on biosimilar medicines issued by the European Commission (EC), “What I Need to Know About Biosimilar Medicines: Information for Patients,” highlights the very different ways the EC and the FDA approach educating the public about biosimilar medicines.

The EC educational guide emphasizes that it has been created by and for patients, with input from the European Medicines Agency (EMA) and EC, and seeks to reassure the public about biosimilar medicines by stressing the EMA’s careful regulation of this developing market. In the United States, by contrast, it is 

 that nearly 70% of consumers don’t know what a biosimilar is, and there also appears to be a significant amount of confusion among US experts about biosimilars. Yet, the FDA is not adequately reaching out to US patients with the kind of guidance its European counterpart is.

While it is true that the EU did get a head start in the biosimilar category—its first biosimilar was approved in 2006 and there are now some 2 dozen biosimilars approved for use compared with the FDA’s 4 biosimilar approvals&mdash;the FDA needs to invest more in educating patients and their physicians on biosimilars. One of the offerings of the FDA is a continuing education course for healthcare providers, but more needs to be done as we will soon see a steady stream of biosimilars entering the market. Although the FDA has made strides in the last year with setting scientific standards for biosimilars and is additionally working with the pharmaceutical industry to develop a regulatory framework, efforts also need to be directed to help shape consumer attitudes toward adoption of this new class of drugs.

The EC guide exploits a user-friendly Q-and-A format and simple examples to illustrate complicated ideas. The guide starts with the history of biosimilars and explains in easy-to-understand language what patients need to know about the biological drugs that biosimilars are based on. It discusses what it means to be “highly similar” to an existing biological medicine that has already been approved. Furthermore, the guide specifies why biosimilars are not the same as generic drugs, and explains why biosimilars have been developed and how they are approved. Above all, the guide reassures patients that “biosimilars are not simply ‘cheap copies’ of reference medicines” and are manufactured following strict quality requirements using state-of-the-art methods subject to strict inspections—similar to other drug manufacturers. Although the EMA evaluates biosimilars using a different set of data compared with other biological medicines, the same high standards of quality, safety, and efficacy apply.  

Most important, the EC patient guide stresses individuals’ empowerment, advocating that patients on biosimilars should work closely with their physicians and pharmacists and that they report any adverse events experienced with these drugs.

The FDA vs the EC: Two Very Different Ways to Address Biosimilar Education

Prescribing physicians play a large role in the adoption of biosimilars for the treatment of patients with rheumatic diseases, so it is important to understand physicians’ perceptions of which patients are suitable for treatment with biosimilars in clinical practice.

 in the European Union suggests that physicians were more likely to consider rheumatoid arthritis (RA) patients suitable for biosimilar infliximab when,

The patients had been in care for a relatively shorter period

Were more involved in their treatment decisions.

The investigators performed a medical chart review of RA patients of physicians (primarily rheumatologists) in hospitals and private practices in the United Kingdom, France, Germany, Italy, and Spain to collect de-identified data on patient diagnoses, treatment patterns, dynamics, and patient symptomology and disease status. Physicians identified whether patients were suitable for biosimilar infliximab, and if they were, rated how likely they would be to prescribe the product to them when it became available. [Biosimilar infliximab (Inflectra/Remsima) was approved by the EMA in September 2013.] The analysis compared patients who were considered suitable for biosimilar infliximab with those who were not considered suitable per physician judgment, excluding those who previously failed infliximab.

Patients currently on (or discontinued within the past 3 months) a biologic drug and who were visiting each center during the screening period were selected for medical chart review. A total of 1204 patients were included in the analysis, 425 of whom were identified by the physicians as being suitable for biosimilar infliximab. Fifty-five percent of these were rated greater than or equal to 5 and 26% at 4, on their likelihood of being prescribed the infliximab biosimilar (7, extremely likely; 1, not at all likely). The physicians were screened for practice duration and patient volume, and were recruited to be geographically representative.

The study also concluded that physicians were not “readily prepared to prescribe the biosimilar to all infliximab biosimilar—suitable RA patients,” and the authors recommend studying this issue further to understand the drivers behind physician perception of which RA patients are suitable for treatment with biosimilar infliximab.

Among physicians, concerns about switching patients from Remicade to biosimilar infliximab remain because the approved infliximab biosimilar has not been designated as interchangeable by the FDA. Some studies have suggested that biosimilar switching is not suitable for all patients. For example, a 2016 Spanish study 

 at the 2016 European League Against Rheumatism Annual Congress suggested antibody-positive patients being treated with Remicade should not be switched to treatment with the biosimilar infliximab because the antibodies will interact with the new drug and potentially lead to a loss of response. Lead author Daniel Nagore, MD, said, “While most studies show there are no significant differences in clinical response between a biosimilar and the original product, some physicians and patient advocacy groups have expressed concern about how interchangeable they really are, and whether it is safe to switch from the brand name version to the biosimilar.”

What Influences Physicians' Decisions About Patient Suitability for Biosimilar Infliximab?

On January 30, 2017, a lawsuit was filed in federal court in Massachusetts against 3 insulin makers—Eli Lilly, Novo Nordisk, and Sanofi&mdash;

 that the companies exponentially raised consumer insulin prices in an organized scheme to drive up prices at the expense of patients who need insulin to live.

The lawsuit, brought by the firm Hagens Berman Sobol Shapiro LLP on behalf of 11 diabetes patients, claims that in the last 5 years alone, Lilly, Novo Nordisk, and Sanofi raised the sticker, or “benchmark,” prices on their insulins by more than 150%. The list prices of insulin 

, often in concert, despite competition between the 3 companies. Humalog, launched 2 decades ago at a price of $21 per vial, has increased to $255 per vial.

The suit charges that the 3 drug companies are in violation of the Racketeer Influenced and Corrupt Organizations Act (RICO) and consumer protection laws in many states because they exploited the drug-pricing system to ensure higher profits for themselves and other players while those living with diabetes are crippled by high insulin costs, sometimes as much as $900 per month. According to Hagens Berman, insulin, a once-affordable drug, is now out of reach for many patients because of “a behind- the-scenes quid pro quo arrangement.” The complaint states that increased list prices of insulin are the result of a “scheme and enterprise” among each defendant and several pharmacy benefit managers (PBMs) in which the drug companies set two different prices for their insulin treatments: a publicly reported list price and a lower, real price, they offer to certain PBMs.

 and take issue with the charges. Lilly stated that it conducts business in compliance with all laws and adheres to the highest ethical standards. Sanofi said the allegations have no merit, and the company will defend against the claims. Novo Nordisk said the company has a longstanding commitment to patients’ access to their medicines and is prepared to vigorously defend itself.

 it would offer a 40% discount on the list price of Humalog for patients forced to pay full price, and Novo Nordisk pledged to limit price increases in the American market to less than 10%.

 Hagens Berman’s statement provides detail of how the firm says the pricing scheme has worked: the PBMs serve as middlemen between health insurers and drug makers, negotiating medicine prices with drug companies on behalf of health insurers. PBMs also design drug formularies for their health insurer clients, ranking drugs based on efficacy and cost, the suit states, which “allows health insurers to funnel patients towards one brand of drug over others.” The complaint alleges that because the insulin prices of the 3 insulin manufacturers are largely interchangeable, the drug companies compete for preferential treatment on the PBM’s formularies, offering the PBMs rebates off their list prices. The PBMs keep a percentage of the difference between the reported list prices and the undisclosed actual price they are able to secure, a difference known as the “spread,” the firm alleges. The larger the spread, the higher the PBM’s profits; the drug maker with the largest spread between list and real price is more likely to secure a PBM’s preferred formulary position, and the business of the PBM’s clients, the suit states.  

 the harm this alleged scheme has caused, with patients resorting to underdosing insulin, using expired insulin, starving themselves to lower blood sugar, and even slipping into life-threatening diabetic ketoacidosis to get insulin from emergency rooms. The law firm’s own investigation shows the 3 companies increased the publicly reported, list prices of Lantus, Levemir, Novolog, and Humalog by more than 150% in the last 5 years while keeping the prices they offer to PBMs constant or even lowering them. The lawsuit charges that rather than competing with each other to offer the lower real price to insurers, the drug companies aim to offer the best price to the PBMs and retaining high list prices. The high list prices result in patients, even those who are insured, facing skyrocketing out-of-pocket (OOP) costs, because of increasingly high deductibles and coinsurance.

The lawsuit says uninsured patients and patients enrolled in high-deductible health plans, plans with high coinsurance rates, and Medicare Part D plans have been seriously injured by Sanofi, Novo Nordisk, and Lilly’s benchmark price hikes.

The suit also seeks certification as a class action lawsuit for all patients with type 1 or type 2 diabetes who had to pay high OOP costs for Lantus, Levemir, Novolog, or Humalog in the past 4 years because they are uninsured, have a high-deductible plan, or have a plan with high coinsurance rates, to reclaim economic losses in an amount to be determined at trial, and to put into place an injunction halting this behavior.

Three Insulin Makers Face Class-Action Lawsuit on Price Fixing

Novartis’s generic subsidiary, Sandoz, has delayed its planned aBLA filing with the FDA for its Humira biosimilar of AbbVie’s adalimumab. Sandoz had intended to complete the filing in the last quarter of 2016, but has pushed it to the first half of 2017. Novartis Chief Medical Officer Vasant Narasimhan stated that the delay was necessary based on discussions with the FDA and ongoing capacity upgrades being made at Sandoz’s production site, along with considerations about the timing of required regulatory inspections.

 there are no issues with the clinical data associated with the biosimilar candidate adalimumab; rather, the delay was undertaken to time inspections appropriately for when the company’s facility will be ready for those inspection. 

The size and location of the manufacturing upgrades is not clear. Sandoz’s biosimilars manufacturing is managed by Novartis Biologics Technical Development and Manufacturing, and three sites have been used for developing and manufacturing Sandoz biosimilars. Two are in Austria and one is in Slovenia.

To date, the FDA has approved only one adalimumab biosimilar—Amgen’s Amjevita&mdash;but that launch is unlikely to occur before 2018 because of AbbVie’s patent lawsuit against Amgen. Humira’s manufacturer, AbbVie, has 

 of Humira eight times in the past few years, an increase of more than 70% (to approximately $49,000 annually before discounts. According to one analysis, by the end of 2015, a year’s treatment with Humira averaged $27,665 after discounts, up 49% from 3 years earlier—a monthly cost equaling more than many people’s mortgages.

Although the cost of a Humira biosimilar has not yet been determined, based on the costs of other approved biosimilars, the discount can be expected to be 15% of the cost of the reference drug, bringing the cost of adalimumab to about what Humira cost before the price hikes of the last several years took place.  

FDA Filing of Sandoz's Humira Biosimilar Delayed 

The field of biosimilars continues to grow as more companies invest in biosimilars, and as the FDA continues to clarify the regulatory processes that must be followed to have products approved and marketed in the United States. Biosimilars are expected to 

generate revenue in the $25-35 billion range by 2020

Many companies have biosimilars in their pipelines, but Novartis is a clear leader with an advanced biosimilar pipeline and products already approved and marketed worldwide, part of an effort to compensate for the loss of revenue due to the expiration of patents on blockbuster drugs and providing cost-effective therapies for rare and life-threatening diseases, 

. Novartis’s biosimilars are marketed by the company’s Sandoz generic division. It was the first manufacturer in the world to have a biosimilar approved and commercialized, and has approved biosimilars in over 75 countries and 250 million patient-exposure days worldwide. 

Sandoz/Novartis has received FDA approval for two of the four currently approved biosimilars: Zarxio, a biosimilar of Amgen’s Neopogen (filgrastim-sndz)--the first biosimilar to be FDA-approved--and Erelzi, a biosimilar of Amgen’s Enbrel (etanercept-szzs). However, because of Amgen’s continuing patent litigation against Erelzi, Sandoz recently announced that it will not be marketing Erelzi before 2018 at the earliest.

Novartis has plans to launch four additional 

by 2020: biosimilars of Humira (adalimumab), Neulasta (pegfilgrastim), Remicade (infliximab), and 

. Worldwide sales of these drugs and Enbrel was over $44 billion in 2015; if Sandoz gains even a small piece of that revenue, biosimilars would become an important part of the Novartis portfolio. The company’s biosimilar pipeline includes oncology and immunology molecules and hematology drugs. In 2015, 

earned $772 million (total revenue for the company’s biopharmaceutical unit was $9.2 billion). 

Novartis’ first US-approved biosimilar Zarxio was introduced in Europe in 2009. In 2013 the biosimilar became the first to pass a reference product in market share, and is prescribed to more than 100,000 patients in more than 40 countries worldwide.

Novartis: The Company at the Forefront of Biosimilar Development

Amgen’s biosimilar adalimumab (ABP 501), 

, has received a positive opinion regarding marketing from the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP).

The active ingredient of ABP 501 is an anti-tumor necrosis factor (TNF)-alpha monoclonal antibody that has the same amino acid sequence as adalimumab. The decision is the first time an adalimumab biosimilar has been recommended for approval in the European Union (EU). ABP 501, branded as Amjevita (adalimumab-atto) in the United States, was approved by the FDA in September 2016. However, Amjevita has not yet been marketed in the US because AbbVie sued Amgen for patent infringement and the 

ABP 501 was recommended for approval for the treatment of certain inflammatory diseases in adults, including moderate-to-severe rheumatoid arthritis (RA), psoriatic arthritis, severe ankylosing spondylitis (AS), severe axial spondyloarthritis without radiographic evidence of AS, moderate-to-severe plaque psoriasis, moderate-to-severe hidradenitis suppurativa, noninfectious intermediate, posterior and panuveitis, moderate-to-severe Crohn’s disease, and moderate-to-severe ulcerative colitis. The CHMP also recommended approval for the treatment of certain pediatric inflammatory diseases, including moderate-to-severe Crohn’s disease (ages 6 and older), severe chronic plaque psoriasis (ages 4 and older), enthesitis-related arthritis (ages 6 and older) and polyarticular juvenile idiopathic arthritis (ages 2 and older).

The CHMP’s positive opinion will be reviewed by the European Commission, which is authorized to approve medicines for the EU. The process typically takes approximately 60 days. If approved, ABP 501 will receive a centralized marketing authorization that is valid for the 28 countries in the EU. Norway, Iceland, and Liechtenstein, members of the European Economic Area, will make corresponding decisions on the basis of the EC’s decision.

EMA Committee Recommends Approval of Amgen's Adalimumab Biosimilar 

The launch of Erelzi, Novartis’s FDA-approved etanercept (Enbrel) biosimilar, will be 

 as a patent fight with Amgen continues in US federal court, according to Richard Francis, global head of Novartis’s Sandoz generic division. Amgen is arguing in US federal court that its biologic Enbrel has patent protection until 2029. The lawsuit won’t reach a conclusion until 2018, Francis stated, adding that while the legal situation is frustrating he believes the company is “carving the landscape out as we go.” 

Erelzi is the first biosimilar of etanercept to be approved by the FDA. It was approved on August 30, 2016, with an indication for the same indications as the reference drug Enbrel: rheumatoid arthritis, plaque psoriasis, ankylosing spondylitis, psoriatic arthritis, and polyarticular juvenile idiopathic arthritis. Amgen sued Novartis over patent issues before the FDA had even approved Erelzi.

Novartis and Amgen are also engaged in a separate legal case concerning Novartis’s Zarxio, a biosimilar of Amgen’s Neupogen (filgrastim), which was approved by the FDA in September 2015. This dispute revolves around whether biosimilar sponsors have to provide 180 days’ notice to the reference product’s company after FDA approval to begin marketing the biosimilar. Novartis is arguing that by making the biosimilar’s sponsor wait until FDA approval to notify the originator company of a launch, the court was creating “an exclusivity windfall” for the originator company that Congress did not intend in the Biologics Price Competition and Innovation Act. Novartis believes the biosimilar sponsor should be able to provide notice earlier in development and be able to launch the biosimilar 

. The Supreme Court recently agreed to consider that case. 

Novartis's Enbrel Biosimilar Marketing Delayed

Biosimilars may not yet be major players in the United States, but as more of these medications gain approval and begin to reach the market they are drawing attention for their potentially revolutionary effect on the development and commercialization of biologics. It’s impossible to predict the future, but analysts can look to the European Union (EU), where 22 biosimilars have already been approved and marketed for 10 years. Biosimilar competition in Europe has been credited with driving down prices of epoetins, human growth hormone, anti-Tumor Necrosis Factor (TNF) agents, and granulocyte colony stimulating factors (G-CSF), and increasing patient access to these drugs where it had previously been low.

In the United States, biosimilars are not going to be priced at the deep discounts seen with generics of small molecule medications, which can be 85% less expensive than the originator drugs. Because biosimilars are based on the large-molecule, highly complex biologics and are difficult to manufacture, biosimilars are also far more complex to develop and manufacture than small molecule generics, and thus more expensive to produce. Pfizer/Celltrion’s Inflectra biosimilar of Janssen’s Remicade (infliximab-dyyb) is priced at only a 15% discount to Remicade. But experts note that even small discounts and reductions can mean big savings. According to a 2016 report by IMS Institute for Healthcare Informatics, cumulative potential savings to health systems in the EU and the US as a result of using biosimilars could exceed EUR50 billion in aggregate 

over the next 5 years and reach as much as EUR100 billion.

In the EU, competition from biosimilars reduced prices across the whole class of drugs, not just the reference product, with reductions in costs of up to 60% in some countries.

As biologics lose patent protection in the US, biosimilars are becoming more interesting to companies with experience in biologics. Concerns about the high costs of biologics has also made biosimilars more compelling to biopharma. The FDA has approved just four biosimilars to date [Sandoz’s Zarxio (biosimilar to Amgen’s Neupogen) (filgrastim-sndz); Inflectra; Amgen’s Amjevita (biosimilar to AbbVie’s Humira) (adalimumab-atto); and Sandoz’s Erelzi (biosimilar to Amgen’s Enbrel (etanercept-szzs)], with only two of them (Zarxio and Inflectra) reaching the market so far. Three of these biosimilars were approved within the last year. (Eli Lilly’s Basaglar is considered a “follow-on biologic” of Sanofi’s insulin Lantus because it was approved through a different regulatory pathway than other biosimilars and became available in December 2016.)

The FDA is approving more biologics than ever, 11 to 12 per year in 2014 and 2015, representing 27% of all new approvals in 2015—up from 14% in 2004. IMS predicts that biologics will account for up to 28% by value of the global healthcare market by 2020, and biosimilar medicines therefore have an increasingly important role to play by competing with original biologics across a range of therapy areas. There are several companies focusing on biosimilars with many products in their pipelines, including biosimilars for Humira, Remicade, and Enbrel.

Yet obstacles to biosimilars in the United States remain an impediment to growth. Physicians  are not familiar with biosimilars and there is not yet the necessary degree of acceptance of biosimilars among providers and patients. Finally, many biosimilars are locked in legal battles with reference product manufacturers that could keep some biosimilars off the market for years to come.

Are Biosimilars Potential Market Disruptors?

The European Union’s European Medicines Agency (EMA) is launching a tailored scientific advice pilot project in February 2017 to support step-by-step development of 

The procedure will advise biosimilar developers on the studies they should conduct, based on a review of the quality, analytical, and functional data they already have available. Standard advice does not include the assessment of existing data, the EMA states.

The pilot is expected to run until it has completed six scientific advice requests, with a maximum of one scientific advice request accepted per month. The program is available to all types of biosimilars, and includes a pre-submission meeting to review the suitability of the data package. The EMA advises biosimilar developers that the data package to be reviewed should be mature in order to fully benefit from the pilot. Data submitted should be directly related to the comparability exercise between the biosimilar and the reference medicinal product and statistical methods used for the comparison of quality data should be presented.

Applicants for the project should provide an overview of the full development plan and include questions related to quality development as well as questions related to the proposed nonclinical and/or clinical development so that the EMA’s Committee for Medicinal Products for Human Use (CHMP) can provide appropriate advice on the next steps of the development based on the quality data available.

The EMA’s Scientific Advice Working Party requires an extra month in addition to normal scientific advice timelines to review applications. A maximum of one Scientific Advice per month can be accepted.

Click here for a link to the EMA’s website showing an up-to-date list of the 