Stanton R. Mehr

Celltrion presented data at the American College of Rheumatology (ACR) meeting on November 14, demonstrating that its product CT-P10 is as safe and effective as Rituxan for the treatment of rheumatoid arthritis (RA).

, investigators tested CT-P10 against both US- and EU-licensed versions of rituximab. The study evaluated pharmacokinetic and pharmacodynamics, as well as safety.

Three hundred seventy-two patients participated in the study. A total of 161 were given CT-P10 and the remainder were given the originator product.

The investigators concluded that the pharmacokinetics of CT-P10 were highly similar to those for the originator products (90% confidence intervals were within the equivalence range of 80% to 125%), and the safety profile was noninferior. Infusion-related reactions occurred in 6 (9.4%) of patients in the biosimilar group, 4 (6.2%) in the US-licensed version of rituximab, and 12 (20%) in the EU-licensed group, and all of these reactions were either grade 1 or 2. Discontinuations as a result of an adverse event occurred in 3.1%, 4.6%, and 1.7% of patients taking the biosimilar, US version, and EU version, respectively.

 at the American College of Rheumatology meeting,  a team of researchers sought to gather efficacy data on the biosimilar versus the two licensed versions of Rituxan, using the DAS28-CRP/ESR as a primary endpoint.They found in this phase 3, controlled study, that the biosimilar was therapeutically equivalent to the other treatment groups, with a change in DAS28-CRP of -2.14 for the biosimilar vs. -2.09 for the originator products. Additionally, the change in DAS28-ESR scores were -2.41 vs. -2.35, respectively. ACR 20, 50, and 70 scores were equivalent as well. No significant differences in adverse events were detected among the groups, and no serious complications were reported.

Biosimilar rituximab is being tested not only in patients with RA but in those with non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia (CLL), and polyangiitis. If it is approved for treatment, Celltrion’s product would likely be the first CD20-inhibiting monoclonal antibody to reach the market in a biosimilar version.

Celltrion announced that on November 17, 

 for use in South Korea for non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis. It will be marketed under the name Truxima in that country.

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Pharmacokinetics of CT-P10 were highly similar to originator products. 

Ritumixab Biosimilar Demonstrates Positive Results in Rheumatoid Arthritis

If the Acting US Solicitor General’s recommendation is accepted, the US Supreme Court will rule on the validity of the timing of the 180-day notification rule as well as on the so-called 

The amicus brief was filed on December 7, in response to a lower court decision on 

, in which the plaintiff did not take actions consistent with the patient dance in readying Zarxio for the market. The lower court ruling, which stated that Sandoz could not file the 180-day notification of its intent to market Zarxio until it received FDA approval, prevented the biosimilar manufacturer from launching until September 2015, 6 months after receiving approval. Immaterial to patent litigation, which begins years before FDA approval (and seems to extend well beyond the notification period in most US cases), this was essentially an additional 6-month period of exclusivity, which was not the intent of the Biologic Price Competition and Innovation Act. In other words, if a manufacturer wanted to launch while still embroiled in patent litigation, that drug maker should be able to do so, “at risk,” which is the position taken by Pfizer and Celltrion in launching Inflectra™. The argument was made that the 180-day notification should be permitted earlier in the process, for instance, when it applies for FDA approval, so it does not interfere with product launch.

Although Zarxio is already on the market, Sandoz has other biosimilars in various stages of approval and development that are still subject to the lower court ruling (e.g., its etanercept biosimilar has been approved, but is awaiting the 180-day period before marketing in 2017).

If the Supreme Court takes up the recommendation, it is likely to hear the case during the current term and vote on it by July 2017.   

Supreme Court will rule on the validity of the timing.

Breaking News: US Asks Supreme Court to Rule on Biosimilar Patent Dance

Consider the following situation: the Food and Drug Administration (FDA) has approved biosimilar-xxyy (no matter for which disease).

The main questions of structural and molecular similarity have been answered by the FDA. The clinical trials for one indication show no clinically meaningful difference compared with the originator drug, and the FDA approves extrapolation to second indication for a different class of disorder.

Assuming the payer will make a decision to cover this agent on a preferred copayment tier for this self-administered biologic, physicians will now have to make their own decisions as to which patients might benefit most from therapy with this biosimilar, and in whom it might be safest, from their point of view, to start prescribing it.

We speak constantly today about overcoming barriers to physician uptake of new biosimilars. A large part of this involves education and information. Their sources of information on biosimilars will be only slightly different than the information pipeline for any biologic. The difference is that this is a biologic, and professional societies (and even patient groups) may have taken a stand to be extra cautious about its use.

Without pressure from payers to switch patients who are stable taking the originator product, it will then be a physician-based or patient-physician decision. Logically, this will be limited to patients who have not been treated with biologics in the past. For these patients, the risk of immunogenicity or adverse events is really no different than if they received the originator product for the first time. And a conversation will often take place with their colleagues about whether they had used the biosimilar, and was the outcome as intended.

However, another conversation that may well take place before prescribing is between the physician and the practice manager. The content of that discussion may be of an administrative nature, such as, “if I order this drug, will it be reimbursed without any problem?” In the case of a payer who has not yet held a Pharmacy & Therapeutics (P&T) Committee meeting to determine coverage, the same question may be asked but more urgently. “Do we even know what the patient copay may be? Do we have to acquire additional prior authorization approvals?” Additionally, the practice manager will wonder whether the biosimilar manufacturer has set up a “hub” to offer the payment and access assistance needed to smoothly order and deliver the product.

Ensuring the comfort of the practice manager is sometimes given too little consideration. This can go a long way to easing the physician into prescribing biosimilar-xxyy for that first patient.

Physicians will make their own decisions as to which patients might benefit most from biosimilars therapy.

The Foundation for Building a Clinician's Confidence Over a Biosimilar Drug

As reported in July, Sandoz received a complete response letter from the US Food and Drug Administration (FDA) in regard to its pegfilgrastim biosimilar application, 

. On its third-quarter earnings call, Novartis provided 

 for FDA’s rejection of this biosimilar. Apparently, further data are required. 

Novartis’ Sandoz unit has several additional biosimilar assets, including its marketed filgrastim-sndz product Zarxio, its recently approved biosimilar to Enbrel, and its investigational infliximab biosimilar (purchased from Pfizer after that company’s acquisition of Hospira). 

Vasant Narasimhan, MD, Novartis’ Global Head of Drug Development and Chief Medical Officer, confirmed, “As noted in the second quarter, we did receive a complete response letter and are continuing to engage in discussions with those at FDA and with EMA. In the US, we have agreed with the FDA to move forward on an additional study to address their data request. We would expect to submit that study to the FDA in 2018.” 

 The biosimilar partnership between Momenta Pharmaceuticals and Mylan took another step recently, when they announced the commencement of its phase 1 study of M834, a biosimilar of 

, will evaluate the pharmacokinetics, safety, and immunogenicity of this biosimilar in comparison with both the US and EU-licensed versions of Orencia in healthy volunteers. This is the 

 in the Momenta—Mylan partnership to reach the clinical trial stage.

Sandoz received a complete response letter from the US Food and Drug Administration (FDA) in regard to its pegfilgrastim biosimilar application, filed in 2015.

Novartis: New Study on Pegfilgrastim Biosimilar Requested by FDA

The prevalence of inflammatory bowel disease (IBD) among adults seems to be increasing significantly, yet there are signs that the utilization of biologics to treat patients with this chronic disease have plateaued. 

In the October 28, 2016 issue of Mortality Morbidity Weekly Review, researchers from the Centers for Disease Control and Prevention (CDC) announced the findings of its 

2015 National Health Interview Survey on IBD

. They estimated that the prevalence of IBD in the US adult population was 3.1 million (1.3% of the total US adult population). A similar study conducted in 1999 found the figure to be 1.8 million (or 0.9% of the adult US population), a 72% increase in number and a 44% increase by proportion of the population. According to the CDC, a dominating factor in this trend is a substantially higher prevalence of IBD identified among adults aged ≥45 years, mostly in Hispanics and non-Hispanic whites, and those in lower socioeconomic levels. The NHIS is based on the survey responses of more than 33,500 American adults.

This raises the question of whether the utilization of biologics used to treat IBD has also increased over this time. 

 was approved in 2002 (the anti-TNF fusion protein 

 was also approved in 1998, but is not indicated for IBD). These remain the two most commonly used agents to treat IBD, especially Crohn’s disease, with Cimzia

a distant third. Based on a single-center study from Stanford University, 

 for adults and children with IBD has not increased proportionately. Use of Remicade

 peaked in 2008, and utilization of Humira continued somewhat slow growth through 2012, the end of the data collection period. Interestingly, biologic use in IBD resulted in dramatic lowering of hospitalization costs, but not in the rate of abdominal surgery in these patients. They attribute this finding to the possible erosion of drug efficacy when given chronically over the long term. However, the Stanford researchers also found that 

, particularly Crohn’s disease, is the primary cost component in health care expenditures. “Pharmacy utilization costs account for nearly one-half (45.5%) of the total CD-attributable costs, exceeding inpatient care costs. Anti-TNF agents alone comprised nearly one-third (29.5%) of total costs,” they said.

The question of whether the biologic utilization pie is growing, shrinking, or remaining the same could have implications for the brand new biosimilar market for IBD.

Prevalence of IBD Increases--Does Utilization of Biologics Increase, Too? 

What has a decade of European experience with biosimilar development and use taught us about their safety and efficacy? According to the authors of a paper published in 

we may have gathered enough evidence to begin to consider altering how these agents are approved, to speed their path to approval.

Investigators from The Netherlands, Austria, Luxembourg, and the United States wondered whether the need for more comparative clinical data to assess biosimilar safety and efficacy will be necessary in the future.

Although the first-generation products epoetin and filgrastim were a good fit for the EU’s biosimilar regulatory pathway requirements, evaluating the clinical benefits of the next- generation oncology products, the monoclonal antibodies, is a bit more complicated. They noted that in some cases, the clinical effect of the monoclonal antibody may be modest, complicating the question of clinical equivalence or similarity. “Even in the case of monoclonal antibodies that have shown efficacy as monotherapies, such as trastuzumab or rituximab,” these agents are commonly prescribed with various combinations of chemotherapy, which complicates “the decision with regard to the most appropriate indication and patient population in which to perform trials to show biosimilarity,” stated the authors. This is especially important in extrapolating indications (consider oncology agents that are used to treat a wide array of tumors).

They pointed out that the European Medicines Agency “is moving away from double-blind equivalence trials and large postmarketing safety studies as the standard to show clinical similarity, because regulatory agencies are realizing that comparative clinical trials are not sensitive enough to show possible differences in safety and efficacy.” This points, once again, to the greater importance placed on the physiochemical description of the biosimilar and on in vitro assays to demonstrate similarity between the biosimilar and the reference product. These authors believe that “requiring clinical investigation in the most sensitive patient populations and strong scientific justification to support extrapolation to other indications” is critical, but the need for additional confirmatory clinical trials would undermine the ability to increase access to potentially cost-saving biosimilars.

They stressed, “To demand confirmatory trials in all possible indications would waste valuable patient, staff, and monetary resources for no substantial gain, and such requirements should be avoided unless extrapolation cannot be justified on the basis of mechanism of action and existing data.”

On the basis of roughly 400 million patient-days of biosimilar experience in Europe without the appearance of any serious safety signals, they believe it may be time to learn from this experience and correct course for the upcoming wave of oncology biosimilars.

According to the authors of a paper published in Lancet Oncology, we may have gathered enough evidence to begin to consider altering how these agents are approved, to speed their path to approval.
 

Lessons From Europe: Is It Time for a Regulatory Course Correction?

A study from Norway on whether switching stable patients with rheumatoid arthritis (RA) treated with Remicade

 to a biosimilar has revealed that outcomes were no different.

 were announced at the United European Gastroenterology Week in Vienna, Austria, on October 18. This investigation was designed to determine how switching to Celltrion’s biosimilar (marketed as Remsima

 in Europe and soon to be marketed as Inflectra

 in the US) would affect patient status. This 2-year, post marketing study was designed to demonstrate noninferiority (not superiority) of Remsima to Remicade.

The approximately 500 patients entering the trial had to be receiving a stable dose of infliximab for at least 6 months at baseline. In this controlled study, half of the patients were switched to Remsima treatment. The results indicated no clinically meaningful difference in safety or efficacy. Although this trial was not designed to demonstrate the possible effects of switching back to the original product, it does bolster the case that in patients with RA, switching from Remicade to the biosimilar poses little risk.

What of switching these products in patients with other approved indications?

More data are needed to determine the effectiveness and safety of this option. In 

 conducted by Celltrion’s marketing partner Pfizer, 3300 patients are being recruited to determine how often patients with inflammatory bowel disease switch from one anti-TNF to another. That study is due to end in June 2019. Will NOR-SWITCH spur US payers to encourage physicians to switch treatments, once Inflectra is launched in late November? It does offer a bit of insulation for proponents, but (1) only for Inflectra/Remsima—Remicade switches in RA not for other indications, and (2) these study results do not apply to other anti-TNFs.

However, Sandoz utilized a multiple-switching study design in one of the studies (Study 302) to 

support FDA approval of its etanercept biosimilar Erelzi™

. In this study of plaque psoriasis, a subgroup of patients were switched between the originator product and Erelzi at weeks 12, 18, and 24, without negative effects.

A study from Norway on whether switching stable patients with rheumatoid arthritis (RA) treated with Remicade® to a biosimilar has revealed that outcomes were no different.

NOR-SWITCH Shows That Switching Infliximab Biosimilar Is Safe

As a result of increasing competition, a smaller player (in the biosimilar field) is seeking to sell its nascent biosimilar business. Merck KGaA (which operates in the US as EMD Serono and is not associated with Merck & Company) has engaged the services of the investment banker JP Morgan Chase to seek 

 instead on multiple sclerosis, where it has a strong marketing position with its product Rebif

, and in several cancer therapeutic approaches. The company’s only late-stage biosimilar is adalimumab (MSB11022), which is currently involved in a 

 that is supposed to be completed by September 2017. The primary endpoint results are slated to be available, however, in December 2016.

According to the announcement, the company’s biosimilars business could be valued at as much as $1 billion, not only based on its adalimumab agent but several undisclosed early-stage biosimilars. However, Merck may not make a big splash with its key product, as Amgen’s adalimumab has already been approved, and it may be one of several biosimilar versions to hit the market in the next few years, pending clearance of patent litigation.

Active biosimilar player Celltrion, from South Korea, has announced its submission of an application to the European Medicines Agency to 

. Interestingly, although it is approved for use in South Korea under the brand name Herzuma

, this biosimilar only commenced phase 1 trials in the US in September for eventual application to the Food and Drug Administration. No timetable has been announced for US submission.

As a result of increasing competition, a smaller player (in the biosimilar field) is seeking to sell its nascent biosimilar business.
 

Merck KGaA Seeks to Exit the Biosimilar Business

According to a 2015 study by RAND, insulin glargine biosimilars/follow-on agents 

 to total cost savings in overall biologic expenditures. This would be substantial, considering the size of the insulin marketplace, and their potential to slow increasing market shares from next-generation long-acting insulins.

But the savings may not be that quick to accrue. When Lilly introduces its version of insulin glargine (Basaglar) to the long-acting insulin market next month, what will the savings be? As a reminder, this product is not a biosimilar, according to its regulatory approval pathway, but a follow-on biologic, which means that it required more clinical trial data.

But the savings may not be that quick to accrue. When Lilly introduces its version of insulin glargine (Basaglar) to the long-acting insulin market next month, what will the savings be? As a reminder, this product is not a biosimilar, according to its regulatory approval pathway, but a follow-on biologic, which means that it required more clinical trial data. For example, Lilly conducted 2 Phase 3 studies (

) with patients with types 1 and 2 diabetes mellitus, respectively) who had been treated prior to enrolling in the investigation. Furthermore, design and development costs of the pen-delivery device must be considered.

On this basis, one should not expect more than 15% discounts off of wholesale acquisition cost. This does not consider possible rebates and individual contracts made with CVS Health and OptumRx to prefer Basaglar and exclude Lantus

 from coverage. However, it does seem reasonable that additional versions of insulin glargine will need to enter the marketplace before general discounts are commonly seen.

When might this occur? The next drug up for approval is a result of the Merck—Samsung Bioepis collaboration. On August 5, 2016, the FDA accepted their application for 

 earlier this year, with the hope of receiving positive news from the EMA before the end of the year.

On November 3, 2016, Biocon and Mylan submitted its application to the European Medicines Agency (EMA) for a biosimilar to insulin glargine. Lilly had submitted its drug as a biosimilar as well to the EMA, and as a result, it is already available in the EU. There is no word as of yet when Biocon/Mylan’s 351(a) application will be submitted to the FDA. Its 500-patient 

 in patients with type 1 diabetes was completed in June 2016. Its 600-patient 

 in patients with type 2 diabetes was estimated to be completed in June as well. An 

 of the agent is underway and will be finished in March 2017. This seems to support—assuming positive results, of course&mdash;a regulatory submission no earlier than Q4 2017.

Therefore, it may be late 2018 before 3 follow-on insulin glargine products are actively competing with Lantus

 and its next-generation insulin glargine brand. By that time, discounts and rebates may mean savings of 30% or more, as the category becomes saturated, to nearly commodity levels.

Insulin glargine biosimilars supposed to contribute 15% to total cost savings in overall biologic expenditures.

Insulin Glargine Update: Price Savings with Basaglar? 

A new survey of US specialists who may be high prescribers of biosimilars in the future shows that education will be needed to convince them of the value of biosimilar agents. The survey (conducted from November 20, 2015, to January 4, 2016) had responses from 1200 US dermatologists, gastroenterologists, nephrologists, oncologists, and rheumatologists. It is meant to be repeated in 2 to 3 years and serves as a baseline snapshot of these physicians’ understanding and attitudes toward biosimilars. At the time the survey was conducted, only Zarxio was approved for use by the FDA.

Sponsored by the Biosimilars Forum, the survey revealed 5 major knowledge gaps. There were shortcomings both in how terms were defined and in the approval process. Although more than 75% of the surveyed physicians had heard the term “biosimilars” used, at the time the research was conducted, they questioned how extrapolation of indications was decided by FDA, had limited knowledge about the interchangeability designation, and did not understand whether biosimilars were expected to have the same safety profile as that of the originator medication. The results of the Biosimilars Forum physician survey were published in 

Only 12% of those responding to the survey indicated that they trusted the extrapolation process. When asked to identify which products that they regularly prescribe within their specialty, only 69% of hematologists and 63% of medical oncologists correctly identified which of these medications were biologics. In comparison, over 90% of gastroenterologists and dermatologists correctly distinguished the biologic agents.

For example, survey questions revealed that most physicians surveyed do not clearly understand the concept of extrapolation as it applies to biosimilars, with only 12% of survey respondents stating that they trust extrapolation of the studied biosimilar indication(s) as the basis to obtain approval of other licensed indications of the originator product. Only 45% of these specialists believed at the time of the survey that biosimilars will be safe and appropriate for use in 

 and existing patients. However, approximately 60% of the specialists surveyed understood that an "interchangeable" biosimilar must be shown to be safe and effective through a series of switches from reference to biosimilar and back again. Yet, 91% agreed with the statement that switching an existing patient to a biosimilar may be appropriate if it would help the patient have better access to his/her medications.

Again, as this was a baseline survey, it would be reasonable to assume that the torrent of articles and education available in the last 12 months has significantly altered these responses. The Biosimilars Forum intends to conduct a similar survey in 2 to 3 years in order to monitor trends in the awareness, knowledge, and perceptions of biosimilars over time.

. Italian and Swiss investigators demonstrated gastroenterologists’ improved comfort levels and knowledge about biosimilars from 2013 to 2016. In the initial 2013 investigation (2 years before their availability in the European Union [EU]), confidence levels and knowledge about biosimilars were found to be low. In the latest survey (with 118 physicians treating inflammatory bowel disease [IBD] responding), conducted 1 year after the introduction of the biosimilar infliximab in Europe, the awareness and confidence levels of IBD specialists were vastly improved. In fact, roughly one-third now believe distinct nonproprietary names are needed for these biosimilars, as opposed to two-thirds in the first survey. According to these respondents, 44% believe the originator and biosimilar agent are interchangeable in practice compared with only 6% in the 2013 survey. In addition, the potential for immunogenicity still tops concern (69%) in the latest results, with less than one-fifth having little or no confidence in the prescription of biosimilars compared with two-thirds in 2013.

Although these results really apply only directly to infliximab, as this was the only biosimilar approved to treat IBD in the EU at the time of the study, it does indicate the path to physician confidence and uptake must be paved with education and practice experience with the agent.

Survey shows education will be needed to convince physicians of the value of biosimilar agents.