Jackie Syrop

South Korean biopharma company Celltrion is planning on filing for 

 for 2 biosimilars by June 2017. This includes its oncology biosimilar drug rituximab (Truxima), biosimilar to Rituxan, and trastuzumab (Herzuma), biosimilar to Herceptin. Both reference biologics are manufactured by Roche.

Truxima would potentially be indicated for the treatment of non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis (RA), Wegener granulomatosis, and microscopic polyangiitis. Truxima is already 

 in the European Union (EU). Celltrion is also awaiting approval of Herzuma in the EU after making its filing in October 2016.

Once approved by FDA, the drugs would be marketed via Celltrion’s US marketing and sales partner Teva Pharmaceutical Industries. Celltrion already has 1 biosimilar 

 for marketing in the US—Remsima, an infliximab biosimilar of Johnson & Johnson’s Remicade&mdash;that is already being sold via partner Pfizer at a 15% discount to the Johnson & Johnson drug.

Celltrion commented that the company plans to quickly drive up their market share in each country to fend off rivals while continuing to raise their reputation in the medical community by accumulating robust prescription data proving the safety and efficacy of their products.

Currently, the FDA has approved 5 biosimilar products, 4 of which are treatments for immune/inflammatory diseases including RA. The other approved biosimilar is Zarxio (filgrastim-sndz), Sandoz’s biosimilar to Amgen’s granulocyte colony-stimulating factor (G-CSF) Neupogen, approved to boost white cell counts after chemotherapy. Truxima and Herzuma would be among the first non-G-CSF oncology biosimilars if approved by the FDA.

The patents of Herceptin and Avastin are expected to retire in 2019. According to some 

, at least 4 more biosimilars may gain US approval on first-cycle review. (There are some previously rejected applications that may be resubmitted for review). The potential new products include:

MYL-1401O, another trastuzumab biosimilar being developed by Mylan/Biocon

ABP 215, a biosimilar of Genentech’s bevacizumab (Avastin) being developed by Amgen/Allergan

Herceptin and Avastin are both blockbuster cancer treatments. Herceptin is indicated for the treatment of breast cancer and stomach cancer; Avastin is indicated for glioblastoma, metastatic colorectal cancer, non-small cell lung cancer, metastatic kidney cancer, advanced cervical cancer, and platinum-resistant ovarian cancer.

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Celltrion Plans Filing for Biosimilars to Rituximab, Trastuzumab

Biologics are the fastest-growing segment of the medication market, and the most expensive within the immune sector. The 

 for these breakthrough specialty biologic treatments for inflammatory diseases costs over $3500. The top 5 drugs in the class include Humira Pen, Amgen’s Enbrel (etanercept), Humira for rheumatoid arthritis (RA), Celgene’s Otezia (apremilast) for plaque psoriasis, and Janssen Biotech’s Stelara (ustekinumab) for plaque psoriasis, psoriatic arthritis, and Crohn’s disease. While Humira and Enbrel together captured 70% of the market share in 2016, Humira alone. the world’s best-selling drug, earned $14 billion in 2015.

Five biosimilars have been approved by the FDA to date, 4 of which are in the autoimmune category and are biosimilars to Enbrel, Remicade (infliximab) and Humira; the fifth is a biosimilar to an oncology drug. Biosimilars of biologics promise lower prices for their versions of these highly effective biologics, and thus can potentially treat more patients. The Congressional Budget Office estimates that potential biosimilar savings over the next 10 years would be $25 billion; other reports estimate that figure at up to $250 billion. Price discounts for biosimilars range from 15% to 25% but that doesn’t account for discounts expected by patients and payers, which could be up to 50% in the autoimmune category. For this to occur, competition has to increase, but so far, the reference biologic makers are doing whatever they can to hold back competition from biosimilars.

The Humira and Enbrel biosimilars that were FDA approved have been hit by patent lawsuits brought by reference drug makers, which has prevented product launch. Patent legislation fights continue to hold back biosimilars in the marketplace, forcing biosimilar makers to wait longer to reach market. For example, AbbVie filed a patent infringement suit against Amgen to block the launch of its biosimilar adalimumab. AbbVie continues to invest in new Humira indications and enhancement for patients with unmet medical needs. Amgen sued Novartis/Sandoz with a patent infringement suit for Enbrel that was 

Slow acceptance of biosimilars is due in part to the fact that many physicians and payers do not agree with using biosimilars for patients with RA, psoriasis, and other inflammatory conditions. Some welcome biosimilars and believe they are a solution to the high prices of biologic treatments, but others are opposed to biosimilars and are concerned they won’t work as well as brand-name reference biologics they would substitute for. Patients too are unsure they want to have biosimilars switched for their effective, breakthrough biologic treatments.

None of the approved biosimilars have an interchangeable designation because their approvals predated the FDA’s 2016 guidance calling on biosimilar makers to produce switching-study data to show interchangeability with reference drugs. In Norway, the government funded an interchangeability study for a Remicade biosimilar, and the ensuing proof of interchangeability had a profound effect on Norway’s use of an infliximab biosimilar.  Some experts say that if major US health insurers sponsored biosimilar interchangeability studies here, there could be a parallel upswing in biosimilar use. However, the downside of the switching-study guidance is that it will raise costs for biosimilar makers and cause longer wait times to marketing—potentially raising the investment hurdle too high and knocking out smaller biosimilar makers.

If biosimilars start moving to market more quickly, brand manufacturers will likely respond with lower product prices, 

 Stephan Gauldi, senior vice president of strategy consulting at Back Bay Life Science Advisors, because they won’t be able to compete on price. “Biologics would emphasize brand and biosimilars would emphasize price, assuming interchangeability is sorted out first,” Gauldi said.

For biosimilars to make inroads in the United States, healthcare providers and patients would have to be better educated about biosimilars. Biosimilars will only be successful if sponsors are able to establish positive perceptions of their products and create a comfort level for patients and providers to accept and adopt biosimilars. Biosimilar makers must define their product and explain how they compare with biologics, and they must be able to answer patients’ questions about efficacy, safety, and side effects, and compete with reference drug makers’ programs providing support and services for branded drugs. “They feel they have the most to lose,” 

 Rafal Kokolus, senior engagement manager at inVentiv Health Consulting.

Biosimilars at the Gates: What's Ahead?

The Biologics Price Competition and Innovation Act (BPCIA) has been considered overly complex and unclear as to many of its procedural requirements. The US Supreme Court is now considering the Federal Circuit Court’s decision in 

, which held that a biosimilar applicant could 

 of the so-called patent dance and that the biosimilar’s notice of commercial launch may only be given after the FDA approves the biosimilar’s application. The Supreme Court’s decision in the case, expected by July, could set a precedent on whether the patent-dance exchange of patent and manufacturing information before FDA approval is necessary and whether biosimilar manufacturers must obey the provision specifying notice of commercial marketing, which effectively adds 6 months to the wait to market the drug after FDA approval. 

One of the big questions biosimilar applicants have had to decide upon is whether to engage in the patent dance at all, and if so, for how long. The procedure takes approximately 6 months to complete, representing a significant delay in commercial launch. Another issue has been when to give the reference drug sponsor (RDS) the 180-day notice of commercial launch required by the BPCIA, which represents another 6 months of delay (and is the reason applicants have been trying different ways to give notice as soon as possible; 

). RDSs have also been uncertain about these steps and whether they have the right to seek legal means of forcing biosimilar applicants to comply with the steps.

To date, companies have used 3 main strategies to address the patent dance, according to an analysis in 

Bloomberg Law Life Sciences Law & Industry Report

, biosimilar maker Sandoz told Amgen, the RDS, that it wouldn’t do the patent dance, but it did attempt to provide notice of commercial marketing. Amgen filed a complaint in the US District Court for the Northern District of California compelling Sandoz to engage in the patent dance and asserting that Sandoz could not provide notice of commercial marketing until after the FDA approved its product. The Court 

 of Sandoz on both counts, finding that the patent dance is not mandatory and that biosimilar applicants need not wait for FDA approval before providing notice. That judge called Amgen’s position “problematic” because it would add an additional 6 months of market exclusivity onto the 12 years they already had enjoyed. Amgen appealed the ruling to the Federal Circuit, which split on the issues, holding that the patent dance is not mandatory and said Amgen’s only remedy for Sandoz failing to engage in the patent dance was to file an infringement suit against Sandoz. The Federal Circuit also held that Sandoz was not allowed to provide notice of commercial marketing prior to FDA approval. This is the case that the Supreme Court is now considering.

Partially completing 1 or more of the patent dance steps.

 which involves Celltrion’s infliximab-dyyb (Inflectra) biosimilar of Janssen’s infliximab (Remicade), is one such example of this strategy. In August 2014 Celltrion filed its biosimilar application with the FDA, which accepted it for review in October 2014. In February 2015, Celltrion provided Janssen notice of intent to market upon FDA approval. Celltrion provided Janssen with its application during the 20-day window to do so, including some, but not all, manufacturing information. Janssen asserted that Celltrion was obligated to give them additional manufacturing information and said Celltrion had not complied fully with the patent dance. Janssen sued Celltrion for infringement of 6 patents, seeking to enforce the patent dance. Four of these patents have been dismissed, but the suit proceeds on the other patent issues. The issue of remedies for alleged noncompliance has also arisen in the case. This case shows that the BPCIA provides “both flexibility and the possibility of litigation disputes over the issue of how much information the biosimilar applicant must disclose and when,” and shows that biosimilar applicants should consider the potential risk of losing the benefit of the damages limitation in the BPCIA when considering patent dance strategies, 

Completing all of the patent dance steps.

 illustrates a case in which the biosimilar maker (Apotex) engaged in the entire statutory procedure of bringing its biosimilar of pegfilgrastim and filgrastim (Amgen’s Neulasta and Neupogen, respectively) to market and was sued because the biosimilar maker gave early notice of intent to market after FDA approval. Amgen filed a preliminary injunction seeking to prevent Apotex from giving notice until after Apotex gets FDA approval. Amgen’s position on notice was upheld by the District Court as well as the Federal Circuit Court on appeal. The trial proceeded on Amgen’s patent infringement claims, and the district court held that Apotex did not infringe on the asserted patents, a decision Amgen has appealed. Apotex petitioned the US Supreme Court on the notice provision but the Court denied the petition for review.

There are still many open questions in the area of biosimilars litigation that the Supreme Court and Federal Circuit Court will continue to weigh in on, and the answers they provide will have significant impact for biosimilar applicants going forward.

The Uncertainty of BPCIA Litigation Strategies and the "Patent Dance"

Oral arguments were heard by all 9 justices of the US Supreme Court on April 26, 2017, in the case 

on the case concerning the so-called biosimilar patent dance laid out by the Biologics Price Competition and Innovation Act’s (BPCIA) biosimilar approval pathway, and whether it is necessary for the biosimilar maker to notify the reference drug maker 180 days prior to marketing.

Sandoz’s attorney, Deanne Maynard, Esq, 

 that if the Court reaffirms the Federal Circuit’s ruling that the patent dance is not mandatory, it will help ensure a consistent interpretation of BPCIA, allowing both biosimilar applicants and reference product sponsors to make more informed choices on how to use the patent dance, particularly in situations where no patents remain.   

Amgen’s attorney, Seth Waxman, Esq, argued that “Congress did not create detailed procedures for resolving biosimilar disputes and repeatedly used the word "shall" merely to have applicants who choose to take advantage of the statute's benefits and use the sponsor's information, then disregard those mandates. The purpose of the BPCIA statute is that the requirements of the patent dance are complied with and the information exchange occurs, and thus all patent litigation is concluded before commercial launch. “That is, in fact, what was said over and over again,” Waxman said.

 of the Sandoz and Amgen attorneys by 7 of the Supreme Court’s justices. Before the session began, Chief Justice John Roberts took the unusual step of announcing that the court would give each side 5 extra minutes, reflecting the complexity of this case. According to 

, both sides received skeptical questioning on a number of points, and Amgen’s counsel seemed to receive significantly fewer questions overall.

Sandoz began with its argument about why the additional 180 days would further delay biosimilars from launching, and explaining why providing a biosimilar application to a reference product sponsor, the patent dance, is optional. Sandoz’s attorney Maynard said the BPCIA created a comprehensive and self-contained scheme for the early resolution of patent disputes. “Regardless of the actions an applicant or sponsor take along the way, the end result is the same: patent litigation,” she said. Courts should apply that comprehensive scheme as written and should not look elsewhere for consequences.

Concerning the 180-day issue, the Justices’ questions focused on 2 points:

Is it possible for a reference product sponsor to write a complaint in good faith before FDA makes a final licensure decision?

Can the FDA come up with a form of tentative licensure that would be given during the 12-year exclusivity period and would allow notice of commercial marketing, maybe according to Amgen’s reading of the BPCIA?

On the question of whether the patent dance is required, several Justices questioned the attorneys on whether a federal system this complicated could be supplemented with an injunctive (court-imposed) remedy under California state law, or perhaps all 50 states’ laws.

Chief Justice Roberts questioned how the reference drug sponsor would know the specifics of a biosimilar application without the biosimilar maker going through the patent dance and providing the application. “You’re suing, saying this thing infringes on our patent. We don’t even know what ‘this thing’ is.”  Amgen’s attorney Waxman said that until FDA decides what the biosimilar will be and authorizes it for specific therapeutic uses and evaluated its manufacturing process, “you can’t give notice of anything.”

Associate Justices Sotomayor and Gorsuch asked what the remedy is. Waxman said, “The remedy question is who, if anybody, can do anything about it, if you don’t comply with ‘shall?’” However, Associate Justice Sotomayor countered that his answer was not quite right: “’Shall’ is if you want to invoke this federal process, this is what you have to do.” Associate Justice Stephen Breyer said, the exchange of information prior to approval isn’t the only remedy.

Associate Justice Anthony Kennedy said he thought it would be within the FDA’s authority to interpret the BPCIA, or it would be sensible for FDA to say, “If you don’t do that and we’ve told you to do that, we’re going to delay the review process.”

Chief Justice Roberts noted that it’s very hard to give a comprehensive answer to the questions presented without considering whether state law allows the same injunction as the federal. “It’s really asking us to put together a puzzle where a big piece is missing,” he said.

Congress explicitly negotiated over the 12 years of exclusivity provided to biologics, Sandoz’s attorney Maynard said, and it should not be extended “in a bizarre way” with the 180-day notice occurring after approval.

The Court will issue a written opinion in late June.

Supreme Court Hears Oral Arguments in Biosimilar Patent Dance 

The FDA has granted Glenmark Pharmaceuticals’ investigational new drug (IND) application to initiate a first-in-human study of GBR 310, a proposed biosimilar of Novartis’s reference drug omalizumab (Xolair). The clinical trial will 

 the pharmacokinetics of GBR 310 in comparison with Xolair in healthy adult volunteers between 18 and 65 years of age.

“GBR 310 has the potential to be among the first biosimilar candidates to be submitted for approval for a respiratory or allergic disease,” said Kurt Stoeckli, President and Chief Scientific Officer at Glenmark Pharmaceuticals. GBR 310, a recombinant DNA-derived humanized immunoglobulin G1 kappa (IgG1k) monoclonal antibody, 

 to free human immunoglobulin E (IgE) in the blood and interstitial fluid and to a membrane-bound form of IgE (mIgE) on the surface of mIgE-expressing B lymphocytes. The patents on the reference drug omalizumab will expire in the US on June 20, 2017, and in Europe in August 2017.

 for the treatment of moderate to severe persistent asthma that is not controlled by inhaled steroids, and for chronic idiopathic urticaria not controlled by  antihistamines. A majority of asthma patients are able to control the disease with long-acting beta agonists (eg, Advair, Symbicort), inhaled steroids, and rescue inhalers, which are the mainstay of asthma maintenance therapy. But some 5% to 15%  of patients have severe asthma, and struggle to control the disease. They usually turn to injected biologicals including omalizumab and GlaxoSmithKline’s mepolizumab (Nucala) to reduce airway inflammation.

If GBR 310 advances through the biosimilar approval process, it has a potentially strong market position. Treatment options for patients with severe asthma are 

 to improve quite significantly, per market research firm GBI Research, with biologics in particular gaining prominence over the small-molecule therapeutics. The worldwide sales of omalizumab touched $755 million in 2015, and currently, about one-third of drugs in the asthma pipeline are biologics, GBI states. Procedures such as bronchial thermoplasty to treat asthma are still regarded by health insurance payers as experimental, with most 

 for the procedure even though the costs of a 1-time treatment can be less than some newer biologics, and its success rate is similar to other approved treatments.

Proposed Xolair Biosimilar Gets FDA Approval for Clinical Trials 

News about the advancement of 2 biosimilar candidates, ranibizumab and teriparatide, were recently reported.

Xbrane Biopharma of Sweden reported positive 

 for Xlucane, the company’s ranibizumab biosimilar of Genentech (Roche)/Novartis’s reference product Lucentis, a treatment for wet age-related macular degeneration (AMD). The Xlucane study was conducted per biosimilar guidelines developed by both the FDA and European Medicines Agency (EMA), and used several pilot-scale R&D batches of Xlucane versus several batches of the reference product. Analyses evaluated 5 key structural components:

Biological activity in terms of growth inhibition on living cells

The company reported that it will address purity, which was said to be slightly low, during production scale-up.

Ranibizumab, a monoclonal antibody fragment 

 from the same parent mouse antibody as bevacizumab, inhibits angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A), which is responsible for excessive blood vessel development in the retina leading to progressive loss of vision. Ranibizumab is indicated for the treatment of AMD, macular edema, degenerative myopia, diabetes complications, and all ocular conditions that lead to vision loss.

With Lucentis facing patent expiration in June 2020 in the United States, and 2022 in Europe, all ranibizumab biosimilars are currently in development, except for Razumab, which was approved as a “similar biologic” in India in 2015.

San Diego-based Pfenex reported that the company’s teriparatide (PF708), a biosimilar of Eli Lilly’s osteoporosis treatment Forteo/Forsteo, began a phase 3 trial in December 2016 that is expected to be completed in April 2018. The study is 

 to compare the effects of PF708 and Forteo in patients with osteoporosis and will compare anti-drug antibodies, plasma area-under-the-curve, and maximum concentration of teriparatide, in addition to mean percentage change in lumbar-spine bone mineral density.

 of parathyroid hormone (PTH) that is identical to a portion of human PTH, and is an effective bone-growing agent. Forteo/Forsteo is indicated for the treatment of osteoporosis in postmenopausal women and men at high risk for fracture and for glucocorticoid-induced osteoporosis in men and postmenopausal women. The patents on Forteo/Forsteo will expire in the United States and in Europe in August 2019. The EMA’s Committee for Medicinal Products for Human Use recommended granting marketing authorization for the Movymia and Terrosa teriparatide biosimilars in November 2016. (India approved teriparatide “similar biologics” in 2010 and 2012; EMA notes that these drugs might not have been authorized following as a strict a regulatory process as is required by EMA.)

Advances in the Development of Ranibizumab and Teriparatide Biosimilars  

The European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP), the European Union (EU)’s drug regulatory agency, 

 of 9 new medications, 3 of which are biosimilars, at its April 2017 meeting. The 3 recommended biosimilars are all products of Sandoz.

 for etanercept-szzs (Erelzi; a biosimilar of reference drug Enbrel), for the treatment of rheumatoid arthritis (RA), juvenile idiopathic arthritis, psoriatic arthritis, axial spondyloarthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, plaque psoriasis, and pediatric plaque psoriasis. Etanercept-szzs, which inhibits tumor necrosis factor-alpha, will be available and injectable solution. (The EU approved another etanercept biosimilar, Benepali, in January 2016.) The 2 other recommended biosimilars, are follow-on biologics to rituximab (Rituxan in the US and MabThera in the EU): 

, and are indicated for the treatment of non-Hodgkin’s lymphoma, RA, granulomatosis with polyangiitis, and microscopic polyangiitis. Rixathon has an additional indication for the treatment of chronic lymphocytic leukemia. Both Rixathon and Riximyo will be available as a 500-mg and 100-mg concentrate for infusion. (The EU 

 another rituximab biosimilar, Truxima, in February 2017.)

CHMP also recommended 2 orphan medications for the treatment of 2 different rare neurodegenerative conditions in children. Biogen’s nusinersen (Spinraza), indicated for the treatment of spinal muscular atrophy (SMA), was 

 under an accelerated assessment program. There is currently no approved treatment for SMA in the EU. The second orphan pediatric drug to be 

 was BioMarin Pharmaceutical’s cerliponase alfa (Brineura), for the treatment of neuronal ceroid lipofuscinosis (CLN2) type 2 disease. Brineura was also reviewed under an accelerated assessment program. There are currently no medicines approved for CLN2 treatment, only options that address symptoms.

Pfizer’s inotuzumab ozogamicin (Besponsa ), which was 

 for the treatment of acute lymphoblastic leukemia (ALL) and has an orphan designation. Besponsa will be the first antibody drug conjugate to become available for treatment of ALL.

Sanofi’s sarilumab (Kevzara), which was 

 for the treatment of RA. Sarilumab is an interleukin-6 receptor inhibitor that will be available as a solution for subcutaneous injection in both pre-filled syringes and pre-filled pens. Kevzara was shown in clinical trials to inhibit the progression of joint damage in RA patients.

Almirall’s dimethyl fumarate (Skilarence) was 

 as a first-line induction and long-term treatment for adults with moderate to severe plaque psoriasis. Skilarence will be available as 30-mg and 120-mg gastro-resistant tablets.

CMP Orphan’s trientine tetrahydrochloride (Cuprior), another orphan drug, was 

 for the treatment of Wilson’s disease, a rare autosomal recessive inherited disorder.

EMA Recommends 9 New Medicines, Including Biosimilars

 a decline in drug spending for its clients in 2016, and the pharmacy benefit manager (PBM) believes unbranded drugs—generics and biosimilars&mdash;are key to the decline in drug spending, now and in the future.

 the FDA’s research showing that the price of a branded drug drops most dramatically with the entry of the first few generic competitors and continues to fall incrementally as additional generic competitors are marketed. CVS noted that The RAND Corporation estimates that the entry of biosimilar products into specialty markets could reduce spending on biologics by an estimated $44.2 billion over the next decade. The United States needs to speed approvals of generics and biosimilars in order to increase competition and drive down prices, the company believes.

At the beginning of 2017, more than 4000 generic drugs were pending approval with the FDA, CVS noted. In comparison, Europe approves drugs more quickly than the United States and has 20 biosimilars on the market compared with just 4 in the United States (5 after the 

 of adalimumab-abda). To unlock cost savings for US patients, taxpayers, and the healthcare system as a whole, the flow of generics and biosimilars must be increased, CVS Caremark stated.

Generic drugs had the largest deflationary impact on prescription drug spending for CVS Caremark in 2014, the company reported. Generic spending fell following a 1.4% increase in generic dispensing rates, along with relatively low overall inflation and falling prices for most generics. Even though fewer generics were launched in 2016, rosuvastatin (the generic for Crestor) was a major approval, the company noted. In addition, many payers have taken a more aggressive approach to promoting generics.

The approval and launch of more biosimilars in the future will also help overall prescription drug spending, especially for specialty drugs, which account for about 36% of what is spent for CVS’ PBM clients. Competition from biosimilars could help bring down prices for these expensive products, CVS Caremark stated, pointing out that although a biosimilar for adalimumab (Humira) was approved in 2016 and more adalimumab biosimilars are in the pipeline, it is expected that patent litigation will delay a launch of any competitive products in 2017.

 CVS Caremark Ties Decline in Its Drug Spending to Generics, Biosimilars

 on April 26, 2017, in the case of Amgen vs Sandoz, which concerns the so-called biosimilar “patent dance” of information exchange between biosimilar makers and sponsors of reference drugs about the impending marketing of a new (biosimilar) product. The decision, expected in July, will have important consequences for all subsequent biosimilars approved by the FDA.

 on whether the patent dance is necessary, but also whether biosimilar makers must obey the “notice of commercial marketing” provision of the Biologics Price Competition and Innovation Act (BPCIA), the law that sets out the legal pathway for biosimilar approval and marketing. If the Supreme Court finds that biosimilar makers must adhere to the notice of commercial marketing provision, it will give an additional 180 days of market exclusivity to the reference drug maker after FDA approval of the biosimilar, thus adding 6 months after FDA approval until the biosimilar can reach the market.

Amgen filed a lawsuit against Sandoz/Novartis because Sandoz did not exchange patent and manufacturing information with Amgen for Sandoz’s filgrastim-sndz (Zarxio), biosimilar to Amgen’s filgrastim (Neupogen). According to Sandoz’s attorney Julia Pike, the company decided to forego the patent dance and tried to speed the process of resolving any patent issues related to marketing Zarxio because in Amgen’s filings with the Security and Exchange Commission, Amgen noted that it did not believe it had any material patents related to Neupogen, which already had 24 years of exclusivity. Pike said that when Congress created the BPCIA, its intention was to settle the patent issues before a biosimilar was marketed rather than as a last dash after FDA approval. Zarxio received 

 in March 2015 and was marketed in September 2015.

In response to Amgen’s suit, a federal circuit court judge ruled that the notification provision in the BPCIA is mandatory, with the 180-day period beginning only upon post-licensing notice, and that an injunction was correct to enforce the provision against Sandoz, which skipped the process of information exchange.

 to hear the case, arguing that the federal circuit turned the requirement for notice into a “grant of 180 days of additional exclusivity for all biological products beyond the exclusivity period Congress expressly provided—delaying the launch of all future biosimilars by six months.”

Sandoz also claimed that not only had the company given Amgen more than 180 days’ notice of intent to market Zarxio, giving Amgen time to bring forth a suit and seek a patent-based injunction, but Amgen’s exclusivity period for Neupogen had expired because Amgen already had enjoyed 24 years of exclusivity. Pike added that Congress had already debated 12 years of market exclusivity—not 12 years plus 180 days. Amgen counters that Sandoz did not follow BPCIA rules and treats the BPCIA’s mandatory procedures for the resolution of patent disputes like an á-la-carte menu from which to pick and choose.

A biosimilar applicant is required to provide the reference drug sponsor with 180 days’ notice after licensure and prior to marketing the product?

A biosimilar applicant is required to provide the reference drug sponsor with a copy of its biologics license application and related manufacturing information, and can a court issue an order enforcing that?

US Supreme Court to Consider Sandoz vs Amgen Biosimilar Patent Dance Case on April 26

A German study of gastroenterologist and patient acceptance of biosimilars to treat ulcerative colitis (UC) and Crohn’s disease (CD) suggests that there is reluctance among patients to accept biosimilars, and a need for better communication with physicians and education about biosimilars. The study, published in 

, examined gastroenterologists’ motivations for prescribing biosimilars, assessed their treatment preferences in relation to prescribing behavior, and explored patients’ attitudes to biosimilars.

In Germany 2 infliximab biosimilars were approved in 2013 (Remsima and Inflectra) and launched in 2015. A biosimilar for etanercept was approved in Europe in January 2016, and approval of other biosimilars that will be potential treatments for inflammatory bowel disease, is very likely to occur in the coming months and years. Other biosimilars, including those for adalimumab and rituximab, are also under development. The authors note that even though Germany has some of the highest market shares in the European biosimilars market, automatic substitution of bio-originators with biosimilars by pharmacists is not allowed and there is still a marked reluctance by physicians to prescribe biosimilars. Although regulatory requirements in Europe (and the United States) ensure that approved biosimilars have the same activity and safety profile as the originator drug and the quality of the production process is guaranteed, “concerns apparently remain,” the authors write.

study used data from a cross-sectional study undertaken in 2015-2016, that involved 25 German gastroenterologists and 136 patients, aged 18 and over, who were being treated for UC (n = 67) or CD (n = 69). Biosimilars accounted for less than 15% of all biologic therapies—88% of gastroenterologists said they preferred to prescribe a reference biological rather than a biosimilar as first-line therapy. This decreased to 72% and 80% for UC and CD, respectively, for second line treatment.

Gastroenterologists were split into 3 groups: investigative (primarily concerned with symptom improvement/disease modification, conservative (primarily concerned with safety), and other (influenced primarily by other factors). Physicians managed at least 1 patient with each disease in each of the following patient groups:

Patient receives biosimilar and was previously biologic-naïve (n = 37)

Patient receives biosimilar and has experience with a bio-originator (reference) biologic (n = 33)

Patient receives bio-originator, starting after February 2015 (n = 34)

Patient receives bio-originator, starting before January 2015 (n = 32)

A great majority (89%) of the investigative physicians and 100% of the conservative physicians said they prescribed biosimilars instead of bio-originators to gain experience with the new products. Forty-four percent of investigative physicians believed biosimilar efficacy is equivalent to the bio-originator, and said lower cost was a consideration; 83% of conservative physicians said lower cost and “economic prescribing” played a role in selecting biosimilars.

Patients, however, showed some reluctance toward using a biosimilar. The mean percentage of patients who accepted a biosimilar without reluctance, having never been prescribed a bio-originator or biosimilar, was 60%, versus 43% of patients currently receiving a bio-originator and with no clinical reason for a change in therapy. Of those being treated with biosimilars,

79% were satisfied with current treatment

At least 35% in each analysis group reported no concerns when starting treatment with a reference biological or biosimilar

41% of previously biologic-naïve patients mentioned potential side effects and potential long-term problems

24% were concerned that they did not know enough about the drug

A small proportion of patients would not accept treatment with a biosimilar, only the bio-originator. Physicians reported that a small proportion (mean 8% to 9%) of patients refused any form of biologic therapy, regardless of the patient’s prior experience with biologic therapy or the reason for a switch in therapy.

The study authors noted that 2 recent surveys of European gastroenterologists conducted a year apart, following greater education and use of biosimilars, found increased confidence in the use of biosimilars and a spike in the number of doctors who considered biosimilars and reference biologics as interchangeable. Cost savings remained the primary objective with using biosimilars among more than 90% of physicians, and immunogenicity was the main concern for 69% of physicians.

The authors conclude that results from their study and other surveys of European gastroenterologists suggest that patient and physician communication is very important, and further education may be needed to determine the role of other factors in influencing the conversations.

“A cautious approach is needed until sufficient long-term data are available for biosimilars to mitigate any concerns that currently exist,” the authors write, and recommend more robust product identification mechanisms to ensure traceability and accurate pharmacovigilance for biosimilar products.