Christina Mattina

German pharmaceutical company Merck KGaA has confirmed that it is far along in talks to sell off its biosimilars unit, which has not yet brought any drugs to the market.

Rumors began swirling in October, amid reports that Merck was seeking a buyer for its biosimilars unit. Chief executive Stefan Oschmann 

 at a press conference today, saying that Merck is in “deep talks” to sell off the division. He did not reveal the identity of the buyer or the selling price of the unit, but its worth is estimated at around $1 billion.

The prospective buyer to gain the division has not yet put a product on the market, but has built solid foundations for eventually becoming competitive. According to Merck’s website, the biosimilar portfolio is focused on therapies for cancers and inflammatory disorders. Last year, it began a phase 3 study of its proposed adalimumab biosimilar to compete with the branded drug, Humira, made by AbbVie. The trial results have not yet been released.

In 2015, Humira cost an average of $27,665 per year after discounts, an increase of almost 50% from its cost 3 years prior. Due to these high prices, it has become a popular target for drug companies hoping to market a less expensive biosimilar to patients with chronic plaque psoriasis. This opportunity means that a number of Merck’s competitors have already gotten a head start on developing a biosimilar for adalimumab.

Amgen’s Amjevita is the only adalimumab biosimilar to be approved by the FDA, but its launch has been delayed by legal roadblocks from AbbVie. 

 from phase 3 trials that showed its adalimumab biosimilar achieved the endpoints for demonstrating efficacy. 

 successful bioequivalence trial results in an announcement the week before.

, Merck began collaborating with India-based Dr. Reddy’s in 2012 to develop a host of potential biosimilars, including ones for adalimumab, rituximab (sold as Rituxan by Roche), and pegfilgrastim (sold as Neulasta by Amgen). The FDA has not yet approved biosimilars for the latter 2 drugs, although its European 

counterpart granted authorization to Celltrion’s

 rituximab biosimilar, Truxima, this February. Mylan and Biocon’s pegfilgrastim biosimilar application is 

 the increasingly crowded biosimilar market, it will likely concentrate its development efforts on multiple sclerosis to capitalize on the success of its interferon beta-1a injection, sold as Rebif. 

Articles

Merck KGaA Close to Selling Biosimilars Division to Undisclosed Buyer 

At the American Academy of Dermatology Annual Meeting, 

 that its proposed biosimilar adalimumab has met its primary endpoint for demonstrating efficacy in clinical trials.

The phase 3 study results found that the proposed biosimilar, GP2017, was in fact slightly more effective than the reference drug, AbbVie’s Humira. The primary endpoint was the proportion of participants with moderate to severe chronic plaque psoriasis who saw a 75% improvement in symptoms, as measured by the Psoriasis Area and Severity Index. After 16 weeks of treatment, 67% of those receiving the biosimilar achieved this benchmark, as did 65% of those on Humira. 

At the end of the first 17-week study period, GP2017 had demonstrated favorable results for safety and immunogenicity, as the occurrence of adverse events and antibody reactions were similar to those observed in patients receiving the reference drug. Any adverse events were consistent with those listed in Humira’s safety profile.

Executives of Sandoz, a subsidiary of Novartis, heralded the trial data as an exciting step towards expanded access to treatment for patients with chronic plaque psoriasis.

"Currently, it is estimated that as few as five percent of eligible psoriasis patients get the biologics they need," said Mark Levick, MD, PhD, global head of development in biopharmaceuticals at Sandoz. "We are pleased the data reinforce the potential of our biosimilar adalimumab, if approved, to be another treatment option for moderate-to-severe chronic plaque psoriasis and other inflammatory diseases."

Sandoz plans to file its application for GP2017’s approval with both the European Medicines Agency and the FDA this year. The FDA filing was originally intended for the last quarter of 2016, but was pushed back due to concerns about the timing of regulatory inspections in conjunction with manufacturing facility upgrades, 

. Chief medical officer Vasant Narasimhan denied that the delay was due to any unfavorable clinical data for the proposed biosimilar.

GP2017 will be racing against another competitor, Coherus’s CHS-1420, as it travels through the development and approval pipeline. Less than a week ago, 

 that its proposed adalimumab biosimilar achieved pharmacokinetic (PK) equivalence with the reference drug in clinical trials and had demonstrated comparable safety and tolerability profiles.

The president and CEO of Coherus, Danny Lanfear, said that the drug maker is confident it can “similarly complete future PK studies with modified formulations, anticipated to commence later in 2017.” He did not specify a timeline for submitting a regulatory application.

There is currently just 1 FDA-approved biosimilar for autoimmune drug adalimumab, Amgen’s Amjevita, but its launch has been held up by patent lawsuits from AbbVie. One analysis in 2015 reported that a yearlong course of AbbVie’s Humira cost an average of $27,665 after discounts, an increase of almost 50% from its cost 3 years prior.

Sandoz Releases Efficacy Data for Its Humira Biosimilar

 that its proposed adalimumab (Humira) biosimilar met the primary endpoints in a bioequivalence study, which signifies an important step towards approval.

The drug, currently referred to as CHS-1420, achieved the necessary criteria for clinical pharmacokinetic (PK) similarity to the reference drug in a randomized, double-blind study. It assessed bioavailability after administration of a 40 mg injection using 3 metrics: maximum serum concentration, area under the time-concentration curve from first to last time point measured, and area under the time-concentration curve from first time point extrapolated to infinity.

This early-stage study, conducted in healthy subjects, also found that CHS-1420 was well-tolerated and did not find any safety differences between the biosimilar and the branded drug. In the announcement, Coherus executives expressed optimism about the study findings and the future of the potential biosimilar.

“Positive results from this study are an essential global regulatory requirement to demonstrate PK bioequivalence on multiple prespecified primary PK endpoints between CHS-1420 and Humira,” said Barbara Finck, MD, chief medical officer of Coherus. “We are pleased to have achieved results which we believe represent a significant reduction in development program risk.”

“This is our second successful CHS-1420 PK study,” added Denny Lanfear, president and CEO of Coherus. “Our ability to achieve these results gives us confidence that we can similarly complete future PK studies with modified formulations, anticipated to commence later in 2017.”

Coherus has 2 other biosimilar products under development, for etanercept (Enbrel) and pegfilgrastim (Neulasta). The company has already filed a Biologics Licens Application in the United States and Europe for the pegfilgrastim biosimilar, while the etanercept biosimilar is in phase 3 studies. 

Adalimumab is used to treat autoimmune diseases like rheumatoid arthritis, Crohn’s disease, and some kinds of psoriasis. Since the patent on Humira expired in 2016, the FDA has approved 1 adalimumab biosimilar, Amjevita, made by Amgen. Its entrance into the market has been delayed by patent lawsuits brought by AbbVie, which manufactures Humira.

Coherus is not the only drug maker jumping into the fray of adalimumab biosimilars. Sandoz, a subsidiary of Novartis, has been developing its own candidate, but 

 with the FDA. Executives said that the delay was unrelated to the drug’s clinical performance; instead, the application was postponed so the company could have time to upgrade its manufacturing facilities before an inspection would be required.

Bioequivalence Endpoints Successfully Met for Humira Biosimilar, Coherus Announces

A recent report predicts that the market for biosimilar drugs to treat diabetes will grow rapidly in the coming years, fueled by impending patent expiries and the rising costs incurred by diabetes patients.

According to the American Diabetes Association (ADA), the total costs of the disease reached $245 billion in 2012, representing both direct medical costs and reduced productivity. Over 29 million Americans have diabetes—a number that grows by about 1.4 million per year&mdash;and in 2013 they paid an estimated $1922 of their $14,999 average annual healthcare costs out of pocket.

Looking at these factors, it is clear why drug developers and patients alike are excited about the prospect of biosimilar drugs to treat diabetes. According to a 

, biosimilar insulin has the “potential to reduce diabetes treatment costs, increase accessibility of insulin treatment, and expand the number of insulin brands.”

In late 2015, the FDA approved Basaglar, an analog of insulin glargine, which was produced by Eli Lilly and Boehringer Ingelheim. It could not technically be approved as a biosimilar product because “no insulin glargine products are currently licensed under the Public Health Service Act, so there is no ‘reference product’ for a proposed biosimilar product,” according to 

Still, Basaglar underwent rigorous testing similar to the processes of the biosimilar approval pathway, as the application had to demonstrate that Basaglar was not only safe and effective, but was also sufficiently similar to the branded drug, Lantus. The approval of the new drug was accelerated by the inclusion of safety and effectiveness data from when the FDA approved Lantus.

Other insulin glargine analogs, including one by Samsung Bioepis and Merck, are currently under review by the FDA, and some are available in the overseas market. The report also predicts that biosimilars will be developed for insulin aspart and insulin lispro when their patents expire. Prior 

 that insulin glargine biosimilars could produce savings of up to 15%, but with the introduction of additional competitors, the price will likely drop further.

The report notes that some drug makers may face challenges in getting insulin biosimilars on the market due to the “stringent regulatory requirements” in the United States. However, it predicted that the allure of selling a more affordable biosimilar alternative to the growing population of diabetes patients will outweigh most companies’ hesitancies about the drug development process.

ADA and other organizations are looking forward to increased biosimilar availability, citing their potential to lower prices and expand access.

“We are excited for the availability of more biosimilar insulins for people with diabetes, with the recent approval of insulin glargine and the ongoing development of aspart and lispro,” said William T. Cefalu, MD, chief scientific, medical, and mission officer of the ADA. “Availability of biosimilars could increase access to analog insulins, which provide more tailored insulin treatment, and improve health outcomes for the nearly 6 million Americans with diabetes who rely on insulin.”

Cefalu emphasized that the promise of biosimilars can only be fulfilled if they are priced substantially lower than brand-name drugs, which can be a difficult endeavor considering their high development costs.

“With regards to cost, the impact of biosimilars is currently unclear. A key challenge to pricing of biosimilars is the production process—it is expensive to produce insulin, and the FDA will only approve a biosimilar product if it has the same mechanism of action, route of administration, dosage form, and strength as the reference product,” Cefalu explained.

“What we saw with the introduction of insulin glargine (Basaglar) in January was a savings of approximately 15% off of the list price of the brand-name insulin glargine. We are hopeful for insulin to be accessible and affordable for all who need insulin.”

Diabetes Drugs Could Be Next Frontier of Biosimilar Development

Celltrion’s Truxima, a biosimilar of rituximab, has been granted approval from the European Medicines Agency (EMA) for its use in several cancers and autoimmune disorders. The drug has already been approved in Korea, and Celltrion plans to submit an application to the FDA this year.

 announcing the approval, Truxima is the first biosimilar monoclonal antibody approved as an oncology therapy. It has been indicated for the treatment of non-Hodgkin’s lymphoma and chronic lymphocytic leukemia, as well as autoimmune disorders (rheumatoid arthritis and granulomatosis with polyangiitis and microscopic polyangiitis).  

 that gave the application the green light for the subsequent marketing authorization. It did so after reviewing data on safety, efficacy, immunogenicity, pharmacodynamics, and pharmacokinetics that demonstrated convincing similarity between Truxima and the reference rituximab, sold by Roche as MabThera. The Celltrion press release declared that these “trials were conducted in over 600 patients and include data up to 104 weeks.”

Truxima is manufactured in Korea, where Celltrion is based. In November, when Korea’s Ministry of Food and Drug Safety approved Truxima, 

 about the drug’s chances of success with the EMA, as its application was then underway, and eventually with the FDA. The company has not yet announced an FDA application, which it said would be submitted sometime in early 2017.

Mundipharma has distribution rights in 7 European countries, and plans to have Truxima on the market starting in the second quarter of 2017. Teva and Celltrion have already formed a $160 million partnership that will allow Teva to sell Truxima in the United States upon its approval by the FDA, according to a 

Celltrion’s manufacturing facilities are undergoing expansion in hopes of boosting production capacity to 310,000 liters by 2021, reflecting its enthusiasm about the potential for biosimilars to disrupt the market and expand access due to their lower price. The press release quoted projections from László Gulácsi, a Hungarian professor and consultant, who said that savings could reach €570 million across the 28 EU countries over a 3-year period, allowing 49,000 new patients to receive the treatment.

"For healthcare systems burdened with high-cost oncology treatments, we are pleased to provide an option that has the potential to offer significant savings whilst ensuring patients retain access to high-quality and effective treatments,” said Celltrion chairman Jung-Jin Seo at a meeting in Paris, according to the press release.

Truxima Receives Approval in EU for Autoimmune, Oncology Indications

The high cost of bevacizumab can impede access to this anticancer agent, particularly in emerging markets. A recent survey of physicians around the world found that a majority of them would be willing to prescribe a biosimilar if it became available, which could potentially lower costs and expand access.

Currently, there is no approved biosimilar for bevacizumab, a monoclonal antibody used to treat advanced solid tumors, including metastatic colorectal cancer (mCRC) and advanced or metastatic non-squamous non-small-cell lung cancer (mNSCLC). In the United States, it is approved for treating glioblastoma (GBM) and metastatic ovarian cancer (mOC), and in the European Union (EU) it is indicated for patients with metastatic breast cancer (mBC). Bevacizumab has been shown to prolong survival in patients with these cancers when combined with chemotherapy.

A survey of 510 oncologists in the United States, the EU, and emerging markets (Brazil, Mexico, and Turkey) has, however, revealed interesting disparities in rates of prescribing and perceptions of access, according to a study recently published in the journal 

Of the surveyed physicians who did not frequently prescribe bevacizumab, those from emerging markets were more likely to cite access as a barrier to prescribing across all tumors types. Further, physicians in the United States and EU found it easier to access the drug when treating patients with mCRC, mNSCLC, and mOC than physicians in emerging markets. US physicians could readily access bevacizumab for treatment of GBM than physicians in the 2 other markets, while EU physicians found it easier to access the drug for mBC.

The predominant reasons for the perceived barriers to access were that the drug’s costs were “not reimbursed by healthcare system/private insurance,” and the “high out-of-pocket (OOP) costs to the patient.” These barriers were most commonly cited by physicians in emerging markets, although 67% of American respondents said lack of reimbursement was a barrier to prescribing the drug for mOC, compared with 55% of physicians in emerging markets and just 24% in the EU.

Roughly 50% of respondents agreed that reducing the amount of bevacizumab cycles would likely or very likely impact patient quality of life and survival, yet some found it necessary to do so. Of the physicians who had to reduce the number of cycles prescribed, the most common reason across all markets and tumor types was the lack of reimbursement. A significantly higher number of physicians in the US (40%) reported they had to reduce the number of cycles for GBM treatment because of high OOP costs to patients, compared with physicians in the EU (18%) and in emerging markets (19%).

Considering these cost-related barriers, it comes as no surprise that 42% to 92% of physicians across all tumor types and markets would definitely or probably prescribe a biosimilar for bevacizumab if it became available. Physicians in all regions cited efficacy and cost as the main reasons they would be willing to prescribe the biosimilar, although the most common rationales against biosimilar prescribing were concerns about efficacy and a lack of clinical trial data. The physicians who probably or definitely would not prescribe a biosimilar indicated that they might change their minds upon seeing more efficacy and safety data and substantial cost reductions compared to the originator.

“Overall, these data demonstrate that access-related issues create a barrier to bevacizumab use worldwide, but particularly among physicians in the EM [emerging markets],” the study authors concluded. “A bevacizumab biosimilar could offer the same opportunity to address the needs of patients with cancer by increasing access to bevacizumab, and generating cost savings that could be redistributed to expand patient access to other biologic therapies.”

Monk BJ, Lammers PE, Cartwright T, Jacobs I. Barriers to the access of bevacizumab in patients with solid tumors and the potential impact of biosimilars: a physician survey. 

. 2017;10(1). pii: E19. doi: 10.3390/ph10010019.

Bevacizumab Biosimilar Could Address Global Barriers to Access

An industry-sponsored survey of specialty physicians in America revealed that their awareness and perceptions of biosimilar drugs can be lacking in some areas, but they would be interested in learning more about the concept.

Researchers from the Biosimilars Forum surveyed 1201 American dermatologists, gastroenterologists, rheumatologists, nephrologists, hematology-oncologists, and medical oncologists who reported prescribing biologic drugs, and published the findings in the journal 

The study was conducted from November 2015 to January 2016, which could contribute to the seemingly low levels of knowledge among the participants, since the first FDA-approved biosimilar had just entered the market in September 2015.

Some participants were seemingly confused about what defines a biologic, despite the fact that all participants reported they prescribed biologic drugs. Medical oncologists, for instance, correctly identified a given drug as a biologic 62.8% of the time. Similarly, the vast majority said they have heard about biosimilars, but knowledge of specifics was low.

Around half of respondents from each specialty correctly said that biosimilars had just become available in the United States within the past year, with the exception of rheumatologists, 55.5% of whom thought that biosimilars were not yet available in the country. While 62.3% of respondents knew that biosimilars must be equally efficient as the original drug and 57.2% said the biosimilar must be comparable in safety, over half (55.2%) disagreed that biosimilars were safe.

There was some confusion regarding the term “interchangeable,” which indicates that a biosimilar has demonstrated its safety and efficacy for back-and-forth switching with the original biologic. Four out of 5 respondents did not know that interchangeability would let pharmacists switch between the originator biologic and its biosimilar products.

Respondents also reported concerns about the approval process. Half were knowledgeable of the concept of “totality of evidence” used to assess biosimilars, and just 12% were comfortable with the concept of extrapolation to approve a biosimilar for other indications based on the originator biologic, although this could be due to knowledge gaps on what the term actually means.

Despite these apprehensions, 91% of respondents said they would be open to prescribing biosimilars to their patients after seeing sufficient evidence on switching and indications. They also indicated they would like to learn more about key biosimilars concepts and their potential impact on drug costs and access.

The study authors wrote that the survey results “highlight a significant need for evidence-based education about biosimilars for physicians across specialties.” They plan to conduct a follow-up survey in 2 to 3 years to examine whether awareness and perceptions about biosimilars have improved as new drugs continue to enter the US and European markets.

Cohen H, Beydoun D, Chien D, et al. Awareness, Knowledge, and Perceptions of Biosimilars Among Specialty Physicians. 

Biosimilar Knowledge Gaps Identified Among US Specialty Physicians

Beginning this month, the European Medicines Agency (EMA) will offer biosimilar manufacturers a chance to receive tailored scientific advice on their drug’s development prior to submission of a formal application. These meetings will resemble some stages of the FDA’s recommended biosimilar development process.

, will give drug makers individualized feedback on data submitted to the agency’s Scientific Advice Working Party before the final marketing authorization application. The pilot differs from the standard scientific advice procedure in that it allows for an in-depth assessment of trial data and offers specific recommendations for future tests and next steps, not just suggestions on the general development strategy.

The pilot will accept 6 participants after reviewing the applications’ suitability. Only 1 request for the tailored advice will be granted per month, and the process will take a month longer than the traditional scientific advice procedure.

In the announcement, the EMA wrote that this pilot aims to “provide developers of biosimilars with advice on the studies/tests they should be conducting” based on the submitted data. It noted that submissions that undergo this enhanced process are not guaranteed acceptance of their final authorization applications.

As the extent of advice offered by the EMA will vary depending on the evidence submitted, the pilot can be compared to 2 stages of the FDA’s biological product development (BPD) process as outlined in 

, “Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants.” In these guidelines, the FDA explains the 5 types of formal meetings that may occur between drug makers and FDA representatives before the drug approval application is submitted.

A BPD Type 2 meeting can be arranged by a drug maker seeking targeted advice to answer a specific question on an issue like study design. This type of meeting can encompass “substantive review of summary data, but does not include review of full study reports.” A Type 3 meeting, meanwhile, offers in-depth data review of full study reports and guidance from the FDA on the proposed drug’s similarity to the reference drug and any further tests needed.

Applicants can request as many of these meetings as necessary throughout the drug’s development, though the FDA does charge a one-time fee to participate in the program. Drug makers are not required to participate in each meeting stage.

According to the draft guidance, the FDA encourages drug makers to use these meetings “to optimize product development and facilitate submission of marketing applications.” The FDA’s 

website on the biosimilar approval process

 notes that manufacturers should take advantage of this opportunity to obtain input at an earlier stage, especially as FDA officials may determine during this review process that an element of the required information to be submitted with the application is unnecessary for that particular drug.

These feedback efforts by the EMA and FDA, therefore, can be invaluable to drug makers preparing to submit biosimilar applications, as the input may expedite the approval process and reduce the number of rejected submissions.

EMA Pilot Will Provide Tailored Advice to Biosimilar Developers, Similar to FDA Process

Sandoz has pulled its pegfilgrastim biosimilar application from consideration by the European Medicines Agency (EMA) after the agency’s Committee for Medicinal Products for Human Use (CHMP) responded to the initial submission with a list of questions. Zioxtenzo, which was intended as a biosimilar for Amgen’s Neulasta, was rejected by the FDA in July 2016.

Last February, Sandoz—a Novartis subsidiary&mdash;presented study results to the CHMP aiming to show that Zioxtenzo could treat neutropenia in cancer patients with the same safety and effectiveness as Neulasta, but the committee was not convinced. After evaluating the documentation, 

 that it could not approve the drug as a biosimilar based on 2 primary concerns.

First, the trial results failed to show that Zioxtenzo produced comparable blood levels of pegfilgrastim, the drug’s active substance that works similarly to the human protein granulocyte-colony-stimulating factor that fights neutropenia by encouraging bone marrow to make more neutrophils. Neutropenia is common in patients receiving chemotherapy and can result in fever and serious infections.

The second concern of the CHMP was that the drug’s manufacturing site did not have a certificate of Good Manufacturing Practice, which is awarded to manufacturers that meet certain standards of quality assurance, personnel qualifications, accurate documentation, labelling practices, and clean premises and equipment. The CHMP said that it would need to inspect the site before Zioxtenzo could be approved.

However, Sandoz chose not to prepare for this inspection and instead withdrew its application completely. 

 to the chair of the CHMP explaining the decision, the company said that it would “not be able to provide the additional information required by the CHMP within the regulatory timeframe for this procedure.” The letter indicated, however, that Sandoz would continue its ongoing clinical trials and left the door open for future resubmissions after it had addressed the committee’s concerns.

The withdrawal followed a similar disappointment in July, when Sandoz received a complete response letter from the FDA indicating that Zioxtenzo had not been approved. Novartis said 

 that it was “working with the agency to address remaining questions,” though it did not elaborate on the nature of the FDA’s concerns.

Sandoz, the generic subsidiary of Novartis, became the first to enter the 

 when the FDA approved its filgrastim biosimilar Zarxio in 2015. It has vowed to launch 4 additional biosimilars by 2020, including Zioxtenzo.

EMA Concerns Prompt Sandoz to Withdraw Neulasta Biosimilar Application

President Donald Trump's executive order freezing hiring for federal jobs could apply to the already-understaffed FDA, which would extend the waiting time for biosimilar approvals.

The hiring freeze order issued January 23, 2017, specifies that federal agencies can exempt any positions it deems necessary to meet “public safety responsibilities,” but it remains unclear whether drug reviewer positions at the FDA would fall under this category. Bob Pollack, former acting deputy director of the FDA Office of Generic Drugs (OGD), wrote in 

 after the announcement that he did not anticipate the exception would apply to FDA staff, grimly noting that “we could be in for a long, unpleasant haul.”

There are currently around 850 vacant positions within the FDA Center for Drug Evaluation and Research, 150 of which are for generic drug reviewers. This dearth of staff combined with a backlog of over 4000 pending generic drug applications has 

 that approvals of new generics and biosimilars could slow to a crawl. OGD expects to receive a record-high 1600 abbreviated new drug applications in the 2017 fiscal year.

“A fully-resourced FDA is critical to reducing the backlog and making sure that patients have timely access to medicines,” the Generic Pharmaceutical Association (GPhA) said in a statement. “The agency itself has recognized the need for more resources to expedite the approval of generics and biosimilars.”

 reported that 8 congressional Democrats sent a letter on Monday to acting FDA Commissioner Stephen Ostroff, cautioning of the potential ramifications of a hiring freeze at the FDA. A main concern was that the freeze could thwart a component of the recently passed 21st Century Cures Act that would fund the hiring of new drug reviewers.

“A hiring freeze at the FDA would conflict with and do significant damage to these bipartisan efforts to fill vacant positions and expand the scientific and technical workforce needed for a robust review of drugs and medical devices,” they wrote.

If the freeze does in fact stall the review and approval of biosimilars, it will eliminate a promising avenue for controlling the cost of prescription drugs. 

 suggests that biosimilar competition can drive down prices across an entire class of drugs, resulting in cost reductions of up to 60%. A slowdown of biosimilar approvals in the United States would prolong the financial struggles experienced by many patients facing skyrocketing drug prices.