Randi Hernandez was science editor at Pharmaceutical Technology from September 2014 to May 2017.

Randi Hernandez

	During a presentation at the 2016 American Society of Clinical Oncology (ASCO) in Chicago on June 3, 2016, Mylan announced that MYL-1401O, its biosimilar to Roche’s Herceptin (trastuzumab), demonstrated comparable efficacy in Phase III clinical trials for the treatment of HER2-positive breast cancer. The molecule is being developed in collaboration with India’s Biocon Ltd. The biosimilar to Herceptin is one of the six biosimilar programs on which Mylan and Biocon will collaborate.
	
	At 24 weeks, the response rates with MYL-1401O combined with taxane chemotherapy vs. Herceptin with taxane chemotherapy were 69.4% and 64%, respectively. Serious adverse events were 38% with MYL-1401O and 36% with Herceptin, demonstrating comparable safety profiles. The abstract presenting the results of this HERITAGE trial was selected for the “Best of ASCO” program in 2016, according to a Mylan press release. Mylan President Rajiv Malik commented in the release, “As one of the first companies in the industry to successfully complete a confirmatory efficacy and safety study comparing a proposed biosimilar to a branded cancer drug, this is a significant milestone for Mylan’s biosimilar program.”

 in Roche’s pharmaceuticals division were up 5% in 2015, and these increases were driven by oncology medicines Herceptin, Avastin (bevacizumab), and Perjeta (pertuzumab)â, as well as Esbriet (pirfenidone)â for idiopathic pulmonary fibrosis. Sales for Herceptin alone increased 10% in 2015 and accounted for 17% of pharmaceutical sales in 2015. It was the second-largest seller for Roche in 2015, closely following sales for Avastin, which dominated 18% of Roche's sales in 2015.

	Other companies, including Pfizer and Amgen, are also developing biosimilar versions to Herceptin (PF-05280014 and ABP 980, respectively). Although the patent expiration date in the United States for Herceptin is supposedly set for 2019, innovator companies are putting their resources into fortifying their patents to defend branded medications against biosimilar competition and are stressing in company press releases that biosimilars are not exact copies.

Articles

Results of the HERITAGE study were announced at the 2016 American Society of Clinical Oncology meeting.

Mylan and Biocon’s Biosimilar to Herceptin Demonstrates Comparable Efficacy

	Foreseeing an uptick in the number of available biosimilars that will be available in Europe, The Dutch Minister of Health (MoH) announced it will set up a system to track biosimilar use and instances of switching that occur between innovator products and biosimilar alternatives. The Netherlands Pharmacovigilance Centre Lareb will aid the MoH in setting up the system and will begin monitoring the patients who are prescribed biologics at five separate hospitals in late 2016.

	Lareb plans to use the information it has obtained to craft a proposal for a national system to support safe switching between biological products. The agency already collects and analyzes reports of adverse reactions of medicines and vaccines.

	The Dutch Medicines Evaluation Board (MEB) 

 the stance that patients should stay on reference products if these patients exhibit a good clinical response. But the agency said in a briefing from March 2015 that based on recent experiences with biosimilars, there is enough evidence to support the use of biosimilars in clinical practice, provided that patients are properly monitored and receive clear instructions for use. To properly trace patients who switch, the MEB supports monitoring by Lareb.

New pharmacovigilance activities seek to support the creation of guidelines for safe switching from innovator products to biosimilars.

Dutch System to Track Biosimilar Use and Switching Announced

	A naturally occurring CRISPR (clustered regularly interspaced short palindromic repeats) system that specifically can be used to modify the RNA of an organism is the newest development in the technology’s evolution. A new study, 

, identifies C2c2, a bacterial protein that can be used as a tool to cleave single-stranded RNA sequences at desired locations. As an RNA-guided RNAse, C2c2 can be harnessed to defend against viral intruders and turn off gene expression of certain conditions, according to researchers.


	Typically, gene silencing is a gene expression manipulation performed by small interfering RNA (siRNA), but the study researchers attest that the C2c2 complex is even more efficient when it comes to editing RNA. Specifically, C2c2 can be used to add to or delete information from existing RNA sequences, and can also be used to tag RNA to learn more information about the function of certain sequences. In addition, C2c2 can be programmed to knock out certain messenger RNA (mRNA), disrupting the DNA-->mRNA-->protein transcription process. C2c2 requires only a single RNA to function, and is “genetically encodable,” the researchers said in a Broad Institute/Harvard 

 accompanying the study. As an RNA-targeting immune system mechanism, they say C2c2 is a promising tool for future RNA manipulation.

	The authors concluded that the CRISPR-C2c2 complex is probably not the only system that can be programmed to alter RNA sequence, and other, patentable editing tools may be on the horizon. They wrote, “It is likely that other, broadly analogous Class 2 RNA-targeting immune systems exist, and further characterization of the diverse members of Class 2 systems will provide a deeper understanding of bacterial immunity and provide a rich starting point for the development of programmable molecular tools for 

	Although the research on CRISPR-C2c2 was conducted by various teams at MIT, the Broad Institute, Harvard University, the National Institutes of Health, Rutgers University-New Brunswick, and the Skolkovo Institute of Science and Technology, the Broad Institute’s Feng Zhang is at the helm of the research and serves as one of the paper’s senior authors. Zhang is notorious for being one of the founders of the CRISPR-Cas9 complex and its applications for editing DNA, however, there is currently an ongoing legal battle between the Broad Institute and the University of California (involving work by researcher Jennifer Doudna and by French researcher Emmanuelle Charpentier) for the patent rights to the technology.

As the battle for ownership over the use of CRISPR to edit DNA heats up, some of the CRISPR pioneers refocus their efforts to demonstrate the technology’s applications for editing RNA.

Using a New CRISPR Effector to Edit RNA

	A technology transfer can be considered a trade secret at a company, which may make some manufacturers resistant to entering into a partnership with an outside partner like a contract manufacturing organization. This data and platform secrecy is vital to keep competitors as bay. Citing an article from P. Lee, Jacob Sherkow wrote that manufacturers with a proprietary technology platform and their “tacit knowledge about scaling up such technology for industrial operation may serve as significant barriers to competitors” (1). These barriers are put up so competitors only find out the “broadest contours” of an innovator’s process, wrote Sherkow. If there are differences between manufacturing a product at the clinical trial level vs. at commercial scale, biologic manufacturers typically keep that information a secret, Sherkow noted.

 spoke to an expert in the field of intellectual property (IP) in the life-sciences industry, Maia Harris, partner in Pepper Hamilton’s IP Litigation Practice Group, to learn about how trade secrets protect the manufacture of biologic drugs and specifically how President Obama’s signing of the Defend Trade Secrets Act (DTSA) into law might affect the protection of trade secrets at biomanufacturing firms.

 What methods are commonly considered trade secrets in the biomanufacturing industry? How are they typically protected?

 Many aspects of commercial biotechnology products (including biologic drugs) could potentially be protected as a trade secret. Manufacturing methods and information are certainly one important aspect; others could include product composition information and analytical, preclinical, or clinical data. Whether any particular aspect of any particular biotech product or method will or can be protected as a trade secret ultimately depends not only on the technology or substance of the information, but also on what steps the owner of a trade secret takes to maintain its secrecy.

	Protection of trade secrets begins with internal procedures. At the most basic level, these could include a careful assessment and ongoing management of who can and cannot access trade secrets; adequate employee nondisclosure, intellectual property assignment, and, where possible, noncompetition agreements for anyone developing or accessing potential trade secret information, and employee training related to the nature of trade secrets and the legal obligations for maintaining them as such; policies for maintaining and storing lab notebooks related to research and development; and a formal review process for publications or other presentations being made by researchers and others. Further steps could include IT security measures and policies for segregating trade secret material from potential centralized and/or unauthorized access; employment of security personnel; and restricted employee access measures. At the end of the day, if the owner of a trade secret ever finds it necessary to bring an allegation of misappropriation as part of litigation, each step it takes to maintain secrecy will be scrutinized. It pays to be careful up front.

 What will the new legislation (Defend Trade Secrets Act) mean for the biomanufacturing industry, specifically?

 For many years now, companies involved with biotechnology development have been looking more and more to trade secrets as a way to protect their innovations. This is partly because of recent changes to the patent landscape in the US, ranging from court decisions making it more difficult to obtain injunctive relief and calling into question the patentability of ‘naturally occurring’ products and methods, to the creation of a new (and now widely used) venue in which the validity of patents may be challenged outside of district court litigation. Reliance on trade secrets was not without its own potential risks, however, including the fact that no single federal law governing the civil enforcement of trade secrets existed prior to the passing of the DTSA.

	In the short term, there are some practical effects of the passing of the DTSA, as some updates to existing employment, nondisclosure, and assignment agreements to ensure compliance with the DTSA will likely be appropriate before a trade secret owner will be able to enforce its trade secrets under the DTSA.

	In the longer term, the DTSA provides trade secret owners with access to federal courts in the event that they need to bring an action alleging misappropriation. And while it may take some time, the hope of many in the legal field is that these cases will ultimately result in a single, more unified, and more predictable legal structure that can be used as the basis of IP portfolio strategy more generally.

 How are trade secrets currently handled with companies that outsource either products or services?

 This is a big issue. Many biopharmaceutical companies outsource at least some part of their manufacturing. Beyond that, however, the potential sharing of trade secrets as a result of such activities as research collaborations, joint ventures, or acquisitions (whether consummated or not, whether successful or not) are all day-to-day risks that need to be managed carefully. There is no one-size-fits-all solution, and each activity that potentially involves sharing a trade secret should be analyzed for purposes of determining the appropriate steps needed to maintain secrecy and minimize risk of misappropriation.  However, many of the same steps described above are equally applicable and necessary for each event that may involve sharing a trade secret, for example, the selection of a limited number of individuals who can access the information, and careful drafting and consistent execution of nondisclosure and other relevant agreements governing all aspects (including the conclusion) of the relationship.

 Does bringing trade secret lawsuits compromise the very trade secrets that are under investigation?

 Any activity that involves potential disclosure of trade secrets poses a potential risk to those very trade secrets. We already touched on employees (many of whom will come and go over time) and outsourcing or other transactions that might involve such information sharing. Biopharmaceutical companies seeking FDA approval for their products must manage that process and the disclosures required as part of it with extreme care. And litigation-in the event it ever becomes necessary-poses another such risk, since a case for misappropriation of trade secrets will, inevitably, involve identifying the allegedly misappropriated trade secret. The good news is that, in those cases brought in federal district court under the DTSA, federal statute requires district court judges to preserve the confidentiality of trade secrets being litigated (18 USC 1835).  Of course, taking active steps to avoid the necessity of litigation where possible is always a good strategy, too.


	1. J.S. Sherkow, "Protecting Products Versus Platforms," 

 (Apr. 14, 2016), doi:10.1038/bioe.2016.4.

PharmTech sat down with an intellectual property lawyer to examine how companies are protected when they engage in activities where sharing of trade secrets must occur.

How the Defend Trade Secrets Act Could Better Protect Manufacturers Who Outsource to CMOs

	On May 30, Samsung Bioepis announced that its biosimilar candidate SB2, launched in partnership with Biogen, received approval from the European Commission and will be available for use in 28 European Union (EU) member states. Named Flixabi, the biosimilar to Johnson & Johnson/Merck’s Remicade (infliximab) will be marketed and distributed in the EU by Biogen.

	Flixabi demonstrated comparable safety and efficacy to Remicade in a 54-week Phase III clinical study of 584 patients with rheumatoid arthritis, producing an American College of Rheumatology 20% (ACR20) response rate of 65.3% compared with Remicade’s rate of 69.2%. Flixabi is approved in Europe for the inflammatory conditions rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and psoriasis.

	The approval of Flixabi makes Biogen "the first company to bring two anti-TNF biosimilars to patients and physicians across Europe," the company wrote in a 

, and Samsung is the first company to develop a second anti-TNF therapy in Europe. To be clear, Samsung Bioepis is a joint venture between Samsung BioLogics and Biogen. Flixabi follows Biogen’s marketing of Benepali, also known as SB4, a biosimilar referencing Amgen's Enbrel (etanercept), across the EU.

	On May 24, 2016, Samsung Bioepis announced that FDA accepted for review the company’s Biologics License Application (BLA) for SB2. If approved in the US, Merck would handle the marketing and distribution of SB2.

Samsung Bioepis and partner Biogen announced on May 30 that the European Commission approved Flixabi for the treatment of six inflammatory conditions.

EU Grants Approval to Remicade Biosimilar Flixabi

	In collaboration with Amplion, a biomarker business intelligence company, and BioMedtracker, a service that tracks a drug’s likelihood of approval (LOA) by FDA, the Biotechnology Innovation Organization (BIO) released a report on May 25, 2016 that examined clinical trial success rates from 2006 to 2015 (1).

	According to the report, across all developmental categories, the overall likelihood that a candidate is approved and makes it to market (beginning from Phase I) is approximately 10%. For biologics specifically, this LOA was found to be approximately 12%. Vaccines, specifically, had an approximately 16% LOA from Phase I.

	If a product fails in clinical trial development, it typically occurs when a product is to advance from Phase II to Phase III; according to the report, approximately 70% of developmental candidates do not advance to Phase III. The authors wrote this was likely due to the fact that Phase II is when proof-of-concept is first tested in human models.

	Of each of the individual phases, Phase I had the highest success rate (approximately 63%), which the report authors said was because this phase is “typically conducted for safety testing and is not dependent on efficacy results for candidates to advance.” They also may have the highest rate because some companies do not publicly disclose failures at this early a stage, contributing to reporting bias.

	Across 14 specific disease categories, oncology medications had the lowest LOA value (approximately 5%), while hematology had the highest LOA (approximately 26%). The failures in the oncology category typically occurred during Phase III transition. Interestingly, although oncology candidates had the lowest chance of approval, those that were approved were pushed through the regulatory process in approximately one year, nearly twice as fast as candidates that were approved in the neurology category. Oncology drugs, the authors noted, were the most likely to benefit from FDA’s expedited approval pathways, contributing to their fast approval rates.

	Authors of the report confirmed that compared with Phase III success rates of drugs that did not incorporate selection biomarkers, success rates for drugs with selection biomarkers had a higher LOA (55% and approximately 77%, respectively). “The large differences in Phase II and III transition success rates are quite convincing, quantitatively, of what many drug developers have long argued anecdotally-enrichment of patient enrollment at the molecular level is a more successful strategy then heterogenous enrollment,” the authors wrote. They did not elaborate, however, on how this biomarker-based strategy would specifically help drive market value or uptake of a medication over one that was approved with the same indication that did not include an accompanying diagnostic test.

In the largest-ever report of its kind, drugs entering clinical development in Phase I were found to have only a 1 in 10 chance of FDA approval.