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

Randi Hernandez

 meant to block Celltrion’s Remsima, a biosimilar to Janssen’s Remicade (infliximab), Janssen names the GE subsidiary HyClone Laboratories as unlawfully making a cell-culture media for Celltrion that is protected by Janssen’s 083 patent. The lawsuit claims Celltrion used this infringing media for the large-scale manufacture of Celltrion’s version of infliximab outside of the United States and plans to use the same media for the manufacture of Celltrion’s infliximab biosimilar within the US. Celltrion’s infliximab biosimilar was recently approved by FDA.

	Specifically, the lawsuit says, "Celltrion controlled the development of the infringing media, directing details of its composition and instructing HyClone to use the combinations of ingredients that together infringe the claims of the 083 patent." Although Janssen claims it asked HyClone to share the details of composition of the media in question, HyClone refused to disclose composition details, saying that it was “custom-made for Celltrion.” Janssen, however, claims that with the information it obtained about the culture media used by HyClone, it had a valid claim of infringement against HyClone. The suit says at least four HyClone employees that worked with Centocor also worked with Celltrion on its cell-culture media, and HyClone has been infringing Janssen’s patent since as early as 2010.

	Janssen lawyers wrote that Hospira may also be liable for infringement “at least as an inducer,” as Hospira was unable or unwilling to provide documentation of its knowledge of the use of the media in question for the manufacture of its biosimilar version of infliximab, Inflectra. The suit alleges that “Hospira knows that ordering infliximab from Celltrion causes the infringement by Celltrion and HyClone of the claims of the 083 patent,” and that ordering infliximab from Celltrion after having this knowledge is grounds for legal action.

	The media formulation, which was produced by Janssen predecessor Centocor, is capable of sustaining a high level of cell growth, according to court documents. It calls for 52 required ingredients and 9 optimal ingredients. Centocor shared the confidential formulation information covered by the 083 patent with HyClone in 2003. HyClone acknowledged the media formulation was a job well done, the lawsuit claims: "HyClone congratulated Centocor on Centocor’s successful design of the 083 media." Nevertheless, Centocor decided not to use HyClone's services for the mass production of Remicade.

Articles

In a lawsuit against Celltrion, Janssen alleges the GE subsidiary infringed one of Janssen’s patents covering the method of making the cell-culture media that HyClone later supplied to Celltrion.

Janssen Alleges HyClone Lab Infringed its Cell-Culture Media Patent

	A drug that was originally approved in 1970 for the prevention of anthrax disease in persons at high risk of exposure to 

, will, thanks to a newer indication, be protected by an Orphan Drug Designation status until 2022. The use of the drug for post-exposure prophylaxis (PEP) of disease following suspected or confirmed anthrax exposure (in combination with antibacterial drugs) makes the vaccine eligible for orphan drug exclusivity. According to FDA documents, the approval for the vaccine as a PEP 

	BioThrax is the first vaccine approved through the Animal Rule, which is characterized by the use of animal studies in place of human trials when human trials are not ethically sound. The vaccine was tested in rabbits and monkeys. BioThrax is the only vaccine licensed for immunization and distribution in the United States for the treatment of anthrax exposure, and its Orphan Drug designation is to 

 (i.e., “For post-exposure prophylaxis of anthrax disease resulting from suspected or confirmed 

 exposure”). The Biomedical Advanced Research and Development Authority (BARDA) awarded a contract for the advanced research and development of BioThrax and for its label expansion as a PEP.

	The Biomedical Advanced Research and Development Authority (BARDA) is funding other antianthrax drugs in development, including Elusys Therapeutics' monoclonal antibody, Anthim. On March 18, 2016, FDA 

 Anthim (obiltoxaximab) injection to treat inhalational anthrax in combination with appropriate antibacterial drugs. It too has Orphan Drug status, and the status will protect the drug until 2023. The main difference between these drugs is that one is a monoclonal antibody, while the other is a vaccine. They would both feasibly be eligible for Orphan Drug status because of this difference, even though they treat the same condition. "Orphan-drug exclusivity protects only the approved indication or use of a designated drug. Exclusivity is not specific to the indication, but is specific to the drug product,” Miko B. Neri, senior director of corporate communications at Emergent BioSolutions, told this publication. "In our case, exclusivity means that no one can develop a biosimilar of BioThrax and get approval before the end of our 7-year exclusivity. Anthim is not a ‘biosimilar’ vaccine to BioThrax, so our products are not comparable."

	Even another mAb in existence to treat anthrax disease (made by GlaxoSmithKline) has an orphan designation, according to an Elusys representative. "In terms of monoclonals, both raxibacumab and Anthim have orphan designation and essentially for the same indication. The reason both can have the designation is that we demonstrated that the products are not the 'same'."

	Emergent focuses much of its efforts on medical countermeasures for for biological and chemical hazards. Its other biodefense candidates in the pipeline include a vaccine to protect against pandemic flu and another for the treatment of the Dengue virus.

A new indication for Emergent BioSolutions’ BioThrax will give the drug market exclusivity through November 2022.

Anthrax Vaccine Nabs Orphan Drug Status

	Previous attempts to treat multiple sclerosis (MS), an autoimmune disease characterized by the breakdown of the myelin sheath on axons and axonal degeneration in the central nervous system, have included a regimen of autologous hematopoietic stem-cell transplantation (aHSCT) following chemotherapy. The prevailing thought behind this treatment was to try to re-program the immune system so that it would stop attacking itself. Although this type of treatment has been marked by some successes, many patients experience disease reactivation shortly after treatment.

	Harold L. Atkins, MD, and Mark S. Freedman, MD, of The Ottawa Hospital and the University of Ottawa, and colleagues hypothesized 

 that for immune cells to truly be re-programmed to fight disease long term, the immune system had to be totally wiped out by chemotherapy (i.e., immunoablation), rather than simply suppressed.

	Twenty-four multiple sclerosis patients who had previously failed on immunosuppressives served as trial participants. All participants were given a strong chemotherapy cocktail of busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin, followed by immune-cell depleted aHSCT. The study differed from others focused on aHSCT in that a high dose of chemotherapy was administered, and autoreactive immune stem cells were eliminated by “immunomagnetic selection” to ensure that no contaminating remnants of autoimmunity remained from the host’s blood. As the study authors wrote, “Graft selection has not been incorporated into most autologous haemopoietic stem-cell transplantation regimens for multiple sclerosis because of cost, regulatory complexities, and potentially delayed immune reconstitution.” The trial did not have a control arm, which is a limitation-but it has one of the longest prospective follow-up periods to date, according to a 

	Approximately 70% of patients experienced activity-free survival three years after treatment. These patients had no relapses or new brain lesions during this period, and had stable Expanded Disability Status Scale (EDSS) scores. “There was one new lesion seen on only one of the first MRIs after the transplant," says Dr. Atkins, but he adds, “that lesion might have occurred prior to the transplant, as the last pre-transplant MRI used for comparison was not right at the time of transplant." The patients had an average of 1.2 relapses per year prior to treatment, and 23 patients suffered no relapses during the trial follow-up period (between 4Â­Â­Â­â13 years). Eight of the patients (35%) showed sustained improvement in disability 7.5 years after treatment, as measured by their EDSS scores. Importantly, no disease-modifying drugs were used during the study period to help control inflammatory activity, according to study authors. In addition, study authors pointed out that the reduction in brain atrophy in their cohort approached the rate that is characteristic of normal aging.

	Despite the promising results of treatment, one patient died from hepatic necrosis and sepsis as a result of transplantation-related complications. Other adverse events after transplantation included fevers (all patients experienced this), urinary tract infections, sinusoid obstruction syndrome, viral infections, plantar warts (9%), shingles (26%), herpesvirus-6 pneumonia (4%), thrombocytopenia (4%), secondary autoimmune events such as hypo- and hyperthyroidism (26%), and other febrile events (67%). A 

 acknowledged that even though this is the first treatment to produce such a high level of disease control, the treatment-related risks “limit its widespread use.” However, Dr. Freedman tells this publication, “no other treatment or medication has matched the transplant relapse rate of zero.” Many other studies looking at aggressive MS report that patients experience disease reactivation within the first five years of follow-up. Freedman says that for this set of patients with treatment-refractory disease, no other treatment option has been as promising. “Most early MS patients today have relapse rates on treatment of about 0.2Â­â0.4 per year-a far cry from our patients that had 4Â­â5x that rate.” he notes. Jan DÃ¶rr, MD, from the NeuroCure Clinical Research Center, CharitÃ©-UniversitÃ¤tsmedizin, Berlin, Germany, wrote in a 

 that even alemtuzumab, which is “considered the most powerful drug for multiple sclerosis, achieved complete control of disease activity in only 32% of patients in a similar cohort.”

 findings may not change the current approaches to treat MS in the short term, wrote DÃ¶rr, “there may be support for considering aHSCT less as a rescue therapy and more as a general treatment option, provided the different protocols are harmonized and optimized, the tolerability and safety profile can be further improved, and prognostic markers become available to identify patients at risk of poor prognosis in whom a potentially more hazardous treatment might be justified.” DÃ¶rr added, “This trial is the first to show complete suppression of any inflammatory disease activity in every patient for a long period.”

	Immunoablation to destroy the autoreactive immune system followed with transplantation by aHSCT also has implications for the treatment of other autoimmune diseases. Dr. Atkins has previously published encouraging results using the same procedure for the treatment of 

Results of a Phase II clinical trial reveal that stem-cell transplantation treatment following complete immune system destruction increases the duration of long-term remission in patients with multiple sclerosis.

New Aggressive Treatment Shown to Halt Symptoms of Multiple Sclerosis for a Prolonged Period

	GE Healthcare Life Sciences and biopharmaceutical company PnuVax have teamed up for a unique partnership, wherein PnuVax can acquire GE’s intellectual property for a Phase I, inactivated vaccine for the treatment of yellow fever, which is a mosquito-borne, viral hemorrhagic fever common in Africa and South America. Under terms of the agreement, PnuVax will purchase a modular FlexFactory from GE to manufacture the product, and GE will assist with production optimization.

	The inactivated version of the vaccine is thought to be safer than the attenuated live version of the vaccine (known as 17D), which can sometimes be problematic for those who are allergic to egg proteins or gelatin, infants, pregnant women, the elderly, and people with immune deficiencies. The new vaccine would contain a viral element that would be incapable of replicating, reducing the risk of the development of viscerotropic disease, a rare but serious reaction to the yellow fever vaccine that mimics wild-type yellow fever.

	The vaccine candidate (XRX 001) was originally developed by Xcellerex, Inc. GE acquired the intellectual property for the investigational product through its acquisition of Xcellerex in 2012. In 

, the vaccine induced neutralizing antibodies in 100% of subjects receiving a high dose and 88% receiving a low dose.

Vaccine supply and demand problems still persist


	The combination of a local, modular manufacturing system in combination with a vaccine for a regional public health problem is an ideal marriage for the treatment of a virus such as yellow fever, said PnuVax officials in a 

. The recent resurgence of yellow fever over the past six months, although not considered a “Public Health Emergency of International Concern” by the World Health Organization (WHO) like the Zika virus, was still labeled a serious health concern by the agency in a meeting on May 19, 2016, reports the 

	The author of a June 8, 2016 article in 

 suggests that the reason there are still an estimated 180,000 cases of yellow fever a year-despite the fact that that an effective vaccine has been in existence since 1937-is because of an issue with vaccine supply and demand. There are currently only six manufacturers of 17D worldwide (Institut Pasteur, Bio-Manguinhos/Fiocruz, Chumakov Institute of Poliomyelitis and Viral Encephalitides, Sanofi Pasteur [France], Sanofi Pasteur [United States], and the Wuhan Institute of Biological Products), and only four of the six are prequalified by WHO to distribute vaccine product internationally. Additionally, wrote the article author, because there are no requirements for the maximum dose of product allowed in each vaccine, the potency of each vaccine varies among the different manufacturers.

 report suggests the following solutions to increase yellow fever vaccine supply: increase the number of stockpiled doses, set an amount limit for the maximum dose of the vaccine (to produce a dose that is essentially optimized to induce protective immunity), engage in dose-sparing, experiment with intradermal drug delivery, conduct further genome studies of yellow fever strains, and finally, switch production of the vaccine from egg-based models to “a continuous cell line” in Vero cells. The PnuVax candidate is produced in Vero cells and adsorbed to an alum adjuvant. Like the PnuVax candidate, Sanofi’s Dengvaxia (CYD-TDV) and Imojev (ChimeriVax-JE) yellow fever vaccines are produced in Vero cells. Unlike the PnuVax candidate, both Dengvaxia and Imojev contain live attenuated versions of the virus.

The inactivated vaccine, manufactured with a GE FlexFactory system, could be associated with fewer adverse reactions than the live vaccine option.

GE Healthcare Sells Rights for Inactivated Yellow Fever Vaccine to PnuVax

	A surge in the demand for a product, such as what was seen when AbbVie’s Humira (adalimumab) won additional indications from FDA, or negative opinion on the price of a medication, such as what occurred when physicians at Memorial Sloan Kettering 

 in 2013 their refusal to prescribe Zaltrap (ziv-aflibercept) instead of cheaper alternatives for the treatment of chronic myeloid leukemia, are events that can cause capacity problems at biomanufacturing facilities (1). These examples of capacity disruptions caused by fluctuations in drug demand-peppered with some survey feedback from anonymous, C-suite level industry professionals-were highlighted in a new report from Patheon and ORC International focused on dealing with inaccurate forecasts for biologics.

	According to the report, capacity estimations are usually decided between Phase II and Phase III clinical trials, and as one anonymous biotechnology executive observed, companies like to lock in commercial pricing at the Phase III stage-which can be a risky proposition when demand is still largely unknown (2).

	Changes to a clinical development plan, such as the addition of new indications, may require additional trials and can be cost-intensive. Regional differences in how the drug is prescribed and accepted by medical professionals may also play into demand and, subsequently, may affect capacity forecasts. Thus, forecasting where a drug is likely to be used is as important as figuring out how much to make, the Patheon/ORC report asserted.


	The survey reported that more than half of its respondents said their company overestimates biologics demand forecasts by approximately 25%. This number may be even higher for all drugs (small- and large-molecule products); in 2013, a 

 study concluded that more than 60% of companies miss their demand forecasts by at least 40% (3).

	When companies cannot produce enough medication to meet demand, the share price of said drug can be dramatically impacted, disclosed an anonymous C-suite executive. Additionally, for orphan products, if demand is not met, an annulment of an orphan status could potentially occur, the report authors wrote.


	Production planning often needs to occur two years in advance, said the report, and long lead times contribute to market uncertainty, as many production variables can change over time. Adapting to future demand, especially in the case of an expedited approval, is “currently not executed well,” the report authors stated. The process has to be commercially capable, noted an anonymous executive quoted in the report, and there is more pressure for process characterization early on in the scale-up of expedited products.

	Patheon/ORC concluded that outsourcing to contract development and manufacturing organizations (CDMOs) is the best way to help companies manage demand and capacity fluctuations, especially when CDMOs are incorporating strategies such as single-use components, dual sourcing for materials, the parallel operation of bioreactors (known as “multiplexing”), and the incorporation of modular design into facilities.

	Although the benefits of outsourcing were well represented in the report, concerns of biotechnology manufacturers about keeping intellectual property secure and the potential problems with scale-up or technology transfer that can occur were not mentioned. Additionally, the benefits of producing biologics through a hybrid approach or through an exclusively in-house model were not described.

121 (22), pp. 4439â4442 (May 30, 2013).
	2. ORC International and Patheon, “Implications of Inaccurate Forecasting on Biologics Drug Substance Manufacturing,” White Paper, 

http://www.patheon.com/en-us/Ideas-in-Action/Material-Details?materialId=59

, accessed on June 7, 2016.
	3. M. Cha, B. Rifai, and P. Sarraf, 

Uncertainty about the demand for a biologic medication can be partly mollified with some well-planned capacity outsourcing, contends a new report by ORC International sponsored by Patheon.

Avoiding Timing Delays in Biologic Production

	Clinical success rates of pharmaceuticals were recently examined in two unrelated reports, and even though both analyses reviewed data collected from the company Informa, both of the studies produced reports with slightly different clinical trial success rates for pharmaceuticals. An analysis 

) drew from Informa’s Pharmaprojects database, while the BIO report 

 five days later on May 25, 2016 used information collected from Informa’s Biomedtracker.

	One of the differences between the reports was the time frame studied in each analysis. The 

 piece by authors Katarzyna Smietana, Marcin Siatkowski, and Martin MÃ¸ller looked at drug success rates from 1996â2014, while the BIO report looked at success rates from 2006Â­â2015. The 

 publication discusses the long-term trend in success rates, while the BIO report focuses on the recent status.

	Because of reporting and dataset differences between the reports, conclusions about clinical success rates from 2014Â­Â­â2015 can’t really be made, asserts Smietana. A major underlying reason is that besides the differing time ranges, the two studies had different methodologies and datasets from which to draw. Explains Smietana, the two methodologies differ: The dataset used in the BIO study includes the success rates of all indications of each product as separate data points. On the other hand, the 

 piece tracked by compound and did not segment based on indication-meaning every compound was counted once, regardless of how many indications it garnered. Products with multiple indications were handled differently in each report, contributing to some calculation differences in success rates. In addition, the dataset used in the 

 analysis included a slightly different range of products according to Smietana, meaning it counted clinical trial and regulatory successes both within and outside of the United States starting from 1995. 

	While Smietana et al. reported that the overall success rate for pharmaceuticals from Phase I to launch increased from 2011 to 2014 (to approximately 12%), BIO reported the overall success rate from 2006 to 2015 was about 10%. According to Smietana et al., the likelihood of approval (LOA) for biologics was 18% by 2014, but according to the BIO calculations, the LOA for biologics was 12%, potentially pointing to a decrease in the approval rate for biologics. Or, it is also possible that the number didn’t really go down, and that the difference in the success rates for biologics reported in the articles was because one report factored in multiple indications separately, while the other did not.

	Importantly, the way the authors of each analysis classified a biologic differed. BIO assigns biologics in line with FDA's BLAs (biologic license applications) (excluding vaccines), and the BIO report states that “in some cases FDA will designate larger molecules, such as proteins and peptides, as NMEs” (new molecular entities). The 

 publication classifies based on how the product is obtained (i.e., what the database calls “material of origin”); hence, some products classified as biologics by Smietana et al. will not be considered as such in the BIO study.

	Because the two analyses used different definitions, time frames, and underlying datasets, Smietana admits, “we’ll likely need to wait another two or three years to see if the success rates are going to stabilize or decline again.”

	“The different cuts in timeframes makes it difficult to directly compare the data, but overall I view these [reports] as quite consistent,” says Michael Hay, head of intelligence products at Informa, who served as an author for both the Biomedtracker and Pharmaprojects reports. “The BIO study purposely includes all indications to better reflect the R&D dollars spent to bring a drug to market for multiple diseases. Oncology is the most common area to see a drug studied in multiple indications and different tumor types behave very differently. This could explain the differences seen in biologics, as many of the recent oncology drugs are monoclonal antibodies,” Hay concludes.

An article in Nature Reviews Drug Delivery reports the clinical success rates of biologics, and these numbers differ from those recently highlighted in a similar BIO study.