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

Randi Hernandez

	The recent resurgence of yellow fever incidences over the past six months has prompted health officials to ramp up the fight against the virus. Like the Zika virus, yellow fever is transmitted primarily through the bite of infected female 

	The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), announced it has begun a Phase I clinical trial of an investigational vaccine to protect against yellow fever virus. The experimental vaccine is being developed by the Danish biopharmaceutical company Bavarian Nordic.

	A live attenuated virus vaccine for yellow fever has actually been in existence since the 1930s, but the Centers for Disease Control and Prevention (CDC) reports that no vaccine efficacy studies have been performed with the yellow fever vaccine, also known as 17D.

	Although 17D is manufactured worldwide at the Bio-Manguinhos Oswaldo Cruz Foundation in Rio de Janeiro, Brazil; the Institute of Poliomyelitis and Viral Encephalitides in Moscow, Russia; the Pasteur Institute of Dakar in Dakar, Senegal; Sanofi Pasteur in Lyon, France; and at Berna, in Berne, Switzerland (formerly produced at the Robert Koch Institute in Berlin, Germany), the only 17D yellow fever vaccine approved for use in the United States (known as YF-Vax) is manufactured by Sanofi Pasteur in Swiftwater, Pennsylvania, according to the CDC. Only four of the six vaccine manufacturers are prequalified by the World Health Organization (WHO) to distribute vaccine product internationally. At a meeting earlier this year, WHO called the recent reappearance of yellow fever a serious health concern.

	Manufacturing and supply issues have limited the amount of 17D that is available on the market. Plus, because the current vaccine options are made from a live attenuated virus, the vaccine cannot be used to treat certain immunocompromised patients. Current options, such as Sanofi’s Dengvaxia (CYD-TDV) and Imojev (ChimeriVax-JE) yellow fever vaccines, are made from live attenuated versions of the virus.

	The NIH-backed vaccine candidate from Bavarian Nordic (MVA-BN-YF) will also be based on a weakened version of a virus, but will use a strain of the Modified Vaccinia Ankara (MVA) virus as a vaccine vector to carry yellow fever virus genes into the body. The MVA smallpox vaccine Imvamune is a non-replicating, highly attenuated live vaccinia virus. According to Bavarian Nordic, more than 7600 people, including 1000 individuals who are immunocompromised, have been safely vaccinated with vaccines using their MVA-BN-based platform. The company is currently in a partnership with Janssen to develop an Ebola vaccine using the same vaccine model.

	A separate company, PnuVax, is taking a different approach to the manufacture of a yellow fever vaccine. The company plans to make an inactivated version, which is thought to be safer than a live attenuated version of the vaccine. PnuVax will use a modular FlexFactory from GE to manufacture the product, and GE will assist with production optimization. Unlike most other existing products and future product candidates, which are produced in pathogen-free chicken embryos, PnuVax would rely on the cell culture of Vero cells for the production of its yellow fever vaccine.

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The Phase I trial will test Bavarian Nordic’s vaccine, which is manufactured using a vaccine vector based on smallpox.The recent resurgence of yellow fever incidences over the past six months has prompted health officials to ramp up the fight against the virus. Like the Zika virus, yellow fever is transmitted primarily through the bite of infected female Aedes aegypti mosquitoes.

NIH-Backed Yellow Fever Vaccine Trial Announced

	AstraZeneca announced on July 26, 2016 that its project launched in collaboration with Moderna Therapeutics for a messenger RNA (mRNA)-based therapy will begin Phase I clinical trials. Product candidate AZD8601 modulates the expression of vascular endothelial growth factor-A (VEG-A), so the hope is that control of the expression of this protein in charge of angiogenesis will have future applications for the treatment of heart disease, diabetic wound healing, and other ischemic vascular disease. The first-in-human trial for the candidate will focus on vascular regeneration of the heart, also known as cardiogenesis.

	“This marks a significant milestone for both Moderna and AstraZeneca as our first partnered mRNA program reaches the clinic. It is a validation of our shared vision to harness the potential of mRNA therapeutics to address serious unmet needs with the goal of improving patients’ lives,” noted Moderna CEO Stéphane Bancel in a press release.

	Promoting vascular regeneration may have important implications for the aforementioned conditions, but overexpression of VEGF-A has also been associated with a poor prognosis in some cancers, specifically in breast cancers. Some cancer medications actually seek to counteract the action of VEGF-A, such as the monoclonal antibody bevacizumab, which was approved by FDA in 2004. There are also a few anti-VEGF medications for the treatment of eye-related diseases that are characterized by retinal occlusion.

 agreement, originally forged in 2013 but amended in 2016, AstraZeneca holds exclusive access to select any target of its choice in cardiometabolic diseases, as well as select targets in oncology, over a period of up to five years for subsequent development in mRNA. Moderna also has antisense collaborations with Alexion, Merck, and the Defense Advanced Research Projects Agency (DARPA) that have garnered up to $550 million in funding. It also has a partnership with the Bill & Melinda Gates Foundation to advance the development of a novel, affordable combination of mRNA-based antibody therapeutics to help prevent HIV.

, Moderna has eight additional mRNA development candidates (other than AZD8601) that are advancing through studies across a pipeline composed of Moderna’s internally led programs and partnered programs, with many of these candidates scheduled to enter the clinic in 2016.

The therapeutic candidate AZD8601is an investigational mRNA-based therapy that will be tested for its ability to regulate the protein that influences vascular tissue growth.

AstraZeneca Begins Phase I Testing of its RNA-Based Therapeutic with Moderna

	Although a number of pharma companies are developing vaccines for Ebola, including GlaxoSmithKline and Johnson & Johnson, Merck announced on July 25, 2016 that it has received a Breakthrough Therapy designation from FDA for its investigational vaccine for the virus. The candidate also got a Priority Medicines (PRIME) status from the European Medicines Agency (EMA). Both of these designations may serve to boost Merck’s version through the regulatory process for an earlier decision.

	The vaccine candidate V920 is the product of a collaboration of Merck and NewLink Genetics. NewLink received $26.1 million of additional funding in April 2016 from the Biomedical Advanced Research and Development Authority (BARDA) of the United States Department of Health and Human Services (HHS) to conduct clinical bridging studies. Overall, BARDA has invested $74.6 million in the NewLink/Merck project since 2014, and the candidate now has a performance period until October 11, 2017, 

 in 2015, those who were immediately vaccinated with Merck’s investigational agent were 100% protected from the virus. The study demonstrated that the vaccine is most likely effective when delivered via a ring vaccination strategy.

The vaccine candidate has also won a Priority Medicines (PRIME) status from EMA.

Merck Receives Breakthrough Therapy Designation for Ebola Vaccine

	Amgen is at it again with biosimilars. Amgen and Allergen’s version of Herceptin (trastuzumab) demonstrated in Phase III clinical trials to be noninferior to Genentech’s (Roche’s) branded version of the drug. Although the investigational candidate ABP 980 was not found to be superior to Roche’s blockbuster drug, it was determined to be comparable in efficacy, immunogenicity, and instances of adverse events. Herceptin is approved for the treatment of early-stage HER2-positive breast cancer, metastatic breast cancer, and gastric cancer.

	ABP 980 is a humanized monoclonal antibody (mAb) that has the same dosage strength as Herceptin and the same amino acid sequence. It is one of the four oncology biosimilars that Amgen and Allergen are developing together. Roche's Herceptin will face patent expiration in 2019 in the United States.

	Roche reported that in 2015, the 5% in increase in its pharmaceutical sales was partially due to sales for Herceptin and that the drug was a "strong growth driver" for the year. According to an investor update on July 21, 2016, Roche's overall profit for cancer drugs rose 4% in the first half of 2016, and Herceptin sales grew 5% during the same period.

	The company said Herceptin sales growth was driven by increased demand for the drug and longer duration of treatment in combination with Perjeta. Herceptin and Perjeta are currently being tested in three Phase III clinical trials for other indications. Herceptin, Perjeta, and Kadcyla were among the strongest growth drivers targeting HER2-positive breast cancer, driving a combined 10% of sales for Roche in the first half of 2016.

Amgen and Allergan’s biosimilar to popular breast cancer drug Herceptin is comparable to the innovator molecule, Amgen recently announced.

No Clinically Meaningful Differences Between Herceptin and Amgen/Allergan Biosimilar

	Scientists in the fields of drug discovery and development have probably wished for an easy mechanism-or a way to “just Google it”-when it came to overcoming experimentation hurdles. Now, these experts in life science may have an ideal platform to tap into the successes and failures of past research decisions thanks to a new technology platform called Bioz.

	Labeled the “world’s first search engine for life science experimentation,” Bioz is a cloud software program that uses natural language processing and machine learning to draw from 26 million life-science articles across 5000 academic journals. According to a Bioz press representative, Bioz includes full text from more than 3700 academic journals within the Bioz platform, “with all usage rights in place.” The platform is free to use and has no eligibility requirements.

	Founded in 2013 by Stanford research scientist Karin Lachmi, PhD, and Bioz CEO Daniel Levitt, the venture is backed by Esther Dyson, who also sits on the board for 23andMe and was an early investor in companies such as Medscape and Flickr. Dyson is also an investor for PatientsLikeMe, a condition-centric help site that encourages data-sharing partnerships between patients and drug industry partners. Bioz is also supported by 5AM Ventures and Astia Angels. According to the company, more than 30,000 users from more than 1000 universities and biopharmaceutical laboratories already use 

	Bioz is important because it does not use paywalls, unlike many of the scientific journals that researchers would find useful in their drug discovery endeavors. As recently described in an article on 

, scientific journals use these paywalls to hold onto profits. But the research that is available publically is severely limited, and bids to get one’s academic institution to pay for access to every journal a researcher may need could get costly. Plus, a researcher may not know what he or she needs unless he or she can read the full paper and assess its contents. Often, an abstract is not enough to let a researcher know if a study’s contents would be valuable to read in full.

	The technology may be especially useful for the selection of reagents, assays, cell lines, consumables, and instruments, says Bioz CSO Lachmi. It could help save some of the trial and error that accompanies product selection and could save some of the $80 billion a year that researchers pour into purchasing decisions for products to run their experiments. Specifically, the “materials and methods” portions of many academic studies-which is usually gated information-could help drive the purchasing decisions of other researchers and lead them to use these study sections to troubleshoot future experiments.

	Products identified and labeled as “Bioz Stars” through a proprietary algorithm give researchers an idea of what products were mentioned most in peer-reviewed papers. The rating-which seems reminiscent of how a journal’s impact factor (IF) is calculated-would be assigned based on qualitative and quantitative parameters, says Bioz, and would remain “unbiased and objective.” According to the Bioz 

, indeed, a journal's impact factor plays into a Bioz Stars rating, and is weighed alongside a paper's recency, something called a "tendency" factor, another item called an "efficacy" factor, and by the relevance of the paper's protocol to the search in question. The ratings range from 1 (concern) to 5 (very good).
	
	Unfortunately, however, the use of the impact factor as a measurement tool has 

-and has recently been labeled as an inaccurate predictor of a paper’s value-as it relies on the 

 (not the median number) of citations. Thus, it would seem that the algorithm results for Bioz could be susceptible to be gamed, just like an impact factor. Also, it may be possible for mistakes to occur if entries are truncated in some way. For example, one problem that may plague supplier mentions could be company name changes-if a product originally were made by SAFC or Sigma-Aldrich, it may now be counted as a MilliporeSigma product since Sigma-Aldrich was acquired, and may not get as high of a Stars rating.

A new website collects and rates information about life-science supplies from academic journals to simplify researcher purchasing decisions.

Open-Access Technology Seeks to Make Drug Discovery Easier

	Although Pfizer and Celltrion's Inflectra (infliximab-dyyb) was approved on April 5, 2016, Johnson & Johnson said in a second-quarter earnings call that the product will not threaten the sales of Remicade for the rest of 2016. J&J Chairman and CEO Alex Gorsky said during the call that this "assumption remains unchanged with the recent FDA approval of Inflectra." Pfizer says it still plans to launch Inflectra in 2016, even though a lab working with Celltrion is 

 by J&J’s Janssen unit for unlawfully using the same cell-culture media for Remicade biosimilars that it used for the production of Remicade.


	Gorsky said that out of 2.4 million patients who've been treated with Remicade, "about 70% of them in fact are getting good relief and good effects" and that these patients are "unlikely to be switched when they're getting a positive response from the therapy." He also said that the size and strength of the Janssen and Johnson & Johnson portfolios will help the company secure Remicade as the therapy of choice with larger healthcare systems and networks.

	This could mean that for 30% of the 2.4 million patients currently on Remicade, approximately 720,000 could feasibly be switched to Inflectra or another biosimilar to Remicade. In addition, new patients who are Remicade-naïve could be added to the patient population as eligible candidates for a biosimilar.

	Dominic J. Caruso, executive vice-president and CFO of Johnson & Johnson, stressed that the waiting period for a biosimilar release for Remicade extends to October 6, 2016. He said that the outcome from an upcoming hearing on J&J's 471 patents covering Remicade this August will likely protect the brand for the remainder of 2016. Overseas, however, the company noted that the decline in Remicade export sales was due to the impact of biosimilars.

Thirty percent of current Remicade patients could be eligible for a switch to competitors such as Inflectra, according to estimates, although J&J doubts this will occur in the United States in 2016.