WuXi AppTec to Expand Facilities and Hire in San Diego

WuXi AppTec, headquartered in Shanghai, China, plans to expand its facilities in San Diego.

WuXi AppTec describes itself as “a leading global pharmaceutical and medical device open-access capability and technology platform company.” That would seem to be a contract research organization (CRO) by a rather complicated name. Its broad services include small molecule drug research and development, cell therapy and gene therapy R&D and manufacturing, drug R&D and medical device testing. It claims to be enabling more than 3,000 collaborators from more than 30 countries.

The company reportedly raised $1 billion from its initial public offering (IPO) on the Hong Kong Stock Exchange. The original filing was for $354 million, but in its first four months as a public company, the shares almost quadrupled. At its peak, the valuation was $13.1 billion. A year ago, Wuxi Biologics also had an IPO and as of September 2018, had a valuation of $13.4 billion.

At its San Diego site, the company plans to establish a center of excellence in screening, discovery biology, pharmacology, and small molecule process R&D, which will also include Phase I GMP manufacturing.

“Having a leading global organization like WuXi significantly invest in San Diego highlights the value of international partnerships, the county’s place on the Pacific Rim and our region’s long-standing support of the life sciences community,” stated San Diego County Supervisor Ron Roberts. “I especially applaud the company’s vision that ‘every drug can be made, and every disease can be treated.’”

WuXi AppTec has 27 locations globally, with 1,700 employees in the U.S.

Most recently, on November 16, the company announced its Laboratory Testing Division’s new Medical Device Testing Center opened in Suzhou, China. That expanded its medical device testing capabilities in the Chinese market, which collaborates with its existing U.S.-based medical device testing centers in St. Paul, Minnesota and Atlanta, Georgia.

The Suzhou facilities in 15,000 square meters. The company noted that via the transfer of its capabilities, operations and quality management system from its U.S.-based centers, the new center will be able to provide comprehensive medical device testing that is in compliance with international quality standards. Those services include biomaterials analysis, toxicology, biocompatibility, risk assessment, product aseptic design microbiology, physical testing of packaging and shelf life, product batch release testing and others.

In the San Diego area, the company indicated it will “add extensively from the local talent base,” although specific jobs numbers were not released.

WuXi began operating in San Diego in 2016 by way of its Shanghai SynTheAll Pharmaceutical (STA) subsidiary. It began providing process R&D and API manufacturing services for early-stage clinical trials.

“This expansion will enable us to better serve our U.S. and global customers, and contribute to the growth and success of the dynamic San Diego biotech ecosystem,” stated Ge Li, WuXi AppTec’s chairman and chief executive officer. “Together with our ecosystem partners, we will continue to strengthen WuXi’s capability and technology enabling platform to expedite the discovery and development of new medicines for patients worldwide, and for a future where every drug can be made and every disease can be treated.”

https://www.biospace.com/article/wuxi-apptec-expanding-facilities-in-san-diego/

Innovate Bio gains

Nano cap Innovate Biopharmaceuticals (INNT +22.8%) bucks the broad market selloff on 65% higher volume. Shares are still down ~90%, however, since July.

Last week, it announced a collaboration with Massachusetts General Hospital aimed at understanding how certain toxins in the intestines may cause liver disease via breaching the gut vascular barrier via ethanol-induced disruption. The company expects the research to enhance its knowledge of how agents like larazotide may prevent the “leaky” barrier from worsening, thereby providing a potential treatment benefit in patients with liver disorders like NASH.

On the working capital front, at the end of September it had $8.1M in cash and equivalents while operations consumed $12.8M during the first three quarters of the year.

In late October, it inked agreements with H.C. Wainwright and Ladenburg Thalmann for the at-the-market sale of up to $40M of common stock.

Next Monday, December 17, management will host an investor update during which it will review its capital plan for its celiac disease clinical program and its NASH development strategy.

https://seekingalpha.com/news/3415712-innovate-bio-23-percent

Junshi Biosciences aims for $414M Hong Kong IPO

China’s Junshi Biosciences may follow in compatriot Innovent Biologics’ footsteps as it tees up to raise $414 million in its Hong Kong IPO, Reuters reported. It’s the latest company looking to list on the Hong Kong Stock Exchange after it relaxed its rules for early-stage biotechs.

Junshi is selling 158.9 million shares at a range of HK$19.38 to HK$ 20.38 ($2.48 to $2.61), according to a term sheet seen by Reuters. The company has 13 biologic drug assets in development, including those for immuno-oncology, inflammation and autoimmune disease, Reuters reported.

While the HKEX’s new rules are certainly more inviting to prerevenue biotechs, listing in Hong Kong does not guarantee success. While Innovent made out with a $421 million deal—and has only gained since it started trading—others have not been so lucky.

Hua Medicine and BeiGene, which closed a $903 million secondary listing in Hong Kong in August, have both dropped since they began trading. And how could we forget Ascletis, the first biotech to list in Hong Kong under the new rules and whose shares dropped 44% after just a month on the HKEX?

Ascletis’ experience may serve as a wake-up call for other preprofit biotechs that want to go public. At the time, investors and bankers spoke of bubbles bursting and said to expect lower valuations for future IPOs in Hong Kong.

“With a surge in China’s biotech industry in recent years, everyone has been a bit overexcited,” said Kevin Xie, who co-founded and heads the healthcare division at the investment bank China Renaissance, Reuters reported at the time.

“As market conditions have become more challenging than a year ago and investor sentiment has cooled, many biotech firms will have to adjust valuations in both primary and secondary markets,” Xie said.

https://www.fiercebiotech.com/biotech/junshi-biosciences-aims-for-414m-hong-kong-ipo-reuters

Gritstone ramps up bispecifics with new antibody therapeutics chief

Gritstone Oncology has appointed Jonah Rainey, Ph.D., to head up its bispecific antibody program as it moves into lead optimization. Rainey, who worked on bispecific antibodies for more than a decade and put in time at MacroGenics and MedImmune, will serve as vice president of antibody therapeutics.

Bispecifics, along with T-cell receptor (TCR) therapies, make up Gritstone’s youngest programs. Gritstone’s lead asset, a neoantigen cancer treatment called GRANITE-001, is headed for a phase 1/2 combination trial with Bristol-Myers Squibb’s Opdivo, thanks to funds raised in the company’s IPO.

The Bay Area biotech filed in August to raise up to $80 million in its Nasdaq debut and priced the offering at about $100 million at the end of September. The company has a second neoantigen treatment, SLATE-001, which is nearing the IND stage.

Gritstone’s approach involves identifying the tumor-specific neoantigens (TSNAs) on a patient’s tumor cells, using machine learning to determine which candidate is most likely to activate tumor-specific T cells and then treating the patient with personalized synthetic TSNAs. GRANITE-001 is given in two parts—first a priming adenoviral vector, followed by monthly boosters of an RNA vector, each containing the same 20 patient-specific TSNAs. SLATE-001 uses the same antigen delivery system as GRANITE-001, but instead of personalizing the treatment to each patient, it contains TSNAs that are shared by a subset of cancer patients, providing an off-the-shelf alternative to GRANITE-001.

Like its other treatments, Gritstone’s bispecifics are based on its artificial intelligence EDGE platform, which identifies tumor-specific antigens—including neoantigens—that are shared between patients with different solid tumors. Gritstone has identified antibodies that bind to peptide-HLA (Human Leukocyte Antigen) complexes and behave like TCRs, activating T cells to attack tumor cells.

“Recent data with BiSAb [bispecific antibodies] in B cell malignancies have shown their ability to elicit a potent and targeted anti-tumor response,” said Gritstone CEO Andrew Allen, M.D., Ph.D., in a statement. “To extend application of BiSAb into solid tumors, we will first identify exquisitely tumor-specific HLAp targets shared between patients, and then develop antibodies that recognize these targets specifically.”

“Under the leadership of Dr. Rainey, who has extensive expertise in antibody engineering and development, we are excited about the potential of TCR-mimetic-based bispecific antibodies to impact solid tumors using a ‘drug-in-a-bottle’ approach,” Allen said.

https://www.fiercebiotech.com/biotech/gritstone-ramps-up-bispecifics-new-antibody-therapeutics-chief

Optimal blood pressure treatment for stroke patients

Aggressive treatment of hypertension in stroke patients could do more harm than good in the long term, according to a new study from researchers at the University of Georgia.

Sixty percent of stroke patients admitted to U.S. emergency rooms have elevated blood pressure, and many studies say that having high blood pressure at the time of stroke can lead to higher rates of death and major disability.

But lowering blood pressure too much with medications may actually be working against the body’s protective response to maintain blood flow into the affected brain tissues.

“This presents a clinical dilemma,” said study author Changwei Li, an assistant professor of epidemiology and biostatistics at UGA’s College of Public Health.

It may be better to keep blood pressure a little higher than normal, closer to 140/90 mmHg rather than a “good” blood pressure of 120/80 mmHg, but that leaves the question of best practices a little open-ended.

“Currently, hypertension treatment for acute stroke patients is based on physicians’ clinical experience and judgement,” said Li. “There is no guideline on how low the blood pressure should be maintained.”

The key is to find the right balance between maintaining blood flow to the brain and reducing negative short- and long-term effects.

To help identify this optimal blood pressure, Li and his co-authors looked at the relationship between blood pressure during stroke and both short- and long-term health outcomes for over 4,000 Chinese stroke patients participating in the China Antihypertensive Trial in Acute Ischemic Stroke study. One group of stroke patients received extensive treatment for high blood pressure while a control group received no treatment at the time of their stroke.

Li and his collaborators tracked blood pressure changes over time in both the treatment and control groups during the first week of hospital admission and compared patient health at one week, three months, one year and two years following the stroke across patients of different blood pressure trajectories.

“We hypothesized that well-managed blood pressure may reduce further tissue death around the affected area and avoid damage to arteries, and both have short-term and long-term benefit to the patients,” said Li.

They found that patients whose systolic blood pressure was maintained at around 140 mmHg experienced fewer negative health outcomes, such as a second stroke, death or cardiovascular disease. Li said the findings provide some clarity for physicians.

“However, the optimal level of blood pressure identified in our study still needs to be confirmed by large-scale randomized controlled clinical trials,” he added.

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Story Source:

Materials provided by University of Georgia. Note: Content may be edited for style and length.

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Journal Reference:

1. Changwei Li, Yonghong Zhang, Tan Xu, Hao Peng, Dali Wang, Tian Xu, Yingxian Sun, Xiaoqing Bu, Chung-Shiuan Chen, Aili Wang, Jinchao Wang, Qunwei Li, Zhong Ju, Deqin Geng, Jintao Zhang, Jing Chen, Jiang He. Systolic Blood Pressure Trajectories in the Acute Phase and Clinical Outcomes in Two-year Follow-up among Patients with Ischemic Stroke. American Journal of Hypertension, 2018; DOI: 10.1093/ajh/hpy174

https://www.sciencedaily.com/releases/2018/12/181210142059.htm

Key cellular mechanism triggers pneumonia in humans

The situation is relatively common, especially in winter. You come down with the flu, which lasts longer than usual. A few days later, you discover you have pneumonia.

The relationship between influenza and pneumonia has long been observed by health workers. Its genetic and cellular mechanisms have now been investigated in depth by scientists in a study involving volunteers and conducted in the United Kingdom.

Published in the journal Nature Immunology, the paper describes for the first time a cellular mechanism that controls the proliferation of pneumococci — the Streptococcus pneumoniae bacteria that cause pneumonia — and their movement from the nose to the lungs. It also reports that in humans, the inflammation caused by the influenza virus impairs the innate immune control of pneumococci.

The study was performed by scientists at the Center for Research on Inflammatory Diseases — CRID, a Research, Innovation and Dissemination Center — RIDC funded by São Paulo Research — FAPESP, and the Liverpool School of Tropical Medicine (LSTM) in the UK. It was supported by the Bill & Melinda Gates Foundation, the UK Medical Research Council (MRC), and the Brazilian Coordination for the Improvement of Higher Education Personnel (CAPES), as well as FAPESP.

“Based on our understanding and analysis of the cellular, genetic and immune response mechanisms, we were able to prove that most flu-related deaths are due to post-flu pneumonia rather than to influenza virus itself,” said Helder Nakaya, a researcher affiliated with CRID and a coauthor of the paper.

The main reason, according to the results of the study, is that influenza virus silences the organism’s innate immune response, in particular inhibiting the action of monocytes — the main type of leukocyte or white blood cell responsible for expelling foreign bodies such as viruses and bacteria.

To conduct the study, the researchers recruited volunteers to be inoculated with attenuated influenza virus and pneumococcus. This procedure is permitted in the UK.

No volunteers suffered from pneumonia during the study.

Researchers on the Brazilian side analyzed and interpreted genetic and cellular data using CEMiTool bioinformatics software developed at the University of São Paulo’s Pharmaceutical Science School (FCF-USP) with FAPESP’s support under the aegis of its Young Investigators grant program.

“The software tool enabled us to analyze the interaction among the various genes in a very large number of samples, given that 140 volunteers took part in the study,” Nakaya said.

Journey of pneumococcus

Live attenuated influenza viruses were obtained from the flu vaccines (Fluenz/Flumist) administered every winter in the UK. Three days after receiving the flu virus, the volunteers received pneumococcus via nasal spray. Blood samples, nasal swabs and nasal cells from the volunteers were analyzed throughout the study, which lasted an entire winter.

“In order for pneumonia to develop, the bacterium must be in the lungs. This same bacterium can live in the nose for a long time without causing symptoms, especially in healthy adults. For some reason, however, especially in more vulnerable patients, the bacterium travels from the nose to the lungs. Our study focused precisely on the mechanisms that clear the bacteria from the nose and prevent it from traveling to the lungs, and on how influenza virus alters this process,” said Daniela Ferreira, a professor at LSTM and principal investigator for the study.

The findings showed that the number of bacteria in the nose increased significantly because of the influenza virus. “Another important point is that excessive multiplication of pneumococcus heightens the patient’s predisposition to transmit it to other people,” Ferreira said. “So there are two problems: an increase in individual susceptibility to pneumonia, and an increase in transmission of pneumococcus in the general population.”

The bacteria multiply in the nose when the influenza virus impairs the immune response by inhibiting monocyte antibacterial activity.

“We analyzed the genes and mechanisms involved in the bacterium’s journey to the lungs. We also identified biological markers that are more expressed in an individual with the virus and uncontrolled bacterial infection. In future we’ll be able to use all this information to develop better vaccines and therapies,” Ferreira said.

Different in humans

The mechanisms of the immune response to colonization by pneumococcus have been thoroughly studied in mice but remain poorly understood in humans. Using for the first time a human experimental challenge model with the attenuated flu virus and pneumococcus, the researchers discovered that in humans, unlike mice, nasal bacterial infection leads quickly to the activation of neutrophils, another type of lymphocyte always present in the human nose, and to the recruitment of monocytes, which clear the nostrils of bacteria by rupturing their vesicles (lysis). Neutrophil recruitment results in control of the bacteria in mice, instead of monocyte recruitment.

This finding “underlin[es] the importance of confirming mouse findings with human data,” the authors stress in the article.

Another finding was that the live attenuated influenza vaccine can be used to control pneumonia, which is a major global health problem and kills more children under five than any other disease. It is also particularly dangerous to the elderly and people with chronic lung disease, immunosuppression and viral coinfection.

“The most important point about this entire process is that people need to be immune to flu. The flu vaccine also proved beneficial to avoiding pneumonia,” Ferreira said.

The researchers are now analyzing the converse situation when infection by the bacteria occurs first and is followed by influenza virus infection.

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Story Source:

Materials provided by Fundação de Amparo à Pesquisa do Estado de São Paulo. Note: Content may be edited for style and length.

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Journal Reference:

1. Simon P. Jochems, Fernando Marcon, Beatriz F. Carniel, Mark Holloway, Elena Mitsi, Emma Smith, Jenna F. Gritzfeld, Carla Solórzano, Jesús Reiné, Sherin Pojar, Elissavet Nikolaou, Esther L. German, Angie Hyder-Wright, Helen Hill, Caz Hales, Wouter A. A. de Steenhuijsen Piters, Debby Bogaert, Hugh Adler, Seher Zaidi, Victoria Connor, Stephen B. Gordon, Jamie Rylance, Helder I. Nakaya, Daniela M. Ferreira. Inflammation induced by influenza virus impairs human innate immune control of pneumococcus. Nature Immunology, 2018; 19 (12): 1299 DOI: 10.1038/s41590-018-0231-y

https://www.sciencedaily.com/releases/2018/12/181210144950.htm

Some brain tumors may respond to immunotherapy

Immunotherapy has proved effective in treating a number of cancers, but brain tumors have remained stubbornly resistant. Now, a new study suggests that a slow-growing brain tumor arising in patients affected by neurofibromatosis type 1 (NF1) may be vulnerable to immunotherapy, which gives the immune system a boost in fighting cancer.

The findings, made by an international consortium led by researchers at Columbia University Vagelos College of Physicians and Surgeons, were published online today in Nature Medicine.

An estimated 100,000 individuals in the United States have NF1, a hereditary disease that can lead to the development of tumors throughout the nervous system, including a type of brain tumor called a glioma. Children usually have a slow-growing type of glioma, whereas adults often have a more aggressive type.

But whether slow-growing or not, gliomas are difficult to treat. Most are highly resistant to chemotherapy, and radiotherapy can aggravate, rather than relieve, symptoms, such as headaches and seizures. Since the tumors typically engulf delicate brain regions, surgery is rarely an option.

Immunotherapy has been successful for some patients with melanoma, lymphoma, and a few other types of cancer. But clinical trials have shown that, so far, it is ineffective for brain cancers in general.

Global Study Looked for Vulnerabilities in NF1 Brain Tumors

Surprisingly little was known about the molecular changes that occur in NF1 brain tumors, which has made it difficult to develop targeted therapies. In this study, researchers from 25 institutions around the world-led by Columbia’s Antonio Iavarone, MD, and Anna Lasorella, MD-performed an in-depth analysis of tumor samples from 56 patients to create the first comprehensive inventory of the genetic, epigenetic, and immune alterations in NF1 gliomas.

“This inventory will give us a much better idea of how to design individualized treatments,” Iavarone says, “but two findings from our study may have immediate clinical repercussions for NF1 patients.”

Many slow-growing NF1 gliomas appear susceptible to immunotherapy

Immunotherapy is ineffective for most brain tumors because the tumors are infiltrated with large numbers of cells called macrophages that thwart the immune system’s attack.

The new study revealed that many slow-growing NF1 gliomas contain few macrophages and produce proteins, called neoantigens, that can trigger an immune system attack.

“We were surprised to find that approximately 50 percent of the slow-growing NF1 gliomas contained large numbers of T cells that have the ability to destroy cancer cells,” says Lasorella. These “high immune” tumors are good candidates for treatment with immunotherapy, which could unleash the T cells, and clinical trials are now being planned.

This study also discovered that a subgroup of brain tumors in patients without NF1 share the same molecular profile as the slow-growing NF1 gliomas. Future studies will have to establish whether these “NF1-glioma-like” brain tumors also exhibit the same immune features and are potentially vulnerable to immunotherapy.

Aggressive NF1 gliomas could be weakened with DNA-damaging drugs

Although aggressive NF1 tumors were packed with macrophages and are likely to resist immunotherapy, the researchers also found that many had a genetic defect that may leave them more sensitive to DNA-damaging therapies.

Cells in these aggressive tumors can reproduce, but the new cells contain many DNA errors. “If we treat the aggressive tumors with DNA-damaging agents, we might be able to introduce even more DNA errors that eventually prevent the cells from replicating and stall the growth of the tumor,” says Iavarone.

Radiotherapy and some current cancer drugs damage DNA, but drugs are also in development that may be more effective in cancer cells with this specific genetic defect.

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Story Source:

Materials provided by Columbia University Irving Medical Center. Note: Content may be edited for style and length.

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Journal Reference:

1. Fulvio D’Angelo, Michele Ceccarelli, Tala, Luciano Garofano, Jing Zhang, Véronique Frattini, Francesca P. Caruso, Genevieve Lewis, Kristin D. Alfaro, Luc Bauchet, Giulia Berzero, David Cachia, Mario Cangiano, Laurent Capelle, John de Groot, Francesco DiMeco, François Ducray, Walid Farah, Gaetano Finocchiaro, Stéphane Goutagny, Carlos Kamiya-Matsuoka, Cinzia Lavarino, Hugues Loiseau, Véronique Lorgis, Carlo E. Marras, Ian McCutcheon, Do-Hyun Nam, Susanna Ronchi, Veronica Saletti, Romuald Seizeur, John Slopis, Mariona Suñol, Fanny Vandenbos, Pascale Varlet, Dominique Vidaud, Colin Watts, Viviane Tabar, David E. Reuss, Seung-Ki Kim, David Meyronet, Karima Mokhtari, Hector Salvador, Krishna P. Bhat, Marica Eoli, Marc Sanson, Anna Lasorella, Antonio Iavarone. The molecular landscape of glioma in patients with Neurofibromatosis 1. Nature Medicine, 2018; DOI: 10.1038/s41591-018-0263-8

https://www.sciencedaily.com/releases/2018/12/181210142053.htm