New combination of anti-obesity drugs may have beneficial effects

Research conducted in the Perelman School of Medicine at the University of Pennsylvania has revealed that a unique combination of hormone-based drugs can produce enhanced weight loss in laboratory tests with obese animals. The research is to be presented this week at the Annual Meeting of the Society for the Study of Ingestive Behavior (SSIB), the foremost society for research into all aspects of eating and drinking behavior.

“Imagine a drug regimen where an obese person would cycle between different drug therapies over the course of a month to achieve a greater degree of body weight loss compared to the effects achieved with either a single drug or the continuous combination of drugs,” said senior author Dr. Matthew Hayes. His team studied the combination of two different drug classes that target different hormones: amylin and glucagon-like peptide-1 (GLP-1). They found that combined treatments acted synergistically to suppress feeding and body weight. They also discovered that the weight loss effects of chronic amylin- and GLP-1-based combination therapies could be enhanced when obese lab animals are cycled through their drug treatments. “The idea of drug-cycling is nothing new,” says lead author Kieran Koch-Laskowski. “Millions of women on birth control pills, for example, already take daily pills that cycle between drug and placebo throughout the month,” she goes on to say.

Perhaps the most exciting finding of the current data coming out of Penn is the fact that the research finds these enhanced weight loss effects with a combination of drugs that are either already FDA approved or in clinical trials for metabolic diseases, “making the translational impact of our work extremely timely and highly clinically relevant!” says Hayes. The authors are now finalizing their research to demonstrate mechanically how these two hormonal systems interact to achieve greater weight loss in the hopes of fast-tracking their findings to new clinical treatments for obesity.

Targeted drug shows promise in rare advanced kidney cancer

Some patients with a form of advanced kidney cancer that carries a poor prognosis benefited from an experimental drug targeted to an abnormal genetic pathway causing cancerous growth, according to research led by a Dana-Farber Cancer Institute scientist.

The drug, savolitinib, showed clinical activity in patients with metastatic papillary renal cell carcinoma (PRCC) whose tumors were driven by overactivity of the MET signaling pathway, but was not effective for patients whose tumors lacked the MET abnormality, said the investigators, led by Toni Choueiri, MD, director, Lank Center for Genitourinary Oncology, and director, Kidney Cancer Center, both of Dana-Farber.

These results from a single-arm, multicenter phase II clinical trial, reported in the Journal of Clinical Oncology, suggest that savolitinib holds promise as a personalized treatment for a subgroup of patients with metastatic papillary renal cell carcinoma, the researchers said.

In the US alone, about 6,400 cases of PRCC are expected to be diagnosed in 2017, compared to a total of 64,000 cases of kidney cancers. The majority of them are classified as clear cell renal cell cancers. Papillary renal cell carcinoma are non-clear cell kidney cancers. No good treatments exist for advanced or metastatic PRCC.

The current trial tested savolitinib, a potent and selective MET inhibitor, in 109 patients with locally advanced or metastatic PRCC. Of the 109 patients, 40 percent had tumors driven by MET, 42 percent had tumors that did not rely on MET, and MET status was unknown in 17 percent of patients.

When the results were analyzed, 18 percent of patients with MET-driven cancers had significant shrinkage of their tumors, and 50 percent had stable disease. By contrast, none of the patients with MET-independent tumors had shrinkage response, and only 24 percent had stable disease.

In addition, the length of time after treatment before the cancer began growing was significantly longer in the MET-driven tumor group – 6.2 months versus 1.4 months.

“These data support the hypothesis that savolitinib has antitumor activity in patients with MET-driven papillary renal cell carcinoma,” the authors wrote. “Our study identified a defined molecular group and highlights the prevalence of MET-driven disease in this rare population of RCC patients.”

Although some patients had their dosage of savolitinib reduced and two patients discontinued treatment because of side effects, the researchers said the drug was generally well-tolerated.

Combination approach improves power of new cancer therapy

An international research team has found a way to improve the anti-cancer effect of a new medicine class called ‘Smac mimetics’.

The team discovered how a protein called MK2 helps to keep cancer cells alive, making them resistant to the anti-cancer effects of Smac mimetics. The findings provide a rationale for combining inhibitors of MK2 with Smac mimetics as a potentially powerful new combination therapy for cancers with few treatment options, such as acute myeloid leukaemia (AML).

The research, recently published in the journal Molecular Cell, was the outcome of a research collaboration between Dr Najoua Lalaoui, Professor John Silke and colleagues at the Walter and Eliza Hall Institute, Australia; Professor Pascal Meier and colleagues at the Institute of Cancer Research, UK; and Professor Manolis Pasparakis and colleagues at the Cluster of Excellence CECAD at University of Cologne, Germany.

Dr Lalaoui said the research helped to advance her team’s previous discovery that combining the Smac mimetic agent birinapant with another new class of anti-cancer agents, called p38 inhibitors, could offer a new approach to treating AML.

“We knew these two agents could be combined, but didn’t fully understand the how they worked together at the molecular level,” Dr Lalaoui said.

“This latest study has pinpointed the MK2 protein as critical for the combination of Smac mimetics and p38 inhibitors to have a potent anti-cancer effect. As well as understanding our previous discovery better, it also highlights MK2 as an exciting new target for anti-cancer therapies, particularly in combination with Smac mimetics.”

Professor Silke said the research was part of a growing trend in the field, taking ‘rational’ approaches to treating cancer better, particularly through selecting combinations of anti-cancer agents.

“By understanding precisely which molecules are helping cancer cells to survive and evade treatment, we can develop smarter ways to kill these cells,” Professor Silke said.

“In the first place, the rational development of combination therapies has the potential to provide new treatments for cancers, such as AML, that have previously had poor outcomes.”

He said another potential benefit of combined anti-cancer therapies could be using each agent at lower doses.

“With a combined approach, the agents could still kill the cancer cell but with fewer harmful side effects on healthy tissues. Our goal is to develop cancer treatments that are both safer and more powerful than are currently available” Professor Silke said.

UTHealth’s Lenard Lichtenberger Tests Effectiveness of Lipidic Aspirin Formulation Against Cancer

Scientists at The University of Texas Health Science Center at Houston (UTHealth) are testing the effectiveness of a soy-enriched aspirin formulation designed to fight colorectal cancer with fewer side effects.

Lenard Lichtenberger, Ph.D., professor of integrative biology and pharmacology at McGovern Medical School at UTHealth, is the principal investigator for the preclinical study funded with a $1.9 million grant from the National Cancer Institute (NCI). The grant was awarded to PLx Pharma Inc., the specialty pharmaceutical company developing this new form of aspirin.

While aspirin reduces the risk of colorectal cancer, daily use can cause ulcers and stomach bleeding. Colorectal cancer is a leading cause of cancer death in the United States claiming more than 50,000 lives in 2013, according to the Centers for Disease Control and Prevention.

First synthesized more than a century ago and hailed as a wonder drug, aspirin has been long known to reduce a person’s likelihood of heart disease and stroke. But, the research into its cancer protection benefits is relatively new.

For example, a popular medical search engine (PubMed) has less than 100 entries for the words aspirin and cancer between 1971 and 1974 compared to more than 4,000 since 2011.

The research into the chemopreventive action of aspirin is so conclusive that the U.S. Preventive Services Task Force recommends that people between the ages of 50 and 69 take low-dose aspirin on a daily basis to prevent colorectal  cancer so long as they consult with their physician first.

Custom built molecule shows promise as anti-cancer therapy

Scientists at the University of Bath funded by Cancer Research UK have custom-built a molecule which stops breast cancer cells from multiplying in laboratory trials, and hope it will eventually lead to a treatment for the disease.

But perhaps even more importantly the method they used to create the molecule has potential to be applied to develop new treatments for a wide range of cancers and other diseases.

The team, from the Department of Biology & Biochemistry, working with colleagues at the University of Queensland in Australia and the University of Bristol, modified a protein which can interfere with cell multiplication in many cancers, including breast cancer, by binding with another protein and rendering it inactive.

They took a small piece of the protein, called a peptide, that is known to be important in binding, and modified it to retain the structure otherwise lost when cut out. The modification has the additional advantage of protecting the peptide from being broken down within cells. The resulting molecule still binds to its target protein and inhibits cancer cell multiplication, but crucially can travel across cell membranes to get at it. The full-sized proteins, which the peptides are taken from, are usually too large to protect from breakdown or to cross protective cell membranes so this removes a literal barrier to developing treatments.

The study is published in the journal ACS Chemical Biology

Dr Jody Mason, one of the lead researchers on the project, said: “Peptides have the potential to be incredibly potent drugs which are exquisitely specific for their target. However they are easily broken down in the body, much like when we eat a steak. We have modified the peptides so that they retain the structure they have within the full-size protein and can therefore bind to the target “

Professor David Fairlie, from the University of Queensland added “This is a particularly challenging cancer target involving intertwined proteins and large surfaces that must be blocked. International collaborations like this one have the potential to combine resources and scientific skills from multiple disciplines to conquer difficult problems in targeting human disease.”

Dr Justine Alford, Cancer Research UK’s senior science information officer, said: “This early study may have laid the groundwork for a potential new treatment for certain cancers by creating a sophisticated designer molecule that can effectively block a cancer-fuelling target in cells.

“Cancer survival is improving, but people still die from their disease, so we need to develop innovative ways such as this that could help more people survive in the future.” The team now intend to continue to work on the molecule to improve its stability, with a long-term view to it eventually becoming a cancer drug, although this is still years away.

They are also interested in finding other candidate peptides for similar trials.

The researchers believe that other small peptides are a promising avenue of research to create new treatments for different types of cancer, and potentially other diseases such as Alzheimer’s disease

FDA approves drug to treat ALS

The U.S. Food and Drug Administration approved Radicava (edaravone) to treat patients with amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig’s disease.

“After learning about the use of edaravone to treat ALS in Japan, we rapidly engaged with the drug developer about filing a marketing application in the United States,” said Eric Bastings, M.D., deputy director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This is the first new treatment approved by the FDA for ALS in many years, and we are pleased that people with ALS will now have an additional option.”

ALS is a rare disease that attacks and kills the nerve cells that control voluntary muscles. Voluntary muscles produce movements such as chewing, walking, breathing and talking. The nerves lose the ability to activate specific muscles, which causes the muscles to become weak and leads to paralysis. ALS is progressive, meaning it gets worse over time. The Centers for Disease Control and Prevention estimates that approximately 12,000-15,000 Americans have ALS. Most people with ALS die from respiratory failure, usually within three to five years from when the symptoms first appear.

Radicava is an intravenous infusion given by a health care professional. It is administered with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period. Subsequent treatment cycles consist of dosing on 10 of 14 days, followed by 14 days drug-free.

The efficacy of edaravone for the treatment of ALS was demonstrated in a six-month clinical trial conducted in Japan. In the trial, 137 participants were randomized to receive edaravone or placebo. At Week 24, individuals receiving edaravone declined less on a clinical assessment of daily functioning compared to those receiving a placebo.

The most common adverse reactions reported by clinical trial participants receiving edaravone were bruising (contusion) and gait disturbance.

Radicava is also associated with serious risks that require immediate medical care, such as hives, swelling, or shortness of breath, and allergic reactions to sodium bisulfite, an ingredient in the drug. Sodium bisulfite may cause anaphylactic symptoms that can be life-threatening in people with sulfite sensitivity.

The FDA granted this drug orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Radicava to Mitsubishi Tanabe Pharma America, Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency is also responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Breast Cancer Drug Dampens Immune Response, Protecting Light-Sensing Cells of the Eye

Tamoxifen could be repurposed to treat degenerative diseases of the retina

The breast cancer drug tamoxifen appears to protect light-sensitive cells in the eye from degeneration, according to a new study in mice. The drug prevented immune cells from removing injured photoreceptors, the light-sensitive cells of the retina in the back of the eye. The study, recently reported in the Journal of Neuroscience, suggests tamoxifen might work for the treatment of age-related macular degeneration (AMD) and retinitis pigmentosa (RP), blinding diseases that lack good treatment options. The study was conducted by researchers at the National Eye Institute (NEI), part of the National Institutes of Health.

Although commonly used for cancer treatment, tamoxifen is used in the laboratory as a tool to activate specific genes in genetically engineered mice. The tool allows researchers to turn genes on and off in specific tissues at will. Wai Wong, M.D., Ph.D., chief of NEI’s Unit on Neuron-Glia Interactions in Retinal Disease, and his team were using tamoxifen for this purpose when they noticed something odd. Xu Wang, Ph.D., staff scientist in the Wong laboratory and lead author of the study, observed that mice treated with tamoxifen gained resistance to light-induced eye injuries. Light injury, induced by exposing mice to short-duration, high-intensity light, normally leads to degeneration of photoreceptors. But in the tamoxifen-treated mice, the team unexpectedly observed little to no photoreceptor degeneration.

The team investigated the effects of tamoxifen on light-induced photoreceptor degeneration in normal mice and mice with a disease similar to RP. Live retinal imaging and tissue analyses showed significantly lower levels of photoreceptor degeneration, compared to control mice that did not received tamoxifen. Tamoxifen-treated mice also demonstrated higher photoreceptor function, compared to controls.

How was tamoxifen exerting this protective effect? In an earlier study in 2015, Wong showed that light injury triggers a neurotoxic immune response in the retina. “The immune system becomes alerted to the stressed photoreceptors and goes into culling mode, clearing them out of the retina,” he explained. Wong and his team surmised that tamoxifen was inhibiting this immune response, rather than protecting the photoreceptors directly.

To investigate this hypothesis, Wong’s team cultured microglia — immune cells in the retina — and found that tamoxifen reduced their ability to remove and kill photoreceptor cells. Tamoxifen also reduced levels of inflammatory cytokines — signaling molecules that trigger inflammation — produced by the microglia.

Tamoxifen did not appear to directly influence the physiology of photoreceptors or protect photoreceptors in the absence of microglia, suggesting that the inhibition of microglia is a key mechanism underlying tamoxifen’s protective effect. The investigators are currently studying at molecular level how tamoxifen is able to inhibit the microglia.

In August 2016, Wong’s laboratory filed a patent for use of tamoxifen in retinal degenerative disorders. The new use of the drug is unexpected, as tamoxifen’s only previously known association with the retina had been a low risk of retinopathy among breast cancer patients.

RP is a group of rare genetic disorders affecting the retina. Worldwide, RP affects about 1 in 4,000 people. Symptoms typically appear during childhood and slowly progress over many years, often causing blindness. AMD is a leading cause of vision loss among people age 50 and older. About two million Americans have AMD, which affects central vision.

The tamoxifen dose used in Wong’s mouse study was equivalent to eight times the FDA-approved dose for breast cancer. The researchers are currently investigating whether the protective effects are retained at lower doses.

The work “sets us up for a clinical trial in the not-so-distant future,” said Wong. “Translation to the clinic can happen reasonably rapidly because tamoxifen, as an FDA-approved drug, already has a well-characterized safety profile,” he explained.

Computer Models Could Allow Researchers to Better Understand, Predict Adverse Drug Reactions

New computer models from North Carolina State University show how a variant of a common protein involved in human immune response binds to the antiviral drug abacavir, causing a severe life-threatening reaction known as the abacavir hypersensitivity syndrome (AHS). The work has implications for predicting severe adverse reactions caused by existing drugs and future drug candidates in subpopulations of patients.

Abacavir is a common anti-HIV drug. However, it is associated with severe allergic reactions in a fraction (5-8 percent) of patients who take it. Previous research determined that this response occurs in patients with a particular variant of a human leukocyte antigen (HLA) known as HLA-B*57:01.

Denis Fourches, assistant professor of chemistry at NC State, and his graduate student, George Van Den Driessche, wanted to know what happens at the molecular level when abacavir and other drugs interact with HLA-B*57:01.

HLA proteins reside on the surface of cells and help the immune system distinguish between its own proteins and those made by infectious agents. HLA proteins and their co-binding peptides serve as signaling proteins that communicate with T-cells, ensuring that all is well. If something foreign – a pathogen, or in this case, a drug like abacavir – binds to the HLA protein, displacing the co-binding peptide and deforming the overall shape of the molecular complex, this change is recognized by immune cells, triggering the immune response.

“There are 15,000 variants of HLA, and everyone carries some of these variants,” Fourches says. “HLA-B*57:01 is one of the first variants studied in the context of a drug-induced immune reaction. We know that it binds with abacavir, but little was understood about exactly what was happening structurally at the molecular level, especially in terms of the relationship with the co-binding peptide. This is a very complex system.”

Fourches and Van Den Driessche created a series of computer models using three-dimensional molecular docking that allowed them to look at the ways in which abacavir docks in the binding site of HLA-B*57:01 – where the co-binding peptide normally docks. The models incorporated 3D structures of abacavir, HLA-B*57:01, and several potential co-binding peptides. The researchers ran molecular modeling simulations to virtually dock abacavir in the HLA-B*57:01 active site in the absence and presence of a co-binding peptide. Finally, they virtually screened an additional set of 13 drugs, some of which are known to cause severe adverse responses that are also suspected of being linked to HLA variants.

“The models allowed us to identify key atomic interactions that cause abacavir and other drugs to bind to the HLA variant protein and ultimately trigger the immune response,” Fourches says. “When you can forecast and understand the elements of the drug that enable the binding to occur, you may be able to create new active compounds that do not have that problem.”

“Our ultimate goal is to use molecular modeling to discover and understand how different drugs can interact with the immune system via direct HLA binding interaction, so that we can better predict the side-effects of new drugs and design drugs with fewer side-effects. This is critical for the personalized medicine of tomorrow.”

Georgetown Announces Phase II Clinical Trial of Nilotinib for Parkinson’s Disease

Georgetown University Medical Center (GUMC) today announces the launch of a phase II clinical trial to study the safety of the cancer drug nilotinib and its effects on clinical outcomes and biomarkers in people with Parkinson’s disease.

GUMC is recruiting volunteers for the study in collaboration with its clinical partner, MedStar Georgetown University Hospital.

The clinical trial is a phase II, randomized, double-blind, placebo-controlled study designed to evaluate the safety and tolerability of low doses of nilotinib, the efficacy on disease biomarkers, and clinical outcomes in people with mid-stage Parkinson’s disease. Fernando Pagan, MD, medical director of the GUMC Translational Neurotherapeutics Program and director of the Movement Disorders Clinic at MedStar Georgetown University Hospital will serve as principal investigator on this study.

As part of the year-long random ascending dose trial, a third of the participants will receive 150mg of nilotinib, another third will receive 300mg of nilotinib and the final third will receive a placebo (inactive drug). Clinical outcomes will be assessed at six and 12 months and compared to assessments at the start of the trial. A one-year open-label extension trial, in which all participants will be randomized to 150mg or 300mg nilotinib, is also planned upon completion of the placebo-controlled trial to evaluate nilotinib’s long-term effects.

The clinical trial follows a proof of concept study conducted at Georgetown (published July 11, 2016 in the Journal of Parkinson’s Disease) providing molecular evidence that nilotinib significantly increased brain dopamine (the chemical lost as a result of neuronal destruction) and reduced toxic proteins linked to disease progression in Parkinson’s disease or dementia with Lewy bodies. Twelve participants were enrolled in the initial study; one patient withdrew due to an adverse event. Researchers say the drug appeared to be safe and well tolerated in the remaining 11 participants who completed the study.

“The early proof of concept study conducted in 2015 and published in 2016 provided encouraging results, but we won’t know the exact effects of nilotinib on Parkinson’s disease until larger trials like this new one are complete,” says Pagan.

“I am pleased to offer this study to my patients, which demonstrates the importance of teaming Parkinson’s care with academic research. Only through clinical trials will we be able to move the field forward so that we can offer better treatments to our patients in the future,” he adds.

Nilotinib is approved by the U.S. Food and Drug Administration at much higher doses for the treatment of chronic myeloid leukemia (CML). In 2016, the U.S. Food and Drug Administration reviewed Georgetown’s investigational new drug application (IND) for the nilotinib study in Parkinson’s disease and informed GUMC investigators that the trial could proceed.

The Parkinson’s study and the recently announced Alzheimer’s clinical trial with nilotinib build on research from the GUMC Translational Neurotherapeutics Program led by Charbel Moussa, MB, PhD. He and his colleagues are examining tyrosine kinase inhibitors, like nilotinib, in the treatment of neurodegenerative diseases. Tyrosine kinases appear to play a role in neurodegeneration, protein clearance and inflammation. (Moussa is an inventor on a US patent owned by Georgetown University and on other pending US and foreign patent applications for use of nilotinib and other tyrosine kinase inhibitors for the treatment of neurodegenerative diseases).

The Parkinson’s study is funded by the generous support of donors. Novartis, the maker of nilotinib, is providing nilotinib and matching placebo free of cost to Georgetown University for all participants while on the study.

More information can be found at ClinicalTrials.gov. Patients and families can sign up to receive more information about the Parkinson’s study and other Georgetown neurodegenerative clinical trials.

Leukemia Drug Combo Is Encouraging in Early Phase I Clinical Trial

In a small study, 67 percent of leukemia patients treated with combination of thioguanine and decitabine responded to treatment

Researchers from Columbia University Medical Center and NewYork-Presbyterian reported that 8 out of 12 patients with relapsed and/or chemotherapy refractory acute myeloid leukemia (AML) or other blood cancers responded to a regimen including the chemotherapy drugs thioguanine and decitabine. Results from this small phase I study were reported at the American Society of Hematology’s annual conference.

“Outcomes are typically poor for older patients with advanced blood cancers, and new therapies are desperately needed to help patients with these cancers achieve remission,” said Mark Frattini, MD, PhD, associate professor of medicine at Columbia University Medical Center (CUMC) and blood cancer specialist at NewYork-Presbyterian. “While our study was small, the response we saw in this phase I, dose-escalating trial was encouraging.”

Previously, Frattini and colleagues had used a proprietary chemosensitivity screening assay to demonstrate that combining thioguanine and decitabine—chemotherapy drugs that are commonly used as single agents to treat patients with AML—restored therapeutic efficacy in leukemia cells from patients with relapsed and/or refractory disease.

In this study, the researchers tested the efficacy of the combination therapy in 12 older patients (median age of 67 years) with relapsed or chemotherapy refractory AML or chronic myelomonocytic leukemia, including 6 patients whose disease progressed after being treated previously with decitabine as a single agent. Of these, 11 patients completed the first treatment cycle, and 6 completed a second cycle, with a median of 3 rounds of treatment. Eight of the 11 evaluable patients responded to the combination therapy, including 6 who achieved a complete remission (5 in complete remission with incomplete count recovery). In addition, all of the patients who had progressed after prior treatment with decitabine alone responded to the combination therapy, demonstrating that the combination could overcome disease resistance to decitabine. Chemosensitivity assay results, obtained before treatment, accurately predicted each patient’s response to the combination therapy.

After treatment with the combination therapy, 4 of the responders went on to have a stem cell transplant.

“The goal of chemotherapy for patients with relapsed and/or refractory AML and other blood cancers is to achieve a remission that enables them to undergo a potentially curative stem cell transplant,” said Dr. Frattini. “With our phase I results, we have shown that this combination therapy can get some patients—including those who failed to respond to or progressed after previous chemotherapy treatment with a single agent such as decitabine—to that point. The next challenge for hematologic oncologists is to reduce morbidity and mortality associated with stem cell transplantation.”

After the study, 2 of the patients who had a stem cell transplant died from transplant-related toxicity, and another relapsed. One patient has remained in remission for more than 2 years.

Reports Preclinical Data Showing LEAPS Vaccine is Successful in Treating Rheumatoid Arthritis

Rheumatoid Arthritis is a chronic inflammatory disease that mainly targets the synovial membrane, cartilage and bone. It affects about 1% of the global population and is associated with significant morbidity and increased mortality. Non-steroidal, as well as steroidal anti-inflammatory medicines and now more commonly the use of anti-TNFα related therapies are the current standard treatment of patients with advanced RA, but information suggests that over half of the RA patients treated do not respond to current anti-TNFα drugs such as etanercept (Enbrel®) and infliximab (Remicade®).

New preclinical data presented by CEL-SCI demonstrated that its investigational new drug candidate CEL-4000 has the potential for use as a therapeutic vaccine to treat rheumatoid arthritis. CEL-4000 has been developed using CEL-SCI’s patented LEAPS (Ligand Epitope Antigen Presentation System) technology. Data were presented by Daniel Zimmerman, Ph.D., CEL-SCI’s Senior Vice President of Research, Cellular Immunology, at the American College of Rheumatology’s Annual Meeting in Washington DC. The poster presentation titled, “A Therapeutic Peptide Vaccine Reduces Pro-inflammatory Responses and Suppresses Arthritis in the Cartilage Proteoglycan G1 Domain-induced Mouse Model of Rheumatoid Arthritis,” was presented earlier this month.

This study was supported in part by funding of a Phase I Small Business Innovation Research (SBIR) grant in the amount of $225,000 from the National Institute of Arthritis Muscoskeletal and Skin Diseases (NIAMS), a part of the National Institutes of Health (NIH). The study was conducted in collaboration with Drs. Katalin Mikecz and Tibor Glant, and their research team at Rush University Medical Center in Chicago, IL.

“These findings, in conjunction with the results from earlier animal studies with LEAPS vaccines, support the potential that LEAPS vaccines may be useful as a therapeutic treatment for different types of rheumatoid arthritis. LEAPS vaccines may be advantageous to other therapies because they appear to act early on the immune system and inhibit the production of disease-promoting inflammatory cytokines. This is a significant step forward in the development of the LEAPS technology,” said Dr. Zimmerman.

This efficacy study evaluated the LEAPS vaccine’s effect in both the Proteoglycan (PG) induced arthritis (PGIA) and the closely related recombinant huG1 domain of PG (GIA) both in animal models of rheumatoid arthritis (RA) having a dominant T helper 1 (Th1) cytokine profile. These animal models were developed and have been studied extensively in Dr. Glant’s laboratory for over 25 years and are closely related to the human condition of many RA patients. The PGIA and GIA model also exhibits rheumatoid factor (Rf), RA-specific antibodies ACPA (anti citrulline peptide antibodies) and tend to develop spondylitis not usually seen in other RA models.

Disease severity, as determined based on the Arthritis Index and histopathology, was suppressed in mice treated with the LEAPS vaccine when compared to controls. As initially reported based on preliminary data in the PGIA model only, the reduction in disease (RA) severity following LEAPS vaccination with CEL-4000 (DerG-PG70 treatment) correlated with up-regulation of T regulatory cells (Treg) and Th2 cytokines (IL-10, IL-4 and TGF-β), reduced proliferation of PG specific T lymphocytes, and decreases in the production of Th1 and Th17 cytokines (IFN-γ and IL-17).

Study Finds Arthritis Drug Significantly Effective in Treating Crohn’s Disease

Researchers at University of California San Diego School of Medicine have shown that ustekinumab, a human antibody used to treat arthritis, significantly induces response and remission in patients with moderate to severe Crohn’s disease. Results of the clinical trial will appear in the November 16 issue of the New England Journal of Medicine.

“A high percentage of the patients in the study who had not responded to conventional therapies were in clinical remission after only a single dose of intravenous ustekinumab,” said William J. Sandborn, MD, professor of medicine at UC San Diego School of Medicine and director of the Inflammatory Bowel Disease Center at UC San Diego Health. “Finding effective new treatment options for this patient population is critical because Crohn’s disease can dramatically impact a person’s quality of life. Patients suffering from this disease may go to the bathroom up to 20 times a day and experience abdominal pain, ulcers and a reduced appetite.”

Crohn’s disease is a chronic inflammatory disease of the gastrointestinal tract that affects approximately 700,000 people in the United States. It can affect any part of the GI tract but it is more commonly found at the end of the small intestine (the ileum) where it joins the beginning of the large intestine (or colon). Crohn’s disease is usually treated with glucocorticoids, immunosuppressants, tumor necrosis factor (TNF) antagonists or integrin inhibitors.

“The drawbacks of these therapies include an increased risk of infection and cancer, and limited efficacy,” said Sandborn. “Ustekinumab has not been associated with an increased risk of serious adverse events.”

The rates of remission response in the randomized study at week six among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving a placebo. The study also found subcutaneous (injected) ustekinumab every 8 to 12 weeks maintained remission in patients.

“This study indicates that ustekinumab may have a long duration of action, a likelihood that may become better understood in future trials,” said Sandborn. “Our current findings offer hope for those suffering from this debilitating gastrointestinal tract disease.”

The Inflammatory Bowel Disease (IBD) Center at UC San Diego Health is dedicated to diagnosing and treating people with IBD from around the world. The center’s leadership in IBD medical research means patient access to clinical trials for the newest therapies and advanced surgical techniques for the treatment of this challenging condition. Care is provided by a multidisciplinary team of specialists in gastroenterology, endoscopy, oncology, surgery, transplantation and radiology.

Large Integrated Health Outcomes Study Reveals Shifting Epidemiology In Drug-Resistant Organisms

A first-of-its-kind study of 900,000 hospital admissions from an integrated health system has yielded insights into shifts in the epidemiology of multi-drug resistant organisms (MDROs) in the community.

New research, funded by OpGen (NASDAQ: OPGN) and conducted by Intermountain Healthcare and Enterprise Analysis Corporation (EAC), found that Methicillin Resistant Staphylococcus aureus (MRSA), Clostridium difficile (C. difficile) and ESBL harboring Gram-negative rods were the most common organisms treated by the Intermountain Healthcare system over an eight-year period between January 1, 2008 and December 31, 2015.

The study examined data from Intermountain Healthcare over an eight-year period to characterize the trends occurring in C. difficile and MDROs. The abstracted electronic data was pulled from patients seen at Intermountain’s 22 hospitals and affiliated clinics who had clinical cultures positive for antibiotic resistant Gram-positive or Gram-negative bacteria and/or laboratory tests positive for toxigenic C. difficile.

The researchers discovered that resistant organisms were found in 1.4 percent of the 900,000 hospital admissions during the study period with most originating from the ambulatory setting. Additionally, researchers found that a 222% increase was observed in the prevalence of C. difficile as well as a 322% increase in ESBL positive organisms. The good news is that the prevalence of MRSA decreased by 32%.

The study measured both the prevalence of infections, as well as impacts on patient care. Economic data are still being analyzed and will be revealed in a future presentation.

Results from the study were presented on Thursday, Oct. 27 at 1:30 p.m., EDT, in the Poster Hall at IDWeek 2016 in New Orleans by Bert Lopansri, M.D., lead author of the study at Intermountain Medical Center, the flagship hospital of Intermountain Healthcare.

Highlights of the study:

• Of the 900,000 hospital admissions during the study period, 12,905 (1.4%) were from patients positive for an MDRO and/or C. difficile.
• While MRSA continues to be the most common MDRO, rates have declined.
• MRSA, ESBL and CRE forms of E. coli were less frequently acquired in the hospital while VRE, multi-drug resistant Pseudomonas, and other CRE’s were more frequently encountered in a healthcare setting.
• 70% of all MDROs and C. difficile cases originated from an ambulatory setting.
• While all-cause, in hospital mortality was relatively low (7%), significantly more patients with MDRO require continued medical care in some capacity.

“For the last 10 to 15 years, the number of antibiotic-resistant bacteria continues to increase. We wanted to turn on the lights and look at all the different types of antibiotic-resistant bacteria that have been highlighted as serious and urgent threats by the Centers for Disease Control to see what the landscape looks like in our system,” said Dr. Lopansri, Chief of the Infectious Diseases Division at Intermountain Medical Center. “Although MRSA still poses the greatest challenge, the rise in ESBLs is a major concern and mirrors findings reported at other centers in the U.S. One concern with ESBLs is that the most common antibiotic used to treat them are carbapenems, known as ‘last-resort’ antibiotics.”

“Our support for a study of this magnitude provides a benchmark to hospitals and health systems on what could be lurking in their facilities as we seek to validate the health and economic impact of our rapid MDRO products and services to improve infection control,” said Evan Jones, Chairman and CEO of OpGen. “The next step in this collaboration will revolve around leveraging our technologies to guide rapid clinical decisions with a goal of reducing the spread of these infections and improving health outcomes.”

Calcium Supplements May Damage The Heart

After analyzing 10 years of medical tests on more than 2,700 people in a federally funded heart disease study, researchers at Johns Hopkins Medicine and elsewhere conclude that taking calcium in the form of supplements may raise the risk of plaque buildup in arteries and heart damage, although a diet high in calcium-rich foods appears be protective.

In a report on the research, published Oct. 10 in the Journal of the American Heart Association, the researchers caution that their work only documents an association between calcium supplements and atherosclerosis, and does not prove cause and effect.

But they say the results add to growing scientific concerns about the potential harms of supplements, and they urge a consultation with a knowledgeable physician before using calcium supplements. An estimated 43 percent of American adult men and women take a supplement that includes calcium, according the National Institutes of Health.

“When it comes to using vitamin and mineral supplements, particularly calcium supplements being taken for bone health, many Americans think that more is always better,” says Erin Michos, M.D., M.H.S., associate director of preventive cardiology and associate professor of medicine at the Ciccarone Center for the Prevention of Heart Disease at the Johns Hopkins University School of Medicine. “But our study adds to the body of evidence that excess calcium in the form of supplements may harm the heart and vascular system.”

The researchers were motivated to look at the effects of calcium on the heart and vascular system because studies already showed that “ingested calcium supplements — particularly in older people — don’t make it to the skeleton or get completely excreted in the urine, so they must be accumulating in the body’s soft tissues,” says nutritionist John Anderson, Ph.D., professor emeritus of nutrition at the University of North Carolina at Chapel Hill’s Gillings School of Global Public Health and a co-author of the report. Scientists also knew that as a person ages, calcium-based plaque builds up in the body’s main blood vessel, the aorta and other arteries, impeding blood flow and increasing the risk of heart attack.

The investigators looked at detailed information from the Multi-Ethnic Study of Atherosclerosis, a long-running research project funded by the National Heart, Lung, and Blood Institute, which included more than 6,000 people seen at six research universities, including Johns Hopkins. Their study focused on 2,742 of these participants who completed dietary questionnaires and two CT scans spanning 10 years apart.

The participants chosen for this study ranged in age from 45 to 84, and 51 percent were female. Forty-one percent were white, 26 percent were African-American, 22 percent were Hispanic and 12 percent were Chinese. At the study’s onset in 2000, all participants answered a 120-part questionnaire about their dietary habits to determine how much calcium they took in by eating dairy products; leafy greens; calcium-enriched foods, like cereals; and other calcium-rich foods. Separately, the researchers inventoried what drugs and supplements each participant took on a daily basis. The investigators used cardiac CT scans to measure participants’ coronary artery calcium scores, a measure of calcification in the heart’s arteries and a marker of heart disease risk when the score is above zero. Initially, 1,175 participants showed plaque in their heart arteries. The coronary artery calcium tests were repeated 10 years later to assess newly developing or worsening coronary heart disease.

For the analysis, the researchers first split the participants into five groups based on their total calcium intake, including both calcium supplements and dietary calcium. After adjusting the data for age, sex, race, exercise, smoking, income, education, weight, smoking, drinking, blood pressure, blood sugar and family medical history, the researchers separated out 20 percent of participants with the highest total calcium intake, which was greater than 1,400 milligrams of calcium a day. That group was found to be on average 27 percent less likely than the 20 percent of participants with the lowest calcium intake — less than 400 milligrams of daily calcium — to develop heart disease, as indicated by their coronary artery calcium test.

Next, the investigators focused on the differences among those taking in only dietary calcium and those using calcium supplements. Forty-six percent of their study population used calcium supplements.

The researchers again accounted for the same demographic and lifestyle factors that could influence heart disease risk, as in the previous analysis, and found that supplement users showed a 22 percent increased likelihood of having their coronary artery calcium scores rise higher than zero over the decade, indicating development of heart disease.

“There is clearly something different in how the body uses and responds to supplements versus intake through diet that makes it riskier,” says Anderson. “It could be that supplements contain calcium salts, or it could be from taking a large dose all at once that the body is unable to process.”

Among participants with highest dietary intake of calcium — over 1,022 milligrams per day — there was no increase in relative risk of developing heart disease over the 10-year study period.

“Based on this evidence, we can tell our patients that there doesn’t seem to be any harm in eating a heart-healthy diet that includes calcium-rich foods, and it may even be beneficial for the heart,” says Michos. “But patients should really discuss any plan to take calcium supplements with their doctor to sort out a proper dosage or whether they even need them.”

According to the U.S. Centers for Disease Control and Prevention, coronary heart disease kills over 370,000 people each year in the U.S. More than half of women over 60 take calcium supplements — many without the oversight of a physician — because they believe it will reduce their risk of osteoporosis.

Researchers Find Fungus-Fighting Compound in Drug Discovery Center Library

Researchers with the Virginia Tech Center for Drug Discovery have identified a compound that blocks the growth of a fungus that causes deadly lung infections and allergic reactions in people with compromised immune systems.

The research team targeted the switch that allows the fungus Aspergillus fumigatus to survive in iron-deficient conditions like the human body. Specifically, they targeted an enzyme known as SidA, which is essential for the synthesis of molecules called siderophores that are made during infection to steal iron from human proteins.

Furthermore, by performing high-throughput screening in the center’s Drug Discovery Screening Laboratory, they found a compound called Celastrol that blocks the growth of iron-producing organelles in the fungus.

The results were published in the journal ACS Chemical Biology.

“This project shows what an asset the screening lab is to the community,” said Pablo Sobrado, a professor of biochemistry in the College of Agriculture and Life Sciences and director of the screening laboratory. “Without the robots and chemical libraries available at the screening lab, this work would not have been possible. We are very fortunate at Virginia Tech to have this facility.”

Aspergillus fumigatus is common and is typically found in soil and decaying organic matter. Most people are exposed to it daily with little consequence, but it can cause lung damage in people with compromised immune systems, such as organ transplant recipients and people with AIDS or leukemia. The mortality rate of this population, when exposed to the fungus, is more than 50 percent, according to the authors.

“Growing antibiotic resistance is demanding the development of target-directed therapies,” said Julia S. Martin del Campo, a postdoctoral research scientist in Sobrado’s lab. “This approach requires the discovery of enzyme inhibitors that block essential pathogen pathways. The discovery of Celastrol as a SidA inhibitor represents the first building block in the development of drugs against A. fumigatus and related pathogens.”

‘Open Science’ Paves New Pathway To Develop Malaria Drugs

Malaria remains one of the world’s leading causes of mortality in developing countries. Last year alone, it killed more than 400,000 people, mostly young children. This week in ACS Central Science, an international consortium of researchers unveils the mechanics and findings of a unique “open science” project for malaria drug discovery that has been five years in the making.

The current gold standard antimalarial treatments are based on artemisinin, a compound developed in the 1970s in China, combined with a partner drug. Yet, resistance to artemisinin and its partners has already emerged in some parts of the world. If the resistance spreads, there are no viable replacement treatments. Given the lack of commercial incentive for industry to develop drugs for neglected diseases such as malaria, and because academic researchers often lack resources to move compounds forward, there is a clear need for new approaches. In response, Matthew Todd from the University of Sydney together with the not-for-profit research and development organization Medicines for Malaria Venture proposed an “open source” solution akin to the open source concept used in software development.

More than 50 researchers from 21 organizations in eight countries added their research to the project, which started with a large set of potential drug molecules made public by the company GlaxoSmithKline. Anyone willing to contribute — anywhere in the world — was welcome to share data and collaborate by adding comments to an electronic notebook as part of the Open Source Malaria Consortium. Some scientists designed and synthesized new generations of the antimalarial compounds; others ran assays and interpreted results. Several rounds of research were conducted, addressing water solubility and structural issues, with all the data being made public in real time. A wide array of scientists, from professors to undergraduates, participated by choice, agreeing that no one would individually seek patents to protect their contributions. The authors note that the current results, while promising, are merely the beginning of the story. They continue to welcome additional contributions, also researched openly and collaboratively.

New Class of Medicinals based on Cannabinoid Molecules, Spurs NEMUS Bioscience Inc. into Action

Q&A with Brian Murphy MD, CEO/CMO, NEMUS Bioscience

Humans produce a range of chemical compounds called cannabinoids that keep the human body stable by binding to receptors on cell membranes and controlling the release of chemical messengers that regulate everything from how humans experience pain to our moods. While most people’s endocannabinoid systems naturally help maintain a state of homeostasis, or stability, conditions such as multiple sclerosis or treatments for diseases like cancer can throw off that balance. Introducing cannabinoids made outside the body might help. Marijuana also contains cannabinoids – at least 66 of them.

Drugs based on cannabinoids, which could treat ailments ranging from arthritis to epilepsy, hold untold potential for the pharmaceutical industry.

The BioConnection.com recently spoke with Dr. Brian Murphy, NEMUS Bioscience’s CEO and CMO on the potential of cannabinoid research.

Q: What is NEMUS Bioscience working on?

Murphy: NEMUS Bioscience (OTCQB: NMUS) was formed to bring a new class of medicinals, based on the 100+ cannabinoid molecules in the Cannabis sativa plant, to a variety of therapeutic markets, especially those of unmet medical need.  Almost every organ in the body possesses cannabinoid receptors giving these compounds tremendous versatility in affecting the course of disease.

Q: What are the main diseases or symptoms you are attempting to target with cannabinoid research?

Murphy: The NEMUS developmental pipeline is currently focused on three therapeutic silos:

1) Palliative care addressing specific indications of chemotherapy-induced nausea and vomiting (CINV) and chemotherapy-induced peripheral neuropathy, a particularly severe pain syndrome associated with certain type of cancer chemotherapy.

2) Ophthalmology: the initial therapeutic indication being pursued is glaucoma, with initial animal studies in models of glaucoma exhibiting an average 45% reduction in IOP, exceeding current IOP reduction standards with currently approved medications and those in development using the same models.

3) Anti-infectives: Nemus is developing cannabinoid-based therapeutics against both bacterial and viral targets, with the initial therapeutic target in this silo being methicillin-resistant Staphylococcus aureus (MRSA). The current MRSA epidemic in the United States accounts for close to $4 billion in associated health-care costs as this bacterium has developed resistance to many antibiotics.  Newer therapies are needed.

Q: Describe your partnership with the University of Mississippi and how has the partnership benefited your research?

Murphy: The University of Mississippi (UM) is the only entity in the United States currently licensed by the federal government to grow, cultivate, and research cannabinoids autonomously.  The University has held that license since 1968 and has a tremendous amount of intellectual capital and experience in the chemistry and physiology of cannabinoid molecules.  That library of molecules and associated intellectual property helps distinguishes us from other companies in the cannabinoid therapeutic space.

Q: What difficulties have you encountered working with pharmaceuticals derived from cannabis?

Murphy: While marijuana is not a legal substance, drug companies are permitted to work with and develop derivatives from the plant and develop these molecules into drugs.  Many leading approved medicinals for cardiovascular disease, cancer, and anti-infectives are derived from plants or as is known in pharma development: botanically derived medications.  There is a designated regulatory pathway from both the DEA and FDA for cannabinoids and NEMUS works diligently to be in compliance with those requirements. To-date, we have not experienced any unexpected challenges outside the norm in developing a new class of compounds to address diseases.

Q: What is your opinion on people who smoke/ eat marijuana to relieve painful physical/ mental symptoms? In other words, why are cannabinoids better than the plant itself?

Murphy: For patients who use plant-derived cannabinoids, there are a number of challenges that “pharmaceuticalized” cannabinoids can hope to overcome:

  1. a) with an approved drug, you know what you’re getting- with the plant, random analyses performed by regulatory labs have shown that the advertised content doesn’t always reflect what is in the plant
  2. b) with an approved drug, the cannabinoid is specifically designed to combat a particular disease process both in formulation, route of delivery, and mechanism of action.  With plant-derived treatments, one-route of administration doesn’t always fit all diseases
  3. c) FDA approved medications are covered by insurance reimbursement; plant-derived cannabinoids have historically not been covered by insurance.  A month’s supply of plant-derived cannabinoids can run into the hundreds of dollars versus a $5-$10 monthly copay for FDA approved medications
  4. d) pharmaceuticalized cannabinoids undergo a rigorous testing process (randomized, double-blind, placebo controlled clinical trials),  Plant derived cannabinoids have not undergone this type of rigorous testing and in many cases, rely on anecdotal evidence where bias reporting can creep in; until this type of rigorous testing is conducted in plant-derived cannabinoids, marijuana dispensaries run the risk of violating FTC regulations if they make claims on the efficacy and safety of their products

Q: What has been your biggest success in your research so far?

Murphy: The biggest success has been validating our prodrug design in the molecular engineering of the cannabinoid molecule in animal studies that permit the therapy to enter the body with more predictable bioavailability and steady-state drug concentrations.  These proprietary molecules are designed to optimize safety and efficacy by permitting routes of administration that bypass first-pass metabolism in the liver.  We look forward to upcoming human testing to further validate the potential benefits of this drug design approach.

For more information, log on to www.nemusbiosciences.com

Pfizer acquires Bamboo Therapeutics to beef up gene therapy arsenal

(Reuters) – Pfizer Inc said it had acquired privately held gene therapy developer Bamboo Therapeutics Inc in a deal worth up to $645 million to boost its presence in the treatment of rare diseases.

Research into gene therapy, which aims to insert corrective genes into malfunctioning cells, goes back a quarter of a century but the field has experienced multiple setbacks and been plagued by safety concerns.

However, the discovery of better ways to carry replacement genes into cells is building optimism.

The U.S. Food and Drug Administration has yet to approve any gene therapies but Europe has approved two – a treatment from GlaxoSmithKline for a rare immune disorder in babies and one from uniQure NV for a serious blood condition.

Genetic material can be delivered to the cells by a variety of means, most frequently using a viral vector.

Bamboo was formed in 2014 to advance the work of Dr. Richard Jude Samulski, who is considered a pioneer in the field after he became the first to realize the potential of using adeno-associated virus’s (AAV) as a vehicle to replace a defective gene with a healthy gene.

Through the acquisition, Pfizer will gain access to Bamboo’s experimental gene therapies for rare diseases such as Duchenne Muscular Dystrophy (DMD), giant axonal neuropathy (GAN), Friedreich ataxia (FA) and Canavan disease.

Focused on neurological and neuromuscular diseases, Bamboo’s drugs are still in the preclinical or early stages of development. Pfizer is paying the Chapel Hill, North Carolina-based company $150 million upfront, and Bamboo stands to make $495 million in milestone payments.

Pfizer has been investing in gene therapies – touted as a one-time cure for intractable and expensive-to-treat diseases – in recent years.

In 2014, the drugmaker entered into a collaboration with Philadelphia-based Spark Therapeutics Inc to develop SPK-9001, a gene therapy for hemophilia B.

Earlier this year, Pfizer signed a collaboration and license agreement with Emeryville, California-based 4D Molecular Therapeutics to develop targeted vectors for cardiac disease.

Other big drugmakers have made similar investments. Bristol-Myers Squibb Co has a tie-up with uniQure to develop gene therapies for heart diseases, while Celgene Corp has teamed up with bluebird bio Inc for cancer.

 

Q&A with TapImmune CEO Dr. Glynn Wilson, on a Vaccine to Prevent Cancer Recurrence, in Multiple Phase II Trials

A vaccine that can prevent the recurrence and metastasis of cancer would save countless lives. In the past century, vaccines have virtually eradicated life threatening diseases including polio and tuberculosis. Medical science may soon be at the point of delivering a cancer vaccine.
Scientists at TapImmune are working closely with leading institutions and a big pharma collaborator including the Mayo Clinic, Memorial Sloan Kettering Cancer Center, the U.S. Department of Defense, and AstraZeneca, to bring such a cancer vaccine to market.
TapImmune’s lead cancer vaccine candidate, TPIV 200 is slated for four Phase II trials this year. Outstanding Phase I results from previous studies conducted at the Mayo Clinic are the impetus for Phase II trials in ovarian and breast cancer.
The Bio Connection recently spoke with TapImmune CEO Dr. Glynn Wilson about TPIV 200.

Q: Tell us about TPIV 200 and what makes it a vaccine, rather than a drug or a treatment?

TPIV 200 works much like vaccines that target other disease such as polio and tuberculosis because it stimulates the body’s cellular immune system to recognize and fight the disease. In this case, TPIV 200 targets cancer cells and in particular, it targets metastatic cancer, which is the biggest threat to survival. TPIV 200 broadly stimulates T-cells to recognize, remember, and attack specific targets (antigens) on tumor cells throughout the body.
TPIV 200 is also an off-the-shelf product, like most other vaccines today. It has been formulated and manufactured as a lyophilized (frozen) product with a long shelf life that can be administered via injection, without having to customize it for a specific person’s cancer cells.
Our clinical trials are designed to test TPIV 200’s efficacy in preventing cancer from recurring in people who have already been diagnosed with, and treated for, cancer, thus serving as a vaccine against cancer recurrence.

Q: Would TPIV 200 only be used in people who have already had cancer? What about people using it in a preventative way?

Since a majority of cancer deaths are caused by cancer recurrence and metastasis, not the original tumor, we see this as the area of greatest need. Indeed, in our target indications, ovarian and triple negative breast cancer, patients are at a high risk of cancer recurrence following standard treatments. That’s why we are evaluating the efficacy of TPIV 200 in preventing or delaying recurrence and metastasis.
We certainly see the possibility of developing a prophylactic, or preventative vaccine, for people who have not had cancer, but to do this you will normally need to demonstrate efficacy in a therapeutic setting. There is growing evidence, in preclinical studies, that a preventive vaccine may be viable. We are currently exploring additional studies in this area. A prophylactic cancer vaccine may potentially be developed based on either the TPIV 200 or TPIV 110 platforms. Or, our own in-house developed PolyStart platform also shows great promise for this.

Q: For a company your size, conducting four simultaneous Phase II trials is really impressive. How are you managing this strategy and why four at the same time?

Two of our upcoming Phase II trials are being conducted and financed in collaboration with world-class organizations. These reduce our clinical development costs significantly and they bring on board some of the top minds in immuno-oncology to work on TPIV 200.
With a $13.3 million grant, the U.S. Department of Defense is fully funding a double-blinded, placebo controlled Phase II study of TPIV 200 in 280 patients with triple negative breast cancer to be conducted at the Mayor Clinic in Jacksonville, Florida.
TapImmune is also collaborating with AstraZeneca on a Phase II trial in 40 patients with platinum resistant ovarian cancer, for a combination therapy of TPIV 200 with AstraZeneca’s anti-PD-L1 checkpoint inhibitor, durvalumab (MEDI4736). This study has begun enrollment and is being conducted at the Memorial Sloan Kettering Cancer Center in New York.
Two other Phase II studies are being funded and conducted by us. We recently dosed the first patient in our Phase II trial of TPIV 200 in triple negative breast cancer. This study, which will enroll 80 patients, is being conducted and funded by TapImmune. Later this year, we plan to commence another company conducted and funded Phase II trial in platinum sensitive ovarian cancer patients. Because we are conducting and funding these trials ourselves, we have greater control over the timing and pace of the trial. This is very helpful in terms of seeing data in the relative near term, and advancing our development timeline.
Our strategy is to move TPIV 200 along on multiple fronts via both our own company sponsored trials and by collaborating with others, to reduce our development costs.

Q: Why do you think AstraZeneca, which can partner with just about anyone chose TapImmune’s TPIV 200? Do you see this collaboration with AstraZeneca expanding into something more?

The collaboration started with the Principal Investigator at Memorial Sloan Kettering, Dr. Jason Konner, who saw the potential of combining a leading checkpoint inhibitor with a T-cell vaccine in ovarian cancer patients. Clinicians at AstraZeneca then reviewed the technical and clinical data on TPIV 200, resulting in the current collaboration. They are a big believer in testing combination therapies and are conducting over a dozen clinical trials of their checkpoint inhibitor durvalumab in combination with other compounds.
It’s premature to say anything about a deepening relationship AstraZeneca at this point, but we are very pleased they saw enough promise in TPIV 200 to conduct a collaborative trial with us. If favorable data emerges from the Phase II trial, that may be the impetus for us to discuss an expanded relationship with AstraZeneca.

Q: Can you tell us more about your other cancer vaccine, TPIV 110?

We plan to initiate a Phase II clinical trial of TPIV 110 at the start of 2017. TPIV 110 is a proprietary HER2neu vaccine technology. The HER2neu antigen is a well-established therapeutic target and plays a role in breast, ovarian and colorectal cancer. Each of these is a potential indication for this vaccine. Like TPIV 200, TPIV 110 was originally developed at the Mayo Clinic and TapImmune has a worldwide exclusive license on these technologies. The Mayo Clinic successfully concluded a Phase I trial in HER2neu breast cancer patients that evaluated TPIV 100, a precursor to TPIV 110 which has 4 Class II antigens. TPIV 100 was found to be safe, well-tolerated, and provided a robust immune response across a broad patient population. 19 out of 20 patients showed a robust T-cell response to two antigens and 15 out of 20 patients showed a response to all four antigens. TPIV 110 has been formulated with an additional 5th antigen, which is a Class I antigen, expected to make it more potent than TPIV 100. We believe TPIV 110 shows great promise and it helps round out our cancer vaccine portfolio.
For more information on TapImmune visit http://www.tapimmune.com (Ticker: TPIV)

A New Way to Nip AIDS in the Bud

When new AIDS virus particles bud from an infected cell, an enzyme named protease activates to help the viruses mature and infect more cells. That’s why modern AIDS drugs control the disease by inhibiting protease.

Now, University of Utah researchers found a way to turn protease into a double-edged sword: They showed that if they delay the budding of new HIV particles, protease itself will destroy the virus instead of helping it spread. They say that might lead, in about a decade, to new kinds of AIDS drugs with fewer side effects.

“We could use the power of the protease itself to destroy the virus,” says virologist Saveez Saffarian, an associate professor of physics and astronomy at the University of Utah and senior author of the study released today by PLOS Pathogens, an online journal published by the Public Library of Science.

So-called cocktails or mixtures of protease inhibitors emerged in the 1990s and turned acquired immune deficiency syndrome into a chronic, manageable disease for people who can afford the medicines. But side effects include fat redistribution in the body, diarrhea, nausea, rash, stomach pain, liver toxicity, headache, diabetes and fever.

“They have secondary effects that hurt patients,” says Mourad Bendjennat, a research assistant professor of physics and astronomy and the study’s first author. “And the virus becomes resistant to the inhibitors. That’s why they use cocktails.”

Bendjennat adds that by discovering the molecular mechanism in which protease interacts with HIV, “we are developing a new approach that we believe may be very efficient in treating the spread of HIV.”

However, he and Saffarian emphasize the research is basic, and that it will be a decade before more research might develop the approach into news AIDS treatments.

Figuring out the role of protease in HIV budding

Inside a cell infected by HIV, new virus particles are constructed largely with a protein named Gag. Protease enzymes are incorporated into new viral particles as they are built, and are thought to be activated after the new particles “bud” out of infected cell and then break off from it.

The particles start to bud from the host cell in a saclike container called a vesicle, the neck of which eventually separates from the outer membrane of the infected cell. “Once the particles are released, the proteases are activated and the particles transform into mature HIV, which is infectious,” Saffarian says.

“There is an internal mechanism that dictates activation of the protease, which is not well understood,” he adds. “We found that if we slow the budding process, the protease activates while the HIV particle is still connected to the outer membrane of host [infected] cell. As a result, it chews out all the proteins inside the budding HIV particle, and those essential enzymes and proteins leak back into the host cell. The particle continues to bud out and release from the cell, but it is not infectious anymore because it doesn’t have the enzymes it needs to mature.”

Budding HIV needs ESCRTs

The scientists found they could slow HIV particles from budding out of cells by interfering with how they interact with proteins named ESCRTs (pronounced “escorts”), or “endosomal sorting complexes required for transport.”

ESCRTs are involved in helping pinch off budding HIV particles – essentially cutting them from the infected host cell.

Saffarian says scientific dogma long has held “that messing up the interactions of the virus with ESCRTs results in budding HIV particles permanently getting stuck on the host cell membrane instead of releasing.” Bendjennat says several studies in recent years indicated that the particles do get released, casting some doubt on the long held dogma.

The new study’s significance “is about the molecular mechanism: When the ESCRT machinery is altered, there is production of viruslike particles that are noninfectious,” he says. “This study explains the molecular mechanism of that.”

“We found HIV still releases even when early ESCRT interactions are intentionally compromised, however, with a delay,” Saffarian says. “They are stuck for a while and then they release. And by being stuck for a while, they lose their internal enzymes due to early protease activation and lose their infectivity.”

Bendjennat says by delaying virus budding and speeding “when the protease gets activated, we are now capable of using it to make new released viruses noninfectious”

How the research was done

The experiments used human skin cells grown in tissue culture. It already was known that new HIV particles assemble the same way whether the infected host cell is a skin cell, certain other cells or the T-cell white blood cell infected by the virus to cause AIDS. The experiments involved both live HIV and so-called viruslike particles.

Bendjennat and Saffarian genetically engineered mutant Gag proteins. A single HIV particle is made of some 2,000 Gag proteins and 120 copies of proteins known as Gag-Pol, as well as genetic information in the form of RNA. Pol includes protease, reverse transcriptase and integrase – the proteins HIV uses to replicate.

The mutant Gag proteins were designed to interact abnormally with two different ESCRT proteins, named ALIX and Tsg101.

A new HIV particle normally takes five minutes to release from an infected cell.

When the researchers interfered with ALIX, release was delayed 75 minutes, reducing by half the infectivity of the new virus particle. When the scientists interfered with Tsg101, release was delayed 10 hours and new HIV particles were not infectious.

The scientists also showed that how fast an HIV particle releases from an infected cell depends on how much enzyme cargo it carries in the form of Pol proteins. By interfering with ESCRT proteins during virus-release experiments with viruslike particles made only of Gag protein but none of the normal Pol enzymes, the 75-minute delay shrank to only 20 minutes, and the 10-hour delay shrank to only 50 minutes.

“When the cargo is large, the virus particle needs more help from the ESCRTs to release on a timely fashion,” Saffarian says.

Because HIV carries a large cargo, it depends on ESCRTs to release from an infected cell, so ESCRTs are good targets for drugs to delay release and let HIV proteases leak back into the host cell, making new HIV particles noninfectious, he says.

Bendjennat says other researchers already are looking for drugs to block ESCRT proteins in a way that would prevent the “neck” of the budding HIV particle from pinching off or closing, thus keeping it connected to the infected cell. But he says the same ESCRTs are needed for cell survival, so such drugs would be toxic.

Instead, the new study suggests the right approach is to use low-potency ESCRT-inhibiting drugs that delay HIV release instead of blocking it, rendering it noninfectious with fewer toxic side effects, he adds.