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Altered virus may expand patient recruitment in human gene therapy trials

For many patients, participating in gene therapy clinical trials isn’t an option because their immune system recognizes and fights the helpful virus used for treatment. Now, University of Florida Health and University of North Carolina researchers have found a solution that may allow it to evade the body’s normal immune response.

The discovery, published May 29 in the Proceedings of the National Academy of Sciences, is a crucial step in averting the immune response that prevents many people from taking part in clinical trials for various disorders, said Mavis Agbandje-McKenna, Ph.D., a professor in the University of Florida College of Medicine department of biochemistry and molecular biology and director of the Center for Structural Biology.

During gene therapy, engineered viruses are used to deliver new genes to a patient’s cells. While the recombinant adeno-associated virus, or AAV, is effective at delivering its genetic cargo, prior natural exposure to AAV results in antibodies in some people. As many as 70 percent of patients have pre-existing immunity that makes them ineligible for gene therapy clinical trials, Agbandje-McKenna said.

The findings provide a road map for designing virus strains that can evade neutralizing antibodies, said Aravind Asokan, Ph.D., an associate professor in the department of genetics at the University of North Carolina, who led the study. At UF Health, the structural “footprints” where pre-existing antibodies interact with the virus were identified using cryo-electron microscope resources provided by the UF College of Medicine and the UF Office of Research’s Division of Sponsored Programs. The UNC researchers then evolved new viral protein shells. Using serum from mice, rhesus monkeys and humans, the researchers showed that the redesigned virus can slip past the immune system.

“This is the blueprint for producing AAV strains that could help more patients become eligible for human gene therapy. Now we know how to do it,” Agbandje-McKenna said.

While the findings prove that one variation of AAV can be evolved, further study in preclinical models is needed before the approach can be tested in humans. Next, the immune profile of one particularly promising virus variant will need to be evaluated in a larger number of human serum samples, and dose-finding studies are needed in certain animal models. Researchers may also need to study whether the same virus-manipulating technique can be used in a broader range of gene therapy viruses, Agbandje-McKenna said.

Although human gene therapy remains an emerging field and has yet to reach patients on a wide scale, researchers elsewhere have used AAV therapy to successfully treat hemophilia, a blood-clotting disorder, in a small trial. It has also been or is now being studied as a way to treat hereditary blindness, certain immune deficiencies, neurological and metabolic disorders, and certain cancers.

The latest findings are the result of more than 10 years of studying the interactions between viruses and antibodies and a long-standing collaboration with Asokan, who heads the synthetic virology group at the UNC Gene Therapy Center, according to Agbandje-McKenna.

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Clinical trial shows experimental drug’s ability to knock down pancreatic cancer’s defense

By adding an experimental drug to a standard chemotherapy regimen, a subset of patients with metastatic pancreatic cancer had a significantly longer period before the cancer progressed as compared with those who received the standard treatment, according to a Phase 2 clinical trial led by an investigator at Fred Hutchinson Cancer Research Center.

The randomized, controlled trial found that when the experimental therapy was given to participants whose tumors had a lot of the drug’s target molecule, they had four months more of progression-free survival than participants in the control group who only had the chemo.

For anyone not familiar with the rapid deadliness of pancreatic cancer, it may be hard to see the significance of the few additional months before disease progression. But time is precious for patients with this cancer: Only about 8 percent of all pancreatic cancer patients survive five years after diagnosis.

Dr. Sunil Hingorani, the faculty member at Fred Hutch who led the trial, is scheduled to present the findings at 10:24 a.m., June 4, at the American Society of Clinical Oncology annual meeting in Chicago. ASCO abstract number 4008.

Hingorani said that the results reassure him that it was the right move to advance the drug, called PEGPH20, into the worldwide Phase 3 trial that opened last year.

“We still haven’t fully proven anything yet, strictly speaking, but I think [this strategy] is very rational,” he said. “Let me put it this way: I think it would be irresponsible not to finish the global Phase 3 trial as the most rigorous test of this hypothesis. I think we’re obligated now to answer the question.”

Hingorani consults for Halozyme, the PEGPH20 drugmaker and the sponsor of these trials. The company began this year to provide funding through Fred Hutch to support Hingorani’s research on the drug.

Hingorani’s earlier research led him to the drug because he believed it could address a challenge posed by many pancreatic cancers: The tumors have very high internal pressures that collapse local blood vessels and prevent cancer-killing drugs from getting in. PEGPH20 reduces those pressures so chemotherapies circulating in the blood can penetrate tumors.

The experimental drug, which was created from the blueprint of a naturally occurring enzyme, breaks down a molecule called hyaluronic acid that is produced in bulk by many pancreatic cancers.

Hyaluronic acid, or HA, is naturally found in the human body; it readily binds water to create a gel fluid, making it an excellent shock-absorber in your knees, for example. But in pancreatic tumors, it spells trouble. As the gel fluid builds up, it raises the tumor’s internal pressure, squeezing local blood vessels shut. Patients whose tumors have a lot of HA also tend to have a poor prognosis.

Hingorani and his team first conducted studies in mice that showed how PEGPH20, in combination with chemo, permanently reduced the amount of pressure-boosting HA inside the mouse tumors. It caused the tumors to shrink and increased the mice’s survival time.

In the Phase 2 trial, patients with late-stage pancreatic cancer were randomly assigned to receive a standard-of-care, first-line combination chemotherapy either with or without PEGPH20. When the results of all 234 evaluable patients on Halo 202 were grouped together, the apparent benefit of PEGPH20 was small ? a matter of just a couple extra weeks of progression-free survival.

“If this was all the potential that this strategy represented, I wouldn’t pursue this [research further],” Hingorani said. “That’s not enough for me.”

But a stark difference emerged when the results were divided up by how much of the drug’s target, HA, patients’ tumors contained: In the subset of 80 patients whose tumors had high levels of HA, adding PEGPH20 to chemo resulted in an average of 9.2 months before disease progression; with chemo alone, this timespan was just 5.2 months.

Hingorani also reported that the unexpected, elevated risk of blood clots associated with PEGPH20 ? which resulted in a temporary halt of the trial in 2014 ? equalized between the patients receiving PEGPH20 and those in the control group, and dropped overall, after the study was restarted, due to the addition of a blood thinner to all patients’ regimens.

“These are the real take-home messages to me, namely, the progression-free survival in target-rich [high-HA] patients and the ability to give the enzyme safely,” Hingorani said.

Because the Phase 2 trial results suggest that the benefit of the experimental drug is restricted to the patients with high levels of HA in their tumors, only patients with such tumors qualify for the new Phase 3 trial. And the Phase 3 trial is designed to offer a more stringent test of the benefits of the new drug than its predecessor: Aimed at advancing the drug toward potential FDA approval, the trial’s goal is to determine whether PEGPH20 actually increases participants’ lifespans, not just their time to disease progression. (It’s possible a treatment could achieve the latter without impacting the former.)

The investigators’ exploratory analysis of the Phase 2 trial data suggested that the experimental drug boosted the lifespans of patients with high-HA tumors to an average of nearly a year after diagnosis ? which, if shown definitively in the Phase 3 trial, could be a new benchmark for this cancer, Hingorani said.

Hingorani launched the Phase 3 trial before handing off its leadership to two other colleagues in the field, Dr. Margaret Tempero of the University of California, San Francisco and Dr. Eric Van Cutsem at the University of Leuven in Belgium. As he steps back from his leadership role on this project, Hingorani is satisfied by the solid scientific foundation the investigators have lain to justify moving forward with the development of this drug.

In light of the grim timelines associated with a pancreatic cancer diagnosis, he said, patients have no time to waste on anything less.

“Patients get one shot on goal, if that, with this cancer,” he said. “No cancer is more daunting than pancreas cancer.”

Treatment-related adverse events for trial participants included peripheral edema (63 percent of those receiving PEGPH20 vs. 26 percent for the control group), muscle spasms (56 percent vs 3 percent), neutropenia (34 percent vs 19 percent), and myalgia (26 percent vs. 7 percent).

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Immunotherapy with DNA vaccine shows promise for HPV-related head and neck cancer

A novel vaccine therapy can generate immune responses in patients with head and neck squamous cell carcinoma (HNSCCa), according to researchers at the Abramson Cancer Center of the University of Pennsylvania. The treatment specifically targets human papillomavirus (HPV), which is frequently associated with HNSCCa, to trigger the immune response. Researchers will present the results of their pilot study during the 2017 American Society of Clinical Oncology Annual Meeting in Chicago (Abstract #6073).

HNSCCa is a cancer that develops in the mucous membranes of the mouth, and throat. While smoking and tobacco use are known causes, the number of cases related to HPV infection – a sexually transmitted infection that is so common, the Centers for Disease Control says almost all sexually active adults will contract it at some point in their lifetimes – is on the rise. The CDC now estimates 70 percent of all throat cancers in the United States are HPV-related. Sixty percent are caused by the subtype known as HPV 16/18.

“This is the subtype we target with this new therapy, and we’re the only site in the country to demonstrate immune activation with this DNA based immunotherapeutic vaccine for HPV 16/18 associated head and neck cancer,” said the study’s lead author Charu Aggarwal, MD, MPH, an assistant professor of Hematology Oncology in the Perelman School of Medicine at the University of Pennsylvania.

The vaccine is delivered as an injection of antigens – which leads the immune system to start producing antibodies and activate immune cells. At the time of injection, physicians use a special device to deliver a pulse of electricity to the area, which stimulates the muscles and speeds the intake of the antigens. Aggarwal noted that this study represents a multidisciplinary approach involving the lab and the clinic.

“This is truly bench-to-bedside and shows the value of translational medicine within an academic medical center,” Aggarwal said.

Penn researchers treated 22 patients with the vaccine. All of the patients had already received therapy that was intended to be curative – either surgery or chemotherapy and radiation. When doctors followed up an average of 16 months later, 18 of those patients showed elevated T cell activity that was specific to HPV 16/18. All of the patients in the study are still alive, and none reported any serious side effects.

“The data show the therapy is targeted and specific, but also safe and well-tolerated,” Aggarwal said.

Because of the positive activity, Aggarwal says the next step is to try this therapy in patients with metastatic disease. A multi-site trial will open soon that combines the vaccine with PD-L1 inhibitors, which target a protein that weakens the body’s immune response by suppressing T-cell production.

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Forge Therapeutics Raises $15M Series A Financing to Develop First Novel Gram-Negative Antibiotic in Decades

Forge Therapeutics, Inc., a biotechnology company discovering first-in-class antibiotics using a breakthrough drug discovery platform, announced today the completion of a $15M Series A financing. The round is led by MagnaSci Ventures, with participation from Evotec AG, Alexandria Venture Investments, MP Healthcare Venture Management, Red Apple Group, and WS Investments. Forge has used its enabling technology to identify a novel LpxC inhibitor effective against multi-drug resistant bacteria ‘superbugs,’ and the funding will support the program into clinical studies.

“This financing is an important step forward to solving the ‘superbug’ epidemic, an urgent global health issue in desperate need of innovation. We’ve been impressed with the strength of the Forge team, their technologies and their commitment to innovating the antibiotic space,” said Brian T. Dorsey, Founding Partner at MagnaSci Ventures. “With our investment and resources, we look forward to working together on developing the first novel antibiotic against Gram-negative bacteria in decades.” In connection with the Series A financing, Mr. Dorsey will be joining Forge’s Board of Directors.

“We are pleased to have such quality investors join us in our pursuit to eradicate deadly ‘superbug’ infections with novel antibiotics stemming from our robust drug discovery engine,” said Zachary A. Zimmerman, Ph.D., CEO of Forge. “The proceeds from this financing, coupled with the non-dilutive monies received from government agencies CARB-X and NIH/NIAID, will advance our LpxC inhibitor into clinical studies.”

With its proprietary chemistry approach, Forge develops small molecule inhibitors targeting metalloenzymes.  Forge’s lead effort is focused on LpxC, a zinc metalloenzyme found only in Gram-negative bacteria and which is essential for bacteria to grow. Forge has discovered novel small molecule inhibitors of LpxC that are potent in vitro, efficacious in vivo, and effective against drug resistant Gram-negative bacteria ‘superbugs.’

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AACR: Phase II Trial Shows Rice Bran Promotes Microbiome Diversity, Slows Growth of Colorectal Cancer Cells

Today at the American Association for Cancer Research (AACR) Annual Meeting 2017, University of Colorado Cancer Center researchers at Colorado State University present results of a phase II clinical trial of 29 people exploring the effects of adding rice bran or navy beans to the diets of colorectal cancer survivors. After the 4-week randomized-controlled trial during which people added rice bran, navy bean powder or neither, both the rice bran and navy bean groups showed increased dietary fiber, iron, zinc, thiamin, niacin, vitamin B6, folate, and alpha-tocopherol. The rice bran group also showed increased microbiome richness and diversity. When researchers treated colorectal cancer cells with stool extracts from these groups, they saw reduced cell growth from the groups that had increased rice bran and navy bean consumption.

Previous work shows the ability of these diets to decrease colorectal cancer risk in animal models. The current trial confirms that people can eat enough bean- and rice bran-enhanced foods to promote gut health at levels shown to prevent colorectal cancer in animals.

Guidelines from the American Institute for Cancer Research recommend reducing the risk of cancer by eating more vegetables, fruits, whole grains and legumes, such as beans. Ryan has established from these studies that eating a half-cup of beans and 30 grams of rice bran per day is enough to see changes in small molecules that can confer protection against colorectal cancer.

“The simple message is, ‘Food is medicine,’ and we are looking at how to simplify that and make it apply to our everyday lives,” says study co-author Regina Brown, MD, assistant professor at the CU School of Medicine and oncologist for CUHealth.

Brown is long-time collaborator of CU Cancer Center investigator and CSU assistant professor, Elizabeth Ryan, PhD. The Ryan Lab in the CSU College of Veterinary Medicine and Biomedical Sciences studies the potential power of navy beans and rice bran to promote digestive health and to prevent metabolic alterations in obesity, heart disease and certain cancers.

“The evidence is there in animals and we can now study this in people. The question is, what are we doing to achieve adequate levels of intake of these foods?” Ryan said. “It’s not enough to say ‘I eat them once in a while.’ That’s not going to work, particularly if you are at higher risk. You have to meet a dose, just like you need a dose of a certain drug, you need to reach intake levels and consume increased amounts of these foods, and that’s where people, including me, are challenged. Not everyone wants to open up a can of beans and eat them every day.”

The two met about 10 years ago, when Ryan was a researcher in CSU professor Henry Thompson’s Cancer Prevention Lab, and Brown was practicing medicine in Fort Collins and caring for her mother, who had uterine cancer.

“It was kind of a novel partnership and had we not dug in our heels it could have died, but I told Elizabeth, ‘Your work is so interesting and so valuable. We have to take this translational research from the benchtop to the clinic.’ I guarantee, nine out of 10 of my patients, the first thing they ask is about their diet,” Brown said.

The study’s lead author is Erica Borresen, Ryan’s research associate and study coordinator, who worked with colorectal cancer survivors to make sure they ate their beans and rice bran provided in meals and snacks, and that they filled out their food logs and gastrointestinal health questionnaires. It was sometimes intimate and awkward, but so is getting a colonoscopy and being treated for colorectal cancer.

“Our participants donated their time and effort, and I want to make sure they understand they are appreciated,” said Borresen, who earned her Master of Public Health at the Colorado School of Public Health, and plans to become a physician’s assistant. “I came to realize I love the patient interaction – that’s one of my favorite parts about coordinating our studies.”

The next phase of Ryan’s research examines effects of the cooked navy bean powder and rice bran on the colon tissue of people who have already had colorectal cancer and are at high risk for recurrence.

“I really feel that there’s hope in this being a practical solution to improve gut health and specifically colorectal cancer prevention,” says Ryan.

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First in Human’ Trial Defines Safe Dosage for Small Molecule Drug ONC201 for Solid Cancer Tumors

Research from Rutgers Cancer Institute of New Jersey examines oral drug that targets cancer cells and spares healthy tissue

A ‘first in human’ clinical trial examining the small molecule drug ONC201 in cancer patients with advanced solid tumors shows that this investigational drug is well tolerated at the recommended phase II dose. That’s according to Rutgers Cancer Institute of New Jersey investigators and colleagues whose research also showed early signs of clinical benefit in patients with advanced prostate and endometrial cancers. The work appears in the ‘OnlineFirst’ section of Clinical Cancer Research (DOI: 10.1158/1078-0432.CCR-16-2658).

At focus is the investigational drug ONC201 that targets a dopamine receptor, a member of the G protein-coupled receptor superfamily residing on the surface of cancer cells, to cause their destruction. ONC201 is the first of a new family of therapeutic compounds called imipridones. Previous research on the study drug conducted by Rutgers Cancer Institute and Oncoceutics, Inc. – which is also supporting this trial – suggests that ONC201 may be capable of turning off proteins that maintain tumor growth and and may help kill cancer cells while sparing normal ones. Pre-clinical study demonstrated ONC201 was effective in laboratory models against a number of solid tumors including colon cancer, brain cancer, triple-negative breast cancer and non-small cell lung cancer.

In this phase I dose-escalation study, 10 patients over age 18 with advanced solid tumors that were resistant to standard therapies were enrolled through Rutgers Cancer Institute between January and July 2015. Participants received a starting dose of 125mg of the study drug, which was taken orally via capsule every 21 days (one cycle). The dosage for this cohort was increased incrementally up to a maximum dose of 625mg, which is five-fold above the dose that was effective in laboratory models. An additional 18 patients were enrolled in an expansion phase between August 2015 and February 2016 and treated at the recommended phase II dose of 625mg in order to collect additional safety, pharmacokinetic and pharmacodynamic information.

There were no drug-related adverse events over Grade 1 in either the dose escalation phase or the expansion phase. The few low grade events that were recorded (nausea, fever) were resolved quickly, note the authors. While the study achieved the aim of identifying the recommended phase II dose of the drug, findings also showed tumor regression in patients with metastatic disease. Results also demonstrated prolonged stable disease following more than nine cycles (27 weeks) of treatment – particularly in prostate and endometrial cancer patients that had lymph node, bone and lung lesion involvement. Out of the 28 participants, 10 completed at least four cycles of treatment with two patients receiving at least nine cycles. The authors note while a 90-year old prostate cancer patient saw his primary tumor and metastatic bone lesion shrink by about 25 percent after taking two 625mg doses of ONC201, a 72-year old patient with advanced clear cell endometrial cancer had a mixed response after two doses, with multiple nodes decreasing by more than 30 percent but experiencing the development of new nodes.

“By exploring a novel agent that targets the cancer but leaves non-cancerous tissue untouched, we have an opportunity to not only provide a new treatment option for patients who have exhausted standard forms of therapy without the typical toxicities associated with anticancer treatment, but to also offer them a therapeutic that may result in a better quality of life since healthy cells are not impacted,” notes Rutgers Cancer Institute medical oncologist Mark Stein, MD, who is an associate professor of medicine at Rutgers Robert Wood Johnson Medical School and lead investigator of the work. “While meaningful to confirm the safety profile of this dosage for ONC201, it is noteworthy that our findings also showed some evidence of clinical benefit to some patients.”

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Pivotal Trial Begins for Breast Fibroadenoma Using Focused Ultrasound

Patients with benign breast tumors may be eligible for a new focused ultrasound–based investigational treatment as part of a pivotal, multi-center clinical study. The trial began last month at the University of Virginia (UVA) Medical Center.

David Brenin, MD, Associate Professor of Surgery and Chief of Breast Surgery at UVA, is the Principal Investigator for the trial. He recently completed a 20-patient pilot study to test the safety and efficacy of the device, Theraclion’s EchoPulse system. Now, in this single arm prospective study, the procedure will be performed in 100 patients at several sites worldwide, including UVA, Montefiore Medical Center, Columbia Presbyterian, Bellevue Hospital Center in New York, and others. As these new sites begin treating, the list of locations will be updated on our website and on clinicaltrials.gov.

“The patient selection criteria have been updated since the pilot study,” says Dr. Brenin. “The new parameters for the size of the fibroadenoma and the range of symptoms should allow us to include more patients. Furthermore, our experience and improvements to the device have allowed us to decrease the overall treatment time.”

EchoPulse is designed to non-invasively ablate benign breast tumors using ultrasound-guided focused ultrasound treatment. Although it is not yet approved by the US Food and Drug Administration, the system received the CE Mark in Europe five years ago, where it is also used to treat breast fibroadenomas and treat thyroid nodules and is also under investigation for other conditions.

“If this multi-center trial is successful, we will seek regulatory approval in the US,” says Theraclion’s Chief Medical Officer, Michel Nuta, MD. “Approval by the FDA would allow many more women to receive precise treatment of breast fibroadenomas non-invasively and on an outpatient basis, enabling them to return to their daily lives almost immediately.”

Patients who are interested in this study at the University of Virginia (IRB# 19437) should contact Research Coordinator Katie Rea via phone (434) 243-0315 or email uvastac@virginia.edu. More information for patients and referring physicians can also be found on the UVA website.

Dr. Brenin plans to present the initial data from the pilot study at the 18th Annual Meeting of the American Society of Breast Surgeons in Las Vegas in April 2017.

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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.

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Two New Trials for Pediatric Brain Cancer Open at UTHealth/Children’s Memorial Hermann

Two new clinical trials for pediatric brain cancer have begun at The University of Texas Health Science Center at Houston (UTHealth) and Children’s Memorial Hermann Hospital.

The pilot trials, approved by the U.S. Food and Drug Administration, both focus on the administration of chemotherapy agents directly into the fourth ventricle of the brain, the most common site for pediatric brain tumors and one that is difficult to access surgically.

“Administering chemotherapy directly to the site of the tumor can enable very high drug levels at the site of active disease while decreasing the likelihood of systemic toxicity,” said David Sandberg, M.D., the Dr. Marnie Rose Professor in Pediatric Neurosurgery at McGovern Medical School at UTHealth, who pioneered the procedure. “Current treatment options can have serious side effects, and we need to do better. Radiation therapy can be harmful to the developing brain and chemotherapy in the high levels needed to cross the blood-brain barrier can cause many side effects as well as damage to organs throughout a child’s body.”

Both trials are designed to target brain tumors that develop in the posterior fossa portion of the brain that includes the cerebellum, brain stem and fourth ventricle.

One trial builds on Sandberg’s previous research that investigated the infusion of methotrexate for pediatric brain tumors. Results of the research, published in October 2015 in the Journal of Neuro-Oncology, showed that some patients with recurrent medulloblastoma experienced a beneficial anti-tumor effect. The new study will look at combining methotrexate with another chemotherapy agent, etoposide, for infusion into the fourth ventricle for medulloblastoma, the most common malignant brain tumor in children. Children with other tumors such as atypical teratoid rhabdoid tumor (ATRT) are also eligible.

The second trial focuses on a different chemotherapy agent for a type of brain tumor called recurrent posterior fossa ependymoma. Ependymomas form from ependymal cells that line the ventricles and passageways in the brain and spinal cord, according to the National Cancer Institute.

The chemotherapy agent, 5-azacytidine (5-AZA), is infused directly into the fourth ventricle. The agent has never been injected into a human brain before but has been shown to be promising in treating ependymomas in the laboratory. No systemic chemotherapy will be given to clinical trial participants.

Both studies are open to patients age 1 to 21.

The procedures will be done at Children’s Memorial Hermann Hospital, where Sandberg is director of Pediatric Neurosurgery. He is also director of Pediatric Neurosurgery at Memorial Hermann Mischer Neuroscience Institute at the Texas Medical Center. Sandberg is a professor in both the Department of Pediatric Surgery and the Vivian L. Smith Department of Neurosurgery at McGovern Medical School.

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University Hospitals Rainbow Babies & Children’s Hospital Opens First Stem Cell Study in Patients with Cystic Fibrosis

Study is first step toward goal of developing therapy to quell CF’s lung inflammation

A 39-year-old man with cystic fibrosis (CF) made history by becoming the first person to receive human adult stem cells in a new research study that researchers hope will someday lead to the development of a therapy to reduce the inflammation and infection caused by CF.

The pioneering subject in the study is Bob Held from Alliance, Ohio, who on Jan. 26 received an infusion of cells called allogeneic human mesenchymal stem cells (hMSC), adult stem cells collected from the bone marrow of healthy volunteers. Mr. Held was diagnosed with CF when he was 16 months old.

Currently, there is no cure for CF, and life expectancy for patients who survive into adulthood is approximately 41 years of age.

“It was a very exciting day for us with the very first participant in the first stem cell trial for cystic fibrosis,” said James Chmiel, MD, the principal investigator of the study at University Hospitals Rainbow Babies & Children’s Hospital.

The Phase 1 trial will assess the safety and tolerability of hMSCs in adult patients with CF.

“This is an early phase trial, and the most important thing is to ensure safety,” said Dr. Chmiel. “This study consists of a single infusion of stem cells. We will follow the study participants for a year to make sure it’s safe. Before applying any therapy on a broad basis, we want to make sure that it’s safe.”

While the goal of the study is safety, Dr. Chmiel hopes this is a first step towards the ultimate goal of developing a therapy to reduce lung inflammation and infection, resulting in longer and healthier lives for people with CF.

“While there’s been a tremendous increase in survival for people with CF from when I entered the field in the 1990s, that’s still not good enough,” said Dr. Chmiel, Director of the Cystic Fibrosis Therapeutics Development Center at UH Rainbow Babies & Children’s Hospital and Professor of Pediatrics at Case Western Reserve University School of Medicine. “While we’ve made great progress, we still have a long way to go.”
The stem cells that Mr. Held received were collected from the bone marrow of a healthy adult volunteer. UH is a national leader in the use of stem cell therapy with hMSCs. Researchers from UH, along with the CWRU School of Medicine, discovered hMSCs. The hMSCs possess many properties that are ideal for the treatment of inflammatory and degenerative diseases, and they possess natural abilities to detect changes in their environment, such as inflammation. The hope is that hMSCs can reduce the inflammation in the lungs caused by CF.

CF’s main effect is on the lungs. They fill with a sticky mucus as a reaction – really an over-reaction – by the body’s immune system to bacteria. The lungs are the source for much of the illness and shortened lifespan seen in CF.

“One of the issues in CF is that people with the disease get bacterial infections in their lungs, and these bacteria incite a vigorous and excessive inflammatory response,” explained Dr. Chmiel. “It’s actually the body’s inflammatory response that damages the lungs. The inflammatory response tries to eliminate the bacteria, but it’s not successful. Instead, the inflammatory system releases molecules that damage the individual’s own airways. The lung disease causes much of the illness and is responsible for the majority of the mortality of the disease.”

The stem cells are donated by healthy adult volunteers who go through a rigorous screening process. The stem cells are cultured in the UH stem cell facility. Volunteers with CF who are in the study receive an infusion through an IV.
“Once in the patient’s body, the stem cell tracks to the area where there’s a significant amount of inflammation, and they take up residence there. The stem cells then respond to the environment, and hopefully reverse some of the abnormalities,” said Dr. Chmiel. “We hope in future studies to demonstrate that the stem cells reduce the infection and inflammation and return the lungs to a more normal state.”

“This therapy aims to turn down the inflammatory response, not eliminate it because we still have to keep the bacteria in check. We want to reduce inflammation and the subsequent lung damage caused by inflammation without allowing the bacteria to proliferate,” said Dr. Chmiel.

A total of 15 clinically stable adults with CF will be enrolled in the study. Support for the study is from the Cystic Fibrosis Foundation.

The patient, Mr. Held, considers himself fortunate to be close to 40 with CF. When he was growing up, he said he’d miss 50 days of school each year because of the disease. Every day, he needs to breathe in aerosols for about two hours in the morning and 1-1/2 hours before bed to keep his lungs functioning. While he hasn’t been sick from the illness since his late teens, he does check himself into the hospital a couple of times a year for precautionary measures and to prevent himself from “getting into a valley” with CF.

His late wife, Michelle, died of CF seven years ago. They had met when they were kids, but didn’t get married until 2012. She died from the disease suddenly 28 days after they married.

“My only regret is that I didn’t ask her out sooner,” said Mr. Held.
He is participating in the study to carry on Michelle’s legacy, and “I am hoping the future generations of CF patients can get better treatments and that eventually a cure will be found for them,” he said.

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Georgetown Clinical Trial of Nilotinib in Alzheimer’s Disease Begins

 A clinical trial to examine the effect of nilotinib on clinical outcomes and biomarkers in people with mild to moderate Alzheimer’s disease has opened at Georgetown University Medical Center (GUMC).

The clinical trial is a phase II, randomized, double blinded, placebo-controlled study to evaluate the impact of low doses of the cancer drug(Tasigna®). GUMC is conducting the study with its clinical partner, MedStar Georgetown University Hospital.

The rationale for using nilotinib is based on laboratory and clinical research conducted by the Georgetown Translational Neurotherapeutics Program (TNP). Nilotinib appears to aid in the clearance of accumulated beta-amyloid (Abeta) plaques and Tau tangles in the brain. Both are hallmarks of Alzheimer’s disease. Nilotinib appears to penetrate the blood-brain barrier and turn on the “garbage disposal” machinery inside neurons (a process known as autophagy) to clear the Tau, Abeta and other toxic proteins.

“In a 2015 proof of concept study at Georgetown, patients with Parkinson’s disease or dementia with Lewy bodies were treated with nilotinib. As my colleagues reported, those who completed the study had a reversal in disease progression, observed both clinically and in key biomarkers—the same biomarkers seen in Alzheimer’s,” explains Scott Turner, MD, PhD, medical co-director of the TNP, who will serve as principal investigator for the study. “But even before the Parkinson’s study, research in the laboratory strongly supported studying this drug in people with Alzheimer’s. The promising results of the Parkinson’s study give an even stronger rationale.”

“When used in higher doses for chronic myelogenous leukemia (CML), nilotinib forces cancer cells into autophagy or cell death. The dose used in CML treatment is significantly higher than what we will use in our Alzheimer’s study,” says Charbel Moussa, MB, PhD, scientific and clinical research director for the Translational Neurotherapeutics Program. “When used in smaller doses once a day, as in this study, it appears nilotinib turns on autophagy for about four to eight hours—long enough to clean out the cells without causing cell death. Toxic proteins that build up again then appear to be cleared when the drug is given again the next day.”

Moussa initially conducted the preclinical research that led to the discovery of nilotinib for the potential treatment of neurodegenerative diseases.

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 Alzheimer’s Drug Discovery Foundation is supporting this clinical trial through a $2.1 million grant to Turner. The study has also received private philanthropic support.

Turner conducts additional clinical research supported by funding to Georgetown University from Lilly, Biogen, Merck, Acadia, and Toyama as well as the National Institutes of Health and Department of Defense.

To learn more about this clinical trial, please click here. To learn about other Alzheimer’s clinical studies, please visit the Georgetown Memory Disorders Program website.

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Patients with Severe Chronic Rhinosinusitis Show Improvement with Verapamil Treatment

A small clinical trial at Massachusetts Eye and Ear found that patients with chronic rhinosinusitis (CRS) with nasal polyps improved with Verapamil therapy

A clinical trial studying the use of Verapamil (a drug currently in use for cardiovascular disease and cluster headache) in alleviating chronic rhinosinusitis (CRS) with nasal polyps revealed significant improvement in the symptoms of this subset of patients. It is the first study of its kind to explore treatment for CRS by inhibiting P-glycoprotein, a protein pump within the nasal lining that Mass. Eye and Ear researchers previously identified as a mechanism for these severe cases of CRS marked by the presence of nasal polyps. The clinical trial results, published online today in the Journal of Allergy and Clinical Immunology: In Practice, suggest that Verapamil represents a promising novel therapy for the treatment of CRS with nasal polyps.

“Recently, we became aware that some of the inflammation in CRS with nasal polyps is generated by the nasal lining itself, when a particular protein pump (P-glycoprotein) is overexpressed and leads to the hyper-secretion of inflammatory cytokines,” said senior author Benjamin S. Bleier, M.D., a sinus surgeon at Mass. Eye and Ear and an assistant professor of otolaryngology at Harvard Medical School. “Verapamil is a first-generation inhibitor that is well-established in blocking P-glycoprotein. In some patients with CRS with nasal polyps, we saw dramatic improvement in their symptom scores.”

One of the more prevalent chronic illnesses in the United States, CRS has been known to cause significant quality of life detriments to affected patients, who often cannot breathe or sleep easily due to obstructed nasal and sinus passages. The presence of nasal polyps represents a particularly severe presentation of the disease. Current treatment strategies (most often long-term steroid use) are plagued by difficult side effects and fail to target an underlying source of the disease.

Motivated by their previous finding of the presence of P-glycoprotein overexpression in the nasal lining of patients with CRS with nasal polyps, the study authors conducted a randomized, double-blind, placebo-controlled clinical trial studying the use of low-dose Verapamil in 18 patients with CRS with nasal polyps. An analysis of these patients demonstrated improved outcomes for those in the Verapamil group in relation to those in the placebo group. However, the researchers also observed that the treatment effect was significantly limited among patients with higher body mass indices. Future studies are being planned to determine if a higher dose of Verapamil may be needed to be therapeutic for some patients.

“Chronic rhinosinusitis with nasal polyps is among our most challenging diagnoses to treat, because these patients essentially have chronic, lifelong inflammation that needs chronic, lifelong treatment,” said Dr. Bleier. “We observed no significant side effects at the doses we used, and we are very encouraged by the results of this first step toward a more targeted therapy for our patients.”

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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.

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After One Dose of Gene Therapy, Hemophilia B Patients Maintain Near-Normal Levels of Clotting Factor

At ASH Meeting, CHOP Hematologist Leads Clinical Trial in Which All Subjects Safely Maintain Factor IX Expression that Curtails Disabling Bleeding

Researchers are reporting the highest and most sustained levels to date of an essential blood-clotting factor IX in patients with the inherited bleeding disorder hemophilia B. After receiving a single dose of an experimental gene therapy in a clinical trial, patients with hemophilia produced near-normal levels of clotting factor IX, allowing them to stop clotting factor infusions and to pursue normal activities of daily life without disabling bleeding episodes.

Lindsey A. George, MD, a hematologist at Children’s Hospital of Philadelphia (CHOP)is the lead investigator of the phase 1/2 clinical trial sponsored by Spark Therapeutics, Inc. and Pfizer, Inc. The American Society of Hematology (ASH) today highlighted updated findings from that trial in a press conference during its annual meeting in San Diego. George will present those study results tomorrow at an ASH plenary scientific session.

Katherine High, MD, a senior author of the study and Spark Therapeutics’s president and chief scientific officer, described the updated interim trial data at today’s press conference. The clinical trial of nine adult hemophilia B patients, aged 18 to 52 years, used a single dose of a gene therapy product engineered to enter patients’ liver cells and direct the production of the blood clotting factor that they lack.

George notes, “Our goal in this trial was to evaluate the safety of the gene therapy product and secondarily, to determine if we could achieve levels of factor IX that could decrease bleeding events in patients.” She added, “These patients have a severe or moderate level of hemophilia, with baseline clotting factor level less than or equal to 2 percent of levels in healthy people. In current treatment, patients with hemophilia give themselves intravenous doses of factor IX up to a couple times a week. While generally effective, factor levels fluctuate, and patients may suffer painful, disabling joint bleeds when their clotting factor levels drop. Such a regimen requires significant planning of daily activities.”

In the current trial, said George, the patients maintained factor levels of approximately 30 percent, enough to lift them out of the severe category. “At these new levels, hemophilia patients do not typically need to self-treat with factor to avoid bleeding events,” she said, adding, “This represents a potential dramatic improvement in their quality of life and a shift in the way we think about treating hemophilia.” A factor level of 30 percent is near-normal, she added, and patients would be expected to experience bleeding only in the event of major trauma or surgery.

One subject self-infused two days after receiving the gene therapy vector. Beyond this, no patients had any bleeding events or required factor for any reason. With significant reduction in bleeding events and factor use, six of the first seven patients reported increased physical activity and all reported improved quality of life. Two additional patients received the gene therapy product too recently to determine quality-of-life measures.

Previous hemophilia gene therapy trials have been frustrated by an immune response to the gene therapy product that limited the success of the therapy. In the current trial, two patients experienced an immune response to the gene therapy that did not result in safety concerns, and were treated with steroids. The patients are still undergoing treatment but have maintained factor IX activity without bleeding.

George reported that she is cautiously optimistic, acknowledging that this trial is a small study, with a short follow-up period as yet. However, as the researchers continue to monitor patients in the current trial, next steps will be to discuss with the U.S. Food and Drug Administration the outlines of a larger, phase 3 clinical trial. No gene therapies for any genetic diseases have yet been approved for clinical use in the U.S.

Formerly a research leader at CHOP, High pursued groundbreaking preclinical investigations in hemophilia B gene therapy and provided scientific expertise to previous gene therapy trials in hemophilia and other genetic disorders at CHOP before moving to Spark Therapeutics, which was spun off from CHOP in 2013. CHOP maintains a financial interest in the company.

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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.

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Smallest-Reported Artificial Virus Could Help Advance Gene Therapy

Gene therapy is a kind of experimental treatment that is designed to fix faulty genetic material and help a patient fight off or recover from a disease. Now scientists have engineered the smallest-reported virus-like shell that can self-assemble. It could someday carry potentially therapeutic DNA or RNA and transfer it to human cells. The report appears in the Journal of the American Chemical Society.

The story of gene therapy is fraught with much hype and high-profile failures. But, hype and failures aside, it remains a promising route to treat a range of ailments, from rare genetic diseases to common conditions such as diabetes. Clinical trials to test various gene therapy treatments are underway. One possible approach is to copy the way viruses behave. When they infect people, viruses inject their genetic material into human cells. Artificial viruses have been engineered to mimic this step, but they tend to clump or are not uniform in size, which can hinder their effectiveness. Max Ryadnov and colleagues wanted to address these issues.

Rather than using full proteins, the researchers used short peptide sequences designed to assemble into tiny gene carriers, which are smaller than previously reported synthetic viruses and even naturally occurring viruses. Lab testing showed that their artificial viral shells were uniform in size and didn’t clump. The particles could encase DNA or RNA and transfer the genetic material to human cells without harm. Depending on the introduced material, the recipient cells then either expressed a new protein or stopped expressing their own protein.

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New Biomarker Breakthrough Could Improve Parkinson’s Treatment

A new, non-invasive way to track the progression of Parkinson’s disease could help evaluate experimental treatments to slow or stop the disease’s progression. University of Florida researchers used functional magnetic resonance imaging to reveal areas where Parkinson’s disease and related conditions cause progressive decline in brain activity.

The study, funded by the National Institutes of Health, was published in the journal Neurology. While current treatments focus on controlling symptoms, biomarkers provide a quantifiable way to measure how medications address not just symptoms, but the neurological changes behind them.

Previous studies have used imaging techniques that require the injection of a drug that crosses the blood-brain barrier.

“Our technique does not rely upon the injection of a drug. Not only is it non-invasive, it’s much less expensive,” said David Vaillancourt, Ph.D., a professor in UF’s Department of Applied Physiology and Kinesiology and the study’s senior author.

The study’s authors – which included researchers from UF’s College of Health and Human Performance and College of Medicine as well as the Medical University of South Carolina – used functional magnetic resonance imaging to evaluate five areas of the brain that are key to movement and balance. A year after the baseline study, the 46 Parkinson’s patients in the study showed declining function in two areas: the primary motor cortex and putamen. Parkinson’s-related disorders evaluated in the study also showed declines: The 13 subjects with multiple system atrophy had reduced activity in three of the five areas, while the 19 with progressive supranuclear palsy showed declines in all five areas. The brain activity of the 34 healthy control subjects did not change.

“For decades, the field has been searching for an effective biomarker for Parkinson’s disease,” said Debra Babcock, M.D., Ph.D., program director at the NIH’s National Institute of Neurological Disorders and Stroke. “This study is an example of how brain imaging biomarkers can be used to monitor the progression of Parkinson’s disease and other neurological disorders.”

The finding builds on a 2015 UF study that was the first to document progressive deterioration from Parkinson’s via MRI, showing an increase in unconstrained fluid in an area of the brain called the substania nigra. An NIH-funded study beginning in November will use both biomarkers to test if a drug approved for symptom relief can slow or stop progressive degeneration.

Katrina Gwinn, M.D., also a program director at the NIH’s National Institute of Neurological Disorders and Stroke, described the effort to identify biomarkers as “an essential part of moving towards the development of treatments that impact the causes, and not just the symptoms, of Parkinson’s disease.”

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Understanding Natural History Studies in Drug Development for Rare Diseases

Q &A with Michelle Berg, Vice President, Patient Advocacy, Abeona Therapeutics Inc.

20150610_Michelle Berg_0039[1]Developing a new drug for patients with a disease, particularly when it’s a disease that affects a relatively small number of patients,  poses unique challenges that do not apply to medical therapies for more prevalent diseases. However, an increasingly common, and particularly important method of addressing the special requirements for developing drugs for treating rare disease is by implementing a natural history study. This type of non-treatment observational study allows for better understanding of the natural progression patients with a rare disease experience and how this information can be assessed to facilitate the product development and regulatory review.

In a natural history study,  patients are assessed as they progress through multiple phases of disease manifestation. An important part of a natural history study is to better identify the tools and assessments needed to evaluate whether a potential drug is demonstrating efficacy and safety in the course of a clinical trial. The study enrolls affected individuals that have progressed through a pre-symptomatic phase and into different stages of disease manifestation. This is important because it helps clinicians evaluate different tools, such as MRI of specific organs, quality of life assessments, and neurological exams, as to whether patients may be able to have clinical efficacy measured after receiving drug treatment once enrolled in a treatment trial. This type of information is often not available, is incomplete, or anecdotal at best for many rare diseases.

Clinical stage gene therapy company, Abeona Therapeutics, is developing potential therapies for a number of rare diseases. Through their supporting foundations and clinical partners, they have completed multiple natural history studies in support of their Sanfilippo syndrome and Batten disease programs. Sanfilippo syndrome types A and B, also known as mucopolysaccharidosis (MPS) type IIIA and type IIIB are fatal, rare genetic diseases that affect children, and currently have no treatment or cure. Juvenile Batten disease, another rare and fatal genetic disease impacting children, is also without current therapy or available treatment.

We asked Abeona Therapeutics’ VP of Patient Advocacy, Michelle Berg, about the importance of natural history studies.

Q: What is a biotech company like Abeona looking for when embarking on a natural history study?

Berg: I’ll focus on the natural history studies involving children impacted by MPS IIIA and MPS IIIB. This was a special collaboration between our partnering hospital and three Sanfilippo foundations. All involved set out with the mutual goal of furthering the understanding for disease progression through this prospective study in both MPS IIIA and MPS IIIB (25 total participants) and to evaluate outcome measures and potential biomarkers. It was important to all to be well prepared for clinical studies and to be sure we were on the right path for safety and efficacy outcomes.

Q: What did the researchers in your natural history find?

Berg: They were able to determine which assessments provided meaningful information that would be relevant to design of the clinical studies. For instance, it became evident part way through that certain assessments were not helpful because of the inability for the participants to complete them and therefore they would not be clinically valuable. Without the type of study, it would not have been known and could have impacted the clinical trials.

Q: With the FDA now embracing and even funding natural history studies for rare diseases, why is this good news for patients?

Berg: With the most recent Guidance issued by the FDA on rare disease drug development, a big take away is that while the agency is not requiring a natural history study, it is strongly recommended prior to initiation of clinical trial. Earlier this year the agency further reinforced their recommendation by putting into place a grant through the Office of Orphan Products Development that could total up to two million dollars. Prospective studies may receive an award of up to $400,000 per year for up to five years while retrospective studies/surveys could be awarded up to $150,000 per year for up to two years. The FDA will start accepting grant applications in October of this year and hopes to initiate awards in Q1 of 2017.

Q: How has this natural history study helped Abeona now that its treated its first patient?

Berg: We’re pleased to have initiated enrollment in the Phase I/II gene transfer study for MPS IIIA. The information gained from the natural history study has helped to focus in on the important data to obtain and how to assess or measure. Additionally, Abeona is pleased to have also received allowance by the FDA for the proposed Phase I/II gene therapy study in MPS IIIB. The completion of the natural history studies enabled both of our MPS programs to move forward.

Q: What do parents need to understand about these studies?

Berg: It’s important to participate in these types of studies so scientists and clinicians can gain a solid understanding for the progression of the specific disease of focus. The information gained from behavioral assessments, MRI’s or biospecimen testing is helpful but so is the input from the parents and caregivers. Collectively, this data helps to shape the design of a clinical trial and what would be important outcomes to look for and the means to assess or test them.

Q: What are the next steps now for Abeona Therapeutics?

Berg: Abeona is focused on continued enrollment for the Phase I/II MPS IIIA trial and initiating the clinical trial for MPS IIIB. Our team of experienced professionals are also working hard to progress the gene therapy programs for juvenile Batten disease and Fanconi Anemia into clinical research.

 

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Cancer Trial for Leukemia Halted after Death of Two Patients

The U.S. Food and Drug Administration placed a hold on a Juno Therapeutics clinical trial of a treatment for a form of leukemia following the death of two trial patients last week.

The Company said in a press announcement that both deaths occurred last week after the patients, who had relapsed or refractory B cell acute lymphoblastic leukemia, took the drug fludarabine before receiving the chimeric antigen receptor (CAR) T cells that Juno had taken from their bodies and re-engineered to better attack cancer cells. Another patient had died earlier in the trial, but “confounding factors” spurred Juno to continue with the study at that time

Juno announced that it has received notice from the U.S. Food and Drug Administration (FDA) that a clinical hold has been placed on the Phase II clinical trial of JCAR015 in adult patients with relapsed or refractory B cell acute lymphoblastic leukemia (r/r ALL), known as the “ROCKET” trial.

Juno has proposed to the FDA to continue the ROCKET trial using JCAR015 with cyclophosphamide pre-conditioning alone. In response, the FDA has requested that Juno submit, as a Complete Response to the Clinical Hold several items including a revised patient informed consent form, a revised investigator brochure, a revised trial protocol, and a copy of the presentation made to the agency yesterday. Juno stated they will submit the requested information to the FDA this week.

Juno’s trials and plans for its other CD19-directed CAR-T cell product candidates, including JCAR017, are not affected.

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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)