New PARP Inhibitor Combo Shows Early Promise for Cancer Patients With and Without BRCA Mutations

A combination of two molecularly targeted drugs, olaparib and the investigational agent AZD5363, was safe and yielded responses in patients with a variety of cancer types, including breast, ovarian, and prostate cancers, regardless of BRCA1/2 mutation status, according to data from the ComPAKT phase I clinical trial presented here at the AACR Annual Meeting 2015, April 18-22.

“In this investigator-initiated clinical trial, we evaluated for the first time whether it is possible to safely combine the investigational AKT inhibitor AZD5363 with olaparib, a PARP [poly ADP-ribose polymerase] inhibitor recently approved by the FDA [U.S. Food and Drug Administration] for treating advanced ovarian cancer associated with defective BRCA genes,” said Timothy Yap, MD, PhD, NIHR BRC clinician-scientist and consultant medical oncologist at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust in London, United Kingdom.

“Here, we are reporting results from the dose-escalation portion of the trial, which showed that it was indeed possible to combine these drugs safely,” continued Yap. “We also observed that several different cancer types responded to the combination, including cancers without BRCA1/2 mutations. These early results are very exciting because preclinical data had suggested that the olaparib and AZD5363 combination had the potential to be effective in a much wider population of patients than just those harboring germline BRCA1/2 mutations.”

Yap also explained that the ComPAKT clinical trial is, to the best of his knowledge, the first phase I clinical trial using a combination of targeted agents to implement an intrapatient dose-escalation design. The design allowed individual patients to receive up to three predetermined escalating doses of AZD5363 in combination with a fixed dose of olaparib, but only if they were tolerating the drug combination well. “This design allowed us to safely complete the dose-escalation phase with at least six evaluable patients at each dose level, and in two schedules of the combination with just 20 patients in 7.5 months, which is unprecedented,” said Yap.

Of the 20 patients enrolled in the dose-escalation portion of the clinical trial, nine had germline BRCA1/2 mutations. The patients had a variety of cancer types including advanced breast, ovarian, prostate, colorectal, cervical, pancreatic, uterine, and bladder cancers; mesothelioma; and gastrointestinal stromal tumors.

According to Yap, since the abstract was submitted, there are now four confirmed RECISTpartial responses, including in a patient with BRCA1/2 wild-type ovarian cancer, two patients with BRCA1/2-mutant breast cancer, and a patient with BRCA1-mutant ovarian cancer. Two patients had ongoing, prolonged RECIST disease stabilization, including a patient with BRCA1/2 unknown breast cancer at six months and a patient with peritoneal mesothelioma at one year with tumor-marker reduction, who had previously responded before developing disease progression on treatment with a PI3K/mTOR inhibitor. One patient with BRCA1/2-mutant advanced prostate cancer also continues to have a sustained response radiologically on MRI and by prostate-specific antigen Prostate Cancer Working Group 2 response criteria at 11 months.

Based on tolerability, the researchers established that the recommended phase II combination dose was 640 milligrams of AZD5363 twice a day for two days each week, plus 300 milligrams of olaparib twice a day. The most commonly observed side effects were nausea, vomiting, fatigue, diarrhea, and anemia. “We are currently assessing the drug combination at the recommended phase II combination dose in two different cohorts of patients within the dose-expansion phase of the trial,” said Yap.The ComPAKT trial is part of the Combinations Alliance jointly supported by Cancer Research U.K., AstraZeneca, and the Experimental Cancer Medicine Center network. It is co-sponsored by The Institute of Cancer Research (ICR) and The Royal Marsden and received research funding from the NIHR Biomedical Research Center at The Royal Marsden and the ICR. Yap received funding for this clinical trial from AstraZeneca and is supported by the NIHR Biomedical Research Center.

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Genomic Testing: The Risk of Knowing Too Much…. part I

Sophisticated tests can generate a wealth of information about a patient’s cancer or disease risk. 
But they also raise serious questions

By Alexandra Goho

​Consider the following: A healthy woman in her early 20s has a family history of breast cancer. She decides to undergo genetic testing to determine her own breast cancer risk. But instead of simply testing for the BRCA1 and BRCA2 gene mutations, her doctor offers her a new kind of test that looks at more than a dozen genes associated with a wide range of tumor types. The results come back. The good news is she doesn’t have any mutations in the two breast cancer genes. The bad news is she has a mutation in a gene called TP53 that is associated with a rare disorder called Li-Fraumeni syndrome (LFS). Women with the inherited disorder have more than a 90 percent chance of developing some kind of cancer—breast cancer, brain cancer, sarcoma, leukemia or another cancer type—during their lifetime.

Kenneth Offit, a cancer geneticist and medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, has seen two cases like this in his clinic. Explaining these kinds of test results to patients is not easy, he says. Although patients with LFS can undergo intensive screening with regular blood tests, MRIs and physical examinations, determining the best screening methods can be a challenge because of the wide range of tumors that can develop. What’s more, there are no treatments for LFS.
While genetic testing for inherited cancer mutations has become more common as an increasing number of people seek to understand their cancer risk, advances in genome sequencing—the process of determining the precise order of the four chemical bases A, T, C and G that make up a person’s DNA—have taken testing to a new level. Instead of testing just one or two genes, companies now offer gene panels that analyze dozens of cancer-related genes simultaneously from a single patient sample. Some tests sequence hundreds of genes, and even entire genomes. The hope is that more comprehensive genomic testing will lead to a more precise understanding of a person’s cancer risk, allowing patients to take preventive measures like routine screening or prophylactic surgery to protect themselves. The additional genetic knowledge could also help protect their family members.
But sequencing that much DNA presents oncologists and patients with a conundrum: The tests generate an enormous amount of information, some of which isn’t yet clearly understood. And even if the findings are understood, they can blindside a person by uncovering an unexpected disease risk or discovering a cancer-associated mutation for which there are no preventive measures or treatments.
“It’s really important for people to know what they’re getting into when they undergo testing with these multigene panels,” says Susan Domchek, a medical oncologist at the University of Pennsylvania’s Abramson Cancer Center in Philadelphia. “They need to talk to their doctor about the pros and cons, because I think there is the assumption that more is better. But like everything, that’s not always true.”

Multigene Panel Testing on the Rise
More than a half dozen major commercial laboratories provide multigene cancer panel tests. Ambry Genetics offers a test called CancerNext that looks at 28 genes associated with breast, ovarian, colorectal, uterine and several other cancers. Myriad Genetics offers Myriad myRisk, a test that looks at 25 different genes and identifies mutations associated with an increased risk for eight types of cancer. “Gene panels are essentially replacing single gene testing,” says Offit, who anticipates that soon physicians will be unable to order some single gene tests from large commercial companies.

The reasons are partly economic. It’s cheaper and more efficient to test multiple genes at once than to test those same genes one by one in individual tests. It can also be easier on patients. For example, if a person with a family history of melanoma and pancreatic cancer tests negative for a CDKN2A gene mutation associated with a high risk of these cancers, it can be reassuring. But a doctor trying to understand the reason for the family history may order more genetic tests to look for other mutations that predispose to these cancers.
“That means more visits to the clinic, more waiting for test results, more time off work,” says oncologist and cancer geneticist Theodora Ross of the University of Texas Southwestern Medical Center in Dallas. “So there are a lot of reasons to do a panel up front.”On the other hand, because some multigene panels cover a wide range of cancers, people may not be prepared to deal with all of a test’s findings. A patient might have a panel test to determine her risk of ovarian cancer and instead discover she has a mutation in a gene called CDH1, associated with a very high risk of developing stomach cancer. Such instances are rare but have big consequences. Doctors routinely recommend that patients with this mutation have their stomachs removed as a preventive measure.

“That is a huge deal and has major issues about quality of life,” says Domchek. And although patients can choose not to receive certain findings, they need to be aware of the consequences of not knowing that information, says Offit, such as the effect on relatives who might want to be warned of an inherited mutation or the impact on any future children.

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Genomic Testing: The Risk of Knowing Too Much… part II

Although doctors routinely talk to their patients in advance about what the tests could reveal, and genetic counselors are frequently involved, how to best communicate all that information to patients is still a work in progress. “I think it’s a fascinating and exciting time, but it’s also a time where we need to focus carefully on both physician and patient education efforts,” says Stacy W. Gray, a medical oncologist at the Dana-Farber Cancer Institute in Boston. “Patients need to understand why they’re being tested and what the implications are, and physicians need to understand enough to know when to offer the different kinds of tests.”

Dealing With Uncertainty

Interpreting the results from a panel test is no easy feat. Some genes on the panels are well-understood in terms of their role in cancer and the amount of risk associated with them. Medical options—screening tests, preventive surgery or drug therapies—are available to patients with mutations in these genes. Other genes on the panel are less understood.

Physicians may know there is some degree of risk associated with mutations in these genes, “but they don’t exactly know what the risk is, how high the risk is, or if this is a risk for people in their 60s or in their 30s,” says Domchek. Finally, some genes on those panels may have mutations that flag clear risks, even though a patient’s family may have no history of that disease, but there are no clear guidelines for how to screen or treat patients with those mutations.

Even more challenging, for every gene in a person’s genome, there can be small variations in the DNA—changes in the normal sequence of A, T, C and G. Most misspellings of genes are harmless, but a small percentage of them can cause disease. When researchers find a new misspelling in a genetic sequence, they call it a variant of unknown significance (VUS), because its role in cancer risk is unknown. “Sometimes a single change in [a DNA letter] is extraordinarily important,” says Domchek, and can increase a person’s cancer risk substantially. “And sometimes it’s no big deal at all and is just a benign chance. How you determine whether it’s important or no big deal isn’t trivial.”

To figure out if a VUS may be harmful or not, and to better understand some of the genes on the panels, Domchek and her colleagues in the fall of 2014 launched a national online registry called PROMPT, which stands for Prospective Registry of MultiPlex Testing. The registry is a collaboration of the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, the Dana-Farber Cancer Institute in Boston, the Mayo Clinic in Rochester, Minnesota, and the Memorial Sloan Kettering Cancer Center in New York City. Together, these institutions have established partnerships with some of the major diagnostic companies in the country, including Ambry Genetics and Myriad Genetics.

The goal is to collect data from thousands of patients nationwide who have had multigene testing for cancer risk and to follow them over many years to learn how their genetic alterations affect their health. Patients who have multigene testing offered by one of the diagnostic companies involved are invited to enter their test results, as well as their personal and family health histories, into the registry. They can choose to identify themselves by name or enter anonymously, and they can invite their family members to participate as well. The researchers are also planning to conduct molecular experiments in the lab to see how different VUS affect gene function.

Fergus Couch, a cancer geneticist at the Mayo Clinic and one of the collaborators on the project, hopes that as his team analyzes the data, it will be able to report back to participating patients with a more precise assessment of their cancer risk. Learning more about a particular VUS, even if the information is provided many years after testing, could offer patients some comfort, especially if the VUS turns out to be harmless. Or, says Couch, he and his colleagues might find that the VUS confers, for instance, a 20 percent increased risk for cancer by age 50. “That patient might say, ‘I’m only 30 years old right now. I can go ahead and have kids and I don’t have to worry too much. I can deal with it later,’ ” says Couch. “Or the patient might do watchful waiting all her life with MRIs and not think too much about surgeries. These are the kinds of things that can be useful for patients and allow patients to better decide how they want to move forward.”

Incidental Findings
Following on the heels of cancer panel tests are even more sophisticated tests that could raise additional questions for people undergoing genomic testing. Advances in genome sequencing have made it cost-effective to sequence not just a dozen genes at once, but a person’s entire exome—the parts of the genome that code for proteins essential to the body’s functioning. But sequencing more DNA inevitably results in finding more mutations. What’s more, the tests can reveal incidental findings, results unrelated to the purpose of the test, in genes involved in a range of illnesses such as heart disease, nerve diseases and inherited eye disorders.

Increasingly, academic centers and commercial labs are offering whole exome sequencing as a diagnostic test for cancer patients. Yet the jury is still out on whether these tests are more useful than panels. Gail Jarvik is a medical geneticist at the University of Washington in Seattle and is conducting a trial of whole exome sequencing in colorectal cancer patients whose cancer is suspected of having a genetic basis. “Our goal really is to see if whole exome sequencing is faster and more efficient than usual-care genetic testing, but also what are the ethical and logistical issues with doing a whole exome and returning genomic results including incidental findings,” she says.

In the trial, doctors or genetic counselors only return to their patients incidental findings that are “medically actionable,” she says. For instance, if a genetic mutation is found that increases cancer risk, doctors can recommend screening or prophylactic surgery. If a variant is related to heart disease, the patient can have imaging tests or get a defibrillator for a heart rhythm abnormality. “In other words, something can be done,” says Jarvik. “There are reasonably useful preventative measures that can be taken.”

She and her colleagues try to set realistic expectations for patients beforehand by telling them that most people do not have genetic changes detected that significantly affect their health. It turns out that only a small percentage of patients will actually have an incidental finding, says Jarvik. “Setting those reasonable expectations has been good for patients, and the general response from them has been good.”

Dana-Farber’s Gray is involved in a similar study looking at whole exome sequencing in patients with advanced lung and colorectal cancer. In this case, the researchers sequence their patients’ tumor genome to help find mutations that can be targeted by existing drugs. But to identify those mutations, the researchers also sequence their patients’ inherited genome for comparison, which can reveal incidental findings. One of her patients is 66-year-old Elizabeth Kenner from Cranston, Rhode Island, who at the age of 62 was diagnosed with stage I lung cancer that eventually progressed to stage IV. She underwent whole exome sequencing and had an incidental finding—a mutation in a colon cancer gene. Because she has no family history of colon cancer and results from her recent colonoscopy were negative, her doctors were reassured—though she’ll continue to get screened. She is happy she had the genomic test. “If they find something and you know about it, you can do something about it,” she says. “If not, I don’t believe you should just close your eyes. I think it’s better to know.”

Researchers are also finding whole exome sequencing to be useful in diagnosing pediatric cancers and in helping to determine which mutations might increase susceptibility to cancer in some children. Sharon Plon, a cancer geneticist at the Baylor College of Medicine in Houston, is investigating whole exome sequencing in children newly diagnosed with brain tumors and other solid tumors in the body. Although such comprehensive testing can identify mutations linked to rare cancers in children that may not be included on many gene panels, the tests can also reveal mutations associated with adult-onset cancers—findings that have implications not only for the future health of the child, but also for that of parents and other family members.

The value of reporting incidental findings when testing pediatric patients is a controversial subject and is still being debated, says Plon. “If you find a mutation that predisposes the patient to an adult-onset cancer, should you disclose that to a child’s parents?” Plon believes doctors should. “It’s likely they inherited that mutation from their parents and it’s probably to the benefit of the child that the parents be aware of that risk,” she says. At the American Society of Human Genetics annual meeting in San Diego in October 2014, Plon presented preliminary findings from her study. Of the 115 children enrolled, three were found to have mutations in the BRCA1 or BRCA2 gene. Whether these mutations are associated with the children’s tumors is still unclear, but Plon says researchers noted a history of breast and ovarian cancer in the children’s families.

Other physicians are uncomfortable with the idea of reporting incidental findings. “They say you’re doing a test that the patient didn’t ask for,” says James Evans, a medical geneticist at the University of North Carolina School of Medicine in Chapel Hill. Yet patients can choose whether they want all the results. In fact, the American College of Medical Genetics recently updated its guidelines to allow patients to opt out of receiving incidental findings. “People are allowed to make their own decisions,” Evans says. “The trick is to make sure they’re educated about it, that they know what it is they are declining.”

Evans is enthusiastic about these new genomic tests and sees many patients benefiting from them. However, like every new technology, physicians need to be thoughtful in how they apply the tests, he says. “Like an MRI, it’s a miraculous technology that gives us great insight into specific problems that patients have, but we don’t give an MRI to everybody, for very good reasons. We should use these tests where they’ve been shown to have some reasonable chance of helping patients.”

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Improving Cancer Outcomes for Patients of All Races and Ethnicities

Great strides have been made in prevention and treatment of cancer. Today Americans are more likely to survive a cancer diagnosis and enjoy a higher quality of life than at any other time in history.However, some groups – in particular, racial and ethnic minorities – experience notably higher incidence of some types of cancer than the general population and/or suffer significantly poorer outcomes.For example, in the U.S., African-American men and women are significantly more likely to die of cancer than men and women of any other race or ethnicity.Moreover, about 70 percent of global cancer deaths occur in low- and middle-income countries.Olufunmilayo I. Olopade, MD, is a fellow of the AACR Academy and the Walter L. Palmer distinguished service professor of medicine & human genetics, associate dean for global health, and director of the Center for Clinical Cancer Genetics at the University of Chicago Pritzker School of Medicine. She is using cancer genomics to improve cancer outcomes for all patients, no matter what their race or ethnicity or where they are in the world.

“I truly believe that once you understand the genetic basis of cancer in a population, then you can look at pathways to disrupt, and get better drugs and better prevention,” Dr. Olopade toldThe Scientist in 2013. “If people were not so afraid of genetic discrimination, we could direct more genomics toward public health.”

Using Cancer Genomics to Reduce Cancer Health Disparities

Cancer health disparities are differences in the incidence, prevalence, mortality, and burden of these diseases that exist among different groups of individuals. Many complex and interrelated factors contribute to disparities in cancer incidence and death.As an international leader in clinical cancer genetics, Dr. Olopade’s research focuses on understanding genetic reasons for cancer health disparities and applying this knowledge to improving cancer prevention and treatment for those at high risk for the disease. Much of her work has centered on breast cancer, a disease that African-American women are more likely to die of compared with U.S. women of any other race or ethnicity. But her vision is to use the same approaches to improve outcomes for all cancers.Dr. Olopade launched one of the first genetic-testing clinics in the country, in 1992, and she told The Scientist that her main project now “continues to be to understand how to use genomics to improve global health and global cancer research.””I’m building a big database of cancer patients I can use to inform the treatment of any patient, no matter where they are in the world,” Dr. Olopade continued. “I think we can democratize how we prevent and treat cancer, so people on the periphery can take advantage of the research going on in the center. With health information tools, we can actually do that.”

DR. OLUFUNMILAYO I. OLOPADE, A PHYSICIAN-SCIENTIST AT THE UNIVERSITY OF CHICAGO, IS WORKING TO REVEAL THE POTENTIAL OF GENOMICS TO ELIMINATE DISPARITIES IN CANCER OUTCOMES.

Understanding the Genetics of Breast Cancer in Different Populations

Even though African-American women are less likely than white women to develop breast cancer, they are more likely to die of the disease. One factor, though, to contribute to this disparity is that African-American women are more likely to develop triple-negative breast cancer, which is not amenable to treatment with antihormone therapies and is more aggressive, with poorer short-term outcomes compared with other breast cancer subtypes.To understand why breast cancer outcomes are worse among African-American women, Dr. Olopade turned to genetics, reasoning that insight might come from looking for genetic abnormalities in breast tumors from patients in Africa. In a series of studies, she found that triple-negative breast cancer was much more common in west Africa than in the United States, and that there was a high chance that indigenous black women in west Africa who had breast cancer carried an alteration, or mutation, in one of two known breast cancer susceptibility genes, BRCA1 and BRCA2.Moreover, many of the BRCA mutations identified by Dr. Olopade and her colleagues among indigenous black women in west Africa were new and would not be picked up in standard BRCA gene testing. As a follow-up to this study, Dr. Olopade’s team looked at breast tumors from African-American women and found some of these novel BRCA mutations.This and other work conducted by Dr. Olopade and her colleagues has shown clearly that genetic risk factors for breast cancer are different for African-American and non-Hispanic white women. These results have important implications for genetic screening for breast cancer. ​For her commitment to developing innovative approaches to reducing breast cancer disparities for the millions of women of African heritage in the United States and abroad, Dr. Olapade  was recognized as a 2005 MacArthur Fellow – the grants that are commonly known as MacArthur “Genius” Awards.

“The MacArthur Award allowed me to really be a physician-scientist,” Dr. Olopade told The Scientist. “I was at the point where I felt I was going to have to choose one or the other. With the additional funding and recognition from the award, I have been able to continue my work in both the clinic and the laboratory.”

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Eye Stem Cell Therapy Moves Ahead

Researchers inject retinal support cells derived from human embryonic stem cells into the eyes of four men with macular degeneration, bolstering evidence of the experimental treatment’s safety.

Scientists in Korea have injected human embryonic stem cell (hESC)-derived retinal support cells into the eyes of four men with macular degeneration, according to a study published today (April 30) in Stem Cell Reports. Three of the men experienced vision improvements in their treated eyes in the year following the procedure, while the fourth man’s vision remained largely the same. The trial adds to growing evidence that injecting hESC-derived cells is feasible, feeding hopes for their future therapeutic use. This latest study follows on two papers published in The Lancet in 2012 and 2014, which similarly demonstrated that hESC-derived cells could be safely injected into the space behind the retina in macular degeneration patients. These studies, sponsored by the Massachusetts-based company Advanced Cell Technology (now Ocata Therapeutics), were the first published accounts describing the application of hESC-based therapies in humans. Korean company CHA Biotech carried out the new trial. Ocata provided the hESCs and some methodological instruction. “Together with the results here in the US, I think this bodes well for the future of stem cell therapies,” said study coauthor Robert Lanza, chief scientific officer at Ocata.Jeanne Loring, a stem cell researcher at the Scripps Research Institute in La Jolla, California, agreed that the apparent safety of the therapy in the subjects tested is encouraging. However, she added, it would be difficult to draw firm conclusions about efficacy based on such a small study. “I think it’s still anecdotal that some people seem to improve,” said Loring.“At least it shows safety,” said Magdalene Seiler, a project scientist at the University of California, Irvine. “Whether it works in the long term is up for debate.”Like many other teams working to develop stem cell-based therapies, the Ocata-led team sought to treat a disease of the eyes in part because the organs are accessible. For the current study, the researchers treated two men with dry age-related macular degeneration, aged 65 and 79, as well as a 40-year-old man and a 45-year-old man, both with Stargardt macular dystrophy, an earlier-onset inherited disease. Both forms of macular degeneration lead to vision loss resulting from the destruction of retinal pigment epithelium (RPE) cells. RPE cells support retinal photoreceptor cells by nourishing them and cleaning up their waste. Without functional RPEs, retinal photoreceptors die.The researchers differentiated hESCs into RPE cells and injected them into one eye of each patient, hoping that the transplanted RPE cells would take root and replace those that had been lost, preventing further loss of photoreceptors. Lanza explained that “the goal of the therapy was not to improve vision.”Even so, the vision of three of the men improved by two to four lines of letters on a standard vision test. The vision of the fourth patient, the older man with age-related macular dystrophy, improved by just one letter —a negligible change.Because of the study size, it is too early to conclude whether the treatment systematically improves vision in patients, said Lanza. However, he hypothesized that patients could have experienced vision improvements because the infusion of new RPE cells revived photoreceptors that had gone dormant but were not yet dead.Lanza was also encouraged to see that the transplanted cells did not form tumors or differentiate into cells other than RPEs, a major concern among researchers in the field. Regulators “don’t really want to see a tooth in the eye or they don’t want to see beating heart cells in the wrong place,” Lanza said. By carefully screening all cells transplanted into patients, researchers were able to avoid transplanting cells that were not fully differentiated and could, therefore, have formed unwanted tissues.The scientists were also relieved to see that the patients’ immune systems did not reject the transplanted cells. Like the brain, the eye is immune privileged, meaning that it is largely inaccessible to immune cells. To be safe, the researchers still gave the patients immunosuppressive drugs for a limited period before and following the surgery. It is unclear whether this was necessary.Finally, by focusing on men of Asian descent, the study added to the diversity of the small group of patients who have received transplanted hESC-derived cells. The previous Lancet studies largely focused on Caucasian patients. Asian and Caucasian patients have different alleles that contribute to risk for age-related macular degeneration.

CHA Biotech is hopeful to get the go-ahead from Korean regulators to proceed with Phase 2 trials using hESC-derived cells to treat Stargardt macular dystrophy this year.Ocata, meanwhile, will start Phase 2 trials for both Stargardt macular dystrophy and age-related macular degeneration in the “next several months,” according to Lanza. Meanwhile, researchers at the RIKEN Center for Developmental Biology in Japan last year began a trial to test induced pluripotent stem cell (iPSC)-derived RPE cells for the treatment of macular degeneration.The new work adds to the climate of hope for stem cell therapies. “It’s inspiring other scientists,” said Loring, whose team is working to eventually treat people with Parkinson’s disease with iPSC-based therapies. “It makes us feel like we’ll be able to do similar things in whatever diseases we’re studying.”

A cluster of nascent retinae generated from 3-D embryonic stem cell cultures. The retinae contain photoreceptor precursors that express normal photoreceptor proteins, including the visual pigment, Rhodopsin (green) and the phototransduction enzyme, Recoverin (red). The precursors from such retinae can be isolated and transplanted into adult mice.

A nascent retina, generated from a 3-D embryonic stem cell culture, containing photoreceptor precursors expressing normal photoreceptor proteins, including the visual pigment, Rhodopsin (green) and the phototransduction enzyme, Recoverin (red).

3-D reconstruction of a transplanted photoreceptor (green) generated from 3D culture of embryonic stem cells. The newly integrated cell resembles a typical rod photoreceptor.

Detail of integrated embryonic stem cell-derived photoreceptors following transplantation into a degenerate adult mouse retina. The transplanted photoreceptors express the essential phototransduction enzyme, alpha-Transducin (red) which is absent in the recipient retina.

Advanced Cell Technology's retinal pigment epithelial cells

An image of a retina from the Janssen R&D CNTO 2476 cell therapy research program

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Breakthrough in ‘editing’ mitochondrial disease DNA

BREAKTHROUGH IN ‘EDITING’ MITOCHONDRIAL DISEASE DNA

Written by David McNamee

Researchers from the Salk Institute for Biological Studies in La Jolla, CA, report success for the first time in using gene-editing technology to prevent multiple human mitochondrial diseases from being passed from female mice to their offspring.

Mitochondria generate the majority of the energy used by cells, with each cell containing between 1,000 and 100,000 copies of mitochondrial DNA. Mitochondrial DNA is passed exclusively through maternal inheritance.

Mitochondrial diseases are inherited maternally and cause a variety of severe conditions that currently have no cure. In patients who have these diseases, mutated and normal mitochondrial DNA are typically mixed together in cells. If the patient has a high percentage of mutated mitochondrial DNA, this can lead to organ failure and serious health problems including seizures, dementia, diabetes, heart failure, liver dysfunction, vision loss and deafness.

Genetic screening of embryos can partially reduce the risk of mitochondrial diseases being transmitted from mother to child, but therapeutic options are limited.

Mitochondrial replacement therapy, a new technique in which healthy mitochondria are provided from a donor, is currently under evaluation in the US. However, this approach is controversial, and because it relies on combining the genetic material of three different people, there have been an assortment of ethical, safety and medical objections.

Editing technique ‘safer, simpler and more ethical’ than mitochondrial replacement therapy

The Salk Institute team trialled an alternative approach in a mouse model, which involves editing the mutated DNA using enzymes called restriction endonucleases and transcription activator-like effector nucleases (TALENs).

Because the approach tested by the Salk team does not require donor DNA, the researchers believe the gene-editing technique is safer, simpler and more ethical than mitochondrial replacement therapy. The enzymes are designed to find specific mutated DNA sequences and make a precise incision that destroys the mutated DNA, while leaving the normal mitochondrial DNA intact.

“This technique is based on a single injection of mRNA into a mother’s oocytes or early embryos and therefore could be easily implemented in IVF (in vitro fertilization) clinics throughout the world,” explains senior study author Juan Carlos Izpisua Belmonte, of the Salk Institute for Biological Studies.

“Since mutations in mitochondrial DNA have also been implicated in neurodegenerative disorders, cancer and aging, our technology could potentially have broad clinical implications for preventing the transmission of disease-causing mutations to future generations,” Belmonte says.

The team used a mouse model that carries two different types of mitochondrial DNA. TALENs and restriction endonucleases were designed to hunt and destroy just one of these types of mitochondrial DNA in the mouse eggs.

Fertilized eggs from the mice were injected with the enzymes. Levels of the targeted DNA were successfully decreased, the authors report, while the healthy mitochondrial DNA was unaffected. The mouse embryos were transferred to female mice where they developed normally and resulted in healthy pups with low levels of the targeted mitochondrial DNA.

What is more, these pups later went on to give birth to healthy offspring themselves, who were also found to have low levels of the targeted DNA, demonstrating that this is a viable approach for preventing transgenerational transmission of mitochondrial diseases.

Approach successfully lowered levels of mutated human mitochondrial DNA

Next, the team tested TALENs that had been designed to target human mitochondrial DNA mutations known to cause two disorders – Leber’s hereditary optic neuropathy and dystonia(LHOND) and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP).

The researchers trialled the TALENs using mouse eggs that contained genetic material from human patients. Again, the technique resulted in a significant reduction of the mutated DNA.

Belmonte believes that his team’s approach will be successful at reducing the percentage of mutated mitochondrial DNA below the threshold for causing disease in humans:

“In our opinion, due to the hundreds of thousands of copies of mitochondrial DNA present in human eggs, and the fact that double-strand breaks in mitochondrial DNA generally lead to the elimination of these molecules, we believe that the selective elimination of mutated mitochondrial DNA in the germline could be safer than nuclear genome editing and therefore might represent a starting point for the study and use of these new technologies in human embryos.”

Before clinical trials begin, however, the safety and efficacy of the method need to be evaluated in eggs from human patients with mitochondrial diseases. The team says they will obtain such eggs from the surplus stock of eggs from IVF clinics that are donated by patients for research purposes.

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Researcher Shares Personal Account of Immunotherapy Advances

About 30 years ago, cancer researcher Drew Pardoll had a revelation. He was treating bone marrow transplant patients who were at risk of developing graft-versus-host disease, a complication in which the T cells from the donor’s graft recognize the patient’s tissues as foreign and attack them.

Pardoll, director of cancer immunology at the Johns Hopkins Kimmel Cancer Center in Baltimore, said patients were often hospitalized for one to two months, but if they survived their GVHD, he was able to tell them their cancer may not recur because the T cells that caused GVHD also were attacking the patient’s tumor.“You could just see in front of your eyes what the immune system could do, and how powerful the immune system was, both for bad and for good,” he said, adding that he first believed then that the immune system could be used to treat cancer.Pardoll shared his personal account of advances in immunotherapy—a treatment that harnesses the body’s immune system to fight cancer—with participants in the Scientist↔Survivor Program at the American Association for Cancer Research (AACR) Annual Meeting 2015 on April 20 in Philadelphia. Early in his career, Pardoll sought to understand the immune system’s potential in killing cancer by studying basic immunology in a laboratory at the National Institute of Allergy and Infectious Diseases (NIAID). After becoming a faculty member at Johns Hopkins, he began to incorporate what he learned at NIAID into his cancer research.

 In the 1990s, he began to genetically engineer tumor cells in mice to produce immunologic factors that would attract dendritic cells, a type of immune cell that can activate T cells. He said that work had led him to develop the cancer vaccine GVAX, an immunotherapy that’s currently being tested in clinical trials for patients with pancreatic cancer, colorectal cancer and acute myeloid leukemia. At the time, he said, a frustrating and disappointing finding emerged from the GVAX trials he and his colleagues conducted.“We could see that we were activating T cells, immune responses by the vaccine against antigens in the tumor, but that was rarely translating to a clinical benefit in tumor regression,” he said.Pardoll said they began to understand that tumors create suppressive signals within their environments that turn off the activated T cells. These signals normally prevent the immune system from attacking the body, but tumors co-opt the body’s natural systems to protect themselves.“As we began to look at tumors with all the tools that molecular biology and genomics gave us, we began to find lots of these inhibitory pathways,” he said. “It was actually kind of scary. How can you get through this gauntlet if you’re a lonely T cell and you’re trying to get in and kill that tumor?”

In 2002, Pardoll and his colleagues became interested in one of the inhibitory pathways, or checkpoints, called PD-1 (programmed cell death-1). The team began working with a small biotech company to develop antibodies that work against PD-1. In 2006, clinical trials began at Johns Hopkins to test these antibodies on patients with melanoma, kidney, lung, colon and prostate cancer. Clinical trial results were dramatic and sustained for some patients, although not all, with melanoma, kidney cancer and lung cancer.Six companies have developed antibodies against PD-1 and its partner, PD-L1. Pardoll said PD-1 targeted drugs likely will be effective against 10 different cancer types.Just five years ago, he said, “Immunotherapy had been left for dead.” Today, it stands as a promising breakthrough in cancer treatment. Pardoll said he has trouble getting used to the mounting enthusiasm surrounding immunotherapy.

Above all, he says, he will always be amazed when a patient undergoing immunotherapy returns to the clinic and their tumor has shrunk.

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Antihistamine could be used as a cheaper hepatitis C therapy, study suggests

RESEARCH TESTING ESTABLISHED FDA-APPROVED DRUGS FIND THAT AN ANTIHISTAMINE COULD HAVE EFFICACY AGAINST HEPATITIS C.

An anti-allergy treatment is effective in treating hepatitis C virus (HCV), a study has found, raising hopes of an affordable weapon in the fight against the virus. The antihistamine, chlorcyclizine hydrochloride, prevents an early stage of HCV infection, most likely by targeting viral entry into host cells, according to research published in Science Translational Medicine[1]on 8 April 2015.Using a cell-based quantitative high-throughput platform, the scientists tested a number of drugs that were already approved by the US Food and Drug Administration (FDA) for their efficacy against HCV.The team, which included researchers from the US National Institutes of Health (NIH) and Hiroshima University in Japan, found that chlorcyclizine strongly inhibited HCV infection in human hepatoma cells and primary human hepatocytes. The antihistamine significantly inhibited infection of HCV genotypes 1b and 2a without substantial toxicity or evidence of drug resistance during four and six weeks of treatment, respectively.

The researchers noted that a number of FDA-approved drugs, including the anticancer agents erlotinib and dasatinib, the cholesterol lowering therapy ezetimibe and the antimalarial drug ferroquine, have shown anti-HCV activities, however, chlorcyclizine showed more compelling in vitro and in vivo activity against HCV infection than the others.Because the data is based only on laboratory and mouse models, it is too soon to say if chlorcyclizine could cure patients of the virus, according to Jake Liang, head of the liver disease branch of the National Institute of Diabetes and Digestive and Kidney Diseases at the NIH, and a lead author of the study. He said that chlorcyclizine would most likely have to be used in combination with existing HCV treatments in order to be most effective. The researchers found that chlorcyclizine’s antiviral effect was “synergistic” with other anti-HCV drugs — including ribavirin, interferon-alpha, telaprevir, boceprevir, sofosbuvir, daclatasvir and cyclosporin A — without producing significant cytotoxicity, indicating it could be used in tandem with established HCV treatments. They also noted that combination regimens for treating chronic HCV infection “lower the chance of developing drug-resistant viral mutations”.

The discovery represents a potentially profound breakthrough in the search for effective and affordable treatments for HCV, which affects around 185 million people around the world and for which there is no vaccine. The virus, which is especially prevalent in Africa and Asia, as well as in high-risk populations such as intravenous drug users, can often remain undetected for many years and can cause cirrhosis of the liver or liver cancer in those with chronic infection. While pegylated interferon and ribavirin has been the standard treatment for a number of years, the discovery of direct-acting antivirals have raised hopes of reducing the health and financial burden caused by the disease, but have also raised questions about affordability. Although some of these newer drugs have been shown to cure HCV in up to 90% of those infected, Solvadi (sofosbuvir), one of the latest treatments, costs around US$84,000 for 12 weeks of therapy, making it inaccessible to many.“The repurposing or repositioning of [chlorcyclizine] in HCV treatment may provide a more affordable alternative to the current costly options, especially in low-resource settings where chronic HCV infection is endemic,” the study says. Chlorcyclizine costs US$0.55 per tablet.Liang said chlorcyclizine could be used in people with all stages of HCV infection, but could be particularly helpful to patients with advanced disease who are undergoing liver transplants. Noting that the drug blocks entry of the virus into cells, Liang added, “this drug can be used theoretically to prevent re-infection during transplantation surgery”.

Because chlorcyclizine is known to cross the blood-brain barrier and cause side effects such as sedation, the researchers said central nervous system penetration of the drug would need to be taken into consideration for future development.

References:

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He S, Lin B, Chu V et al. Repurposing of the antihistamine chlorcyclizine and related compounds for treatment of hepatitis C virus infection. Science Translational Medicine 2015.doi: 10.1126/scitranslmed.3010286.

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Hepatitis C: latest advances in therapy

The availability of new protease inhibitors is revolutionising treatment of hepatitis C virus infection.

Hepatitis C is a global health problem, with an estimated 185 million people infected with the virus worldwide, with three to four million new infections each year. This is an estimated figure based on available prevalence data and supported by the World Health Organization.

There are six major genotypes of the virus, known as hepatitis C genotypes 1 to 6. Genotype 1 is the most prevalent worldwide, comprising more than 46% of all cases, of which one-third are in east Asia. Genotype 3 comprises 30% of all cases, while genotypes 2, 4 and 6 account for around 23% of cases. Genotype 5 accounts for the remaining 1%[1].

Recent years have seen an evolution in the treatment of hepatitis C infection, with new antivirals emerging at remarkable speed that promise cure rates never previously thought possible. This led to the licensing of several new hepatitis C treatments by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) in late 2014, with further treatments in development and expected to be licensed in 2015 or 2016.

Lifecycle

Hepatitis C virus (HCV) is a blood-borne single-stranded RNA flavivirus. RNA viruses mutate to a greater extent than DNA viruses, resulting in difficulty for the body’s immune system to locate and destroy them. Steps in the life cycle of HCV include entry into the host cell (hepatocyte); uncoating of the viral genome; translation of viral proteins; and viral genome replication followed by assembly and release.

Non-structural proteins are essential for the viral life cycle processes and are the primary targets for the new antiviral medicines (see ‘Sites of action of new hepatitis C medicines’). In particular, the viral enzyme NS3/4 protease (important in viral protein production) and non-structural proteins NS5A and NS5B (which play a role in HCV replication) are targets.

Figure 1. Sites of action of new hepatitis C medicines[2]

NS3/4 Protease Inhibitors	NS5A Inhibitors	NS5B Inhibitors
Telaprevir	Daclatasvir	Sofosbuvir
Boceprevir	Ledipasvir	Dasabuvir
Simeprevir	Ombitasvir
Asunaprevir	MK-8742
Paritaprevir
MK 5172

Transmission and prognosis

There are several routes for hepatitis C virus transmission.

People who inject drugs (PWID) are at risk, largely due to sharing unsterilized injecting paraphernalia. Around 50% of PWID in the UK are chronically infected with hepatitis C virus[3].

Vertical transmission from mother to child occurs in around 2% of mothers living with hepatitis C, although it can be as high as 20% in mothers co-infected with HIV. This risk increases in mothers who are viraemic (the infection is in the bloodstream) and are also infected with HIV[4].

Sexual exposure is a rare cause of transmission, and is estimated to account for less than 1% of cases. However, the risk increases in those who engage in sexual practices in which the risk of blood contact is increased[5].

Transfusion is now a rare cause of transmission following improved donor screening and viral inactivation of plasma products. Before these developments, patients who received infected blood products (e.g. haemophiliacs) were at the highest risk of contracting hepatitis C infection.

Occupational exposure is a possible risk (e.g. needle stick injuries), which can be minimised by safe working practices.

Other possible causes include tattooing, acupuncture, dental work and piercing. These risks can be minimised if good infection control practices are followed.

Hepatitis C is termed a silent killer as it causes slow but progressive liver damage. After initial infection with hepatitis C virus, around 75–85% of patients will fail to clear the virus and will become chronically infected[6]. These patients will often be asymptomatic until they present with signs of end-stage liver disease (e.g. ascites, hepatic encephalopathy).

The remaining 15–25% of individuals go on to clear the infection and develop antibodies. It is important that patients are informed that spontaneous clearance of hepatitis C does not mean they are immune, and re-infection can occur. There is no vaccine to protect against hepatitis C infection.

It is estimated that around 30% of chronically infected patients will develop cirrhosis within 20 years of their original infection and 5% will develop hepatocellular carcinoma (HCC). Deaths in the UK as a result of end stage liver disease or HCC secondary to hepatitis C have quadrupled since 1996.

In England, only 3% of chronically infected hepatitis C patients are treated in England each year. Risk factors for accelerated progression of the disease include male gender, older age, obesity, infection with HIV, diabetes, and a significant alcohol history.

Anti-hepatitis C antibodies are usually present three to six months after infection. Diagnosis is made through a hepatitis C antibody test and a confirmatory hepatitis C RNA test to assess for active infection. Oral fluid testing is possible in some clinics but it is of lower sensitivity and specificity.

Treatment

The primary aim of hepatitis C antiviral treatment is for a patient to achieve viral eradication, or sustained viral response (SVR). The traditional time point for assessing if an SVR had been achieved was at 24 weeks post-treatment (SVR24), although 12-weeks post-treatment (SVR12) is now widely recognised as an appropriate assessment point.

Secondary aims of treatment include preventing transmission of the virus, preventing progression of liver damage, and improving patients’ quality of life.

Response rates to treatment are dictated by genotype, treatment history and patient specifics such as age, gender and other infections present. The stage of liver disease is also an important predictor of viral response. Traditionally, those with advanced fibrosis or cirrhosis achieve lower treatment response rates.

Peginterferon and ribavirin combination therapy is an established treatment for hepatitis C infection. Peginterferon is available as two forms: pegyalted interferon alfa-2a and alfa-2b. Both are administered once weekly by subcutaneous injection. The recommended starting dose of alfa-2a for the treatment of hepatitis C is 180mcg once weekly. The recommended dose for alfa-2b is 1.5mcg per kg per week. The dose of either peginterferon may be adjusted (lowered) depending on clinical factors, such as presence of thrombocytopenia or low mood.

Ribavirin is an oral tablet administered twice daily with food. The dose is dependent on the patient’s weight, but a range of 800–1200mg a day is common. The dose of ribavirin is often adjusted to account for the presence or absence of anaemia.

Treatment duration ranges from 24 to 72 weeks, with SVR24 rates of around 40–50% in patients with hepatitis C genotype 1, and 40–80% in patients with genotypes 2–6[7].

The peginterferon/ribavirin regimen has an extensive side effect profile, including cytopenia and mood disturbances. This limits its use in some patients, and it is estimated around 27% of patients prescribed a peginterferon stop treatment due to adverse effects[8]. Side effects of ribavirin include dermatological effects (e.g. dermatitis, pruritis, urticaria and photosensitivity) and haematological abnormalities (e.g. anaemia).

Boceprevir and telaprevir were licensed by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) in 2011. These medicines directly inhibit the replication stages of hepatitis C, and are licensed in Europe for use in genotype 1 patients in conjunction with peginterferon and ribavirin; telaprevir was discontinued in the United States in October 2014. The SVR24 rates in patients who have not previously been treated for hepatitis C are around 75% with telaprevir and 68% with boceprevir; SVR rates are lower in patients who have already been treated for hepatitis C or those with cirrhosis[9].

Boceprevir and telaprevir require a strict dose regimen, and are typically used in combination with a peginterferon. The licensed treatment duration is linked to a strict response guided protocol, where specific viral responses for both agents need to have been achieved for the regimen to continue. They require patients to take a large number of tablets (four 200mg tablets three times a day for boceprevir; three 375mg tablets every 12 hours, or two 375mg tablets every eight hours, for telaprevir), and have a treatment duration of 24–48 weeks.

Both boceprevir and telaprevir are substrates and inhibitors of the cytochrome P450 isoenzyme CYP3A4 and, as a result, they interact heavily with a number of medicines, including tacrolimus and ciclopsporin, methadone, buprenorphine, statins, phenytoin and carbamazepine.

Boceprevir and telaprevir also have numerous side effects, including anaemia, pruritis, rashes, loss of appetite, thrombocytopenia, nausea and diarrhoea.

With the emergence of more effective and better tolerated antiviral agents, it is likely the use of boceprevir and telaprevir for genotype 1 hepatitis C will decrease significantly, as they are less clinically effective than newer agents.

Sofosbuvir is an NS5B nucleotide inhibitor approved by FDA in December 2013 and the EMA in January 2014. The NS5B RNA-dependent polymerase is responsible for replication of hepatitis C RNA.

Sofosbuvir is effective across all hepatitis genotypes, and is taken once daily as a 400mg single tablet. It has limited drug-drug interactions as it is not metabolised by the cytochrome P450 isoenzyme CYP3A4. For patients with hepatitis C genotype 2, sofosbuvir is used with ribavirin for 12 weeks. Patients with other genotypes require a combination of sofosbuvir, peginterferon and ribavirin to enable a 12-week treatment duration; if a patient is intolerant to interferon and only sofosbuvir and ribavirin can be prescribed, then the treatment duration is extended to 24 weeks.

The clinical efficacy of sofosbuvir has been examined in a number of phase III trials, which included a proportion of difficult to treat populations, such as patients with cirrhosis. One single-group open-label study, which looked at patients prescribed sofosbuvir with interferon and ribavirin for 12 weeks in 327 previously untreated patients with hepatitis C genotypes 1,4,5 and 6, found the sofosbuvir group had an overall SVR12 of 90% (80% in patients with cirrhosis)[10].

For genotype 2 and 3, the Phase III Fission study highlighted that genotype 2 did very well with sofosbuvir and ribavirin alone for 12 weeks, with an SVR of 97%, but genotype 3 did far less well, with an SVR of only 56%, which was less than the comparators of interferon and ribavirin[11]. Further analysis for genotype 2 and 3 was completed in the Valence study, which extended treatment of sofosbvir and ribavirin to 24 weeks for genotype 3 patients. SVR12 rates increased to 85%.

Simeprevir, a NS3/4A protease inhibitor, was approved for use by the FDA in November 2013 and the EMA in March 2014. The licence allows use in combination with a peginterferon and ribavirin in genotype 1 and 4 patients. It is also licensed for use alongside sofosbuvir for those patients who are deemed unsuitable for interferon and require urgent treatment.

Treatment with simeprevir follows a response-guided protocol, similar to that used for boceprevir and telaprevir. Treatment durations range from 24–48 weeks depending on the patient’s genotype, disease stage and treatment history. The recommended dose of simeprevir is 150mg once daily for 12 weeks, followed by peginterferon and ribavirin for the remainder of treatment. Simeprevir is also licensed to be used in hepatitis C genotype 1 and 4 alongside sofosbuvir (with or without ribavirin); if this regimen is followed then the total duration of treatment is 12 weeks.

Simeprevir is better tolerated than the first generation protease inhibitors, with general malaise, fatigue, photosensitivity and rash as the most commonly reported side effects. It also requires patients to take fewer tablets and has a more simplified dosing regimen.

The Quest I and II studies examined the efficacy of simeprevir 150mg daily with peginterferon and ribavirin for 12 weeks, followed by peginterferon and ribavirin alone for the remainder of the course (24 or 48 weeks as guided by the viral response) in hepatitis C genotype 1 patients. The average SVR12 rate was 80%, with the lowest success rate in patients with genotype 1a who possessed the Q80K polymorphism (a naturally occurring polymorphism that occurs in certain strains of HCV)[12].

The estimated prevalence of hepatitis C genotype 1a with Q80K polymorphism in Europe is 19%[13]. The EU license for simeprevir recommends testing for the Q80K polymorphism in patients with hepatitis C genotype 1a before starting treatment; if Q80K is detected, an alternative treatment should be considered.

The use of simeprevir and sofosbuvir as a combination therapy was evaluated in the COSMOS study, a randomised phase lla study conducted in two cohorts of patients with hepatitis C genotype 1. Patients in both cohorts were randomly assigned to receive simeprevir 150mg once daily with sofosbuvir 400mg once daily (with or without ribavirin) for either 12 or 24 weeks. The cohorts included patients who had not previously received treatment or had not responded to treatment, and patients with and without cirrhosis.

SVR12 was achieved in 93–96% of patients treated for 12 weeks. The addition of ribavirin to the combination did not appear to contribute to higher SVR rates[14].

Daclatasvir, an NS5A inhibitor, was approved by the EMA in August 2014 for use in combination with other medicines for the treatment of hepatitis C genotypes 1, 2, 3 and 4. The recommended dose is 60mg once daily for 12 to 24 weeks. The dose should be reduced to 30mg when used with potent CYP3A4 and/or P-glycoprotein inhibitors, and increased to 90mg once daily when used with CYP3A4 and/or P-glycoprotein inducers.

One phase IIa study looked at treatment with daclatasvir 60mg once daily in combination with sofosbuvir 400mg once daily (with or without ribavirin) for 12 or 24 weeks in patients with hepatitis C genotypes 1, 2 and 3. The patients did not have cirrhosis, although some had previously received treatment for hepatitis C. SVR12 was achieved in 99% of patients with hepatitis C genotype 1, 96% with genotype 2, and 89% with genotype 3[15].

The evidence base available suggests that daclatasvir is well tolerated, with fatigue, headache and nausea reported as common side effects.

Harvoni, a fixed dose oral combination treatment combining sofosbuvir 400mg and ledipasvir 90mg, was authorised by the EMA in November 2014 for the treatment of hepatitis C genotype 1, 3 and 4, including those co-infected with HIV.

The recommended dose is one tablet once daily for 8, 12 or 24 weeks, depending on whether the patient has cirrhosis and if they have previously received treatment. Peginterferon is not used with this treatment, and ribavirin is only used in patients with cirrhosis.

Overall, the studies for Harvoni show a well tolerated regimen, with headache and fatigue being the most commonly reported side effects.

Viekirax, an oral combination of paritaprevir, an NS3/4A inhibitor, boosted with ritonavir co-formulated with ombitasvir, an NS5A inhibitor, was approved for use by the EMA in January 2015 for the treatment of hepatitis C genotype 1. This combination is co-administered with dasabuvir, an NS5B inhibitor, which was also approved by the EMA in January 2015.

Future treatments are likely to focus on new combinations of antivirals which use more potent protease inhibitors and do not require treatment with peginterferon.

Merck Sharpe and Dohme is currently developing a fixed dose, interferon-free combination for hepatitis C genotype 1, 4, 5 and 6. This combination, which is in phase II trials, includes MK5172, a NS3/4a protease inhibitor, and MK8743, an NS5A protease inhibitor.

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References:

[1] Messina JP, Humphreys I, Flaxman A et al. Global distribution and prevalence of hepatitis C virus genotypes.Hepatology 2014. 

[2] Schinazi R, Halfon P, Marcellin P et al. HCV direct-acting antiviral agents: the best interferon-free combinations.Liver Int.2014;34(Suppl1):69–78.

[3] London Joint Working Group on Substance Misuse and Hepatitis C. Practical Steps to Eliminating Hepatitis C: A Consensus for London. London:2014. 

[4] Yeung LT, King SM & Roberts EA. Mother to infant transmission of hepatitis C virus. Hepatology 2001;34(2):223.

[5] Terrault NA, Dodge JL, Murphy EL et al. Sexual Transmission of HCV among Monogamous Heterosexual Couples: the HCV Partners Study. Hepatology 2012. 

[6] Zaltron S, Spinetti S, Biasi SL et al. Chronic HCV Infection: epidemiological and clinical relevance. BMC Infectious Dis2012;12(Suppl 2).

[7] Fried MW, Shiffman ML, Rajender R et al. Peginterferon Alfa-2a plus Ribavirin for Chronic Hepatitis C Virus Infection. N Engl J Med 2002:347(13):975–982.

[8] Gaeta GB, Precone DF, Felaco FM et al. Premature discontinuation of interferon plus ribavirin for adverse effects; a multicentre survey in “real world” patients with chronic hepatitis C. Aliment Pharmacol Ther. 2002;16:1633–1639. 

[9] Jacobson I, McHutchinson JG, Dushieko G et al. Telaprevir for Previously Untreated Chronic Hepatitis C Virus Infection. N Engl J Med 2011;354(25):2405–2416.

[10] Lawitz, E, Mangia A, Wyles D et al. Sofosbuvir for Previously Untreated Chronic Hepatitis C Infection. N Engl J Med2013;368:1878–1887.

[11] Zeuzem S,  Dusheiko GM, Salupere R et al. Sofosbuvir and Ribavirin in HCV Genotypes 2 and 3. N Engl J Med2014; 370:1993–2001.

[12] Jacobson I, Dore GJ, Foster GR et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial.The Lancet 2014;384(9941):403–413.

[13] Ghany, M, Gara N. QUEST for a cure for hepatitis C virus: the end is in sight. The Lancet 2014;384(9941):381–383.

[14] Lawitz E, Sulkowski MS, Ghalib R et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. The Lancet 2014;384(9956):1756–1765.

[15] Sulkowski MS, Gardiner DF, Rodriguez-Torres M et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014;370(3):211–221.

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