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FDA panel unanimously approves simeprevir for HCV genotype 1
  the FDA & the Janssen Briefing Documents Oct 24 Hearing - (10/23/13)
Sofosbuvir Briefing Documents/Hearing Oct 25 - (10/23/13)
October 24, 2013 healio.com, AP, Bloomberg
The FDA's Antiviral Drugs Advisory Committee today voted that available data overwhelmingly supports approval of simeprevir in combination with pegylated interferon and ribavirin for treatment of hepatitis C genotype 1 infections. J&J, Medivir, Gilead Sciences Inc. and AbbVie are among companies developing new pills for hepatitis C to alleviate the burden of current treatments, including interferon injections, which can cause flu-like symptoms. The market for hepatitis C drugs may reach more than $100 billion over a decade, according to Bloomberg Industries. Advisers tomorrow will consider a hepatitis C therapy from Gilead.
The Food and Drug Administration issued a positive review Wednesday for a highly anticipated hepatitis C drug from Gilead Sciences (GILD), saying the pill cures more patients in less time than currently available treatments.
The panel voted 19-0 with no abstentions after researchers presented study results demonstrating the once-daily protease inhibitor pill manufactured by Janssen Pharmaceuticals, a Johnson & Johnson company, was superior to placebo in achieving a sustained virologic response (SVR) in treatment-naive patients with HCV and those who relapsed after prior pegylated interferon and ribavirin (PR) therapy.
"I thought the evidence was pretty overwhelming," committee member Dean Follmann, PhD, chief, biostatistics research branch, National Institute of Allergy and Infectious Diseases, said. "It was probably the easiest vote I ever had."
Presenters provided safety and efficacy details from four double-blind, placebo-controlled studies - two phase 3 studies on treatment-naive patients, one phase 3 study on prior relapsers and one phase 2b study on prior relapsers and nonresponders.
The studies demonstrated positive SVR results in most cases, but a subpopulation of HCV patients - those with genotype 1a and a Q80K polymorphism - responded similarly to controls in naive or relapse trials.
Due to the reduction in efficacy apparent in these subjects, the FDA's Division of Antiviral Products stated it intends to recommend screening all genotype 1a subjects for the Q80K viral polymorphism before beginning simeprevir with PR therapy in order to potentially consider alternative treatment options. During discussion of the proposal, the panel voiced questions over whether it was enough to suggest physicians "consider" alternative treatment as opposed to "recommending" another treatment.
The panel also discussed aspects of simeprevir's safety profile and agreed without a vote that a recommendation for sun-protection measures should be included with the warnings and precautions section of simeprevir's prescribing information because of photosensitivity reactions during clinical trials.
Additional skin reactions during clinical trials also prompted discussions of whether skin rash should be included in the warnings and precautions section. The question arose because of apparent differences between presentation and management strategy for rash and photosensitivity.
"There are varying opinions about what should be on the label in what sections," Committee Chairman Yoshihiko Murata, MD, PhD, division of infectious diseases, University of Rochester School of Medicine and Dentistry, said in summarizing the discussion. No final vote was conducted on the discussion point.
The panel also advised that further postmarketing studies should be conducted to better define potential risks to several portions of the population and means to optimize use of simeprevir.
A final decision by the FDA is expected next month.
On Friday the same panel of experts will review another experimental hepatitis C drug from Gilead Sciences Inc. Many analysts expect the drug, known as sofosbuvir, to become the leading treatment for the disease, based on research showing it cures 90 percent of patients with the most common form of hepatitis C in 12 weeks.
An FDA background report on sofosbuvir concluded that adding the medication to standard drug therapy cured 90% of those with HCV genotypes 1, 4, 5 and 6 during a 12-week period.
Roughly 3.2 million people in the U.S. have hepatitis C, a blood-borne disease that causes liver damage and is blamed for 15,000 deaths a year. J&J is one of a half-dozen companies working to develop more effective treatments for the virus as it threatens to become a major health epidemic among baby boomers and middle-age Americans.
''We clearly need better drugs and the evidence is strong that this is a better drug,'' said panelist Dr. Curt Hagedorn of the Central Arkansas Veterans Healthcare Service.
New Brunswick, N.J.-based J&J is seeking approval to combine its pill with the long-established drug cocktail used to treat the most common form of the virus. Despite the unanimous vote Thursday, the panel's endorsement came with a number of conditions.
The panelists stressed that the drug is less effective in patients with a common genetic mutation called Q80K, and that people with the abnormality should be screened out so they can receive other drugs. The group also said the drug's label should warn patients and doctors that sunburn is a common side effect. Finally, panelists said that the FDA should require J&J to conduct additional studies of the drug's effectiveness in minorities, especially African-Americans who are disproportionately infected.
''They shouldn't have any trouble finding these patients in the U.S.,'' said panelist Dr. Marc Ghany of the National Institutes of Health, noting that the company's research has overwhelmingly involved white patients.
The FDA meeting comes as federal health officials urge all baby boomers to get tested for the virus, which can go unnoticed for decades before causing symptoms. People born between 1945 and 1965 are five times more likely to have the virus than people of other age groups. Many of them contracted the virus by sharing needles or having sex with an infected person in their youth. The disease was also spread by blood transfusions before 1992, when blood banks began testing for the virus.
For the last 20 years, the standard treatment for hepatitis C has involved a grueling one-year regimen of pills and injections. These two antiviral drugs, known as ribavirin and interferon-alpha, cause flu-like side effects including nausea, diarrhea and muscle achiness. The introduction of new drugs from Merck and Vertex Pharmaceuticals in 2011 helped shorten the treatment period and boost cure rates as high as 75 percent.
J&J's simeprevir appears to be slightly more effective than the standard of care, curing 80 percent of patients who had not previously been treated for the disease, according to studies submitted to the FDA. More significantly, the drug helped most patients cut the amount of time they had to take the traditional drug cocktail, with its unpleasant side effects, to six months rather than one year. Additionally, panelists said the drug's once-a-day dosage should be far more manageable for patients than the current drugs from Merck and Vertex, which require taking 12 pills or six pills a day, respectively.
''Reducing exposure to interferon and ribavirin is a wonderful thing, especially with a drug that is easier to take than the other options,'' said Dr. Demetre Daskalakis, associate professor at Mt. Sinai School of Medicine in New York.
Genetic Defect
The Q80K polymorphism was found in 48 percent of U.S. patients with a genotype 1a hepatitis C infection in clinical trials compared with 19 percent of patients in Europe, J&J said. The mutation is almost nonexistent in those with a genotype 1b infection.
A study of an all-oral combination of simeprevir with Gilead's sofosbuvir has shown that the regimen mitigates the effect Q80K has on simeprevir, Gaston Picchio, hepatitis disease area leader at J&J's Janssen unit, said during the meeting.
Data from the study is expected to be released in November at the American Association for the Study of Liver Diseases' annual conference in Washington. J&J, the world's biggest seller of health-care products, and Medivir, based in Huddinge, Sweden, are seeking approval for their once-daily pill to treat chronic hepatitis C patients with the genotype 1 infection. About 70 percent of U.S. patients have the genotype 1 form of the disease. Hepatitis C is divided into 6 genotypes.
The most common major side effects of simeprevir were rash and photosensitivity. Panel members agreed with the FDA that the prescribing information for the drug should include a recommendation for patients to use sun protection and avoid tanning beds.
The agency's reviewers state that the "shorter 12-week duration translates into a better tolerated side effect profile," adding that "no major safety issues associated with sofosbuvir have been identified to date."
Foster City-based Gilead Sciences is one of a half-dozen companies working to develop more effective treatments for hepatitis C, and many analysts predict the company's drug will eventually outperform its competitors. The FDA is expected to make a decision on the drug by Dec. 8.
Drugmakers see hepatitis treatments as a potentially lucrative market because the disease is expected to grow into a major public health problem as the baby boom generation ages. People born between 1945 and 1965 are five times more likely to have the virus than people of other age groups, and the Centers for Disease Control and Prevention is urging all baby boomers to get tested for the disease. Many Americans contracted the virus by sharing needles or having sex with an infected person in their youth.
For most of the last 20 years, the standard treatment for hepatitis C has involved a grueling one-year regimen of pills and injections that causes flu-like symptoms and cures less than half of patients. Then in 2011, the FDA approved two new drugs from Merck and Vertex Pharmaceuticals that raised the cure rate to about 65 and 75 percent, respectively, when combined with the older treatments.
Gilead's once-a-day pill appears to push the cure rate even higher.
In a company study of 327 patients with the most common form of the disease, 90 percent of participants had undetectable levels of the virus after 12 weeks of treatment. The form of the disease studied in the trial accounts for about 75 percent of hepatitis C cases in the U.S.
Gilead's drug was not as effective in treating two less common forms of the disease that account for about 25 percent of cases in the U.S. Among those patients, sofosbuvir cured about 67 percent of patients who had not previously taken other hepatitis C drugs.
But even for those patients, the FDA says Gilead's drug represents an important step forward.
The company's approach used only pill-based medications -- sofosbuvir and another antiviral drug -- while excluding interferon, the injectable medication that is the backbone of standard treatment, which can cause nausea, diarrhea and other unpleasant side effects.
For patients with the less common subtypes of the disease, Gilead's approach "provides the first all-oral, interferon-free treatment, as well as a shorter treatment duration and improved safety profile," according to the FDA's review. Gilead is racing against other drugmakers to develop the first all-pill approach to treating the most common form of hepatitis C, long viewed as the holy grail of treatments by drugmakers. Similar efforts are underway from Abbott Laboratories, Bristol-Myers Squibb, Vertex Pharmaceuticals and others.
Citi analyst Yaron Weber said the FDA's review was "overall favorable and may potentially lead to a broad label" for Gilead's drug. He predicts the drug could reach annual sales of $2.74 billion.
Pharmaceutical industry consulting firm Decision Resources estimates the total market for hepatitis C drugs will grow to more than $23 billion by 2018. Sales of the drugs are expected to decline to $17.5 billion by 2021 as more patients are cured of the virus.
FDA Panel Recommends Approval of Simeprevir for Hepatitis C
Medscape Troy Brown, RN October 24, 2013
An advisory committee to the US Food and Drug Administration (FDA) unanimously recommended simeprevir (Janssen) for the treatment of chronic hepatitis C virus (HCV) genotype 1 (GT1) infection, combined with peginterferon alfa and ribavirin in adults with compensated liver disease (including cirrhosis) who are treatment na•ve or who have failed previous interferon therapy with or without ribavirin. Simeprevir is an HCV protease inhibitor, and if approved it will be the third HCV protease inhibitor approved in the US. Boceprevir (Victrelis, Merck) and telaprevir (Incivek, Vertex Pharmaceuticals, Inc) were approved in 2011, according to background information provided by the FDA. The proposed dose is 150 mg once daily, in combination with peginterferon alfa and ribavirin. "We clearly need better drugs, and the evidence is strong that this is a better drug than we have," voting member Curt H. Hagedorn, MD, Chief, Medicine Service, at Central Arkansas Veterans Healthcare Service, in Little Rock, Arkansas, noted.
The vote follows a discussion of data from 3 phase 3 randomized, double-blind, placebo controlled clinical trials (C208, C216, and HPC3007) in patients with chronic HCV GT1. Patients in the treatment groups (N = 781) were given simeprevir 150 mg daily for 12 weeks plus peginterferon and ribavirin (PR) for 12 weeks, followed by PR only for either 12 or 36 weeks based on the individual's virologic response to therapy. Patients in the control groups (N = 397) were given placebo for 12 weeks combined with PR for 48 weeks. Those in trials C208 and C216 were treatment-na•ve, and those in HPC3007 had received 24 weeks or more of a pegylated interferon-based treatment and had relapsed within 1 year after the last medication dose. Efficacy data from C208 and C216 were pooled because the studies were nearly identical in design.
The trials' primary endpoint was sustained virologic response 12 weeks after the anticipated end of treatment (SVR12), which was defined as an undetectable HCV RNA at treatment end and HCV RNA < 25 IU/mL 12 weeks after the anticipated end of treatment.
The pooled results from C208 and C216 showed an SVR12 rate of 80% in the treatment group and 50% in the control group. For the relapsed patients in HPC3007, the SVR12 rate was 79% in the treatment group and 36% in the control group.
Secondary endpoints for all 3 trials included SVR24 and SVR 72. Both endpoints correlated well with the primary endpoint of SVR12, but data were incomplete at the week 60 data cut-off.
SVR rates were lower in patients with a high baseline viral load, advanced disease on liver histology (bridging fibrosis and cirrhosis), older age, African American ethnicity, and absence of the IL28B CC genetic polymorphism.
The presence of the Q80K HCV GT1a polymorphism (commonly found in GT1a patients in the US) at baseline had a substantial impact on the efficacy of simeprevir. In the pooled trials, the differences in SVR12 rates in GT1a patients with the Q80K polymorphism were not statistically significant between the treatment (58%) and control (55%) groups. In HPC3007, the SVR12 rates for those with the Q80K polymorphism were 47% in the treatment group and 30% in the control group.
In those without the Q80K polymorphism, the SVR12 rates were 84% in the treatment groups vs 43% in the control group for the 2 pooled trials, and 78% in the treatment group vs 24% in the control group for the relapser trial. The committee recommends screening all patients with GT1a infection for the Q80K viral polymorphisms before initiating simeprevir (combined with pegylated interferon and ribavirin) and considering alternative treatment options for those with this polymorphism.
SVR12 rates were significantly higher in the simeprevir arm compared with the placebo arm in all other subgroup analyses.
Mean simeprevir area under the concentration-time curve 24-h postdose (AUC24h) values were 2.4 and 5.2-fold higher, respectively, in HCV-uninfected subjects with moderate or severe hepatic dysfunction, compared to healthy controls. Mean simeprevir AUC24h values were also approximately 3.4-fold higher in HCV infected patients of East Asian ancestry, compared with the pooled Phase 3 population which was about 91% Caucasian. For this reason, the committee would like to see additional studies in patients of East Asian origin.
A total of 4 deaths occurred in the treatment groups, and they were judged to be unrelated to treatment.
In the pooled analysis, 2% of those in the simeprevir group had serious adverse events, versus 3% of those in the control group during the initial 12 weeks. A total of 3 patients (0.4%) in the simeprevir group had significant adverse events, which were determined to be related to simeprevir by the study investigator; 1 patient experienced major depression and 2 patients experienced photosensitivity reactions.
Other common adverse events were rash (218 [28%] treatment groups; 79 [20%] control groups), influenza like illness (203 [26%] treatment groups; 84 [21%] control groups), pruritis (168 [22%] treatment groups; 58 [15%] control groups), and nausea (173 [22%] treatment groups; 70 [18%] control groups).
"I think this is a great opportunity at treating more HCV infected patients," said voting member Amanda H. Corbett, PharmD, BCPS, FCCP, a clinical associate professor at the University of North Carolina at Chapel Hill's Eshelman School of Pharmacy.
"Efficacy was clearly demonstrated and the safety profile is clearly favorable," explained voting member Thomas P. Giordano, MD, MPH, an associate professor of medicine at Baylor College of Medicine, medical director of HIV services at Harris Health System, and a research scientist at HSR&D Center of Excellence, Michael E. DeBakey VA Medical Center, in Houston, Texas.
Several committee members remarked on the need for postmarketing studies in racial and ethnic minorities, patients coinfected with HIV, and other underrepresented populations. A number of members suggested that the FDA should be more proactive with the pharmaceutical industry at the beginning of the clinical trial process to ensure a more diverse study population that more accurately represents the clinical population being studied.
Bloomberg News
Gilead's Hepatitis C Pill Works Better Than Current Therapy (3)
By Anna Edney October 23, 2013
Gilead Sciences Inc. (GILD:US)'s experimental hepatitis C drug that lessens side effects and reduces length of treatment time is safe and effective against the disease, U.S. regulators said.
The medicine, sofosbuvir, has "a favorable benefit-risk assessment," Food and Drug Administration staff said today in a review ahead of an Oct. 25 meeting of advisers to discuss the therapy. The FDA also will host an advisory panel tomorrow for Johnson & Johnson (JNJ:US) and Medivir AB (MVIRB)'s hepatitis C drug simeprevir.
Gilead, J&J, Medivir, AbbVie Inc. (ABBV:US) and Bristol Myers Squibb Co. are among companies working on new hepatitis C drugs that alleviate the burden of current treatments that include interferon injections, which can cause flu-like symptoms. The total market for hepatitis C drugs may reach more than $100 billion over a decade, according to Bloomberg Industries.
For some patients, sofosbuvir "provides the first all-oral, interferon-free treatment, as well as a shorter treatment duration and improved safety profile compared to the current standard of care interferon-based regimen," FDA staff wrote in the report.
Sofosbuvir is estimated to generate $2 billion in sales next year, according to the average of eight analysts' estimates compiled by Bloomberg.
Decision Date
The FDA didn't find any heart risks associated with sofosbuvir after Bristol-Myers and Idenix Pharmaceuticals Inc. discontinued development of drugs in the same class last year based on cardiovascular safety concerns.
Gilead is seeking FDA approval of once-daily sofosbuvir combined for the majority of patients with pegylated interferon and another pill call ribavirin, both of which make up the backbone of current treatment for the virus as part of a regimen that can last as long as 48 weeks. Sofosbuvir can cut the treatment time to 12 weeks. J&J's simeprevir gets therapy down to 24 weeks.
The FDA is scheduled to decide whether to approve sofosbuvir by Dec. 8, and simeprevir by Nov. 27.
For the majority of current patients interferon and ribavirin are combined with Merck & Co.'s Victrelis and Vertex Pharmaceuticals Inc. (VRTX:US)'s Incivek. Victrelis, Incivek and J&J's simeprevir are protease inhibitors that battle genotype 1 hepatitis C, the most common form of the disease. Sofosbuvir is the first in a new class of drugs called nucleotide polymerase inhibitors and is effective across all six hepatitis C genotypes.
Patient Population
About 4 million Americans have the disease, which can cause liver cirrhosis, according to the National Institutes of Health. The disease can be passed through infected blood or body fluids, most commonly through needle-sharing by drug users. About 70 percent of U.S. hepatitis C patients carry the genotype 1 infection.
Gilead studied an all-oral combination of sofosbuvir and ribavirin for genotype 2 and genotype 3 patients and a combination with pegylated interferon and ribavirin for patients with the other genotypes, including 1, who haven't been treated before.
Sofosbuvir combined with pegylated interferon and ribavirin for 12 weeks cured 90 percent of patients with genotypes 1,4,5 and 6 who hadn't been treated before, Gilead said. FDA staff found data on patients with genotypes 5 and 6 to be insufficient to determine dosing because Gilead only studied 7 patients total with those types of hepatitis C.
New Data
"This is a two- or three-stage program," John McHutchison, senior vice president of liver disease therapeutics at Gilead, said in an interview. "This is the first approval."
Gilead is researching an all-oral combination of sofosbuvir and another Gilead drug ledipasvir the company hopes will hit the market about a year after sofosbuvir itself.
"Sofosbuvir seems to be the future of many of these highly effective all oral regimens," McHutchison said.
FDA workers recommended yesterday potential simeprevir users be screened for a genetic mutation called Q80K polymorphism that renders the drug ineffective. No such suggestion was made regarding sofosbuvir.
Data from a mid-stage study on a combination of simeprevir and sofosbuvir with or without ribavirin are expected to be released in early November at the American Association for the Study of Liver Diseases' annual conference in Washington, D.C.
New group of oral hepatitis C drugs near U.S. approval
By Deena Beasley
Oct 23 (Reuters) - Patients infected with the liver-destroying hepatitis C virus should soon have better treatment options as new tablets from Gilead Sciences and others approach U.S. regulatory approval.
Gilead's experimental drug sofosbuvir is the first of a new group of oral therapies to be considered by the U.S. Food and Drug Administration, which has convened an advisory panel for Friday.
The treatment is seen as the crown jewel of Gilead's $11 billion purchase of biotechnology company Pharmasset and aims to replace some of the pills and injections now on the market.
"Treatment will become simpler, shorter and safer...a broader group of patients can be treated," said John McHutchison, head of liver disease therapeutics at Gilead.
In a pre-hearing report issued on Wednesday, FDA staff concluded that sofosbuvir is safe and effective as part of a combination regimen for the hepatitis C virus (HCV).
The deadline for a regulatory decision on the drug is Dec. 8. Wall Street analysts have forecast sales of $1.85 billion next year, assuming a price of $85,000 per patient, according to ISI Group. HCV affects about 3.2 million Americans, killing more than 15,000 each year, mostly from illnesses such as cirrhosis and liver cancer.
The often-undiagnosed virus is transmitted through contaminated blood. While infection rates have dropped since the early 1990s - due in part to the introduction of blood and organ screening - many older adults remain at risk, according to the Centers for Disease Control and Prevention, which has called for baby boomers to be routinely tested for the virus.
Standard treatment has been a combination of interferon, given by injection, and ribavirin, a pill. But both drugs have side effects and neither works directly against the virus. In addition, the regimen is not that effective for many people living with HCV, especially those with hard-to-treat genotype 1 infections.
Technological advances over the past decade have enabled the development of direct-acting antivirals (DAAs) that specifically target the virus. Two new antiviral drugs, Incivek from Vertex Pharmaceuticals Inc and Victrelis from Merck & Co , have cured more HCV patients in recent years, but both are protease inhibitors and are still used in combination with interferon and ribavirin. Protease inhibitors are designed to block certain enzymes the virus needs to replicate.
Gilead's drug is part of a new class known as nucleotide analogue inhibitors, or "nukes," designed to block a different enzyme the virus needs to copy itself. The company says the therapy is more difficult for the body to overcome, and expects treatment times to be shorter and easier to endure. It first sought FDA approval to use sofosbuvir along with ribavirin as an all-oral therapy for genotype 2 and 3 infections, or about 28 percent of the U.S. HCV population. It is also seeking approval to use the drug in combination with both ribavirin and interferon for more common genotype 1 infections, and plans to file next year for an all-oral treatment regimen for those patients.
"We have a very, very high barrier to resistance," McHutchison said. He estimates that around 70 percent of U.S. HCV patients have genotype 1, up to 20 percent are infected with genotype 2, and 8 percent have genotype 3.
Gilead is the world's largest maker of branded drugs to treat HIV, the virus that causes AIDS, but has turned to hepatitis C treatments to diversify its pipeline.
"Before we acquired Pharmasset we did a lot of due diligence," McHutchison said. "I think we picked the right nuke."
Sanford Bernstein analyst Geoffrey Porges believes Gilead's advantage over competitors in the HCV field may be increasing as it becomes more clear that a nuke-based regimen has fewer limitations in terms of dosing convenience and breadth of genotype effectiveness.
"We are approaching an inflection point for hepatitis C for Gilead," he said. It is a competitive field, and there have been setbacks for some. Vertex said in July that the FDA had placed a partial hold on a mid-stage study of its experimental hepatitis C nuke. Bristol-Myers Squibb last year discontinued development of one of its experimental drugs after a patient died of heart failure during a clinical trial and several others were hospitalized.
While Gilead is perceived to be in the driver's seat in the race to produce all-oral treatments, Bristol-Myers is expected to present Phase III data on an interferon-free treatment for genotype 1 patients at next month's meeting of the American Association for the Study of Liver Diseases in Washington D.C.
That regimen will consist of daclatasvir, which blocks a protein called NS5A that plays a central role in HCV replication. Bristol-Myers sees daclatasvir as the backbone of its hepatitis program, along with its protease inhibitor asunaprevir.
Bristol-Myers plans to begin testing a triple oral therapy early next year. Companies like AbbVie and Boehringer Ingelheim are also spending millions to develop new hepatitis C treatments.
Gilead's McHutchison said data on another of his company's all-oral regimens - sofosbuvir combined with NS5A inhibitor ledipasvir - will be presented at a medical meeting in April, and the company plans to file for FDA approval in the first half of next year.
He said sofosbuvir has so far been tested in more than 3,000 patients and there have been no issues with heart problems or other side effects beyond those linked to drugs with which it has been combined.
Earlier trials of the company's all-oral combination for genotype 1 resulted in more than 95 percent of patients being cured, McHutchison said. (from Jules: Abbvie reported 97% cured in their phase 2 study of their oral combination, BMS 94%, Boehringer Ingelheim 95% in a smaller phase 2 study, Merck will present at AASLD next month, Vertex is researching their own nucleotide in combination with oral DAAs from these other companies, and Janssen too is studying an all oral regimen)
Some analysts believe the FDA panel could support the use of sofosbuvir in combination with protease inhibitors, such as the J&J drug, for genotype 1 patients, even though the companies have not asked for such a label. "This could boost (sales) estimates in 2014," according to a research note from Goldman Sachs.
The FDA advisory committee will also hear comment this week on Johnson & Johnson's application to sell simeprevir, an experimental protease inhibitor designed to target genotype 1 HCV.

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