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Hemofilie B; nog steeds on track?

1. [verwijderd] 2 januari 2013 12:14

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   inmiddels moet het ongeveer alweer zo'n 34 maanden geleden zijn dat de eerst behandelde patienten werden behandeld. Zover ik heb begrepen is er nog steeds geen reden om dit af te schrijven.
   
   uit het rapport van 25 aug 2011 www.amtbiopharma.com/uploads/financia... :
   
   Hemofilie B
   AMT blijft werken met St. Jude’s Children’s Hospital in de VS, dat momenteel een klinisch onderzoek
   financiert en uitvoert in de VS en het Verenigd Koninkrijk. De eerste resultaten zijn veelbelovend. De
   patiënten vertonen stabiele en blijvende expressie van het Factor IX stollingseiwit en kunnen het toedienen
   van eiwitvervangende therapie, de huidige standaardbehandeling die tot drie maal per week een
   intraveneus toediening vereist, verminderen of zelfs stoppen. De hemofilie B gentherapie vereist
   daarentegen één enkele toediening die een blijvende werkzaamheid biedt – de eerste patiënt werd bijna 18
   maanden geleden behandeld en heeft tot nu toe geen waarneembare vermindering van het voordeel van
   deze behandeling vertoond. Dit is het tweede gentherapieprogramma waarin AMT een rol speelt waarin de
   klinische werkzaamheid op de lange termijn wordt aangetoond na slechts een enkele behandeling. Dit
   onderstreept AMTs positie als wereldwijd toonaangevend op het gebied van gentherapie.
   
   ----
   
   Ik denk dat het de moeite is om deze trial met aandacht te volgen, want zet heel wat zoden aan de dijk!
   De goedkeuring van Glybera moet voor enig tegenwicht in de cashburn zorgen en nieuwe avonturen steunen.
   
   Mocht iemand nog aanvullende info hebben mbt Hemofilie B, dan verneem ik (en velen met mij mag ik aannemen) dat graag.
   Op het gebied van gentherapy valt nog heel erg veel eer te behalen en wanneer je bedenkt dat UniQure daarmee in de voorste gelederen zit....
2. [verwijderd] 2 januari 2013 12:19

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   uit het rapport van 3e kwartaal 2012
   
   www.uniqure.com/uploads/News/Business...
   
   Encouraging progress also continues on our SanfilippoB and Hemophilia B programs, with both expected to begin
   clinical development within the next 12 months.
3. flosz 2 januari 2013 12:41

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   Haal dat vraagteken maar weg hoor ivet. Btw: een gelukkig 2013 met een uitermate bescheiden zorgverbruik!
   
   Dec.2011:
   www.nejm.org/doi/full/10.1056/NEJMoa1...
   
   Dec. 2012:
   MEMPHIS, Tenn. — Derek Houser ate a quick lunch, settled into a hospital bed and waited for his life to change.
   The 33-year-old partner in a financial services office in Waco, Texas, was born with hemophilia B, an inherited disorder that prevents his blood from clotting. He depends on injections of clotting factor to stanch potentially debilitating and dangerous internal bleeding episodes.
   That's why Houser spent a recent sunny afternoon in St. Jude Children's Research Hospital hooked to an IV drip bag, receiving a single treatment of gene therapy that has been shown to greatly lessen the severity of the ailment. He's the last patient enrolled in a hemophilia B study coordinated by St. Jude and University College London.
   St. Jude researchers this week reported at the annual conference of the American Society of Hematology in Atlanta that the latest round of therapy involving Houser and others appears to provide long-term help by reprogramming patients' bodies to produce more of the protein known as Factor IX, which is essential for clotting.
   Almost exclusively a disease of men, hemophilia B is caused by a glitch in the gene that makes Factor IX. Sufferers often are afflicted with spontaneous internal bleeding, which can cause chronic damage to the joints around which the blood pools.
   In the therapy pioneered at St. Jude and University College, an altered virus is used as a vector, or agent, to carry the gene that triggers production of Factor IX. Suspended in an IV solution containing the plasma protein albumin, the adeno-associated virus is used as vector because it targets the liver, where the Factor IX is produced, but doesn't cause disease in humans, or work its way into human DNA.
   Since 2010, seven patients have undergone the therapy in London. This year, three patients at St. Jude have been treated with higher doses of the vector.
   The results show clear benefits from the therapy, researchers said. Of the first eight patients enrolled in the study, all began producing higher levels of the clotting agent, with five no longer needing the preventive therapy to avoid bleeding.
   The patients previously had been producing almost no Factor IX, but after therapy, their blood levels of it rose from less than 1 percent to as much as 6 percent.
   "Anything over 1 percent will improve the clinical course of the patient" said Dr. Arthur Nienhuis, a member of St. Jude's Department of Hematology whose lab helped develop the therapy method. "Clearly, the treatment does work."
   In the earlier patients, production of the clotting factor has been sustained for two years now.
   Houser and another patient treated at St. Jude, 23-year-old Chris Potwora of Vancouver, Wash., said they enrolled in the study after researching clinical trials on hemophilia. Both said they were confident the therapy can help them and future patients.
   "It's not going to get worse," Potwora said. "And if no one goes into the study, the science goes nowhere."
   Dr. Andrew Davidoff, chairman of St. Jude's department of surgery and one of the study's investigators, said initial results suggest the therapy is both safe and effective. St. Jude officials hope it eventually can be used on children, he said, "to catch them before the ravages of bleeding."
   www.therepublic.com/view/story/hemoph...
   
4. flosz 2 januari 2013 12:42

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   A Giant Step for Gene Therapy
   Exciting gene therapy study helps patients with hemophilia B.
   
   Chris Potwora doesn’t remember life without hemophilia.
   He was just a little tyke when doctors realized that his blood failed to clot properly. For Potwora, a skinned knee could be dangerous. A tumble from a bicycle could be deadly. Football or other contact sports? Out of the question. As a result, the boy endured frequent injections of Factor IX, a protein that helped his blood clot.
   “I used to go camping with my dad, and we’d take Factor IX along in the cooler,” Potwora recalls. “It’s something I’ve always dealt with, so I didn’t know any different.”
   All that changed when Potwora spent a week at St. Jude Children’s Research Hospital earlier this year. On Valentine’s Day of 2012, he became one of the first people in the world to receive a novel kind of gene therapy.
   After that, Potwora discontinued his regular injections of Factor IX.
   
   A factor of nine
   Hemophilia is an inherited disorder that primarily affects males. Because they lack an essential protein needed to help the blood clot, individuals with the disease may bleed profusely after minor injuries or may spontaneously bleed into their joints. About one in 30,000 boys inherits hemophilia B, which is caused by a mutated F9 gene. These individuals lack sufficient amounts of clotting Factor IX. People with severe hemophilia require regular transfusions of the protein to prevent bleeding episodes. Besides being painful and inconvenient, the frequent injections are expensive, costing as much as $400,000 a year.
   Enter gene therapy.
   For years, researchers believed that hemophilia B could be cured by adding a normal F9 gene to replace the function of the faulty one. The healthy gene would then command cells to produce the missing Factor IX protein and—voilà!—the patient’s blood would clot normally.
   St. Jude hematologist Arthur Nienhuis, MD, and his colleagues have spent decades seeking the best method for delivering healthy genes into the body. The therapeutic gene could not be inserted directly into a cell; instead, it must hitch a ride with a carrier that could transport its cargo to the desired location. The logical vehicle would be a virus, which has a natural tendency to infect cells and replicate within them. If a virus could be engineered so that it could infect cells and introduce its genetic material but not replicate, then the normal F9 gene could be introduced into a target cell. This genetically engineered virus is called a vector.
   One obstacle to using a viral vector is that a patient’s immune system might attack and destroy the foreign invader. Scientists homed in on what is called an adeno-associated virus (AAV), a benign virus that does not cause disease in humans. When injected into the bloodstream, the AAV tends to travel directly to the liver, the site where Factor IX is normally produced.
   
   Designing a unique vector
   In the 1990s, St. Jude postdoctoral fellow Amit Nathwani, MD, PhD, and surgeon Andrew Davidoff, MD, began collaborating with Nienhuis to develop a gene therapy approach for hemophilia. The relationship continued when Nathwani later moved to University College London (UCL).
   Davidoff, now St. Jude Surgery chair, says the success of the subsequent gene therapy trial is due in part to a vector design that is unlike any other. The research team, which included John Gray, PhD, of St. Jude Experimental Hematology, chose a virus called AAV8 to deliver the genetic material into the liver.
   “Our vector design is unique in certain aspects,” Davidoff explains. “All clinical trials before ours that used adeno-associated virus used a type called AAV2. Almost all humans have been exposed to that virus and have some degree of immunity against it. We chose AAV8, because only 5 to 10 percent of humans have been exposed to it. To qualify for our trial, patients could not have had prior exposure to AAV8.” Because the participants had never encountered AAV8, their immune systems would be less likely to recognize and attack it.
   The vector used in the study was produced at the Children’s GMP, LLC, which is located on the St. Jude campus. St. Jude was the first pediatric research center to have an on-site Good Manufacturing Practices facility. The Children’s GMP produces biopharmaceutical products under government-approved manufacturing guidelines.
   Because the gene therapy treatment must be perfected on adults before it could be used on children, the team approached UCL hemophilia expert Edward G.D. Tuddenham, MD, PhD, to recruit adult patients. Six men enrolled in the first phase of the study, which occurred in London. Each participant received a one-time gene therapy treatment that was delivered via a simple intravenous infusion.
   Of the initial group of participants, two received low doses of the vector, two received intermediate doses and two received higher doses. Factor IX levels rose in all of the men, with the ones receiving the most vector enjoying the highest increases. One high-dose recipient experienced a mild immune response in the liver, which was successfully quelled with short-term steroid treatment.
   
   Read all about it
   A New England Journal of Medicine report on the study generated international headlines. The clinical trial had offered the first proof that gene therapy could reduce the symptoms of hemophilia B. Four patients discontinued their regular protein injections altogether; the two who received the lowest doses required injections much less frequently than before the study.
   The participants’ lifestyles changed dramatically. For the first time in their lives, they could run marathons or play soccer without bleeding into their joints.
   “Clearly it was a life-transforming experience, because they went from acquiring Factor IX infusions two or three times a week and in constant risk of bleeding to essentially being clinically normal,” Nienhuis observes.
   Although any level above 1 percent is therapeutically significant, the eventual goal of the hemophilia B trial is to achieve and sustain factor levels exceeding 15 percent. The study’s participants continue to maintain levels ranging from 2 to 6 percent. Most importantly, those results have persisted for more than two-and-a-half years.
   “This is clearly the first study that has documented long-term expression of a therapeutic transgene,” Davidoff says.
   
   
5. flosz 2 januari 2013 12:42

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   Vervolg.
   
   Looking ahead
   The gene therapy study continues to accrue adult patients, all of whom receive high doses of the vector. Potwora was the first patient to receive his treatment at St. Jude. Ulrike Reiss, MD, of St. Jude Hematology notes that Potwora experienced a minor liver inflammation, which was treated with steroids. Potwora now takes Factor IX only after incurring an injury, such as when he recently broke his toe.
   The trial’s next phase will use a vector in which researchers have removed the viral particles that lack DNA. Davidoff believes this improvement will further reduce participants’ immune reactions and will enable clinicians to deliver more genetic material into the liver. The modified vector is currently in production in the Children’s GMP, LLC. Eventually the St. Jude team hopes to extend gene therapy to children with hemophilia B, as well as to individuals with Gaucher disease, hemophilia A and galactosialidosis.
   For Nienhuis, a pioneer in the field of gene therapy, these trials are the culmination of his life’s work.
   “It’s a grand experience, to see it come to fruition,” admits Nienhuis, former president of the American Society of Gene Therapy. “If you had asked me 30 years ago whether we could ever treat a disease by simply injecting a virus into the bloodstream, I would have said, ‘It’s not likely.’ But clearly the biology was very different from what we expected. It definitely works.”
   Potwora is adjusting to life without regular injections of Factor IX.
   “It was weird getting used to it at first,” admits the recent college graduate and future medical student. “I was interested in the clinical study because I didn’t want to take the factor anymore, but as a pre-med student I also had an academic interest in gene therapy. I knew they need these kinds of studies in order for the field of gene therapy to move forward. I think it’s really interesting from a scientific perspective and really helpful from a clinical one. When I’m a doctor, I’d really like to see this be an option for treatment, because there are a lot of conditions it could help.”
   www.stjude.org/SJFile/AutumnProm12_re...
   
6. flosz 2 januari 2013 13:34

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   Dec.2012
   Stable Factor IX Activity Following AAV-Mediated Gene Transfer in Patients with Severe Hemophilia B
   
   Introduction: We are conducting a phase I/II clinical trial of factor IX gene transfer for severe hemophilia B. In the trial we are using a serotype-8 pseudotyped self-complementary adeno-associated virus (scAAV) vector expressing a codon-optimized coagulation factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco). We have previously reported the early safety and efficacy of our novel gene transfer approach in six patients with severe hemophilia B following a single peripheral vein infusion of one of three vector doses (low [2x1011 vector particles (vp)/kilogram weight (kg)], intermediate [6x1011 vp/kg], or high dose [2x1012 vp/kg]) (Nathwani et al, NEJM 365:2357-65, 2011). AAV-mediated expression of FIX at 1-6% of normal was established in all six participants with an initial follow-up of between 6-14 months following gene transfer. We now report longer follow-up of these participants, as well as data from two additional participants recently enrolled at the high dose level.
   Methods: We have now infused scAAV2/8-LP1-hFIXco in eight subjects with severe hemophilia B (FIX activity, <1% of normal values). Vector was administered without immunosuppressive therapy, and participants have now been followed for 3 months to 2½ years. FIX activity, serum transaminases, vector genomes in secretions/excretions, antibodies to FIX and AAV8, and AAV8 capsid-specific T-cells were monitored during the follow-up.
   
   Results: Each of the participants currently has AAV-mediated activity of FIX at 1 to 6% of normal levels. These levels have been stable in each during the follow-up period which is now greater than 1½ years for the first six participants. Five of the eight participants have discontinued FIX prophylaxis and remain free of spontaneous hemorrhage; in the other three, the interval between prophylactic injections has increased. None of the participants in the low or intermediate dose cohorts had evidence of transaminitis; each currently has FIX activity of 1-3% for over 1½ years. Of the four participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid-specific T cells in the peripheral blood; two others had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these three participants received a short course of glucocorticoid therapy, which rapidly normalized their aminotransferase levels and maintained FIX levels in the range of 4 to 6% of normal values. The fourth participant has not had transaminitis three months after vector administration.
   
   Conclusions: This represents the first successful, long-term, gene therapy-mediated expression of a therapeutic protein from an AAV vector delivered to human liver. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. Larger numbers of patients followed for longer periods of time are necessary to fully define the benefits and risks and to optimize dosing. However, this gene therapy approach, even with its risk of mild, transient transaminitis, has the potential to convert the bleeding phenotype of patients with severe hemophilia B into a mild form of the disease or to reverse it entirely for a prolonged period of time following vector administration. (ClinicalTrials.gov number, NCT00979238)
   
   ash.confex.com/ash/2012/webprogram/Pa...
   
   Estimated Enrollment: 18
   Study Start Date: August 2009
   Estimated Study Completion Date: July 2029
   Estimated Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
   clinicaltrials.gov/ct2/show/NCT009792...
   
7. rationeel 11 januari 2013 20:18

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   "I think rumors of our death were highly overexaggerated," John Maraganore, CEO of Alnylam Pharmaceuticals, said this week during a meeting with us. But back in 2010, the future seemed grim for RNA interference and Alnylam ($ALNY). Swiss drug giant Roche ($RHHBY) pulled the plug on research in the field. Alnylam and other developers hadn't lived up to the hype about the gene-silencing drugs, which face delivery challenges to reach disease targets deep in the body. Yet in the last 12 months, the Cambridge, MA-based biotech's stock price has jumped 130%, and the company showed that its technology could produce potential medicines such as its lead candidate for familial amyloidotic polyneuropathy, ALN-TTR02, which could be in Phase III development later this year.
   
   Read more: - FierceBiotech www.fiercebiotech.com/slideshows/look...
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8. rationeel 11 januari 2013 20:27

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   SHIRE:
   
   HUMAN GENETIC THERAPIES
   ACE Inhibitor-Induced Angioedema(2) FIRAZYR (EU) Registration 2012
   Duchenne Muscular Dystrophy (DMD)(3) HGT4510 2a
   Hunter syndrome CNS HGT2310 1-2
   Metachromatic Leukodystrophy ('MLD') HGT 1110 1-2
   Sanfilippo A syndrome HGT 1410 1-2
   Sanfilippo B syndrome HGT 3010 Pre-clinical
   Santaris collaboration
9. Prof. Dollar 16 januari 2013 00:29

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   Microgene treats muscular dystrophy in dogs
   www.futurity.org/health-medicine/micr...
   
   Ik weet niet of er een link is met uniQure?
   Wel zie je dat het onderzoek elders gewoon door gaat, en met succes.
   
10. rationeel 16 januari 2013 20:06

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    Conference: NVGCT Spring Symposium March 15 & 16, 2013
    The 2013 Spring Symposium of the Netherlands Society of Gene & Cell Therapy will be held on March 15 & 16, 2013. Venue: Congrescentrum De Werelt, Lunteren The Netherlands.
    
    Confirmed speakers: Jörn Aldag (uniQure) & Dick van Bekkum (Cinderella therapeutics). Keynote speaker: Bobby Gaspar (UCL Institute of Child Health, London, UK), Gene therapy for primary immune deficiencies.
    
12. harrysnel 22 februari 2013 00:43

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    Niet direct Uniqure maar zeker interessant. Biomarin gaat samenwerking aan met St. Jude (ook hier weer Nathwani) maar dan voor hemofilie A.
    
    BioMarin Licenses Factor VIII Gene Therapy Program for Hemophilia A From University College London and St. Jude Children's Research Hospital
    
    SAN RAFAEL, Calif., Feb. 21, 2013 (GLOBE NEWSWIRE) -- BioMarin Pharmaceutical Inc. (BMRN) announced today that it has licensed a Factor VIII gene therapy program for hemophilia A from University College London (UCL) and St. Jude Children's Research Hospital. The company expects to select a development candidate this year, initiate and complete IND-enabling toxicology studies next year and initiate proof of concept human studies by the end of 2014. The license and commitment to support the research program was made possible by UCL Business, UCL's wholly-owned technology transfer company, working with Professor Amit Nathwani of the UCL Cancer Institute.
    "Gene therapy is emerging as a powerful and viable way to treat genetic disorders and is complementary to our current suite of commercial products and research programs," said Jean-Jacques Bienaime, Chief Executive Officer of BioMarin. "Hemophilia is an attractive target for gene therapy as factor levels in the blood serve as good biomarkers, relatively low factor levels are required for a clinically important benefit in severe patients and the current standard of care of intravenous infusions three times a week is quite onerous. We remain committed to maintaining a rich pipeline with the goal of filing an IND every twelve to eighteen months."
    Mr. Cengiz Tarhan, Managing Director of UCL Business said, "This is an excellent partnership for UCL Business, which combines the world class translational research strengths of Professor Nathwani and his team with the significant development and commercialization capabilities of BioMarin to progress this ground breaking therapy for hemophilia A."
    Professor Stephen Caddick, Vice-Provost (Enterprise) at University College London added, "UCL and BioMarin each bring distinct strengths to the partnership. UCL is a world leader in the biomedical sciences, with an unremitting commitment to outstanding research and translation into healthcare benefits for patients. We welcome this partnership which will continue to build on the excellence of our research to fully explore the potential of gene therapy as a life-saving treatment for people with hemophilia."
    Andrew Davidoff, M.D., Chair, Surgery, St. Jude Children's Research Hospital, added, "We are pleased that our research with UCL on gene therapy for hemophilia has led to the development of a potential therapeutic tool for treating this devastating disease. This licensing agreement underscores St. Jude's commitment to rapidly translating our research into effective clinical interventions."
    finance.yahoo.com/news/biomarin-licen...
    
    
13. bilbo3 7 november 2013 12:25

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    In onderstaand artikel blijkt dat het onderzoek van children hospital st Jude en Childrens hospital Philadelphia hetzelfde onderzoek is.
    
    Dit was mij nog niet bekend, voorzover ik weet heeft Uniqure de rechten van St Jude, maar vanuit philadelphia heeft een spin off plaatsgevonden: Spark theraputics, deze hebbern naast een vergevorderde trials voor blindheid, ook rechten op hemophilia B.
    Weet iemand hoe dit precies zit?
    
    www.nytimes.com/2011/12/11/health/res...
    
    Treatment for Blood Disease Is Gene Therapy Landmark
    
    By NICHOLAS WADE
    
    Published: December 10, 2011
    
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    Medical researchers in Britain have successfully treated six patients suffering from the blood-clotting disease known as hemophilia B by injecting them with the correct form of a defective gene, a landmark achievement in the troubled field of gene therapy. Hemophilia B, which was carried by Queen Victoria and affected most of the royal houses of Europe, is the first well-known disease to appear treatable by gene therapy, a technique with a 20-year record of almost unbroken failure.
    
    Enlarge This Image
    
    University College London
    
    A virus carrying a replacement gene for blood clotting was used by University College London researchers to help six patients.
    
    “I think this is a terrific advance for the field,” said Dr. Ronald G. Crystal, a gene therapist at Weill Cornell Medical College. “After all the hype in the early 1990s, I think the field is really coming back now.”
    
    Gene therapy has had minor successes in very rare diseases but suffered a major setback in 1999 with the death of a patient in a clinical trial at the University of Pennsylvania. Another gene therapy trial treated an immune deficiency but caused cancer in some patients.
    
    The general concept of gene therapy — replacing the defective gene in any genetic disease with the intact version — has long been alluring. But carrying it out in practice, usually by loading the replacement gene onto a virus that introduces it into human cells, has been a struggle.
    
    The immune system is all too effective at killing the viruses before the genes can take effect.
    
    The success with hemophilia B, reported online Saturday in The New England Journal of Medicine, embodies several minor improvements developed over many years by different groups of researchers.
    
    The delivery virus, carrying a good version of the human gene for the clotting agent known as Factor IX, was prepared by researchers at St. Jude Children’s Research Hospital in Memphis. The patients had been recruited and treated with the virus in England by a team led by Dr. Amit C. Nathwani of University College London; researchers at the Children’s Hospital of Philadelphia monitored their immune reactions.
    
    Hemophilia B is caused by a defect in the gene for Factor IX. Fatal if untreated, the disease occurs almost only in men because the Factor IX gene lies on the X chromosome, of which men have only a single copy.
    
    Women who carry a defective gene on one X chromosome can compensate with the good copy on their other X chromosome, but they bequeath the defective copy to half their children. About one in 30,000 of newborn boys have the disease, with about 3,000 patients in the United States.
    
    Dr. Nathwani and his team reported that they treated the patients by infusing the delivery virus into their veins. The virus homes in on the cells of the liver, and the gene it carries then churns out correct copies of Factor IX. A single injection enabled the patients to produce small amounts of Factor IX, enough that four of the six could stop the usual treatment, injections of Factor IX concentrate prepared from donated blood. The other two patients continued to need concentrate, but less frequently.
    
    Treating a patient with concentrate costs $300,000 a year, with a possible lifetime cost of $20 million, but the single required injection of the new delivery virus costs just $30,000, Dr. Katherine P. Ponder of the Washington University School of Medicine in St. Louis notes in her commentary in The New England Journal of Medicine, calling the trial “a landmark study.”
    
    The patients have continued to produce their own Factor IX for up to 22 months, said Dr. Edward G. D. Tuddenham, director of the Hemophilia Center at the Royal Free Hospital in London. One patient, a geologist, had a good response at first, but his level of Factor IX has declined to 1 percent of normal, the level at which the disease kicks in.
    
    “We attribute this to the fact that he had an inflammation, and although we treated it promptly, we should have been quicker off the mark,” Dr. Tuddenham said.
    
    The patient cannot be injected again with the same virus because his immune system is now primed to attack it. “He’s very philosophic about it, but he’s a scientist, and his motivation is to help the science,” Dr. Tuddenham said.
    
    Twenty more patients will be treated to assess the best dose of the virus, the goal being the highest dose that does not set off an immune system attack, Dr. Tuddenham said. “We are pretty close to the sweet spot,” he said. If all goes well, a genetic treatment for hemophilia B “could be available for widespread use in a couple of years.”
    
    In a trial in 2006, a patient injected with a corrective gene produced his own Factor IX but only for 10 weeks. The designer of that treatment, Dr. Katherine A. High of Children’s Hospital of Philadelphia, said the new therapy had worked because the delivery virus had been made more efficient and because the research team had treated the patients with steroids to suppress immune system attacks on the virus.
    
    “I think it’s incredibly exciting, and I say that even though these people are my competitors,” she said. Dr. High is listed as a co-author of the report because her laboratory helped monitor the patients and provided proof for regulators that the virus would not insert its human gene into the patients’ sperm and make the change hereditary.
    
    A serious problem with other delivery viruses is that they insert themselves randomly into chromosomes, sometimes disrupting a gene. The virus used by Dr. Nathwani’s team, known as adeno-associated virus-8, generally stays outside the chromosomes, so it should not present this problem. Still, patients will need to be monitored for liver cancer, a small possibility that has been observed in mice.
    
    “I don’t think it’s a showstopper, but it’s a critical safety issue that has to be assessed,” Dr. High said.
    
    Patients have little or no immunity to the adeno-associated virus, which infects rhesus monkeys. The virus has a propensity for making liver cells its target, which is good for the therapy because these cells are the natural producers of Factor IX. However, liver cells do not live forever and slowly replenish themselves, possibly limiting how long the therapy will last.
    
    About 80 percent of hemophilia cases are of the type known as hemophilia A, which is caused by defects in a different blood-clotting agent, Factor VIII. Researchers have focused on hemophilia B, in part, because the Factor IX gene is much smaller and easier to work with.
    
14. Prof. Dollar 7 november 2013 13:52

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    De concurrentie gaat verder. Hier ook:
    www.genengnews.com/gen-news-highlight...
    
15. Tex Mex 8 november 2013 02:02

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    Mooi. Maar het gaat hier niet om gentherapie.
16. Tex Mex 8 november 2013 02:17

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    Volgens mij is in het veld van de gentherapie de concurrentie nog niet zo heel breed als het gaat om hemofilie B. Als het gaat om de markt van recombinant factor IX, nu de standaardtherapie, is de markt veel competitiever. De grotere farmaceuten hebben hier cruciale belangen (en zijn niet erg gebaat bij het slagen van gentherapie, al hebben de recombinant stollingsfactoren ook nog andere indicaties dan alleen in hemofilie patienten).
    
    Op www.clinicaltrials.gov registreer je als medicijnontwikkelaar (commercieel of niet-commercieel) de klinische trials die je op een bepaald moment uitvoert. Voor Amerikaanse studies is dit verplicht. Als een niet-Amerikaanse partij in de USA medicijnonderzoek verricht is hij ook verplicht om dat te registreren. Deze verplichting is er o.a. om het bestaan van deze studies aan patienten kenbaar te maken. Bijkomend doel is dat je als onderzoeker achteraf je vraagstelling niet meer kunt aanpassen aan je resultaten, als blijkt dat de eerder in de studie gestelde eindpunten niet bereikt worden (lees: tegenvallende resultaten). Vanuit wetenschappelijk oogpunt komt het ook sterker over om je studie aan te melden op clinical trials.gov, ook als je als niet-Amerikaanse partij die verplichting niet hebt.
    
    Overigens is het niet verplicht om een fase 1 studie aan te melden, daaropvolgende fases wel.
    
    Momenteel staan er in clinicaltrials.gov (in vergelijking met alle andere studies (>100) naar hemofilie B (slechts) 5 gentherapie studies naar hemofilie B aangemeld:
    
    2004: Safety of a New Type of Treatment Called Gene Transfer for the Treatment of Severe Hemophilia B. Phase 1-2. Doel om 15 patienten te includeren; Terminated 2006.
    Locations: The Children’s hospital of Philadelphia, The hemophilia center of western Pennsylsvania, Stanford University. Sponsor: Avigen.
    
    Dus voortijdig afgebroken. Ik denk om de reden die in bovenstaande post van Bilbo3 door dr. Catherine High wordt geschetst: het ingebrachte gen werkte maar 10 weken.
    
    2007: Gene Transfer for Subjects with Hemophilia B Factor IX Deficiency (AAV2-hFIX). Phase 1. The study is active, but not recruiting participants. Doel inclusie van 9 patienten in 3 groepen van 3 zal dus zijn bereikt.
    Locations: Children’s Hospital of Philadelphia, Hemophilia Center of Western Pennsylvania.
    Laatste statusupdate: oktober 2013. Estimated Primary Completion Date: augustus 2015.
    
    2009: Dose-Escalation Study of A Self Complementary Adeno-Associated Viral Vector For Gene Transfer in Hemophilia B (scAAV 2/8-LP1-hFIXco). Phase 1. Recruiting: doel om 18 patienten (3 groepen van 6) te includeren.
    Locations: Stanford Medical School, St. Jude Children’s Research Hospital, Katharine Dormandy Hemophilia Centre and Haemostasis Unit London. Estimated Primary Completion Date: mei 2014!
    
    Dit is dus de studie waaraan UniQure zijn bijdrage levert. Ik ga er min of meer van uit dat UniQure de AAV-vector levert, al kan ik dat niet met een verwijzing onderbouwen; het gen (niet de vector) wordt mogelijk ingelicenseerd, net als bij Glybera: het gen komt van Xenon Therapeutics in Canada).
    In december 2011 resulteerde deze studie in de publicatie van de resultaten bij de eerste 6 patienten in de NEJM (http://www.nejm.org/doi/full/10.1056/NEJMoa1108046, eerste auteur Nathwani Tuddenham). Aan deze publicatie zullen ook wel enige maanden analyse en schrijfwerk zijn voorafgegaan. Ik weet niet of in de tussentijd de inclusie van de volgende 6 patienten is doorgegaan. Hoe dan ook, in mei 2013 is de status van deze studie door St. Judes nog geupdate in clinicaltrials.gov: er waren toen nog steeds patienten nodig voor inclusie.
    
    Dr. Catherine High wordt overigens ook als een van de co-auteurs van de NEJM publicatie genoemd, maar dit is volgens mij meer een wetenschappelijke courtesy. Vanuit commercieel oogpunt heeft ze juist een heel ander belang (zie Spark Therapeutics).
    
    2012: Hemophilia B Gene Therapy – CCMT at CHOP (= Children’s Hospital of Philadelphia) (AAV8-hFIX19). Phase 1-2. The study is active, recruiting. Doel inclusie: 15 patienten in 3 groepen van 5.
    Locations: The Children’s Hospital of Philadelphia, University of Pittsburgh. Australia: Royal Prince Alfred Hospital, not yet recruiting.
    Laatste statusupdate: oktober 2013. Estimated primary completion date: oktober 2019.
    Dit is volgens mij de studie waar Spark Therapeutics control over genomen heeft. Dr. Catherine High is een van de co-founders van Spark, en hier liggen haar commerciele belangen.
    Zoals Frenky_Tornado op 01-11-2013 op het draadje over de waarde van uniqure suggereert, dat er onderzoek van Spark plaatsvindt met eerder materiaal van AMT/UniQure acht ik onwaarschijnlijk. De enige link die ik naar UniQure kan vinden is het bovengenoemde artikel uit de NEJM uit december 2011, waarvan dr. High co-auteur is. Deze verwijzing op de site van Spark Therapeutics is dus louter een verwijzing naar de wetenschappelijke carriere van de aan Spark verbonden dr. High. In het hierboven door Bilbo3 geposte stuk geeft dr. High ook toe dat ze met haar laboratorium medewerking heeft verleend aan haar competitors.
    
    2012:
    In 2012 kondigde Baxter en Chatham een samenwerkingsverband aan naar gentherapie voor hemofilie B, gebruik makend van platform van Asklepios BioPharmaceutical (AskBio). (http://www.reuters.com/article/2012/06/04/idUS105317+04-Jun-2012+BW20120604). Ook Chatham verwijst naar het stuk uit de NEJM van december 2011: ook (vector)technologie van Chatham is gebruikt in deze studie. Dit kan ik alleen moeilijk rijmen met de veronderstelling dat UniQure de vector levert.
    In Clinicaltrials.gov: Open-Label Single Ascending Dose of Adeno-associated Virus Serotype 8 Factor IX Gene Therapy in Adults With Hemophilia B (AskBio009). Sponsor Asklepios Biopharmaceutical. Phase 1-2. The study is active, recruiting. Inclusie: 16 patienten. Gestart in september 2012, estimated primary comletion date: november 2019.
    Locations: in totaal 12 in de USA, waarvan er momenteel 8 centra ook recruteren.
    Laatste status update: september 2013.
    
    2013: Tot slot, de samenwerking van Fidelity met ReGenX Biosciences (leidend tot Dimension Therapeutics) heeft nog niet geleid tot klinische studies.
    (http://Dimensiontx.com/therapeuticprograms.php).
    
    Ditzelfde ReGenX Biosciences heeft ook de AAV-vectors geleverd voor de studies van het Children’s Hospital of Philadelphia (lees: Spark).
    
    Belangrijkste conclusie wat mij betreft:
    
    Op de korte termijn gaat het tussen UniQure en Spark.
    UniQure is in 2009 gestart met zijn fase 1 (ook dose escalating) studie en verwacht in mei 2014 deze studie te completeren. In mei 2013 was Uniqure nog wel bezig met het recruteren van patienten.
    
    Spark heeft control gekregen over de fase 1-2 studie vanuit Philadelphia, gestart in 2012. Primary completion date oktober 2019. Philadelphia heeft de inclusie van zijn fase 1 studie reeds afgerond, Estimated Primary Completion Date: augustus 2015.
    
    Op de langere termijn zullen er binnen een redelijk grote markt misschien nog enkele partijen bijkomen.
    
17. Prof. Dollar 8 november 2013 10:44

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    quote:

    Tex Mex schreef op 8 november 2013 02:17:

    Dit is dus de studie waaraan UniQure zijn bijdrage levert. Ik ga er min of meer van uit dat UniQure de AAV-vector levert, al kan ik dat niet met een verwijzing onderbouwen; het gen (niet de vector) wordt mogelijk ingelicenseerd, net als bij Glybera: het gen komt van Xenon Therapeutics in Canada).
    

    Tex Mex, bedankt voor het delen van je research.
    
    Kan je hier wat mee?
    www.hemophilia.org/NHFWeb/MainPgs/Mai...
    
    Het bericht stampt uit het AMT tijdperk. In hoeverre de rechten zijn overgegaan naar uniQure is mij niet bekend.
18. Tex Mex 14 november 2013 11:06

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    Graag gedaan en dank voor de link. Heb al geruime tijd met veel waardering de bijdragen van o.a. Prof. Dollar en Ivet gelezen. Derhalve blij dat ik ook een keer een zinnige bijdrage kan leveren aan dit kwalitatief/inhoudelijk goede forum.
    
    Dit was inderdaad de missing link die nog ontbrak in mijn verhaal. Hoewel ik het ook niet zeker weet, lijkt het mij alleszins redelijk om te veronderstellen dat de rechten op de vector zijn mee verhuisd van AMT naar UniQure.
    
    In mei 2014 zou de hemofilie studie volgens clinicaltrials afgerond moeten zijn ('primary completion'). Het zou mooi zijn als dan 180 dagen na verschijnen prospektus t.b.v. IPO mooie resultaten gebracht kunnen worden. Wellicht samen met clinical data met betrekking tot porfyrie, die in 2014 worden verwacht en start clinical trial San Fillipo. De porfyrie trial is overigens niet aangemeld in clinicaltrials.gov, waarschijnlijk omdat het een studie betreft die in Europa wordt uitgevoerd. Maar dat is niet iets voor op het hemofilie draadje...
19. [verwijderd] 14 november 2013 11:55

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    quote:

    Tex Mex schreef op 14 november 2013 11:06:

    Graag gedaan en dank voor de link. Heb al geruime tijd met veel waardering de bijdragen van o.a. Prof. Dollar en Ivet gelezen. Derhalve blij dat ik ook een keer een zinnige bijdrage kan leveren aan dit kwalitatief/inhoudelijk goede forum.
    
    Dit was inderdaad de missing link die nog ontbrak in mijn verhaal. Hoewel ik het ook niet zeker weet, lijkt het mij alleszins redelijk om te veronderstellen dat de rechten op de vector zijn mee verhuisd van AMT naar UniQure.
    
    In mei 2014 zou de hemofilie studie volgens clinicaltrials afgerond moeten zijn ('primary completion'). Het zou mooi zijn als dan 180 dagen na verschijnen prospektus t.b.v. IPO mooie resultaten gebracht kunnen worden. Wellicht samen met clinical data met betrekking tot porfyrie, die in 2014 worden verwacht en start clinical trial San Fillipo. De porfyrie trial is overigens niet aangemeld in clinicaltrials.gov, waarschijnlijk omdat het een studie betreft die in Europa wordt uitgevoerd. Maar dat is niet iets voor op het hemofilie draadje...
    

    de waardering is geheel wederzijds!
    
    Dank voor het compliment, want het valt niet mee voor iemand zonder academische graad bijdragen te leveren aan een forum dat vnl. van academische inhoud en niveau is.
    
    En idd; als in mei gunstige resultaten worden getoond mbt hemofilie, dan maak ik me niet zo druk over de waarde van UniQure na de lockup-periode.
    
    Overigens staat mij dan voor ogen om slechts een gedeelte te verkopen; ik zet het graag voort met een deel dat ik voor langere termijn niet direct nodig heb qua geld. Hoewel ik voor mijn doen relatief veel in UniQure heb zitten, zal ik ook meer spreiding moeten nastreven.
    
    mvg ivet
    
    
20. [verwijderd] 14 november 2013 12:56

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    Even een aanvulling:
    
    Ik heb met Jörn Aldag en Aicha Diba contact gehad en die verzekerden me allebei dat we ons niet ongerust hoeven te maken, hierover.
    
    Ze zijn op de hoogte van alle ontwikkelingen en verzekerden me dat het goed zit.
    
    Groeten,
    
    Frank
21. bilbo3 14 november 2013 14:14

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    inzake reactie texmex, eaarvoor nog mijn dank.
    
    op de site van spark tref ik onderstaand artikel aan:
    de link naar clinicaltrials.gov levert de studie
    2009: Dose-Escalation Study of A Self Complementary Adeno-Associated Viral Vector For Gene Transfer in Hemophilia B (scAAV 2/8-LP1-hFIXco). Phase 1. Recruiting: doel om 18 patienten (3 groepen van 6) te includeren.
    Locations: Stanford Medical School, St. Jude Children’s Research Hospital, Katharine Dormandy Hemophilia Centre and Haemostasis Unit London. Estimated Primary Completion Date: mei 2014!
    op.
    dit is de studie van Uniqure, maar ook sparks verwijst hiernaar. mijn vraag is voor wie zijn de studieresultaten en rechten?
    
    
    Original Article
    
    Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B
    
    Amit C. Nathwani, M.B., Ch.B., Ph.D., Edward G.D. Tuddenham, M.B., B.S., M.D., Savita Rangarajan, M.B., B.S., Cecilia Rosales, Ph.D., Jenny McIntosh, Ph.D., David C. Linch, M.B., B.Chir., Pratima Chowdary, M.B., B.S., Anne Riddell, B.Sc., Arnulfo Jaquilmac Pie, B.S.N., Chris Harrington, B.S.N., James O'Beirne, M.B., B.S., M.D., Keith Smith, M.Sc., John Pasi, M.D., Bertil Glader, M.D., Ph.D., Pradip Rustagi, M.D., Catherine Y.C. Ng, M.S., Mark A. Kay, M.D., Ph.D., Junfang Zhou, M.D., Yunyu Spence, Ph.D., Christopher L. Morton, B.S., James Allay, Ph.D., John Coleman, M.S., Susan Sleep, Ph.D., John M. Cunningham, M.D., Deokumar Srivastava, Ph.D., Etiena Basner-Tschakarjan, M.D., Federico Mingozzi, Ph.D., Katherine A. High, M.D., John T. Gray, Ph.D., Ulrike M. Reiss, M.D., Arthur W. Nienhuis, M.D., and Andrew M. Davidoff, M.D.
    
    N Engl J Med 2011; 365:2357-2365December 22, 2011DOI: 10.1056/NEJMoa1108046
    
    Comments open through December 16, 2011
    
    Share:
    
    
    AbstractArticleReferencesCiting Articles (187) Comments (4)
    
    Background
    
    Hemophilia B, an X-linked disorder, is ideally suited for gene therapy. We investigated the use of a new gene therapy in patients with the disorder.
    
    Full Text of Background...
    
    
    
    Methods
    
    We infused a single dose of a serotype-8–pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) in a peripheral vein in six patients with severe hemophilia B (FIX activity, <1% of normal values). Study participants were enrolled sequentially in one of three cohorts (given a high, intermediate, or low dose of vector), with two participants in each group. Vector was administered without immunosuppressive therapy, and participants were followed for 6 to 16 months.
    
    Full Text of Methods...
    
    
    
    Results
    
    AAV-mediated expression of FIX at 2 to 11% of normal levels was observed in all participants. Four of the six discontinued FIX prophylaxis and remained free of spontaneous hemorrhage; in the other two, the interval between prophylactic injections was increased. Of the two participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid–specific T cells in the peripheral blood; the other had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these two participants received a short course of glucocorticoid therapy, which rapidly normalized aminotransferase levels and maintained FIX levels in the range of 3 to 11% of normal values.
    
    Full Text of Results...
    
    
    
    Conclusions
    
    Peripheral-vein infusion of scAAV2/8-LP1-hFIXco resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. (Funded by the Medical Research Council and others; ClinicalTrials.gov number, NCT00979238.)