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Hemophilia A and B

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  1. Vitavita 25 januari 2017 13:12
    Prof. Dollar 25 jan 2017 om 12:50

    Ergens op de site van uniQure:

    Hemophilia A
    As another indication important to uniQure’s efforts in liver/metabolism, the Company is in pre-clinical evaluation for a gene therapy to treat hemophilia A. We expect to provide an update on this program sometime in the first half of 2017.

    Het is drie maanden geleden alweer niet specifiek benoemd in de corporate review. Ook in de outline key initiatives 2017 is er geen woord aan gewijd. Een slecht voorbode? Niet in staat een groter gen te verpakken? En anderen kunnen dat wel... Dat zou echt een lachertje zijn!
  2. Vitavita 25 januari 2017 13:17
    deel 1

    Biotech is driving hemophilia towards what the experts have termed the ‘precipice of a therapeutic revolution.’ From gene therapy to antibodies, here is the most exciting hemophilia treatment technology that promises to change the lives of patients suffering from the disease within the upcoming years.

    Hemophilia is a genetic disorder that impairs blood clotting. When one of the genes encoding for clotting factors is absent or deficient, a simple injury can turn into a serious health risk. Since these genes are located on the X chromosome, the disease is much more common in males than females. In numbers, the disease afflicts more than 187,000 people worldwide. The most frequent form, hemophilia A, affects the clotting factor VIII in over 150,000 patients. The second, hemophilia B affects over 30,000 people with factor IX deficiency.
    There is currently no cure for hemophilia, once known as the mysterious ‘Royal Disease‘ that monarchs across Europe inherited from Queen Victoria. People living with this disease may require up to 3 infusions per week of clotting factors as a prophylactic therapy, as well as emergency treatment in case of an injury. Still, patients experience repeated bleeding episodes, and in 30% of severe hemophilia A cases, they develop inhibitory antibodies against the recombinant clotting factors that make them unresponsive to the standard hemophilia treatment.

    The biotech industry is changing these circumstances by targeting the hemophilia market, expected to hit €14B by 2024. A number of technologies including therapeutic antibodies, RNAi and cell therapy are fighting to become the go-to treatment; gene therapy might be the first.

    Why Gene Therapy?
    Gene therapy offers the promise of correcting genetic diseases with a one-off treatment by delivering a functional DNA copy, commonly using viral vectors. Of all the diseases out there, many biotechs have decided to focus their gene therapies in hemophilia. To understand why we talked with Matt Kapusta, CEO of uniQure, a Dutch biotech leading its development.

    “It proved to be a strong and relatively easy proof-of-concept indication,” says Kapusta. The key aspects are that the disease is monogenic, drug delivery to the liver is simple, and results are easily measured through well-characterized biomarkers that make measuring results easy.
    For patients and healthcare providers, this technology could significantly reduce expenses. “The cost of the replacement therapy alone, excluding logistics, distribution and nursing care, is between 300k and 400k dollars per year,” says Kapusta. “A product like ours that has demonstrated 6.5 years of durability could save up to $3M.”

    The Biotech Battlefield
    Several biotechs are racing to launch the first gene therapy for hemophilia. Shire, which until recently was leading the race in hemophilia B, dropped its program last year because of inconsistent results. The company is now turning to a new program for hemophilia A using the same technology. This move has placed Spark Therapeutics and uniQure on the lead.

    “We have a very good shot at being the first to market in hemophilia B,” says Kapusta. UniQure is getting ready to start regulatory processes and aims at running a pivotal trial by 2018.
    Traditionally, pharma has gone after the bigger hemophilia A market, leaving hemophilia B for biotechs. In the case of gene therapy, this trend is also based on the molecular biology behind the disease. The gene coding for the factor IX protein is simply smaller than that for factor VIII, and therefore easier to fit in the viral vectors used for gene delivery.

    This has not discouraged biotechs from tackling hemophilia A though, with BioMarin on top as the only company that has reached clinical trials. To overcome the size limit, it has deleted a region from the factor VIII protein that is not necessary for clotting.

    Gene therapy is not a perfect solution, though. In some cases, patients can develop immunity against a particular viral vector or foreign DNA sequences. Bioverativ, a spin-off from Biogen, is trying to circumvent this problem by using lentiviruses, which are less immunogenic and protect the DNA cargo by inserting it the host genome.

    For its part, Sangamo Biosciences has opted for an in vivo genome editing therapy. Its viral vectors also deliver zinc finger nucleases that insert the desired gene in the host genome. However, both strategies have toxicity and mutagenesis risks associated with the insertion of foreign DNA.

  3. Vitavita 25 januari 2017 13:18
    Ditch the Viruses, here comes Cell Therapy
    Promethera wants to get rid of the problems associated with viral vectors and make way for cell therapy instead. CEO John Tchelingerian told us, “pharma companies are starting to understand that viral vectors are not the ‘magic bullet’ to make gene therapies work in the long run.”

    Promethera’s Hepastem technology grows cells from the liver of healthy donors that are then injected into patients with liver disease. Now, the Belgian company is interested in combining Hepastem with genetic constructs to create a safer delivery system.
    “We plan to attract strategic partnerships around our program in hemophilia B, and potentially hemophilia A,” commented Tchelingerian. Although still in early research stage, this hemophilia treatment could make a big difference for patients in which gene therapy does not prove effective.

    What else is out there?
    Since gene therapy is not for everyone and cell carriers are still far from the market, what other options are there to improve hemophilia treatment?

    Sanofi and Alnylam have decided to bid for RNAi therapy. Their candidate fitusiran, which could start Phase III trials soon, blocks the anticoagulant protein antithrombin. However, some are skeptical about the technology after failures from companies like Roche, Merck, Abbott and Alnylam itself.

    Other biotechs like Sobi, Bioverativ or Glycotope are aiming for coagulant factors with an extended half-life, which could reduce dosing and protect patients from spontaneous bleeding. Meanwhile, Apitope is developing a drug that can treat and prevent resistance to coagulant factor infusions in up to 96% of cases.
    But Roche seems to have one of the most promising candidates. ACE910 (emicizumab) is an antibody that mimics the factor VIII protein with a half-life of 4 to 5 weeks that is effective in patients with resistance.

    “Emicizumab is easier, simpler and faster,” Guy Young from the Children’s Hospital Los Angeles told Nature. “I think it has the potential to be transformational for patients – really, truly, life-altering.”

    With these characteristics, the big pharma could bench Novo Nordisk’s NovoEight, a recombinant factor VIII launched in 2014. Although results from clinical trials raised safety concerns, development will continue and according to Bloomberg, the drug could bring Roche over €600M in sales in 2021.

    What’s next?
    Unfortunately, a cure for hemophilia doesn’t still seem feasible yet. “Our gene therapy was never intended to be a cure, which would entail restoring close to 100% of Factor IX activity, and it’s highly unlikely that we or others would get to that level,” admitted uniQure’s CEO, Matt Kapusta. “So we’re trying to transition patients with severe hemophilia to a mild disease.” For patients, this will mean getting rid of frequent infusions and significantly improving their quality of life.

    The sheer numbers of innovative hemophilia treatment hint at a brighter future for patients in the next few years. In the words of Jan Hartmann and Stacy Croteau from Harvard Medical School, “hemophilia is now at the precipice of a therapeutic revolution.”

    According to their paper in the American Journal of Hematology, these innovations “address gaps in our current approach to hemophilia management but do not provide a one-size fits all opportunity.” Therefore, the next step will be individualized treatments where each patient is matched with the most suitable therapy.
  4. Prof. Dollar 25 januari 2017 15:06

    Vitavita schreef op 25 januari 2017 13:48:

    "“We have a very good shot at being the first to market in hemophilia B,” says Kapusta. UniQure is getting ready to start regulatory processes and aims at running a pivotal trial by 2018."

    Licht het aan mij of schiet het echt niet op?
  5. Vitavita 22 december 2017 16:48
    Hemofilie A: allerlaatste letter van het bericht ;-))

    gepubliceerd: 20 december 2017.

    Gentherapie werkt bij hemofilie B

    Onderzoekers van het Erasmus MC zijn er, samen met collega's van drie andere umc's, in geslaagd een gentherapie succesvol te laten werken tegen de bloedingsziekte hemofilie B.

    Gentherapie is een behandeling waarbij een gen of genfragment wordt ingebracht in de lichaamscellen. Zo wordt een fout in het DNA 'gerepareerd'.

    In de Europese studie, geleid door prof. Frank Leebeek van de afdeling Hematologie van het Erasmus MC (foto rechts), zijn een tiental patiënten met hemofilie B behandeld. Zij hoeven zich na de gentherapie niet meer te prikken met stollingsmiddelen. De wetenschappers presenteerden hun bevindingen tijdens het congres van de American Society of Hematology in Atlanta en tevens in het vakblad Blood.

    Frank Leebeek HematologieBloedingen
    Hemofilie B wordt veroorzaakt door het ontbreken van stollingsfactor IX (negen). Door deze stoornis in de stolling krijgen ernstig aangedane patiënten spontane bloedingen, meestal in hun gewrichten en spieren. Die kunnen uiteindelijk leiden tot gewrichtsschade en ernstige invaliditeit.

    Grote belasting
    De huidige behandeling bestaat uit het regelmatig toedienen van stollingsfactoren. Hiermee wordt het aantal bloedingen verminderd, maar kunnen deze nog steeds optreden. Deze behandeling vormt een grote belasting voor de patiënt, die zichzelf levenslang twee tot drie keer per week moet prikken. Bovendien is de therapie zeer kostbaar: zo'n € 200.000 per jaar per patiënt.

    De studie toonde aan dat gentherapie bij patiënten met ernstige hemofilie B leidt tot verhoging van stollingsfactor IX. Daarmee kon het aantal bloedingen sterk worden verminderd. In de studie werden zes van de in totaal tien patiënten behandeld in de hemofiliebehandelcentra van het Erasmus MC, UMCG, AMC of het UMCU. De overige vier kwamen uit Duitsland of Denemarken en zijn behandeld in Duitsland.

    Dosering gen
    Gentherapie vond plaats door gebruik te maken van een aangepast, niet-ziekmakend virus waarin het factor IX gen is ingebouwd. In de studie zijn twee verschillende doseringen toegediend van een AAV-5 virus-FIX gen product (vector), ontwikkeld door uniQure Biopharma te Amsterdam. De toediening gebeurde door een éénmalige infusie van dertig minuten bij tien patiënten.

    Naar de lever
    Het ingebrachte virus ging via de bloedbaan naar de lever, bracht het factor IX gen in de levercellen, waarna het factor IX vervolgens werd aangemaakt. Bij alle patiënten was na de therapie factor IX meetbaar in het bloed (gemiddeld 4,8% bij de lage dosis en 7,2% bij de hoge dosis). Hierdoor traden 90% minder spontane bloedingen op.

    Van de negen patiënten die zichzelf tevoren regelmatig stollingsfactor toedienden, konden acht hiermee stoppen na de gentherapie. De meesten hebben in de laatste negen maanden geen bloedingen meer gehad. Door de gentherapie is een totale kostenbesparing aan stollingsfactoren bereikt van ongeveer € 2 miljoen per jaar.

    De bijwerkingen waren minimaal, berichtten de onderzoekers. Deze bestonden uit milde en tijdelijke leverfunctietest-afwijkingen. Sommige patiënten zijn inmiddels ruim twee jaar na behandeling met stabiele en doorgaande expressie van factor IX.

    Prof. Leebeek concludeert: "Deze baanbrekende experimentele studie toont aan dat gentherapie veilig en werkzaam is voor patiënten met hemofilie B en dat het aantal bloedingen en het gebruik van kostbare stollingsfactoren dankzij de therapie sterk afneemt. We gaan nu in Rotterdam een grotere vervolgstudie doen, met dertig tot veertig patiënten, en ook een studie naar hemofilie A."
  6. Vitavita 22 december 2017 16:55
    - Hemophilia A occurs in 1 in 5,000 live male births. Hemophilia A is about four times as common as hemophilia B. The number of people with hemophilia in the United States is estimated to be about 20,000 individuals.

    - The worldwide incidence of hemophilia is not well known, but estimated at more than 400,000 people. Approximately 75% of people with hemophilia around the world still receive inadequate treatment or have no access to treatment.
  7. Vitavita 15 april 2018 16:11

    Gentherapie, een behandeling die genetisch materiaal van de patiënt verandert, kan veel zorgkosten besparen. Dat zegt Frank Leebeek, hoogleraar binnen het Erasmus MC, in een podcast voor BNR die deel uitmaakt van de serie podcasts ‘Tech & Medicijnen’

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