$QURE new product candidate AMT-180, a novel hemophilia A gene therapy that has the potential to treat all hemophilia A patients including those with past and current inhibitors. uniqure.com/R&D%20Day%20Full%20Sl...
Approximately 30 percent of patients with severe hemophilia A will develop an inhibitor that neutralizes the infused Factor VIII (FVIII) activity. This patient population has in the past been excluded from gene therapy approaches in clinical development.
AMT-180 is a one-time, intravenously-administered, AAV5-based gene therapy incorporating a proprietary modified Factor IX gene, Super9™, that has been demonstrated in preclinical studies to circumvent inhibitors to FVIII.
A proof-of-concept study demonstrated that administration of Super9 resulted in clinically relevant FVIII mimetic activity in hemophilia A mice and was not associated with hypercoagulability in wild-type mice.
Another study in non-human primates demonstrated that a single dose of AMT-180 resulted in expression levels that translate into FVIII mimetic activity expected to be clinically relevant in hemophilia A patients with or without inhibitors. In addition, Super9 induced clinically relevant thrombin activation in FVIII-depleted human plasma with or without inhibitors.
These data show that AMT-180 may lead to durable expression in hemophilia A patients and may provide long-term prevention of bleeds.
uniQure incorporates novel synthetic promoter developed by Synpromics in new preclinical target www.synpromics.com/news-media/uniqure...
$QURE #ASGCT19 APRIL29-MAY2,WASHINGTON,D.C. Towards AAV5-Mediated Gene Therapy for Hemophilia A with a Factor IX Variant that Functions Independently of FVIII
Up to approximately 30% of patients with severe hemophilia A develop inhibitors that prevent efficacy of replacement therapies with infused blood coagulation factor VIII (FVIII) products. As a result, these patients are dependent on an on-demand therapy with bypassing agents such as activated prothrombin complex, activated recombinant factor VII, or a bispecific antibody linking FIX(a) to FX(a). Previously developed factor IX (FIX) variants demonstrating cofactor-independent activity are capable of promoting coagulation in the absence of FVIII both in vitro and in vivo. Experiments in hemophilic mice have shown that administration of DNA minicircles encoding these novel FIX variants resulted in FVIII-independent coagulation (Quade-Lyssy et al. J. Thromb. Haemost. 2014). However, the use of DNA minicircles by hydrodynamic injections is not suitable for human application due to the harsh procedure and transient expression of the transgene. T herefore, a powerful approach would be to investigate the feasibility of delivering these FIX variant transgenes using AAV5 vectors. Two FIX variants (FIX-FIAV and FIX-IDAV) were selected, in which four amino acid substitutions lead to their FVIII-independent function. Once activated, these variants most likely negate the requirement for FVIII by resembling the conformation of cofactor-mediated activated FIX (FIXa). In vivo assessments of the AAV vectors were performed in wild-type and hemophilic mice as well as in non-human primates. Administration of the AAV vectors to mice and non-human primates was well-tolerated and did not show possible induction of thrombogenicity following analysis of coagulation activation markers in plasma. Most importantly, the obtained transgene expression levels in the non-human primates will translate to therapeutic meaningful FVIII mimetic activity in patients. Our data support that AAV5 gene therapy development based on a FIX variant is feasible and indicate that therapeutic relevant FVIII mimetic activity could be achieved in hemophilia A patients using this approach.
uniQure Announces New Preclinical Data in Hemophilia A and Fabry Disease in Oral Presentations at the 22nd ASGCT Annual Meeting
LEXINGTON, Mass. and AMSTERDAM, the Netherlands, May 02, 2019 (GLOBE NEWSWIRE) -- uniQure N.V. (NASDAQ: QURE), a leading gene therapy company advancing transformative therapies for patients with severe medical needs, will present today new preclinical data on its gene therapy candidates AMT-180 for the treatment of hemophilia A and AMT-190 for the treatment of Fabry disease. These data will be featured today in back-to-back oral presentations at the 22nd American Society for Gene and Cell Therapy (ASGCT) Annual Meeting in Washington D.C.
AMT-180 for Hemophilia A
Hemophilia A is an X-linked bleeding disorder resulting from a deficiency in coagulation Factor VIII that serves as a cofactor for Factor IX in the activation of the coagulation cascade. About 30 percent of the hemophilia A patient population develops inhibitors to Factor VIII over the course of the disease.
AMT-180 comprises a recombinant AAV5 vector incorporating a proprietary modified Factor IX hat, when activated through normal mechanisms, induces thrombin generation independently of Factor VIII.
Data from multiple in vitro and in vivo studies show that a single intravenous administration of AMT-180 results in dose-dependent, therapeutically meaningful Factor VIII-independent activity as measured by thrombin generation and one-stage clotting assay. AMT-180 is a differentiated approach that is suggested to be hepatocyte-friendly and non-thrombogenic based on the studies conducted to date and is expected to reduce and potentially prevent bleedings in hemophilia A patients with and without inhibitors.
AMT-180 Preclinical Data Findings
Proof-of-concept for AMT-180 was established through studies across two different animal models. The oral presentation at ASGCT features the following data:
Preclinical studies in FVIII-depleted human plasma show that AMT-180 induced clinically relevant thrombin activation, and up to 29% of Factor VIII-independent activity, in plasma with and without inhibitors.
The mechanistic proof-of-concept of AMT-180 was demonstrated in a hemophilia A mouse model, where a single intravenous administration of AMT-180 resulted in sustained, dose-dependent hemostatic effect as measured by one-stage clotting assay.
The studies further demonstrate that AMT-180 shows activation kinetics similar to native FIX and is not hyperactive.
A pilot study in non-human primates demonstrated that a single administration of AMT-180 resulted in sufficient FIX protein expression that translates to clinically relevant Factor VIII-independent activity in humans. No elevation of coagulation activation markers or signs of thrombi formation were observed.
“Data from these preclinical studies show the exciting potential of AMT-180 to provide clinically meaningful Factor VIII-independent activity after a one-time administration.” stated Sander van Deventer, M.D., Ph.D., chief scientific officer at uniQure. “We are particularly encouraged by the broad potential of AMT-180 in treating both patients with and without inhibitors, and the unique approach of AMT-180 that potentially circumvents durability issues because of its hepatocyte-friendly profile.”
$QURE presentation AMT-180 #HemopihiliaA uniqure.com/2019%20ASGCT%20-%20Hemoph...
Prof. Dollar schreef op 28 mei 2019 20:36:
Vandaag heeft BioMarin data voor hun hemofilie A gentherapie bekendgemaakt. De duurzaamheid (de werking op langere termijn) lijkt af te nemen en ze mikken nu op het aantal bloedingen (hoe minder des te beter) als blijk van effectiviteit.
Dit is het mogelijke scenario dat QURE heeft voorspeld en hun heeft aangezet tot een nieuwe benadering. Interessante ontwikkeling. Hopelijk presenteert QURE eind dit jaar nieuwe pre-klinische data en wordt de inhaalmanoeuvre ingezet.
In dit kader nog de volgende opmerking van Hank Fuchs, President Biomarin, gemaakt in een Earnings Call Biomarin, April 25, 2019:
"..Uniqure is out now, passed two years."
BioMarin’s 2019 Stock Gains Erased After Release of Gene Therapy Data
By Josh Nathan-Kazis
May 28, 2019 4:45 p.m. ET
Shares of BioMarin Pharmaceutical , which specializes in cutting-edge gene therapies, fell 5.2% on Tuesday, wiping out its gains for the year, after the company reported data on two studies of a gene therapy it is developing to treat hemophilia A.
Analysts saw good news and bad news in the report. On the one hand, the results were strong enough to allow BioMarin ? (ticker: BMRN) to submit the treatment to regulatory agencies in the U.S. and Europe for approval. On the other hand, the results showed that the long-term efficacy may not be as good as was hoped.
The treatment “doesn’t seem to have the legs to look like a true ‘cure,’ ” Evercore ISI analyst Josh Schimmer wrote in a note out Tuesday.
The back story. BioMarin is an early leader in the gene-therapy field, which seeks to cure chronic and fatal illnesses by altering the genetic makeup of patients. It is one of a number of companies working on gene therapies for use in patients with severe hemophilia A, a condition in which their blood doesn’t clot, putting them at risk of severe or even fatal bleeding.
BioMarin’s drug, called valoctocogene roxaparvovec, is part of two separate clinical studies. Investors have been waiting for updates on the studies, though some analysts have said that the company is in a strong position regardless of the results, as Barron’s reported earlier this month.
The company’s shares were up 4.8% between the start of the year and last Friday. The iShares Nasdaq Biotechnology ETF (IBB) was up 5.6% over the same period.
What’s new. BioMarin reported on both studies of its hemophilia A treatment on Tuesday. On its Phase 1/2 clinical trial, it provided three years of data that it said showed that the drug could improve the quality of life for people with hemophilia A.
“These data confirm that valoctocogene roxaparvovec has the potential to profoundly impact the lives of people with severe hemophilia A through a sustained reduction in bleeds and factor VIII usage,” Hank Fuchs, president of global research and development at BioMarin, said in a statement.
The company also provided an update on its Phase 3 trial of the same drug, saying that it had met criteria to submit the drug to regulators.
Analysts struck balanced tones. Joseph P. Schwartz, an analyst at SVB Leerink, said that the Phase 1/2 results were better than expected, but that the Phase 3 study raised questions, because responses among those patients seemed to be less promising. He said that the company said it was still going over the data. Schwartz reiterated his Outperform rating on the stock.
At Cowen, analyst Phil Nadeau wrote that the drug appeared viable. “Perhaps the key question is [valoctocogene roxaparvovec’s] place in the treatment paradigm,” he wrote. He said that he continues to see the company’s shares as undervalued.
Looking ahead. Interest now turns to the FDA certification process. BioMarin said in a statement that the company would announce the timing for its applications in the last quarter of this year.
Meanwhile, BioMarin shares took a serious body-blow Tuesday—one that doesn’t match the generally measured tone taken by analysts.
“Overall we see [valoctocogene roxaparvovec] as a decent start for gene therapy...and BMRN remains in the pole position for now,” Evercore ISI’s Schimmer said.
Write to Josh Nathan-Kazis
AAV5- mediated Gene Therapy for #HemophiliaA with a Factor IX Variant that Functions Independently of FVIII
Background : Expression of AAV- encoded factor VIII by hepatocytes may not be stable in time and up to approximately 30% of severe hemophilia A patients develop inhibitors that prevent efficacy of replacement therapies with infused blood coagulation factor VIII (FVIII). These patients are dependent on on- demand therapies with bypassing agents e.g. activated prothrombin complex, activated recombinant factor VII, or a bispecific antibody linking FIX(a) to FX(a). Hence there is a need for FVIII- independent approaches in hemophilia A. Previously, factor IX variants have been developed that can promote cofactor- independent coagulation in the absence of FVIII, in vitro and in hemophilic mice upon injection of DNA minicircles (Quade- Lyssy et al. 2014). However, hydrodynamic DNA injections are not suitable for human application due to the harsh procedure and transient expression. Aims : To investigate the feasibility of delivering the FIX variant transgenes using AAV5 vectors. Methods : C57Bl6 mice, FVIII- KO mice and Cynomolgus Macaques were injected with AAV vectors encoding FIX variants at 5x10 13 or 9x10 13 gc/kg. FIX protein and activity levels were determined by ELISA and chromogenic assay. FVIII- independent activity in the FVIII- KO mice was determined using the one stage clotting assay. Thrombotic and liver function markers were measured as well as vector distribution and mRNA expression in different organs. Results : Two FIX variants were selected with four amino acid substitutions leading to their FVIII- independent function. AAV5 vector administration to C57Bl6, FVIII- KO mice and non- human primates was well- tolerated and did not show possible induction of thrombogenicity. FVIII- independent restoration of coagulation was confirmed in the FVIII- KO mice upon AAV delivery of the factor IX mutants. Importantly, the obtained transgene expression levels in the non- human primates will translate to therapeutic meaningful FVIII- independent activity. Conclusions : Our data indicate that development of AAV5 gene therapy based on a FIX variant is feasible and may translate in therapeutic relevant coagulation activity in hemophilia A patients.
$QURE #ISTH2019 onlinelibrary.wiley.com/doi/pdf/10.10... twitter.com/floszcrxl/status/11422118...
Opportunities in Hemophilia Drugs Market by 2019-2026
July 5, 2019 11:11
Global “Hemophilia Drugs Market” Report provides detailed information related to the overall market and value forecast over a period, from 2019 to 2026. The report on Hemophilia Drugs Market also studies the various inhibitors as well as Leaders of the Global Hemophilia Drugs market in both quantitative and qualitative conducts in order to provide precise information to the readers.
Iemand informatie over deze rapport ??
Towards AAV5-mediated Gene Therapy for #HemophiliaA with a Factor IX Variant that functions independently of FVIII www.uniqure.com/investors-newsroom/IS...
Low predicted immunogenicity risk associated with FIX variants that can promote coagulation in the absence of FVIII www.uniqure.com/investors-newsroom/un...
Nathwani discussed the current status of the #hemophilia A gene therapy programs. #ISTH2019 twitter.com/profmakris/status/1147997...
No mention of Freeline's Hem A. Considering his affiliation with the company does it mean their program has been discontinued?
This is the most up to date newsletter about treatments for #haemophilia. It has been produced by the European Haemophilia Consortium @EHC_Haemophilia for use by European national patient organisations twitter.com/profmakris/status/1180970... www.ehc.eu/wp-content/uploads/EHC-New...
#ASH19 $QURE 1110 Evaluation of a Blood Coagulation Factor IX Variant That Functions Independently of Factor VIII As an Alternative Treatment for #HemophiliaA uniqure.com/investors-newsroom/2019.1...
Hemophilia A Gene Therapy, AMT-180, Continues to Show Activity, Safety in Animals
AMT-180 is a gene therapy being developed by uniQure to treat hemophilia A patients, including those with FVIII inhibitors. The therapy uses a harmless adeno-associated virus (AAV) vector, called AAV5, to deliver a modified version of the F9 gene to promote blood clotting independently of FVIII. Normally, FVIII works with factor IX (FIX) to activate blood coagulation.
Earlier preclinical data showed that a single intravenous administration (directly into the bloodstream) of AMT-180 safely led to durable blood clotting activity that was independent of FVIII in animal models of hemophilia A.
New data announced at ASGCT continues to show blood clotting activity with AMT-180 in mice and non-human primates.
The therapy was also well-tolerated in both animal models, and was not associated with an increase in the levels of coagulation activation markers linked to a higher risk of thrombogenicity (formation of blood clots that may block blood circulation).
In addition, findings demonstrated a clear relationship between the RNA levels of the modified FIX and the protein levels found in the animals’ blood. (RNA is the molecule that works as a template for the production of proteins.)
Dose-dependent increases in FIX levels were also observed in non-human primates.
“These data support meaningful hemostasis [ability to stop bleeding] in hemophilia A patients with and without inhibitors following administration with AMT-180,” the investigators wrote.
In a separate presentation, “A Single Administration of AAV5-hFIX in Newborn Juvenile and Adult Mice Leads to Stable hFIX Expression up to 18 Months after Dosing,” company researchers showed that a single dose of AMT-060 (AAV5-hFIX), uniQure’s first-generation gene therapy for hemophilia B, was sufficient to maintain activity of the modified FIX for up to 18 months in mice treated very early in life.
The number of copies of the artificial gene construct found in the animals’ liver remained stable over the entire study, results showed. At the same time, levels and activity of the modified FIX in the animals’ blood were both maintained up to 18 months (the last assessment).
“The question of whether re-treatment will be needed is an important issue in gene therapy. These data show that there was almost no loss of the transduced [genetically-modified] cells following administration of AAV5-hFIX during the life span of the mouse,” Sander van Deventer, MD, PhD, executive vice president, research and product development at uniQure, said in a press release.
“This suggests that the AAV episomes [artificial genetic material] were transferred to daughter cells during cell division — a very important finding in terms of AAV biology and an encouraging sign for the longevity of gene therapy in humans,” van Deventer added.
uniQure also presented new findings from preclinical studies of other two potential gene therapies — AMT-150 for spinocerebellar ataxia type 3 and AMT-190 for Fabry disease.
Direct naar Forum