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Hemofilie B; nog steeds on track?

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[verwijderd] 8 februari 2019 11:20

twitter.com/profmakris/status/1093793...

[verwijderd] 8 februari 2019 13:04

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flosz 8 februari 2019 13:15

Encouraging gene therapy data give uniQure an injection of confidence as it preps PhIII showdown with Spark

Gene therapy company uniQure started the week in style with the news that it’s dosed the first patient in its Phase III trial — a crucial step toward its quest for the best-in-class, first-in-market title in hemophilia B gene therapy. And today it’s offering an update on the kind of mid-stage data it’s armed with.

Mean Factor IX levels hit 38% of normal levels 12 weeks after the three patients tracked in the Phase IIb study received the one-time injection, reaching what the company calls “the normal range” and well above the 12% commonly regarded as sufficient to substantially reduce spontaneous bleeds.

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It’s the first look at data three months post-administration — significant because most patients don’t begin to start plateauing until that point, CEO Matt Kapusta tells me in a preview of the results, which follows an upbeat snapshot in November on six-week data.

So have they reached the peak in FIX levels? Probably not, Kapusta said.

The best way to glean that is we actually did a Phase I/II study with the first generation product that is nearly identical to the AMT-061 and included patients that were at the same dose. […] Of the 9 patients that were off of prophylaxis, 8 of them had Factor IX activity that was higher at 52 weeks or — their latest measurement was higher than what it was at 12 weeks. […] So we don’t know if that will continue to be the case, but that’s probably — looking at those kinetics from the Phase I/II study suggests that there is potential for meaningful increases going forward.

Since the patients began dosing at different times, uniQure also gleaned insights into the (slightly) longer term FIX activities: 48% for the first patient at week 16; 25% for the second patient at week 14; and 51% for the third patient at 12 weeks.

“It’s not unusual to have a three, maybe four-fold multiple between your minimum and your maximum,” Kapusta says. “Here of course we’ve got about a two-fold. So in our view the variability is actually tighter.”

A chief rival of Spark Therapeutics — which is tapping into hemophilia as a follow-up to its groundbreaking gene therapy for the eye — Lexington, MA- and Amsterdam-based uniQure $QURE pleased investors and analysts back in November when it reported mean FIX levels of 31% at six weeks.

While careful to note that “we don’t love commenting on other people’s data,” Kapusta cited the high levels of FIX activity, low immunogenicity — none of uniQure’s patients have required immunosuppression so far — and the fact that it doesn’t exclude patients with pre-existing antibodies to AAV vectors as reasons to believe that they have a “highly comparable if not potentially an optimized or superior target product profile.”

But the real showdown will take place in the pivotal stage, as uniQure catches up with a Phase III program that Spark partner Pfizer began last summer.

With 20 active sites across the US and Europe, uniQure’s Phase III is expected to enroll 50 patients by the end of the year. Top-line data on the primary endpoint — FIX activity after six months — should be ready in late 2020, paving the way for a BLA submission in 2021, Kapusta said.
twitter.com/ambertongpw/status/109384...

flosz 8 februari 2019 13:18

$QURE #EAHAD2019 slides uniqure.com/AMT_061%20EAHAD%20Oral%20...

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flosz 8 februari 2019 13:49

Encouraging gene therapy data give uniQure an injection of confidence as it preps PhIII showdown with Spark twitter.com/ambertongpw/status/109384...

flosz 8 februari 2019 16:48

Uniqure turns the screw on Spark and Pfizer
In the race to develop a haemophilia B gene therapy Uniqure now has the upper hand.
twitter.com/bymadeleinea/status/10938...

flosz 8 februari 2019 19:40

$QURE #EAHAD2019 - Poster - HOPE-B: Study design of a Phase 3 trial of an investigational gene therapy AMT-061 in subjects with severe or moderately severe #HemophiliaB uniqure.com/EAHAD%202019%20-%20Poster...

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flosz 9 februari 2019 00:10

After Earlier Dramatic Gene Therapy Collapse, uniQure's Hemophilia B Therapy Showing Promise twitter.com/biospace/status/109396616...

Vitavita 4 maart 2019 17:37

www.markmanadvisors.com/blog/2019/3/4...

Does Uniqure or Spark Therapeutics own the key patents covering FIX-Padua for hemophilia B?
March 4, 2019, Zachary Silbersher

Uniqure ($QURE) and Spark Therapeutics ($ONCE) are squaring off over who will soon provide the best haemophilia B gene therapy. Uniqure’s stock recently received a boost from positive data from a phase IIb trial. Uniqure’s AMT-061 and Spark’s fidanacogene elaparvovec each remain in clinical trials, while the companies jockey for who will reach the market first, and who will be best in class. Meanwhile, the companies have acknowledged that intellectual property issues may be critical to which drug will come out on top. Will the patent issues cloud either drug’s commercial performance?

Spark, which has partnered with Pfizer ($PFE) for its factor IX drug, recently stated that the intellectual property issues surrounding the drugs appear to be “somewhat confused.” The confusion appears to stem from the fact that both drugs utilize the Padua-variant of Factor IX (FIX-Padua), and both appear to have some claims on the intellectual property rights to use it.

Uniqure has stated that the Padua-variant of Factor IX is “patent-protected.” Uniqure’s prior gene therapy candidate, AMT-060, previously used the wild-type FIX variant. That variant, however, lacked sufficient efficacy, which forced Uniqure to switch to the Padua-variant. To do so, Uniqure announced that it acquired patents that provided protection for the FIX-Padua variant. The patents were acquired from Paolo Simioni, a hemophilia expert from the University of Padua, Italy. Among related EU patents and applications, Uniqure acquired U.S. Patent No. 9,249,405. The assignment of the ‘405 patent to Uniqure has been publicly recorded with the Patent Office.

Meanwhile, Spark appears to have licensed considerable intellectual property that may potentially cover its hemophilia products. This includes several patents from the Children’s Hospital of Pennsylvania that relate to different aspects of FIX, such as a patent application for “modified AAV vectors for delivery of factor IX”; a patent relating to “an adjunct therapy to reduce inhibitory antibodies against factor IX administered via gene therapy”; a patent application related to “certain modifications to a FIX gene that enhances secretion of factor IX”; and an application relating to “modified factor IX expression cassettes.”

Several questions remain, such as, who owns the patent covering the FIX-Padua variant, and can that patent be used to block out its competitor’s drug completely from the market? On the first question, Uniqure has claimed that its ‘405 patent “broadly covers a hyperactive variant of Factor IX carrying an R338L mutation (often referred to as ‘FIX-Padua’) and its use in gene therapy for the treatment of coagulopathies, including hemophilia B.” The ‘405 patent itself claims “a modified recombinant FIX (factor IX) polypeptide comprising at least 70% identity to SEQ ID NO: 2 and a leucine in position 338 of SEQ ID NO: 2.”

Meanwhile, Spark appears to have built up an arsenal of patents that may not necessarily cover the Factor IX variant itself, or as well as the Simioni patent, but may nevertheless cover tangential aspects of FIX gene therapy that Uniqure may stumble upon. The strength of Spark’s licensed patents will depend upon how integral they are to developing a gene therapy for hemophilia B. They may not cover Factor IX itself, but may nevertheless cover core technologies that Uniqure’s AMT-061 cannot design around.

Overall, the patent landscape opens up a number of different scenarios. Technically, both companies may infringe one or more of each other’s patents—thus, creating a scenario where both are entitled to an injunction (or royalties) to each other’s product. Rather than depriving the public of any gene therapy for hemophilia B, this would more likely sooner result in some sort of cross-license that essentially eviscerates the patent issue. They key factor in that scenario will be who has the leverage to demand a royalty from the other.

Alternatively, both companies may be able to design around each other’s patents, thus effectively eviscerating any uncertainty regarding patent issues. This could nevertheless require considerable litigation to untangle and resolve. That could mean several years before any certainty over the patent issues is reached.

At a high level, Uniqure’s ‘405 patent appears to be the relative strongest threat, since it purports to cover a key ingredient in Spark’s proposed therapy. However, several questions remain regarding the strength of this patent. The first one is the breadth of its coverage. As discussed above, the ‘405 patent itself claims “a modified recombinant FIX (factor IX) polypeptide comprising at least 70% identity to SEQ ID NO: 2 and a leucine in position 338 of SEQ ID NO: 2.” There is clearly room here for Spark’s fidanacogene elaparvovec to have designed around. That is essentially a technical question, which we have not investigated, but would be the first question that needs to be addressed to adequately handicap the relative threat to Spark’s drug by Uniqure’s patents.

Another question relates to the validity of the ‘405 patent. Simioni has described his FIX invention as “naturally occurring.” Because of this, Spark has questioned whether the patent is valid, and whether a naturally-occurring mutation can be patent-protected. That question is warranted. Patents covering naturally-occurring phenomena may not comprise “patent eligible” subject matter under Section 101 of the Patent Statute. The line between eligible and ineligible subject matter for patents within the pharmaceutical space remains a dicey and fine one, which continues to be debated at the Federal Circuit, as illustrated by a recent decision (Vanda Pharmaceuticals, Inc. v. West-Ward Pharmaceuticals.). A more thorough analysis of this issue is required to adequately assess the strength of Uniqure’s patent position.

The intellectual-property situation between Unique’s and Spark’s pending hemophilia B drugs remains uncertain. But the company with the right patents may eventually tackle the market, even if not first to market and not best in class. If either of these drugs is a commercial success, expect considerable patent challenges ahead.

flosz 10 mei 2019 14:20

$QURE #HTRSNASTH2019 AMT-061 Phase 2b Poster: mean FIX of 47.1% at 26 weeks!
A Single Infusion of AMT-061 (AAV5-Padua hFIX) is Safe and Effective in Adults with #HemophiliaB: Interim Results from Dose-Confirmation Phase 2b Trial
www.uniqure.com/uniQure%20HTRS-NASTH%...

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pim f 11 mei 2019 20:16

www.streetinsider.com/Corporate+News/...

flosz 24 mei 2019 21:59

How to discuss gene therapy for haemophilia? A patient and physician perspective.
onlinelibrary.wiley.com/doi/pdf/10.11... $QURE $ONCE Freeline etc.
twitter.com/floszcrxl/status/11320123...

flosz 28 mei 2019 10:07

Therapeutic hFIX activity achieved after single AAV5-hFIX treatment in hemophilia B patients and NHPs with pre-existing anti-AAV5 NABs doi.org/10.1016/j.omtm.2019.05.009
Thx. @ Anna twitter.com/ja_majus/status/113327766...

[verwijderd] 4 juni 2019 17:00

6 juli op ISTH 9 maanden FU data van de fase IIb trial:

OC 01.1 - AMT-061 (AAV5-Padua hFIX variant) an Enhanced Vector for Gene Transfer in Adults with Severe or Moderate-Severe Hemophilia B: Follow-up up to 9 Months in a Phase 2b Trial Speaker: Adam Giermasz, United States

flosz 22 juni 2019 01:31

A M T- 0 6 1 ( A A V 5 - P a d u a h F I X variant) an Enhanced Vector for Gene Transfer in Adults with Severe or Moderate- Severe #HemophiliaB: Follow- up up to 9 Months in a Phase 2b Trial

Background : Gene therapy for hemophilia offers the potential of sustained- disease amelioration with a single treatment. AMT- 061 is an investigational gene therapy for hemophilia B comprised of an adeno- associated virus serotype 5 (AAV5) vector containing a codon- optimized Padua variant human factor IX (FIX) gene with liver- specific promoter. Aims : Confirm that a single dose of AMT- 061 will provide a minimum- therapeutic response of FIX activity 6- weeks post- dose in participants with severe or moderate- severe hemophilia B. Methods : Phase 2b, open- label, multi- center trial (NCT03489291) in adult males requiring FIX prophylaxis and without active hepatitis or uncontrolled HIV. Participants were not excluded based on neutralizing antibodies to AAV5. Participants received a single intravenous dose of AMT- 061 (2x10 13 gc/kg) and will be followed for 5- years. The primary endpoint was FIX activity at Week 6. Secondary endpoints include e- diary recordings of bleeds and FIX concentrate use, laboratory parameters, joint health, patient- reported outcomes, and adverse events (AEs). Results : All participants had FIX < 1% (severe FIX deficiency) and had neutralizing activity to AAV5 at baseline. Following AMT- 061 treatment, FIX activity increased rapidly (Figure) and achieved a mean of 31% at Week 6. FIX activity increased further to a mean of 38% at Week 12. As of 13 Dec 2018, FIX activity was 48% at Week 16, 25% at Week 14, and 51% at Week 12 in participants 1- 3, respectively. There were no bleeds post- treatment and no requirement for FIX replacement. Alanine aminotransferase levels did not rise above normal limits after dosing for all participants. One participant experienced 2 mild AEs possibly related to treatment (self- limiting headache and slightly elevated CRP). Updated results to 26- 39 weeks of follow- up will be presented.
$QURE #ISTH2019 onlinelibrary.wiley.com/doi/pdf/10.10... twitter.com/floszcrxl/status/11422115...

Stable Expression of FIX and Maintained Reductions in Bleeding and Factor IX Consumption Following AMT- 060 Gene Therapy with up to 3.5 Years of Follow Up in Adults with Severe or Moderate- Severe #HemophiliaB

Background : Gene therapy aims to provide a long- term therapeutic effect from a single administration, yet knowledge on durability is limited. AMT- 060 is an adeno- associated virus serotype 5 (AAV5) vector with a codon- optimized wildtype human factor IX (FIX) gene and liver- specific promoter studied in 10 participants with severe/ moderate- severe hemophilia B (Phase 1/2 study, NCT02396342). We previously reported up short- term follow- up. Aims : To describe follow- up data for up to 3.5- years post- AMT- 060. Methods : Adult males with FIX activity =2% and a severe bleeding phenotype received a single intravenous infusion of AMT- 060 (5x10 12 gc/kg, Cohort 1, n=5) or (2×10 13 gc/kg, Cohort 2, n=5). Assessments included FIX activity, FIX replacement use, annualized bleeding rate (ABR), treatment- related adverse events (TRAE), vector shedding, immunological and inflammatory biomarkers up to 3.5 years (Cohort 1) and 3 years (Cohort 2).
$QURE #ISTH2019 onlinelibrary.wiley.com/doi/pdf/10.10... twitter.com/floszcrxl/status/11422117...

flosz 6 juli 2019 10:46

Mean FIX of 47.1% at 26 weeks
twitter.com/floszcrxl/status/11268277...

Mean FIX of 45% at 36 weeks
twitter.com/brianhaemophil1/status/11...

flosz 6 juli 2019 11:16

AMT-060
twitter.com/brianhaemophil1/status/11...
twitter.com/brianhaemophil1/status/11...

flosz 6 juli 2019 13:48

$QURE #ISTH2019 AMT-061 Phase 2b
www.uniqure.com/Giermasz_ISTH%202019_...

$QURE #ISTH2019 AMT-060 Phase I/II #HemophiliaB
www.uniqure.com/ISTH%202019%20AMT-060...

flosz 8 juli 2019 18:15

No evidence of germline transmission of vector DNA following intravenous administration of AAV5-hFIX to male mice www.uniqure.com/investors-newsroom/un...

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flosz 8 juli 2019 19:49

Nathwani (UCL/St. Jude, Freeline) showed stable FIX level for 8 years after wild type fix gene therapy in #hemophilia. #ISTH2019 twitter.com/profmakris/status/1147992...
Nathwani summarised the #hemophilia B gene therapy data. Although with the Padua mutant you can get 40% and with wild type 5% the amount of FIX antigen in the two is the same. #ISTH2019 twitter.com/profmakris/status/1147997...

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