uniQure « Terug naar discussie overzicht

With the approval by the European Commission in November 2012.....

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Omlaag ↓

Prof. Dollar 21 mei 2015 14:33

quote:
invoorentegenspoed schreef op 21 mei 2015 13:22:
als ik als leek het zo vrij mag vertalen: werkzaamheid lastig uit te drukken en verder geen discussie over de veiligheid.
[..]

Eigenlijk hetzelfde mechanisme als met CAT, CHMP en EU. Er is een nieuwe situatie waarop men niet volledig kan terugvallen op een bestaand referentiekader, iemand moet verantwoording nemen (als het fout gaat moet iemand de schuld krijgen) en vervolgens schuiven ze het naar elkaar. Ook nu dekt de G-BA zich in. Dat is politieke besluitvorming. Ideaal is anders, maar dit is prima zo.

[verwijderd] 21 mei 2015 15:19

Waarom geen persbericht van QURE om dit te kaderen?
Nu gaat BLUE de show stelen.
Wellicht morgen als BLUE is uitgeraasd?

flosz 21 mei 2015 16:10

Precies El G.

USA aandeelhouders vragen ook om een reactie van $QURE op de beslissing van de G-BA. Kom op Aicha, zet de PB- machine aan....

anyone know what time to expect $QURE news today? Will decision/discussion details even be released today? cc @srqstockpicker
twitter.com/biomoneytrees

Prof. Dollar 21 mei 2015 16:33

quote:
El Gaucho schreef op 21 mei 2015 15:19:
Waarom geen persbericht van QURE om dit te kaderen?
Nu gaat BLUE de show stelen.
Wellicht morgen als BLUE is uitgeraasd?

Een mooie vraag voor op de AVA. Waarschijnlijk zullen ze zeggen dat vermarkting (en communicatie) bij Chiesi ligt... Ben je ook op de AVA aanwezig?

[verwijderd] 21 mei 2015 16:56

Nee ben niet op de AVA.
Heb wel bij QURE aangedrongen op wat info over GBA in de pers te plaatsen want de kadering die nu wordt gegeven klopt echt niet.

Bijvoorbeeld
$1 million gene therapy drug, world's most expensive, hits snag with cost regulator in Germany that wants more data: ow.ly/NeZTo

Deze tweet klopt echt niet, maar verklaart wel het sentiment. Een gemiste kans m.i. want on balance wordt Glybera wel vergoed voor een jaar.

Maar goed gelijk hebben en gelijk krijgen zijn 2 verschillende dingen.

Ik denk dat we nu de grootste potentieel negatieve zaken hebben gehad, behoudens grote onverwachte gebeurtenissen. De balans van de Bristol Myers Squibb deal en het Celladon debacle plus Glybera achtbaan is een koers van rond de 28 euro en een hoop meer bekendheid van QURE.

Het volume is wel erg laag vandaag. Men weet gewoon niet wat te doen denk ik.

flosz 21 mei 2015 17:06

German cost watchdogs look askance at uniQure's $1.4M gene therapy
www.fiercepharma.com/story/german-cos...

[verwijderd] 21 mei 2015 17:28

Ik blijf mezelf herhalen: wat ook deze club weer 'vergeet' te vermelden is dat Glybera tot die tijd gewoon vergoed wordt. Lang genoeg om ongeveer alle ERNSTIGE patienten die er in Duitsland zijn te behandelen.
Maar goed, het zal wel een keer duidelijk worden. Jammer is dat de negatieve kadering de overhand heeft gekregen en niet meer te corrigeren is.

Ik heb er deze tekst onder geplaatst:
I think what all the above analysis fail to mention is that until June 2016 Glybera will be fully reimbursed at 1,1 million euro per patient. That means that almost all patients can be treated, cause one set of shots does the job. Good news for the patients! And good for uniqure

flosz 21 mei 2015 18:00

See comment: DrMedValue t.co/Br3s02FJxa Glybera $QURE t.co/2B8pWhNuOi

Bijlage:

Prof. Dollar 21 mei 2015 18:17

Uit het jaarverslag:
"The G-BA assessment will be followed by negotiations with the Statutory Health Insurance (SHI) and only at the end of this process will a final price be set."

In combinatie met dit feit:
"Roughly 90 percent of the population in Germany are statutorily insured and entitled to receive benefits to maintain and restore their health."

Vraag ik mij af hoe vlot en voorspoedig die onderhandelingen gaan lopen.

[verwijderd] 21 mei 2015 18:39

Let hierbij op het woordje final.

Je hebt een jaar om te onderhandelen en tot die tijd wordt de prijs die je hebt gezet vergoed. Eventueel moet je verschil tussen final en je eigen prijs terugbetalen, maar omdat je zusatznutzen als orphan drug per definitie positief is kunnen ze de vergoeding niet op 0 euro zetten, dus het terugbetaalrisico is niet al te groot. Een perfect circulaire redenering die de markt niet snapt, maar uniQure ook niet toelicht. En dat is zo jammer.... Maar goed het kwaad is al geschied.

Zo langzamerhand hoop ik wel dat er eens iemand opstaat die me vertelt wat er in mijn redenering niet klopt of me gewoon gelijk geeft. We gaan het zien.

[verwijderd] 21 mei 2015 19:15

In de handel viel mij opnieuw op dat de druk kunstmatig omlaag gericht is...met 300aandelen werd de koers 40 cent lager gezet. Geen actie die bij een particulier past (incidenteel).

Something is cooking IMO

Prof. Dollar 21 mei 2015 19:19

quote:
invoorentegenspoed schreef op 21 mei 2015 19:15:
In de handel viel mij opnieuw op dat de druk kunstmatig omlaag gericht is...met 300aandelen werd de koers 40 cent lager gezet. Geen actie die bij een particulier past (incidenteel).

Something is cooking IMO

Met datzelfde lage aantal gaat het ook omhoog.

flosz 21 mei 2015 19:55

www.deutsche-apotheker-zeitung.de/pol...

Sp.
www.eleconomista.es/empresas-finanzas...

It.
borse.quifinanza.it/News/2015/05/21/s...

flosz 21 mei 2015 21:36

Glybera

Procedural steps taken and scientific information after the authorisation

The CHMP, having reviewed the evidence of compliance with the specific obligations and the impact of the data submitted by the MAH on the benefit/risk profile of the medicinal product, concluded that Marketing Authorisation of Glybera should be varied. Minor changes are introduced to update the status of the quality annex II obligation to update the deadline for providing the information on virus safety up to July 2015.

www.ema.europa.eu/docs/en_GB/document... $QURE

flosz 21 mei 2015 21:46

EMA Issues New Guideline on Gene Therapy
Posted 21 May 2015
By Michael Mezher

The European Medicines Agency (EMA) is seeking feedback on a new draft guideline aimed at clarifying the scientific evidence necessary to support the authorization of new gene therapies.

Background
Gene therapy works by modifying a patient's genes to correct for genetic issues. Researchers have been studying gene therapy for the past 30 years, but few products have reached advanced stages of development. Because so few gene therapies have been submitted for authorization, regulators haven't yet worked out how best to assess them.

In Europe, gene therapies are regulated as advanced therapy medicinal products (ATMPs) under Regulation (EC) No. 1394/2007, and are further defined in Part IV of Annex I to Directive 2001/83/EC. Thus far, EMA has only authorized a single gene therapy, Glybera, which treats a rare condition called lipoprotein lipase deficiency (LPLD).

Regulatory Challenges
As the first authorized gene therapy, Glybera's regulatory path was fraught with challenges. Speaking to Reuters, Tomas Salmonson, then acting chairman of EMA's Committee for Medicinal Products for Human Use (CHMP) said EMA's "established ways of assessing the benefits and risks of Glybera were challenged by … uncertainties associated with data provided."

Glybera was initially given a negative opinion by EMA's Committee on Advanced Therapies (CAT), but after several reexaminations and a request for review by the European Commission (EC), it was eventually authorized under "exceptional circumstances." To maintain Glybera's authorization, its sponsor was required to provide EMA with follow-up data each year and establish a patient registry for long-term monitoring.

Eventually, Amsterdam Molecular Therapeutics (AMT), Glybera's original developer, was liquidated and its assets sold to another company, UniQure. In a circular sent to its shareholders, AMT cited "regulatory setbacks" as a factor in its dissolution.

In April, Regulatory Focusreported that the German Federal Joint Committee (G-BA) had postponed its benefit assessment of Glybera after EMA's rapporteur for Glybera said the therapy lacked efficacy. Since then, CAT has maintained its positive opinion for Glybera, though G-BA announced today it found the additional benefits of Glybera to be "unquantifiable."

New Guideline
EMA's draft Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products is intended to answer questions that might arise during the development of a gene therapy. EMA says it used the lessons learned from its recent experience reviewing gene therapies and providing scientific advice for others in development to develop the draft guideline.

According to the agency, the guideline should help developers of gene therapies that are unfamiliar with regulatory submissions to meet the agency's requirements. Additionally, the draft guideline follows the order of the common technical document (CTD), which should make it easier for companies to follow since they are required to use the CTD when submitting for marketing authorization.

The three main sections of the 42-page document outline considerations companies should take when designing non-clinical and clinical programs, as well as quality considerations that should be made in designing and manufacturing the product itself.

Because gene therapies rely on a biological vector (viral, bacterial, cellular), companies must carefully consider the chosen vector's properties, and maintain "full documentation of the [vector's] origin … history and biological characteristics." Additionally, EMA recommends vectors be "produced from well-characterized bacterial or virus seeds and/or cell banks," which in turn should be qualified and controlled to protect from contamination.

For non-clinical programs, companies should pay careful attention to "potential in vivo effects of the transgene or recombinant nucleic acid sequences, the vector backbone … and of the excipients including any carrier or support medical device employed." When designing non-clinical studies, companies should also ensure they have selected suitable end-points and control groups.

While the same requirements as other medicinal products generally apply to the clinical development of gene therapies, EMA recognizes that there may be cases where adhering to certain guidelines may be impossible. In such cases, companies must be able to justify any deviation from existing clinical requirements.

In place of pharmacokinetic studies, which are not relevant for many gene therapies, other studies should be performed to address the excretion of gene therapies and the risk of them being transmitted to others.

Because of differences in gene therapies compared to traditional pharmaceutical substances, classical dose finding principles may not be applicable. In these cases, EMA says companies should instead establish a "minimal effective dose and a maximum tolerable dose.”

For gene therapies using viral vectors, companies should evaluate the chosen vector for complications that may arise if patients have been previously exposed to the parent virus. Additionally, for therapies that require multiple doses over time, the product should be evaluated for immune response as well to ensure any developed response does not interfere with the product's therapeutic effect.

www.raps.org/Regulatory-Focus/News/20...

Facilitating the development of gene therapies

EMA invites feedback on its new draft guideline

www.ema.europa.eu/ema/index.jsp?curl=...

www.ema.europa.eu/docs/en_GB/document...

flosz 22 mei 2015 10:08

G-BA's Glybera assessment in line with uniQure's expectations

Published on Thursday, May 21, 2015
Germany's Federal Joint Committee (G-BA) issued a final benefit assessment stating that the additional benefit was not quantifiable from gene therapy Glybera alipogene tiparvovec from uniQure N.V.(NASDAQ:QURE) to treat lipoprotein lipase (LPL) deficiency. uniQure chief commercial officer Hans Rohde told BioCentury the decision was in line with the benefit assessment that uniQure had requested and will allow the company to proceed with pricing negotiations in Germany, which are expected to last three to six months. G-BA had postponed its assessment of Glybera earlier this month (see BioCentury Extra, May 7).
"This is what had been requested based on the number of patients we had and the lack of statistically significant data we could provide," he said, adding that uniQure believes the decision will not negatively affect pricing negotiations.

In November, partner Chiesi Farmaceutici S.p.A (Parma, Italy) filed a pricing dossier for Glybera with G-BA that pegged the price of the gene therapy at EUR 1.1 million ($1.4 million) for a 62.5 kg patient (see BioCentury Extra, Nov. 24, 2014).

G-BA will re-evaluate Glybera's benefit on June 1, 2016. The agency did not request specific safety or efficacy data from uniQure. Rather, it will review data already required by EMA on outcomes in patients treated with Glybera.

Glybera is an adeno-associated virus (AAV) vector carrying the lipoprotein lipase (LPL) gene. It was approved in Europe in 2012 to treat LPL deficiency in patients with recurring, acute pancreatitis, a rare disorder. Chiesi expects the first patient in Europe to receive Glybera in mid-2015.

uniQure lost $1.22 to $26.66 on Thursday.

www.biocentury.com/dailynews/company/...

flosz 22 mei 2015 12:10

Clinical efficacy and safety
The clinical efficacy and safety of Glybera has been evaluated in three interventional clinical studies with AAV1-LPLS447X in LPLD subjects.

Two of these clinical trials were preceded by prospective observational studies to assess fasting triglycerides (TG) level and symptoms and signs of LPLD in subjects maintained on a low fat diet. Strict compliance with dietary fat restriction was difficult.

Standard genetic analysis (sequencing) was used in the clinical studies of Glybera. An appropriate CE marked test or full gene sequencing should be used to confirm the diagnosis.

Clinical trial CT-AMT-010-01

AAV1-LPLS447X was administered to 8 LPLD patients in a 12-week, open label dose escalating study (1 x 1011 gc to 3 x 1011 gc per kg body weight i.m.). AAV1-LPLS447X gene therapy was well-tolerated. No drug-related serious adverse events occurred and no dose-limiting toxicity was observed. In half of the subjects a T-cell response to the vector was seen. Compared to pre-administration, a transient and variable reduction in median triglyceride levels was recorded for all patients.

Clinical trial CT-AMT-011-01
The aim of this open label, dose escalating study was to assess the safety profile and reduction of fasting plasma triglyceride (TG) levels after 12 weeks post Glybera administration in 14 LPLD patients. All patients were controlled on low fat diets in the 12-week main study period. The first 2 patients enrolled received a dose of 3 x 1011 gc/kg, the next 4 patients received a dose of 3 x 1011 gc/kg with immunosuppressant regiment (oral ciclosporin and oral mycophenolate mofetil from the day after Glybera administration until Week 12) and the final 8 patients received a dose of 1 x 1012gc/kg with immunosuppressant regiment. Glybera was well tolerated. T-cell responses were seen in roughly half of the patients without clinical sequelae. From the triglyceride data the 1 x 1012 gc/kg dose appears the most optimal.

Clinical trial CT-AMT-011-02
This is an open-label study of alipogene tiparvovec at a fixed dose of 1x1012 gc/ kg body weight administered by a single series of intramuscular injections. Five eligible subjects were included in the study with all subjects receiving alipogene tiparvovec. Subjects also received a daily oral dose of 3 mg/kg/day cyclosporine and 2 g/day of mycophenolate mofetil starting three days before administration of alipogene tiparvovec through week 12. A single intravenous bolus of methylprednisolone (1 mg/kg bodyweight) was given 30 minutes prior to alipogene tiparvovec administration. One patient was diagnosed with pulmonary embolism 7 weeks after therapy. A reduction of triglycerides for up to 12 weeks in some individual patients has been observed. A demonstrable improvement of postprandial CM metabolism was shown in 5/5 patients up to week 14 and in 3/3 patients who were followed up to 52 weeks.

All interventional studies continued into long term follow up studies. The patients in CT-AMT-010-01 have been followed for up to 4 years (n=6) post therapy administration, those in CT-AMT-011-01 for up to 2 years (n=13), and those in CT-AMT-011-02 for up to 1 year (n=1).

flosz 22 mei 2015 12:11

SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES

This being an approval under exceptional circumstances and pursuant to Article 14(8) of Regulation (EC) No 726/2004, the MAH shall conduct, within the stated timeframe, the following measures:

The MAH shall set up a long term surveillance programme/ disease registry to collect information on the epidemiology of the disease and the demographics, safety, and the effectiveness outcomes of patients treated with Glybera.

The registry should be performed according to an agreed protocol.

The patients enrolled in clinical studies (CT-AMT-010-01, CT-AMT 011-01, CT- AMT 011-02) should be followed up in the LPLD registry.

Due date: Before launch of the product in each country

All patients treated with Glybera should be enrolled in the registry and systematic data collection carried out to enrich the database:
1) on efficacy data such as biochemical markers as part of normal practice and frequency and severity of pancreatitis and

2) on safety including immunogenicity against Glybera and LPL. 3) Dietary diary and quality of life data should also be recorded.

The diagnosis of LPLD has to be confirmed by genetic testing. 15 years follow-up is recommended for every patient treated.

Due date: PSUR/ annual reassessment

Assessment of postprandial chylomicron metabolism in at least 12 patients before 12 months and 24 months after treatment with Glybera to be chosen in addition to the patients included in study CT-AMT.011.02; and eight healthy subjects in the second study.

Due date: December 2018/July 2017 for the healthy volunteer study

Assessment of immune response at baseline, 6 months and 12 months in at least 12 newly treated patients.

The studies should be performed according to an agreed protocol.

The studies shall enroll at least 4 subjects per year starting in June 2015.

Results from the study to be reviewed annually.

Re-evaluation of immune responses from all patients enrolled in study CT-AMT- 011-01 by using a validated assay method should also be provided.

The assay to be used in the study needs to be agreed.

Due date: PSUR/ annual reassessment

OBLIGATION TO CONDUCT POST-AUTHORISATION MEASURES The MAH shall complete, within the stated timeframe, the following measures:

To improve the virus safety profile of the product, an additional manufacturing process step should be developed and validated to ensure that the process is capable of inactivating or removing at least the maximal baculovirus load used in production. Ideally, the inactivation or removal capacity of this additional step should be higher than the maximal baculovirus load.

Due date:31.07.2015

www.ema.europa.eu/docs/en_GB/document...

Bijlage:

flosz 22 mei 2015 18:27

Tragende Gründe zum Beschluss des Gemeinsamen Bundesausschusses über eine Änderung der Arzneimittel-Richtlinie (AM-RL):

Anlage XII - Beschlüsse über die Nutzenbewertung von Arzneimitteln mit neuen Wirkstoffen nach § 35a SGB V - Alipogentiparvovec

www.g-ba.de/downloads/40-268-3224/201...

flosz 26 mei 2015 10:59

22-05-2015: Final minutes of meeting held on 20-23 April 2015

Glybera (EMEA/H/C/002145/II/0038), Orphan, (alipogene tiparvovec), MAH: uniQure biopharma B.V., Rapporteur: Elaine French, CHMP Co-ordinator: Greg Markey, “Update of section 5.1 of the SmPC based on the final CSR for Study CT-AMT-011-05, a retrospective clinical records review study undertaken to generate further long-term follow-up data on the incidence and severity of acute pancreatitis episodes in LPLD subjects who previously participated in clinical studies with alipogene tiparvovec or AMT-10.”Request for Supplementary Information adopted on 20.11.2014.
The Committee was updated on the discussions from the April CAT Plenary meeting.
The Committee agreed to the 2nd Request for Supplementary Information as adopted at the CAT together with a specific timetable.

www.ema.europa.eu/docs/en_GB/document...

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