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

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flosz 20 augustus 2013 19:42

Orphan conditions with authorized treatments (at least one per condition) are ordered by prevalence (number of patients per 10,000 in the European Union). Analysis from data on file at the European Medicines Agency (EMA; cut-off: November 2012); in situations where a condition was listed more than once (and with varying prevalence), the lowest prevalence was listed. Ultra-rare conditions (the boxed indications in the figure) were defined as having a prevalence of equal to or less than 0.1 per 10,000 persons in the European Union. Lipoprotein lipase deficiency, targeted by Glybera (alipogene tiparvovec), represents the third rarest disease for which a medical treatment has so far been authorized. The pivotal data submitted for these ultra-rare conditions are listed for comparison in Table 1. ALL, acute lymphoblastic leukaemia; CEL, chronic eosinophilic leukaemia; CFTR, cystic fibrosis transmembrane conductance regulator; HPC, haematopoietic progenitor cell; Ph+, Philadelphia chromosome positive; SGCA, subependymal giant cell astrocytoma. *Treatment in patients who require intrathecal analgesia. ‡With platelet-derived growth factor receptor (PDGR) gene rearrangements. §C1 esterase inhibitor deficiency.

Furthermore, surrogate markers for clinical outcome existed for these conditions (Table 1). By contrast, lipoprotein lipase deficiency results in pancreatitis in otherwise often phenotypically healthy individuals — a complication that is not only influenced by various factors including diet, but that also exhibits a much more unpredictable and fluctuating disease course with intermittent healthy periods. Therefore, it would — in theory — be necessary to conduct either a large clinical study enabling for a sufficiently high event rate (which is not feasible for an ultra-rare disease) or a long follow-up in order to detect a sufficient number of events in a smaller patient population (how long would be feasible in a pre-approval situation?). So, to counterbalance the inherent limitations of the clinical database, an approval “under exceptional circumstances”15 with post-approval supplementation of the database was the most appropriate route.

The way forward
In our view, the message to the scientific community is positive: both committees had complementary approaches. They delivered within the spirit of the legislation and took a scientific approach recognizing the rarity of the disease and the difficulties in obtaining comprehensive data. They acknowledged the evolution of science and considered the data as a whole. It is common in science that in borderline situations two experts can reach different conclusions when balancing certainties and uncertainties. However, this balanced and weighted scientific view of both committees, as briefly highlighted here, resulted in a seemingly 'black and white' outcome, as for a regulatory opinion there are only two possible decisions (positive or negative), and only this was visible to the scientific community.

flosz 20 augustus 2013 19:45

During the approval procedure the two committees closely collaborated, and they will continue to strengthen their collaboration based on increasing experience. This will be facilitated by the recent inauguration of the EMA Scientific Coordination Board16, which involves all chairpersons of the EMA committees. We do not agree that this is “the perfect bureaucratic response”17, as it is not another committee that complicates procedures but a body that takes a more strategic and coordinative role under the umbrella of the EMA's missions and visions. Its creation is not a consequence of the Glybera procedure, but a logical step towards the fulfilment of the EMA's goal to ensure efficient operation of its core business — principles that were already published in early 2011 (Ref. 18).

The role of the CAT was recently challenged6, 7, 8, 9, 10, 11, 12, given that the CHMP is required by legislation to make the final opinion. This may be perceived as though the CAT is not heard, or that it lacks the power to foster innovation and create a fruitful environment for its stakeholders to develop and gain the approval of ATMPs. However, this assumption is not only incorrect but also oversimplified. Besides the fact that the CHMP fully supports innovation, the CAT has considerable influence at the early stage of ATMP development, for example, by systematically reviewing and discussing the CHMP's scientific advice procedures for ATMPs, by participating in the innovation task force meetings concerning ATMPs at the EMA, or when issuing certificates on quality and/or non-clinical data. The approach that the legislator had taken when drafting the ATMP regulation was not intended to separate the licensing procedure for ATMPs from that of other human medicines; it would be difficult to explain to patients why an ATMP should have a different standard compared to a conventional medicine, and it would not be helpful to exclude the CHMP's extensive experience of reviewing dossiers including those for drugs targeting rare diseases.

In conclusion, we submit that both committees' deliberations and conclusions illustrate their openness towards innovative approaches to drug development and their willingness to exercise flexibility where scientifically appropriate. The history summarized above also provides a reminder of the regulators' challenge to balance early availability of promising treatments with a need to uphold appropriate standards of evidence, and in borderline situations a different opinion of independent experts can never be fully excluded. We contend that a 'black and white' view of the regulatory procedure for Glybera (or any other similar scenario), as has been expressed in the literature, is not correct; rather, the opinions of the two committees illustrate the shades of grey involved in such procedures and also highlight the shared dedication of the committees to patients and innovation.

www.nature.com/nrd/journal/vaop/ncurr...

Bijlage:

[verwijderd] 20 augustus 2013 22:01

Leesvoer voor de amerikanen!

Prof. Dollar 20 augustus 2013 22:16

@Flosz: Bedankt voor het delen.

@Dr. No: Dat zullen ze ook wel doen. Daarnaast kan uniQure nu ook meer data voorleggen.

BNP 20 augustus 2013 23:20

Allereerst @Flosz, bedankt voor het delen. Nu is mijn Engels wel goed, maar ik vraag het toch liever voor de zekerheid aan jullie.

Als ik het goed begrijp, is het onderwerp van discussie, het feit dat Glyberea eerst is afgewezen, en later toch goedgekeurd. De betrokken commissies leggen uit, dat het soms over de nuances gaat, en dat dit een uitzonderlijk geval betreft.

Verder meen ik ook te lezen, dat binnen een weliswaar kleine populatie, de resultaten uitzonderlijk positief waren met betrekking tot Glybera.

Als mijn Engels ontoereikend is, en mijn conclusie onjuist, dan hoor ik dat graag van jullie.

Prof. Dollar 22 augustus 2013 12:17

@BNP:

"[..] en dat dit een uitzonderlijk geval betreft"
"[..] de resultaten uitzonderlijk positief waren met betrekking tot Glybera."

Uitzonderlijk betekent hier niet "geweldig goed" (mocht je dat zo hebben bedoeld) maar de lastige case die AMT heeft voorgelegd.

AMT heeft namelijk tijdens de review het onderzoek gewijzigd, door te focussen op een (nieuwe) afhankelijke variabele die het effect van Glybera beter zichtbaar zou maken. Daarbij was die variabele (nog) niet gevalideerd, wat zorgende voor nadere analyse, discussie en onderbouwing.
Van de eerste patiënten heeft men geen data van die nieuwe variabele, daarom zagen de commissies graag data van nieuwe patiënten. En dat is lastig omdat de populatie klein is. Alternatief: de huidige patiënten heel lang volgen, maar dat gaat financieel nooit lukken. En wellicht ten koste van patiënten die nooit een oplossing krijgen.

Omdat er geen bijwerkingen zijn en de eerste ervaring van patiënten gunstig besluit men goedkeuring te verlenen onder bijzondere omstandigheden. Het is ook een signaal dat de commissies innovatie willen stimuleren in plaats van te blokkeren. uniQure moet met Glybera flink onderzoek (monitoring) blijven doen.

flosz 30 september 2013 09:06

EMA gives details of new 'future-proof' structure

The European Medicines Agency (EMA) has started a shake-up of its operating structure as it adapts to the evolving demands of its regulatory function.
…..
….
At the time, the EMA noted that a lesson learnt from the Glybera review was that the agency needed to create a more adaptive regulatory framework for new medicines.

..
www.pmlive.com/pharma_news/ema_gives_...

bilbo3 13 oktober 2013 23:27

Vertaling van een actueel russisch artikel.
Wie weet of Van deventer op 11 oktober ergens (en waar) heeft gesproken, hij is namelijk weer wat concreter over Europa (binnenkort) en US (2014.

Irina Mamikonyan
DE DRUG GLIBERA KOSTPRIJS VAN $ 1.600.000 KAN IN RUSLAND VERSCHIJNEN

De drug Glibera kostprijs van $ 1.600.000 kan in Rusland verschijnen
De drug wordt reeds goedgekeurd door de EMA en zal binnenkort beschikbaar zijn op de Europese markt. Het bedrijf is ook van plan om het product in de VS, Canada, Brazilië, Mexico, Pakistan, China, Turkije en de GOS-landen te verkopen.

UniQuro Nederlandse biotechnologie bedrijf is van plan om de drug in Rusland te commercialiseren voor de behandeling van enzymdeficiëntie lipoproteinazy (LPL) - Glibera (Glybera), meldde 11 oktober de wetenschappelijk directeur van Sandre van Deventer verslaggevers bij het Internationaal Symposium van gen-en mobiele technologieën.

De drug wordt reeds goedgekeurd door de EMA en zal binnenkort beschikbaar zijn in de EG. Daarnaast verwacht het bedrijf aan de goedkeuring van de FDA ontvangen en is van plan om de Amerikaanse markt Gliberu in 2014. De kosten van geneesmiddelen (voor eenmalig gebruik) is $ 1.600.000

Enzymdeficientie lipoproteinazy (LPL) wordt gekenmerkt door het feit dat het menselijk lichaam niet optreedt vetmetabolisme, worden opgenomen in het voedsel. De ziekte is een van de wees, en wordt gediagnosticeerd in een of twee personen per 1 miljoen inwoners.

Glibera is gebaseerd op adeno-geassocieerd virus (AAV), dat geïntegreerd is in het genoom van LPL-gen. AAV eigenschap is de mogelijkheid om hun genoom integreren in de gastheercel. LPL wordt voornamelijk gesynthetiseerd in het spierweefsel, waardoor een reeks van enkelvoudige intramusculaire injectie van het geneesmiddel in de dij Glibera kan de vervanging van een defect gen op zijn werkkopie, die in feite de drug vervangt de vervormde gen.

"Hoewel we niet weten hoe lang het medicijn werkt, maar zeker niet minst 5-7 jaar", - zei Deventer. Volgens hem, de kosten vergelijkbaar met de behandeling van drugs substitutietherapie, maar bij ontvangst een injectie Glibery genoeg.

Precies wanneer het geneesmiddel gaat naar de Russische markt - is nog onbekend, maar volgens een topmanager van het Nederlandse bedrijf, heeft uniQuro al een overeenkomst met de Italiaanse Chiesa Farmaceutici SpA, die een kantoor in Moskou heeft ondertekend, op de commercialisering van het geneesmiddel in Rusland, maar ook in Brazilië, Mexico, Pakistan, Turkije, GOS-landen en China.

Deventer eerlijk toegegeven dat hij niet weet wie zal betalen voor de behandeling van LPL in Europa en Rusland. "Elk land heeft zijn eigen aanpak. In de meeste gevallen, het betalen, natuurlijk, de overheid "- besloot hij.

Foto: pharmafile.com

flosz 14 november 2013 15:24

Sept., 2013. PIP: www.ema.europa.eu/docs/en_GB/document...
*************
European Medicines Agency updates on development of its policy on publication and access to clinical-trial data

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

flosz 14 november 2013 16:24

From Mutation Identification to Therapy:
Discovery and Origins of the First Approved
Gene Therapy in the Western World
online.liebertpub.com/doi/pdfplus/10....

flosz 4 april 2015 00:04

2.11.1.1. Glybera MAH: UniQure Biopharma B.V. CAT Rapporteur: E. French
(EMEA/H/C/002145/II/34) Orphan II/34
Scope: submission of final study report AMT011-02
For information: For adoption:
Revised timetable

2.11.2. Other PA Activities
2.11.2.1. Glybera
(EMEA/H/C/002145/S/0039), (alipogene tiparvovec), MAH: UniQure Biopharma B.V. Orphan. Second Annual Reassessment For information:
Updated Rapporteur’s assessment report
For adoption:
Draft Opinion
CHMP Co-ordinator: G. Markey See also 2.11.2.1.
CAT adopted the revised timetable.
CAT Rapporteur: E. French CHMP Co-ordinator: G. Markey PRAC Rapporteur: J. Williams

CAT adopted by consensus the Draft Opinion of the 2nd Annual assessment of Glybera.
Minor changes are introduced in Annex II to update the status of the quality specific obligation (update of the deadline for providing the information on virus safety ).

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

Page4/19

flosz 10 april 2015 11:14

of 3 September 2013
on the acceptance of a modification of an agreed paediatric investigation plan for alipogene tiparvovec (Glybera), (EMEA-000292-PIP01-08-M01) in accordance with Regulation (EC) No 1901/2006 of the European Parliament and of the Council..
Paediatric investigation plan for alipogene tiparvovec
..........
.......
1. Waiver
1.1. Condition: Treatment of hyperchylomicronaemia
The waiver applies to:
• The paediatric population from birth to less than 2 years of age;
• for solution for injection, for intramuscular use;
• on the grounds that the specific medicinal product is likely to be unsafe.

2. Paediatric Investigation Plan
2.1. Condition: Treatment of hyperchylomicronaemia
2.1.1. Indication(s) targeted by the PIP
Treatment of lipoprotein lipase deficiency

2.1.2. Subset(s) of the paediatric population concerned by the paediatric development
From 2 to less than 18 years of age.
2.1.3. Pharmaceutical form(s)
Solution for injection, for intramuscular use

2.1.4. Measures

Non- clinical
Number of measures:5

Study 1: Pharmacology study of a comparison of the level and persistence of lipoprotein expression in young and mature mice
Study 2: Pilot study of biodistribution and germ line transmission in juvenile mice
Study 3: Toxicity and biodistribution study in immature mice
Study 4: Exploratory toxicity/efficacy study in mice and cynomolgus
macaques
Study 5: Juvenile toxicity study in mice

Clinical
Number of measures:2
Study 6: LPLD Registry: observational, multicentre, longitudinal pharmaco-epidemiologic study in lipoprotein lipase-deficient (LPLD) patients, either treated or not treated with alipogene tiparvovec
Study 7: Open label, single dose, uncontrolled trial to evaluate safety and efficacy of alipogene tiparvovec in children from 2 to less than 18 years of age diagnosed with lipoprotein lipase deficiency

3. Follow-up, completion and deferral of PIP
Concerns on potential long term safety and efficacy issues in relation to paediatric use: Yes
Date of completion of the paediatric investigation plan: By December 2021
Deferral for one or more measures contained in the paediatric investigation plan: Yes

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

flosz 10 april 2015 17:04

Duration of Effect of Alipogene Tiparvovec Treatment, Which Was Administered in Other Studies
This study has been terminated.(Business reason)
March 27, 2015
clinicaltrials.gov/ct2/show/NCT01447901

flosz 17 april 2015 13:35

Ter aanvulling post El Gaucho 16-04-2015 21.09u.: www.iex.nl/Forum/Topic/1286603/106/Wa...
www.g-ba.de/downloads/39-261-2233/201...

German regulator puts UniQure gene therapy appraisal on hold
FRANKFURT, April 17 (Reuters) - A German regulator for new drugs has suspended the assessment of the Western world's first gene therapy, UniQure's Glybera, after an adviser to the European drugs watchdog voiced concern over the treatment.

Glybera, designed to treat a very rare blood disease, came with a preliminary price tag of 1.1 million euros ($1.2 million), before standard German drug pricing discounts.

German body G-BA was due to issue an assessment of the drug's benefits by the end of this month but it said late on Thursday it had decided to miss the legal deadline to get more clarity on the drug's benefits.

An adviser for biotech drugs to the European Medicines Agency, a so-called rapporteur, last week said in a report that Glybera, which is marketed by UniQure's unlisted Italian marketing partner Chiesi, lacked efficacy.

"Even if the suspension of the procedure violates the legal deadline, the decision is justified and without alternative," G-BA head Josef Hecken said in a statement.

"Judging from the statements about the rapporteur's report, his findings must be worrisome."

The European Medicines Agency's CHMP committee will consider the rapporteur's report on Glybera at its regular monthly meeting in London next week.

The drug has already had a tortuous journey to market as regulators have struggled to assess its effectiveness because of the very small number of patients available for clinical tests.

The G-BA's verdict on the drug benefits will play a key role in future negotiations about the reimbursement price between the drug companies and Germany's statutory health insurance funds.

Glybera fights a genetic disease called lipoprotein lipase deficiency (LPLD) that clogs the blood with fat.

The medicine was approved in Europe two years ago but its launch was delayed to allow for the collection of six-year follow-up data on its benefits.

www.reuters.com/article/2015/04/17/he...

flosz 20 april 2015 23:14

EMA/CHMP Agenda of meeting to be 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.

• Request for Supplementary information / Opinion : For adoption

P.23

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

bilbo3 20 april 2015 23:26

Dus als ik het goed begrijp, dan komt er een verzoek om nadere informatie.
Of is dit het voorstel om Glybera toch te accepteren?

flosz 20 april 2015 23:51

Nadere informatie imho. Er zijn ook zaken die besproken worden zonder vermelding in deze "openbare" agenda.
Ik weet niet of dit mbt Qure idd. zo is.

Uit post 04-04-2015 00:04U. (Minutes 19/20-02-2015).

Scope: submission of final study report AMT011-02
For information: For adoption:
Revised timetable

Second Annual Reasses2.11.1.1. Glybera MAH: UniQure Biopharma B.V. CAT Rapporteur: E. French
(EMEA/H/C/002145/II/34) Orphan II/34
Scope: submission of final study report AMT011-02
For information: For adoption:
Revised timetable

2.11.2. Other PA Activities
2.11.2.1. Glybera
(EMEA/H/C/002145/S/0039), (alipogene tiparvovec), MAH: UniQure Biopharma B.V. Orphan. Second Annual Reassessment For information:
Updated Rapporteur’s assessment report
For adoption:
Draft Opinion
CHMP Co-ordinator: G. Markey See also 2.11.2.1.
CAT adopted the revised timetable.
CAT Rapporteur: E. French CHMP Co-ordinator: G. Markey PRAC Rapporteur: J. Williams

CAT adopted by consensus the Draft Opinion of the 2nd Annual assessment of Glybera.
Minor changes are introduced in Annex II to update the status of the quality specific obligation (update of the deadline for providing the information on virus safety ).

flosz 23 april 2015 11:44

Publ.d.d. 22-04-2015

Committee for Advanced Therapies (CAT)

Agenda for the meeting on 16-17 April 2015

2.11. Type II Variations

2.11.1. Glybera – alipogene tiparvovec; Orphan; EMA/H/C/002145/II/34

UniQure Biopharma B.V.; Scope: submission of final study report CT-AMT—011-02 Rapporteur: E. French; CHMP Coordinators: G. Markey

Action: for adoption
Document tabled:
RSI

2.11.2. Glybera – alipogene tiparvovec; Orphan; EMA/H/C/002145/II/37-G
UniQure Biopharma B.V.; Scope: PI update section 4.8 and 5.1 (five years FU of final CSR

study 011.01) and FU of 011.3
Rapporteur: E. French; CHMP Coordinators: G. Markey

Action: for adoption
Document tabled:
RSI

2.11.3. Glybera – alipogene tiparvovec; Orphan; EMA/H/C/002145/II/38
UniQure Biopharma B.V.; Scope: PI update section 5.1 (final CSR study 011.05) (FU of

011.03)
Rapporteur: E. French; CHMP Coordinators: G. Markey

Action: for adoption

Document tabled:
RSI
Presentation on regulatory options

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

flosz 5 mei 2015 21:08

On April 8, 2015, uniQure received a copy of a preliminary assessment report on Glybera prepared by the rapporteur designated by the Committee for Advanced Therapies (CAT) of the European Medicines Agency (EMA), which is the committee that advises the Committee for Human Medicinal Products (CHMP) on gene therapies. The preliminary report was a response to the Company’s submission to the EMA on September 5, 2014 of a Type II variation, which proposed an amendment to the Glybera Summary of Product Characteristics (SPC) to reflect certain information from the six-year follow up data included in the Company’s final clinical study report. The preliminary assessment report, which represented the sole view of the rapporteur, stated that Glybera lacked efficacy and therefore the benefit-risk balance was negative. The rapporteur’s preliminary report was provided to the CAT for further discussion in advance of the CAT’s monthly meeting on April 16-17.

On April 24, the Company received a copy of the final assessment report prepared by the CAT and endorsed by the CHMP, which states the following:

“At the April CAT meeting, the CAT discussed the negative rapporteur recommendation on the benefit risk of Glybera. The CAT did not agree with the negative view of the rapporteur and concluded by majority on the following recommendation presented below:

The efficacy of Glybera needs to be considered in its totality as defined in the initial approval taking into account, the criteria considered at time of initial approval.”

In accordance with the Company’s Type II variation request, the CAT will continue to evaluate the six-year follow up data and has requested supplemental information, which the Company is currently preparing.

The Company continues to believe that the clinical data from its Glybera development program, including the six-year follow-up data, support the long-term value and efficacy. However, the Company can provide no assurance regarding the final conclusions of the EMA and G-BA. Any adverse outcomes could require the Company to expend significant additional resources to support its conclusions or could have a material negative impact on the revenue expectations for Glybera.

services.corporate-ir.net/SEC/Documen...

Een PBtje (d.d.24-04-2015) blijft toch moeilijk.....

[verwijderd] 5 mei 2015 21:32

Dit is voor Uniqure op dit moment toch de beste uitkomst?

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