Programs

Glybera^® EU, Lipoprotein Lipase Deficiency

Program: AMT-011, Organ: Muscle

 

We filed Glybera® (alipogene tiparvovec) for LPLD for marketing authorization with the EMA on 23 December 2009 and the EMA commenced its formal review on 20 January 2010. The data package of our dossier of Glybera® now includes three interventional clinical studies conducted in the Netherlands and in Canada, in which a total of 27 LPLD patients were administered the drug. One follow-up study is still ongoing. In one of the studies postprandial chylomicron metabolism was studied. In addition, a case note review study of historical data on hospital presentations due to abdominal pain from 17 patients already treated with Glybera and 5 untreated LPLD patients has been concluded.

In all studies conducted the therapy proved to be well tolerated and no material safety concerns were observed. Importantly, a single administration of Glybera® resulted in a long-term, clinically important reduction in the occurrence of acute pancreatitis episodes – which represent the most debilitating complication of LPLD. The case note review study showed a significant reduction in the frequency of hospital presentations for pancreatitis and severe abdominal pain related to the pancreas. Chylomicron metabolism, poor prior to Glybera administration, proved to be much improved at 14 and 52 weeks after one-time Glybera administration in the subjects tested, indicating sustained LPL activity in blood, which could be taken as a marker of efficacy.

After filing, AMT supplemented the initially submitted data package with additional data which became available in the course of 2010 and 2011. Also, AMT has had multiple meetings with the Committee for Advanced Therapy (CAT) and/or the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMA) since filing. On 23 June 2011, the CHMP adopted a negative opinion, following one such a meeting, and notified AMT that they did not consider Glybera® approvable ‘at this time’. AMT then decided to ask for a re-examination of the clinical data package, and quickly filed an application for this. Also, AMT initiated a study to examine further how already treated patients handle chylomicrons over time; aiming at sharing first results of this study before the end of 2011. Because Glybera is an advanced therapy medicine, it was first assessed by the Committee for Advanced Therapies (CAT). During the re-examination, the CAT concluded that the concerns which led to the earlier negative opinion could be addressed with additional post-marketing studies, and issued a positive recommendation. Whilst the CHMP still considered Glybera to be potentially valuable in the treatment of this very rare disease, it took a different view than the CAT and on October 21, 2011 maintained their recommendation that Glybera should not be granted marketing authorisation.

 

Glybera™ US and Canada, Lipoprotein Lipase Deficiency

Program: AMT-011, Organ: Muscle

Glybera® for LPLD has received orphan drug designation from the regulatory authorities in Europe and the United States. Due to the nature of the underlying disease and its low prevalence we do not expect that a competitive treatment will be developed which could prevent us from getting orphan drug status.

We filed Glybera® (alipogene tiparvovec) for LPLD for marketing authorization with the European Medicines Agency (EMA) on 23 December 2009 and the EMA commenced its formal review on 20 January 2010. The data package of our dossier of Glybera® now includes three interventional clinical studies conducted in the Netherlands and in Canada, in which a total of 27 LPLD patients were administered the drug. One follow-up study is still ongoing. In one of the studies postprandial chylomicron metabolism was studied. In addition, a case note review study of historical data on hospital presentations due to abdominal pain from 17 patients already treated with Glybera and 5 untreated LPLD patients has been concluded.

In all studies conducted the therapy proved to be well tolerated and no material safety concerns were observed. Importantly, a single administration of Glybera® resulted in a long-term, clinically important reduction in the occurrence of acute pancreatitis episodes – which represent the most debilitating complication of LPLD. The case note review study showed a significant reduction in the frequency of hospital presentations for pancreatitis and severe abdominal pain related to the pancreas. Chylomicron metabolism, poor prior to Glybera administration, proved to be much improved at 14 and 52 weeks after one-time Glybera administration, indicating sustained LPL activity in blood, which could be taken as a marker of efficacy.

On June 24, 2011, following one such a meeting, the CHMP notified AMT that they did not consider Glybera® approvable ‘at this time’. After having reviewed and considered the CHMP’s letter and communications, AMT believes that there is an indication from the CHMP that Glybera could receive approval and that the opinion issued in June 2011 was a reflection of insufficient proof of clinical benefit of Glybera as a result of low patient numbers tested for chylomicron handling for at least 12 months post treatment. The CHMP also indicated that if certain additional data from already treated patients would confirm earlier shared results by the end of 2011, an approval may be possible. AMT therefore decided to ask for a re-examination of the clinical data package, and quickly filed an application for this. Also, AMT is initiating a study to examine further how already treated patients handle chylomicrons over time; aiming at sharing first results of this study before year end.

Assuming no unforeseen adverse events or delays, we expect to receive another opinion of the CHMP on our MAA by end of 2011. If the CHMP's opinion is positive, a decision from the European Commission for marketing authorization is expected to follow approximately mid Q1 2012.

We expect that if we are granted marketing authorization in Europe, the authorization granted to us shall be a "marketing authorization based on exceptional circumstances" (see "Government regulation and product approval – General regulation in the European Union – Marketing approval").

Hemophilia B

Program: AMT-060, Organ: Liver

A Phase I/II exploratory clinical trial to assess the safety and efficacy of different doses of hemophilia B gene therapy is being conducted by St. Jude. AMT will build on the outcome of this trial, and is preparing for additional clinical development work to establish safety, tolerability and proof-of-concept with a Factor IX gene therapy produced using AMT’s proprietary production system.

This gene therapy has a huge market and partnering potential as it could replace Factor IX replacement entirely. AMT intends to partner it in the short- to mid-term.

Acute intermittent porphyria

Program: AMT-021, Organ: Liver

AMT has demonstrated that its product results in normalization of the PBGD protein in an animal model of AIP. It completely prevented the occurrence of attacks and significantly ameliorated the neuropathy that develops in untreated mice. AMT’s partner at the Centro de Investigación Médica Aplicada (CIMA) has shown persistence of expression of genes in the liver for more than a year, using AAV-mediated delivery methods similar to AMT-021Patient enrollement in a pre-treatment observational study has commenced and a clinical study with apatient treatment is expected to begin in 2012.

AMT intends to market the product itself.

Parkinson’s Disease

Program: AMT-090, Organ: Brain

PD is a neurodegenerative disorder that affects the sufferer’s motor skills, speech, and other functions so that every action becomes increasingly difficult or eventually impossible. The symptoms are caused by degeneration and death of nerve cells in the specific part of the brain that produces dopamine, a chemical which sends messages in the brain to control movement.

At present, there is no cure for PD, but medications or surgery can provide relief from the symptoms. The most widely used form of treatment is still L-dopa in various forms, which is converted to dopamine in the central nervous system. From previous studies – preclinical and clinical - there is a consistent line of evidence that the infusion of GDNF protein into the brain is effective in PD. GDNF stimulates the formation of dopamine and prevents further degeneration of dopaminergic neurons.

AMT’s aim is to inject recombinant AAVs (Adeno Assosiated Viruses) that carry the gene for GDNF into the brain.

Duchenne Muscular Dystrophy (DMD)

AMT has demonstrated, in a mouse model of the disease, lifetime therapeutic efficacy. More recently, the company has shown successful delivery of this therapy in the heart and skeletal muscles of mice. AMT is further developing the delivery methodology and optimizing the technique for delivering to skeletal muscles using a porcine model. These latest results are expected to be a good predictor for the efficacy of this approach in humans and therefore represent an important value inflection point in the development of this program.

Preclinical studies were performed in collaboration with the Prof. Bozzoni’s group at the University of Rome. AMT intents to commercialize the project itself, but is also flexible to work with suitable partners.

Sanfilippo B

Sanfilippo syndromes are a group of rare lysosomal storage diseases which affect between 1/60,000 to 1/140,000 live births and in which an autosomal recessive genetic defect results in the accumulation of partially degraded oligosaccharides of heparan sulfate. There are four biochemical subtypes of Sanfilippo syndrome (types A to D). SanfilippoB represents about 20% of Sanfilippo cases. Early neurological symptoms are observed usually during the first 5 years of life, leading to a progressive deterioration of cognitive abilities. Affected children require specific care after the age of 6 and progressively develop profound mental retardation with minimal somatic manifestations. Death occurs usually before the age of 15 although some patients do survive beyond the age of 20. There is currently no available treatment for Sanfilippo syndrome.

Together with Prof J.M. Heard (Institut Pasteur, Paris) AMTs’ goal is to develop a gene therapy for SanfilippoB through the introduction of a functional gene into the patients’ brain cells. Proof-of-concept (PoC) for this product was shown recently in two preclinical models (Ellinwood et al, 2011). In parallel to the PoC studies a cGMP compliant process has been established at AMT and an extensive safety and toxicity program has been initiated by Institute Pasteur; based on these results an explorative clinical phase I/II study is expected to be initiated in 2012.

AMT research is focused on the development of cures for rare and most of the time congenital diseases (orphan diseases). Its research efforts will fill an unmet medical need for the treatment in the areas of metabolic disorders, ocular diseases and disorders of the central and peripheral nervous system. In addition, several pre-clinical studies are in progress, which could allow us to target selected non-orphan diseases associated with serious morbidity or high mortality caused by a genetic defect.

Quick Links

Glybera® EU, Lipoprotein Lipase Deficiency
Program: AMT-011, Organ: Muscle

Glybera™ US and Canada, Lipoprotein Lipase Deficiency
Program: AMT-011, Organ: Muscle

Glybera® HLP 5
Program: edit here, Organ: edit here

Hemophilia B
Program: AMT-060, Organ: Liver

Acute intermittent porphyria
Program: AMT-021, Organ: Liver

Parkinson’s Disease
Program: AMT-090, Organ: Brain

Sanfilippo B

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Neither any press announcement nor any other document made available on this website constitutes an offer to sell, an invitation to induce an offer or the solicitation of an offer to acquire, Securities in Amsterdam Molecular Therapeutics (AMT) Holding N.V. or Kairos Therapeutics B.V. and cannot be relied upon for any investment contract or decision. Furthermore, such documents do not constitute a recommendation by Amsterdam Molecular Therapeutics (AMT) Holding N.V. or any other party to sell or buy Securities.

Unless otherwise determined by Amsterdam Molecular Therapeutics (AMT) Holding N.V. and permitted by applicable law and regulation, copies of the contents of the following pages (including documents posted thereon) are not being, and must not be, released or otherwise forwarded, distributed or sent in or into the United States or any other jurisdiction where their extension or availability (and/or any transaction contemplated thereby) would breach any applicable law, and persons receiving such documents (including custodians, nominees and trustees) must not distribute or send them in, into the United States or any other jurisdiction where to do so would breach any applicable law.

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DISCLAIMER – IMPORTANT

THE MATERIALS YOU ARE SEEKING TO ACCESS ARE BEING MADE AVAILABLE ON THIS WEBPAGE BY AMSTERDAM MOLECULAR THERAPEUTICS (AMT) HOLDING N.V. IN GOOD FAITH AND FOR INFORMATION PURPOSES ONLY. THE MATERIALS CONTAINED HEREIN ARE NOT FOR RELEASE, PUBLICATION OR DISTRIBUTION, DIRECTLY OR INDIRECTLY, IN WHOLE OR IN PART, OR DIRECTED AT OR ACCESSIBLE BY PERSONS LOCATED IN THE UNITED STATES OR ANY OTHER JURISDICTION WHERE TO DO SO WOULD CONSTITUTE A VIOLATION OF THE RELEVANT LAWS OR REGULATIONS OF SUCH JURISDICTION.

Please read this notice carefully - it applies to all persons who view this webpage. Please note that the disclaimer set out below may be altered or updated. You should read it in full each time you visit the site.

Non-Dutch persons

Viewing the materials made available on this website may not be lawful in certain jurisdictions. In other jurisdictions, only certain categories of person may be allowed to access such materials. Any person resident outside the Netherlands who wishes to access these materials must first satisfy themselves that they are not subject to any local requirements that prohibit or restrict them from doing so.

The materials made available on this website do not contain, constitute or form part of, and should not be construed as, an offer, or the invitation or solicitation to subscribe for or purchase any securities ("Securities") mentioned in the materials and nothing contained herein shall form the basis of, or be relied on in connection with, any offer or commitment whatsoever.

The Securities have not been (nor will be) registered under the US Securities Act of 1933, as amended (the "US Securities Act"), or the securities laws of any state or other jurisdiction of the United States, and may not be offered, sold, resold, taken up, exercised, renounced, transferred or delivered, directly or indirectly except pursuant to an exemption from, or in a transaction not subject to, the registration requirements of the US Securities Act.

No Securities will be offered or allotted directly or indirectly into, or by use of the mails of, or by any means or instrumentality of interstate or foreign commerce of, or any facilities of a national securities exchange of, the United States, unless an exemption from registration under the US Securities Act, is available. This includes, but is not limited to, facsimile transmission, electronic mail, telephone and the internet. Accordingly, copies of materials made available on this website and any related documents will not and must not be mailed or otherwise transmitted, distributed or forwarded in or into the United States.

The materials contained herein have not been submitted to or reviewed by the US Securities and Exchange Commission (the "SEC") or any state securities commission of any other jurisdiction, and neither the SEC nor any such state securities commission of any other jurisdiction has (a) approved or disapproved, (b) passed upon the merits or fairness of, or (c) passed upon the adequacy or accuracy of the disclosure of any materials contained herein. Any representation to the contrary is a criminal offence in the United States.

If you are not permitted to view materials on this webpage or are in any doubt as to whether you are permitted to view these materials, please exit this webpage.

Basis of access

Access to these materials is being made available on this webpage by Amsterdam Molecular Therapeutics (AMT) Holding N.V. in good faith and for information purposes only. Any person seeking access to this webpage represents and warrants to Amsterdam Molecular Therapeutics (AMT) Holding N.V. that they are doing so for information purposes only.

Neither any press announcement nor any other document made available on this website constitutes an offer to sell, an invitation to induce an offer or the solicitation of an offer to acquire, Securities in Amsterdam Molecular Therapeutics (AMT) Holding N.V. or Kairos Therapeutics B.V. and cannot be relied upon for any investment contract or decision. Furthermore, such documents do not constitute a recommendation by Amsterdam Molecular Therapeutics (AMT) Holding N.V. or any other party to sell or buy Securities.

Unless otherwise determined by Amsterdam Molecular Therapeutics (AMT) Holding N.V. and permitted by applicable law and regulation, copies of the contents of the following pages (including documents posted thereon) are not being, and must not be, released or otherwise forwarded, distributed or sent in or into the United States or any other jurisdiction where their extension or availability (and/or any transaction contemplated thereby) would breach any applicable law, and persons receiving such documents (including custodians, nominees and trustees) must not distribute or send them in, into the United States or any other jurisdiction where to do so would breach any applicable law.

Confirmation of understanding and acceptance of disclaimer

I certify that I am not located in the United States or any other jurisdiction where the release, publication or distribution of these materials would be unlawful.

I have read and understood the disclaimer set out above and agree to be bound by its terms.

I confirm that I am permitted under applicable law and regulation to proceed to the electronic versions of these materials and receive information of the kind contained in this website.