Blog: MDEX News

April 2008 MDEX News

Mon, 05 May 2008 20:13:27 GMT

Clinical Trials:

AVI 4658, a morpholino antisense oligomer to induce exon 51 skipping.

The first two patients tolerated well the intramuscular injection of the morpholino antisense. Data from these 2 patients were discussed with the Safety Monitoring Committee (SMC) on 11th March 2008 who were pleased with the reports and the lack of any adverse events relating to AVI 4658. However, in line with all studies involving drug manufacturers, outcome data on the current clinical trial is confidential and will not be released until the trial is completed.
Following discussion with the Safety Monitoring Committee and members of the MDEX consortium, it was decided to file some essential protocol amendments ahead of the recruitment of the next patients. These amendments to the protocol are being submitted to the regulatory body MHRA.

AVI BioPharma is in the final phase of submitting an application to MHRA for the systemic exon 51 PMO Trial which will be performed in collaboration with the MDEX consortium.

PTC 124, a small molecule drug taken orally has the potential to treat genetic disorders that carry a nonsense mutation. Approximately 10% of DMD boys carry nonsense mutations. A Phase 2b trial in Europe on DMD and BMD subjects is due to commence later this year. Newcastle, Oswestry and London ICH/GOSH will participate in this trial. All three study centres have site approval from NREC for the trial. PTC Therapeutics held an Investigator meeting in Newcastle on 28-29 February 2008. All three

MDI

Discussions are ongoing between the MDEX consortium and MDI for further funding, preferably involving clinical trials.

TREAT-NMD AON workshop

A workshop to update studies on AON design and systemic delivery will be held between invited scientist of TREAT-NMD and the MDEX consortium on 10th May 2008 at ICH in London.

The Move
The move of the Neuromuscular Unit (NMU) from Imperial College London to the UCL Institute of Child Health (ICH) and GOSH commenced on the 1st December 2007 with Francesco’s appointment with ICH.
All muscle pathology, laboratory researcher and clinical personnel have now moved to the new site.

Francesco’s new contact details are as follows:
Address: Dubowitz Neuromuscular Centre, 1st Floor Institute of Child Health, 30 Guildford Street, London WC1N 1EH.
Tel: 020 7905 2111 Fax: 020 7905 2832 email: f.muntoni@ich.ucl.ac.uk

The standard email format for staff who moved to the ICH is <initial.surname@ich.ucl.ac.uk>

Your comments would be welcome and any news that you would like to include in the May issue should be sent, latest a few days before the end of the month.
Please note my change of email address to k.ganeshaguru@ich.ucl.ac.uk

February 2008 MDEX Newsletter

Thu, 10 Apr 2008 10:17:54 GMT

Welcome to the February 2008 MDEX Newsletter. This monthly Newsletter is intended to update all within the MDEX consortium about news and activities in the past month.

Clinical Trial: AVI 4658, a morpholino antisense oligomer to induce exon 51 skipping.

The second patient who consented in December and injected with the trial drug on 29 January 2008 had the EDB muscle biopsy done on Tuesday 26th 2008. Both the injection of the antisense and the subsequent muscle biopsy were well tolerated. Data from this patient will be presented to the Safety Monitoring Committee (SMC) on 11th March 2008.

Results from the pre assessment studies on a third patient are pending.

A candidate 4th patient will have pre assessment studies done during the first week of March. The study is still actively recruiting patients.

AVI BioPharma has appointed Dr Leslie Hudson as their new Chief Executive Officer (CEO). Dr Hudson received his BSc (Imperial College) and PhD (Middlesex Hospital Medical School) from the University of London. Dr Hudson has already been in touch with Francesco to discuss the status of the current study and future collaborations.

MDI

MDI held a one day information seminar on Advances in Care of DMD in Dublin on Sunday 2nd March 2008. Kate Bushby was one of the invited speakers.

The Move
The move of the Neuromuscular Unit (NMU) from Imperial College London to the Institute of Child Health (ICH), UCL commenced on the 1st December 2007 with Francesco’s appointment with ICH. The first batch of NMU laboratory and associated staff (~seven) moved to ICH on the 14th February 2008.

The second batch comprising a larger proportion of the staff to include lab and clinical personnel will move on the 1st April 2008.

Francesco’s new contact details are as follows:
Address: Dubowitz Neuromuscular Unit, 1st Floor Institute of Child Health, 30 Guildford Street, London WC1N 1EH.
Tel: 020 7905 2111 Fax: 020 7905 2832 email: f.muntoni@ich.ucl.ac.uk

Your comments would be welcome and any news that you would like to include in the March issue should be sent, latest a few days before the end of the month. k.ganeshaguru@imperial.ac.uk

January 2008 MDEX Newsletter

Mon, 04 Feb 2008 14:55:10 GMT

Honours
The chair of the Scientific Advisory Board for the MDEX Consortium Professor Kay Davies has been made a Dame of the British Empire (DBE) in the New Years honours list. Congratulations.

Clinical Trials
AVI 4658
This trial is ACTIVELY recruiting. The first patient who had his IM injection of the trial drug AVI 4658 at St Mary’s Hospital in December 2007 had EDB muscle biopsy on 8 January 2008. A clinical and laboratory report was submitted to the trial Safety Monitoring Committee (SMC) on 18 January 2008. The SMC approved the report and agreed for the trial to proceed to the next patient.

The second patient who consented in December was injected with the trial drug on 29 January 2008 and all seems well.

Pre assessment studies on a third patient were done in mid-January 2008.

There is ongoing discussion with AVI BioPharma on how to structure the planned systemic delivery trial.

PTC124
A Phase 2b efficacy and safety study of PTC124 in subjects with nonsense-mutation-mediated Duchenne and Becker Muscular Dystrophy is planned for multiple centres in Europe. Subject to funding, this may include the MDEX consortium centres in Newcastle and the Institute of Child Health, London. This study is planned to start recruitment in early 2008.

Prosensa systemic 20ME trial for exon 51.
Following the positive outcome of the intramuscular 2OME antisense oligonucleotide study in Holland, Prosensa is planning a systemic trial of the same antisense across several European countries, and TREAT-NMD will be involved in facilitating this study.

Your comments would be welcome and any news that you would like to include in the February issue should be sent, latest a few days before the end of the month. k.ganeshaguru@imperial.ac.uk

December 2007 MDEX Newsletter

Sat, 29 Dec 2007 21:25:05 GMT

Welcome to the December MDEX Newsletter. This monthly Newsletter is intended to update all within the MDEX consortium about news and activities in the past month.

Clinical Trial
The trial is now recruiting. The first patient who consented on October 26th had his IM injection of the trial drug AVI 4658 at St Mary’s Hospital on Tuesday 18th December 2007. All appears to have gone as anticipated. The BBC is following up this patient and filmed the IM injection. They will return to film the biopsy procedure and subsequently the effect that the injection had on dystrophin restoration in the biopsied muscle. There are currently no plans to broadcast.

Informed consent and assent to participate in this trial was obtained from a second patient on 6th December 2007. Pre assessment studies on this patient will be done in mid-January 2008.

Additional two patients have been contacted to discuss possible participation in the trial.

The Move
The move of the Neuromuscular Unit (NMU) from Imperial College London to the Institute of Child Health (ICH), UCL commenced on the 1st December 2007 with Francesco’s appointment with ICH.
Under TUPE regulations, a consultation period of 30 days for the inter university transfer of NMU staff commenced on 7th December. The first batch of NMU laboratory and associated staff will be transferred on the 1st of February 2008.

In agreement with the Head of the Division of Medicine at the Hammersmith Hospital, and the Dean at ICH, the current phase l/ll clinical trial will continue to be conducted under the auspices of Imperial College London.

Francesco’s new contact details are as follows:
Address: Dubowitz Neuromuscular Unit, 1st Floor Institute of Child Health, 30 Guildford Street, London WC1N 1EH.
Tel: 020 7905 2608 Fax: 020 7905 2832 email: f.muntoni@ich.ucl.ac.uk

Wish you a joyous and peaceful festive season
and the very best for 2008

Your comments would be welcome and any news that you would like to include in the January issue should be sent, latest a few days before the end of the month. k.ganeshaguru@imperial.ac.uk

November 2007 MDEX Newsletter

Mon, 10 Dec 2007 21:56:02 GMT

Welcome to the November MDEX Newsletter. This monthly Newsletter is intended to update all within the MDEX consortium about news and activities in the past month.

Clinical Trial
The trial is now recruiting. The first patient who was consented on Friday 29th October 2007 is planned to have the antisense oligomer injected before the end of December. Another patient has been contacted and will attend in early December to discuss possible participation to the trial.

MHRA
MHRA held an Investigator’s interview and an inspection of the laboratory facilities involved in the DMD PMO clinical trial CRO490 at Imperial College London Hammersmith Hospital Campus on 28th and 29th November 2007. The interview and the laboratory inspection centered on various issues relating to the conduct of the trial. The trial team felt that all went well and a report from MHRA will be available in due course.

Representatives of AVI BioPharma (Peter O’Hanley & Janet Christensen) and the MDEX Consortium (Francesco Muntoni, Dominic Wells & Steve Wilton) met with MHRA advisers on 6th November 2007. The meeting was to obtain advice on a proposed application to MHRA by AVI BioPharma for a systemic phase I/IIa clinical trial in DMD patients with the AVI-4658 PMO.

Press Release and BBC Broadcast
The MDEX agreed version of the press release is now available on the Imperial College London and on the Imperial Healthcare NHS Trust websites.
Enquiries by patients and families of affected individuals are still being received following the BBC broadcast on 19th October 2007, to participate in the exon 51 proof of principle phase l/lla clinical trial.

Publication
Congratulations to the Oxford Group on the following DoH funded publication.
Yin H, Lu Q, Wood M; Effective exon skipping and restoration of dystrophin expression by peptide nucleic acid antisense oligonucleotides in mdx mice; Molecular Therapy, advance online publication, October 2007.

PPUK
The 5th International Duchenne Conference (2-4 November 2007) in London UK, organised by PPUK held a round table workshop on the first day for scientists and clinicians to review current trends in research and treatment of DMD. The workshop was successful and Nick indicated that it will be regular feature in future conferences.

MDI
Following their two successful meetings in October (3rd and 18th) MDI will again meet with representatives of their (Irish) government this week.

SAB – MDEX
A joint meeting of the Scientific Advisory Board (SAB) and MDEX Consortium was held on 16th November 2007 at the Muscular Dystrophy Campaign (MDC) headquarters. An update on the science and the clinical trial was presented and discussed.

The Move
The move of the Neuromuscular Unit (NMU) from Imperial College London to the Institute of Child Health (ICH), UCL commences on the 1st December 2007. Francesco’s appointment with ICH is from 1st December with honorary appointments at Imperial College London and Imperial Healthcare NHS Trust until the move is completed in spring of 2008. The NMU laboratories and associated staff will start their move early in 2008 and will be updated on the MDEX monthly newsletter.
The current phase l/ll clinical trial will continue to be conducted under the auspices of Imperial College London.
Francesco’s new contact details are as follows:
Address: Dubowitz Neuromuscular Unit, 1st Floor Institute of Child Health, 30 Guildford Street, London WC1N 1EH.
Tel: 020 7905 2608 Fax: 020 7905 2832 email: f.muntoni@ic.ac.uk

Your comments would be welcome and any news that you would like to include in the December issue should be sent, latest a few days before Christmas. k.ganeshaguru@imperial.ac.uk

October 2007 MDEX Newsletter

Tue, 06 Nov 2007 22:27:05 GMT

Welcome to the October MDEX Newsletter. This monthly Newsletter is intended to update all within the MDEX consortium about news and activities in the past month.

Clinical Trial Authorisation
The last hurdle before the clinical trial has now been cleared. The clinical trial is now declared open on the Clinicaltrials.gov website. The first patient was consented on Friday 29th October 2007 and is currently undergoing the preparatory work to confirm his eligibility for the trial. This include re-confirmation of the mutation, growing skin fibroblasts for MyoD transfection and antisense oligos challenge, neuropsychiatry evaluation and echocardiography, which are ongoing.

MHRA
An Investigator’s interview and an inspection of the laboratory facilities involved in the DMD AO clinical trial CRO490 at Imperial College is planned by MHRA for the 28th and 29th November 2007. The interview and the laboratory inspection will centre on various issues relating to the conduct of the trial.

BBC News Broadcast and Press Release
Fergus Walsh the BBC Science Correspondent interviewed Francesco in the NMU, followed with an interview of one of the patient and family. These interviews and additional material about the forthcoming Clinical Trial was broadcast on BBC News at 6 and 10pm, BBC News 24 and Radio 4 on Friday 19th October 2007. A video of the broadcast was available on the BBC website. There was also a press release. We received over 50 enquiries from families and friends of affected individuals in the UK and abroad after the broadcast. All enquiries were responded with a copy of the Q&A and the clinicaltrials.gov website.

PPUK
The 5th International Duchenne Conference organised by PPUK (nick@ppuk.org) will be held on the weekend of 2-4 November 2007 at the Holiday Inn Bloomsbury, Coram Street, London WC1N 1HT. Visit the PPUK website www.ppuk.org for an agenda and other details. PPUK has organised a forum for young adults with DMD to meet the clinicians and scientists who will attend this meeting and discuss in detail implications and expectations related to the antisense trial strategy.

MDI
MDI had two successful meetings in October (3rd and 18th) with representatives of their (Irish) government. The government have agreed "in principle" to the funding for a trial and have said they are looking into it in detail; it was also commented that the precise mechanisms by which Irish patients could participate to such a trial and how much to involve the local structures requires further discussion. Their local politician has offered to ask a parliamentary question in the Dail (equivalent of the House of Commons) as to what exactly "agreed in principle” means. Members of MDI will be at the PPUK conference and will consult with members of the MDEX Consortium.

Your comments would be welcome and any news that you would like to include in the October issue should be sent, latest a few days before the end of the month to k.ganeshaguru@imperial.ac.uk

September 2007 MDEX Newsletter

Thu, 11 Oct 2007 18:55:01 GMT

Clinical Trial Authorisation

last hurdle before the clinical trials has now been cleared. Due to the postal strike, a FAX copy of the final approval from MHRA was received on Friday 5th October 2007. Congratulations to all. The clinical trial is now open.

Patient Recruitment

We have continued to recruit children for the preparatory studies, subject to authorisation from MHRA (now received), in which further information on the preservation of the foot muscles is obtained with muscle imaging (MRI) and the efficacy of the antisense to allow dystrophin production is tested in cultured skin cells, which are “forced” to become muscle cells following transfection with a viral vector. During this month (September), one patient has attended the Hammersmith Hospital for these preparatory studies. Clinical Research Governance Office Staff from the Clinical Research Governance Office of Imperial College London conducted a mock inspection of facilities that will be associated with the AON trials on Wednesday 5th September 2007. The facilities inspected include the Pharmacy and the Clinical Research Unit at St Mary’s Hospital where injection of the AON will be carried out and the offices in the Paediatrics Department, Hammersmith House, Hammersmith Hospital where documentation from the trial will be stored. Their report concluded ‘Overall the study is well organised and the team knowledgeable and enthusiastic’.

PPUK

The 5th International Duchenne Conference organised by PPUK (nick@ppuk.org) will be held on the weekend of 2-4 November 2007 at the Holiday Inn Bloomsbury, Coram Street, London WC1N 1HT. Visit the PPUK website www.ppuk.org for an agenda and other details. PPUK has organised a forum for young adults with DMD to meet the clinicians and scientists who will attend this meeting and discuss in detail implications and expectations related to the antisense trial strategy.

MDI

Jimmy Mooney and his colleagues at Muscular Dystrophy Ireland have secured a meeting with their Junior Minister for Health for the 3rd of October 2007 to discuss funding for DMD to be included in their government budget in December 2007. Francesco and others have provided MDI with an update of the forthcoming clinical trial and an appraisal of future studies. A further meeting is scheduled for 18th October 2007

Publication

An epub version of the following manuscript was published in Human Gene Therapy 18, 798-810 (September 2007)Comparative analysis of antisense oligonucleotide sequence for targeted skipping of exon 51 during dystrophin pre-mRNA splicing in human muscle.Arechavala-Gomeza V, Graham IR, Adams AM, Popplewell LJ, Aartsma-Rus A, Kinali M, Morgan JE, van Deutekom JC, Wilton SD, Dickson G, Muntoni F. Your comments would be welcome and any news that you would like to include in the October issue should be sent, latest a few days before the end of the month to k.ganeshaguru@imperial.ac.uk

August 2007 MDEX Newsletter

Thu, 11 Oct 2007 18:53:00 GMT

GTAC

Following the request of a protocol modification from MHRA (information on contraception and amendment of one inaccuracy), a revised version was deposited with GTAC in July. Final approval from GTAC was received on 14th August 2007.

MHRA

Following the request from MHRA of a protocol modification and additional information from AVI-Bio Pharma, a revised version of the protocol was deposited also to MHRA in July, together with the relevant additional information from AVI-Bio Pharma. At the time of writing, final approval from MHRA is awaited and should arrive at the beginning of September.

Clinical Research Governance Office

Staff from the Clinical Research Governance Office will conduct a mock inspection of facilities that will be associated with the AON trials on Wednesday 5th September 2007. The facilities to be inspected include the Clinical Research Unit and the Pharmacy at St Mary’s Hospital where injection of the AON will be carried out and the offices in the Paediatrics Department, Hammersmith House, Hammersmith Hospital where documentation from the trial will be stored.

The month of August

Many are away during the month of August and consequently there is less to report on the activities of the various groups. This is also reflected on the many ‘out of office’ responses that are received during this month! Patient recruitment for preparatory studies has also been affected by the holiday season. Come September, we hope normal activities will resume. Your comments would be welcome and any news that you would like to include in the August issue should be sent, latest a few days before the end of the month to k.ganeshaguru@imperial.ac.uk

July 2007 MDEX Newsletter

Thu, 11 Oct 2007 08:29:43 GMT

MHRA

We are still waiting for MHRA to respond with a final letter of acceptance to our resubmission of the 27.06.07. Their requests are technical information on the shipping and preparation of the morpholino from USA to London and this has now been provided by AVI Biopharma and the UK Importer.

Patient Recruitment

Recruitment of patients to the trial has not yet been initiated as it can only start after MHRA has allowed the study to be opened. However we are continuing to recruit children for the preparatory studies, in which further information on the preservation of the foot muscles is obtained with muscle imaging (MRI) and the efficacy of the antisense to allow dystrophin production is tested in cultured skin cells, which are “forced” to become muscle cells following transfection with a viral vector. During this month (July), four patients have attended the Hammersmith Hospital for these preparatory studies.

Clinical Trial Nurse

A part-time clinical trial nurse, Laurrelle Hugh-Carre has been appointed for the AON Phase l/ll Clinical Trial at the Hammersmith Hospital. She will help the path of patients recruited both into the preparatory studies and the subsequent clinical trial.

Staff News Congratulations to Drs Jennifer Morgan and Susan Brown, both in the Dubowitz Neuromuscular Centre, Hammersmith Hospital Campus on their elevation as Readers at Imperial College. The group celebrated the promotions with a dinner on 23.07.07.

AVI BioPharma Devon Stage, Clinical Trials Project Manager from AVI BioPharma, Portland, USA visited the Hammersmith Hospital on 23-24 July. She provided training on GCP, recording on CRF and other aspects on clinical trials to Laurrelle and Guru. She also visited the Clinical Research Unit at St Mary’s Hospital.

TREAT-NMDA workshop-meeting on ‘Outcome measures for experimental studies in Duchenne Muscular Dystrophy’ was held in Naarden (Amsterdam), The Netherlands on 30.06.07 – 01.07.07. A report on this meeting can be found on http://www.treat-nmd.eu/assets/documents/TREAT-NMD_CoI_newsletter_No13.pdf Your comments would be welcome and any news that you would like to include in the August issue should be sent, latest a few days before the end of the month to k.ganeshaguru@imperial.ac.uk

June 2007 MDEX Newsletter

Thu, 11 Oct 2007 08:10:25 GMT

Meeting of the MDEX Consortium

The quarterly meeting of the MDEX consortium was held in the morning of Tuesday the 12th of June. The members of the consortium welcomed the newly appointed Dr K Ganeshaguru (Guru), who will work as a project coordinator in collaboration with Dr Jenny Versnel.Towards the end of the meeting external charities joined the meeting and Mr Jimmy Mooney, from Muscular Dystrophy Ireland was appraised of the progress of the study but also about the potential to recruit children from Ireland at later stages of the study. MDI is funding a particular aspect of the laboratory research which is taking place in Prof George Dickson and Dr Wood laboratories, and he presented Professor Dickson with a cheque relative to the next study period.

Scientific Advisory Board (SAB) meeting

The quarterly SAB meeting was held on Tuesday 12th June 2007 at the MDC site. The various groups updated their progress on their sciences for the past quarter**. This was followed by a teleconference with AVI (Janet Rose Christensen) in Portland, USA. Various aspects of AVI’s participation in MDEX consortium studies were discussed, and in particular the status of the submission of documents to MHRA for the study approval was discussed. Members of SAB appeared to be satisfied with the response from AVI.(** conclusions to be included in the quarterly minutes)

MHRA

A letter of acceptance (subject to submission of 2 documents & minor changes in the trial protocol) for the Phase l/ll trials with AVI-4658 was received on 22.06.07. Congratulations to all involved in this application and best wishes with the trial outcome. The 2 requested documents have now been submitted to MHRA (27.06.07).

Patient Recruitment

As soon as the trial will be declared open, patients will be contacted for the pre-trial assessment and consent. A part-time administrator to assist with the recruitment of patients at the Hammersmith Hospital has been selected and will be in post soon.

Publications

The following manuscript was sent and acceptance for publication (subject to minor reviews) was received on 25.06.07 from the Journal Human Gene Therapy. Comparative analysis of antisense oligonucleotide sequence for targeted skipping of exon 51 during dystrophin pre-mRNA splicing in human muscle. Arechavala-Gomeza V, Graham IR, Adams AM, Popplewell LJ, Aartsma-Rus A, Kinali M, Morgan JE, van Deutekom JC, Wilton SD, Dickson G, Muntoni F.

TREAT-NMD

A workshop-meeting on ‘Outcome measures for experimental studies in Duchenne Muscular Dystrophy’ will be held in Naarden (Amsterdam), The Netherlands this week-end (30.06.07 – 01.07.07). Attendees from the MDEX consortium are Francesco Muntoni, Kate Bushby, Volker Straub, Serge Braun and Dominic Wells. Your comments would be welcome and any news that you would like to include in the July issue should be sent latest a few days before the end of the month to k.ganeshaguru@imperial.ac.uk