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MLD Gene Therapy San Raffaele

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May 2019 – US & EU approval application dates

Recent Publications About MLD Gene Therapy

June 2016 - Hospital Exemptions, EU Orphan Drug Status

April 2015 - PI/II Expansion Recruiting Completed

December 2014 - 6 More Patients to Be Recruited

October 2014 - Filing for Trial Amendment - Hope to more treat more patients

September 2014 - PI/II trial recruiting closed, GSK exercises gene therapy technology option, no compassionate access

December 2013 - GSK's gene therapy option - exercise update

October 2013 - Recruiting update

July 2013 - Gene Therapy Clinical Trial update (exciting 3 year post therapy reports)

Video interviews with the trial Principal Investigators - What is gene therapy?, how is it being applied to MLD?, etc.

March 2013 - Gene Therapy Clinical Trial update (2 year post therapy reports - Jan 2012)

January 2012 - Gene Therapy Clinical Trial update (1 year post therapy informal reports)

GlaxoSmithKline (GSK) Collaboration (Oct 2010)

Gene Therapy with HSCT Phase I/II Clinical Trial launches (March 2010)

Orchard Therapeutics announces target US FDA gene therapy registration date

Orchard Therapeutics has made their first formal public announcement of a target US registration date. The EU filing is targeted for 1H 2020 with the US filing about a year later, 1H-mid 2021. Registration starts the formal approval process by the FDA, EMA, and various individual EU country regulatory agencies. See their press release here.

Recent Publications

Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial The Lancet Jun 2016 Maria Sessa · Laura Lorioli · Francesca Fumagalli · [...] · Alessandra Biffi

Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy
Science Jun 2103 Alessandra Biffi · Eugenio Montini · Laura Lorioli · [...] · Luigi Naldini

EU Orphan Drug Designation secured by TIGET in 2007, EU/3/07/446.

Update June 2016 - Hospital Exemptions – pre-symptomatic infantiles

The formal clinical trial is full recruited. During this period of assessment and monitoring San Rafaelle is offering a Hospital Exemption for pre-symptomatic infantiles. This is somewhat like a compassionate access program where, as we understand it, San Rafaelle covers the direct medical expenses but the family is responsible for all travel, lodging and perhaps indirect medical expenses.

No symptomatic patients nor are any juveniles being accepted under the current Hospital Exemption.

Update April 2015 - Expansion Recruiting is complete ... no current trial openings

Recruiting is currently closed for the expanded Phase I/II Gene Therapy trial. A total of 20 patients have been recruited.

As per the trial definition, the 2-year outcome data is being studied as patients reach that milestone to assess results and prepare for a Phase II/III trial or whatever additional studies are warranted. Many of the trial patients have already reached the 2 year milestone.

We know the researchers and trial sponsors are anxious to make the therapy available outside of Milano, including into the US, however, no formal statements have been made about the next steps or timing. We have invited Dr. Biffi to our July MLD Family Conference™ to give us, and the attending families, an update and to answer questions.

A MLD Foundation meeting with GSK in December 2014 indicated continued strong involvement by GSK in the current research underway in Milano, internal efforts to understand how to scale the vector manufacturing to additional sites, a desire to better serve more patients in other countries and at new sites, agreement to more actively partner with MLD Foundation to keep the MLD community updated, and an internal focus to expedite whatever further studies and registrations are required by the various regulatory agencies based on the Phase I/II results to date.

Update December 2014 - Trial Expanded to Add 6 More Patients

The Phase I/II trial has been expanded to add 6 more patients, bringing the total to be treated to 20. Recruiting is underway now with a number of the slots already filled.

Update October 2014 - Filing Trial Amendment - Hope to more treat more patients

We have been told that the San Raffaele Gene Therapy team is submitting a protocol amendment that, if approved, may allow them to treat additional patients under the Phase I/II guidelines. This amendment must be approved by the Italian authorities before any patients can be formally enrolled.

As you might expect, patients are currently seeking evaluation to be considered if/when the trial re-opens. These patients may be required to re-qualify to meet inclusion criteria when they begin therapy.

We are seeking additional clarity with regard to whether this is a trial extension or if this is a Compassionate Access program. We are also asking about funding for this expansion. If the therapy is part of a trial expansion the costs will likely be covered by the researchers, however, if this is a Compassionate Access program a significant financial burden will be the patient's responsibility.

The San Raffaele team has confirmed the final Phase I/II clinical trial patient under the current protocol will be transplanted later this month.

Update September 2014 - Updates, PI/II trial recruiting closed, PI/III trial recruiting is not open, GSK exercises option, no compassionate access

We continue to keep in close contact with both the Milano/San Raffaele and GSK research teams. Earlier this year in a very low key way, GSK publicly conveyed their execution of the gene therapy technology option. Having visited Milano twice in the last year, we can vouch that GSK has been working very closely with the San Raffaele researchers on the current and next phases of the trial.

The San Raffaele team has reported the Phase I/II clinical trial is fully populated with the last patient de-identified and schedule for transplant early fall 2014.

Results reported by the families that have loved ones participating in the trial so far are quite encouraging. We must caution that some data is up to 4 years old, while other is much more recent. The only formally released scientific analysis was at the two year point of the first 3 MLD patients (see July 2013, below). This is a trial and there is much data to be analyzed and published.

Since the involvement of GSK, to our knowledge, there has been no more compassionate access.

There is no formal word from GSK or the San Raffaele team about the start of Phase II/III and the reopening of recruiting. While the researchers are currently inviting families to be evaluated in Milano, they cannot make any commitments about trial participation, and if you are considering such a visit you should be aware that your loved one will have to be re-assessed and meet all trial inclusion criteria when trial recruiting opens. That means that if your loved one seems to meet an arbitrary set of criteria today, he/she may not when the trial recruiting starts.

We are requesting (fall 2014) a meeting with the GSK development team, under non-disclosure agreement, to try to optimize the Phase II/III trial design and subsequent FDA registration to benefit families.

We will keep you posted on any and all progress and information from Milano.

Update December 2013 - update on GSK exercise of gene therapy option

No formal announcement has been made by GlaxoSmithKline or the San Raffaele Telethon Institute with regard to the recent deadline for GSK to exercise its option on the gene therapy.

Update October 2013 - update on recruiting

We have been advised that there is one more pre-symptomatic late infantile slot open in the trial. We are working to help recruit for that candidate.

Update July 2013 - preliminary therapy results (2 year outcome data published for 3 patients)

Data on 6 patients treated over the past 3 years with this gene therapy are reported to have had "significant improvement". This mirrors the outcomes that have been reported directly by families.

In all six children, replacing a broken gene with a normal one "completely prevented the onset or the progression of the disease," said Dr. Naldini. "Three years after the start of the clinical trial the results obtained from the first six patients are very encouraging: the therapy is not only safe, but also effective and able to change the clinical history of these severe diseases." Dr. Naldini is Scientific Director of the San Raffaele Telethon Institute for Gene Therapy and Professor of Cell and Tissue Biology and Gene and Cell Therapy at the “Vita Salute San Raffaele” University School of Medicine, Milan, Italy. He has been working on, and pioneered the use of, these vectors for gene therapy over the past 12 years.

The team transplanted the final Phase I/II MLD patient earlier this year so it will be a several years before the entire Phase I/II studies are completed and results are published, but it is our hope, and the desire of the researchers, that the Phase II/III trial start by the end of the year based on the Phase I/II preliminary data.

As best we know, GSK has until October to exercise their option to further develop the therapy. This funding is key to covering the costs of an expanded trial with more patients involved.

You can read articles reporting on the research at the links below . The formal journal Science report is by subscription only. Please note that while the results so far are very promising the term "cure" used in these articles is premature and inappropriate (in our opinion). The doctors are saying "very promising", it's the press that's getting carried away with "cure". This report is from data from 3 pre-symptomatic MLD patients - we have a long ways to go (winter 2016) to get to data from all trial participants and after that (Phase II/III perhaps) for data on early symptomatic patients.

Science Magazine - Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy (abstract of the formal article on the gene therapy)

Telethon Foundation - The HIV Virus Used To Cure Two Severe Genetic Diseases
Wall Street Journal - De-fanged HIV Shows Promise in Gene Therapy
International Business Times - Aids Virus Used to Cure Severe Genetic Diseases
IB Times - HIV Cured 6 Children Suffering Two Crippling Diseases...

We are often asked about concerns that the use of a HIV vector might give someone HIV. This is not the case. They are not using the actual AIDS/HIV virus, only the aggressive vector that transports the virus to the rest of the body, specifically in MLD's case past the blood brain barrier into the brain. The bad stuff specific to HIV is removed from the vector and replaced with the enzyme protein that is needed to prevent MLD. There is no risk of getting HIV, but they are carefully monitoring the vector to make sure it doesn't have any long term negative affects on the patient.

Update March 2013

MLD Foundation visited Dr. Biffi and Dr. Naldini at the San Raffaele Institute in Milano and we are pleased to report that recruiting of the full Phase I/II trial cohort of 8 was achieved with the last transplant occurring mid-March 2013. A small compassionate access cohort is being recruited while the last patients progress through the 2-year assessment in March 2015. The results to date look good, but the observations are early and limited. Initial trial families are very encouraged by what they see in their children.

At year 2 post-therapy GMFM skills, residual ARSA activity, and long-term lentiviral-vector safety are the key observations. The initial three trial participants have reached this two year point. The trial investigators are preparing to publish results on these three participants.

Please note the collaboration with GSK has milestones and options that GSK may execute. This will be key to funding and launching the Phase II/III follow-on trial.

Video interviews with the Principal Investigators

Check out the detailed video interview by MLD Foundation with Dr. Biffi about the trial and its medical science.
A follow-on interview was made with Dr. Biffi in March 2010 just as the gene therapy trial was launching.



The trial coordinators produced a promotional video (Jan 2012).


Here is an pictorial explanation of the therapy:

Telethon has provided some other resources, including a history of the development of their gene therapy that dates to 1995 here:
Fondazione Telethon resources & Information

Gene Therapy Clinical Trial update - January 2012

We have been told by the researchers that all of the the trial participants are all doing well. Enrollment for the trial has been slower than expected.

Also, we have been informally told by trial participants the following apparently good news. It is premature to draw any scientific or statistically valid conclusions, but the insight is worth considering:

  • Patient 1 is approximately 18 months post-transplant and one parent told another that he was making improvement in motor skills and speech (as observed last summer on his anniversary date)
  • Patient 2 will be one year post transplant on February 17th. He is "a normal 2-year old" according to mom but they are awaiting 4 more months which is the date his older sibling had onset of notable symptoms (he is not showing any early signs).
  • Patient 3 will be one year post transplant approx. February 24th
  • There are two other who have been transplanted - we do not know those dates.

Again, it is premature to draw any conclusions - but we remain encouraged by this therapy.

Telethon & San Raffaele Announce GSK Collaboration

Oct 2010, GlaxoSmithKline PLC (GSK), Fondazione Telethon and Fondazione San Raffaele today announced a new strategic alliance to research and develop novel treatments to address rare genetic disorders, using gene therapy carried out on stem cells taken from the patient's bone marrow (ex vivo). The alliance capitalizes on research performed at the San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), a joint venture between Fondazione Telethon and Fondazione San Raffaele established since 1995.

Fondazione Telethon will receive an upfront 10 million euro payment from GSK and is eligible to receive further payments upon successful completion of a number of predetermined development milestones.

GSK will co-develop with Fondazione Telethon and Fondazione San Raffaele, six further applications of ex vivo stem cell therapy, the first of these will be metachromatic leukodystrophy (MLD). Read the press release here.

Gene Therapy with HSCT Phase I/II Clinical Trial - Now Recruiting!

A Gene Therapy with HSCT Phase I/II Clinical Trial started recruiting in late March 2010. The protocol uses the patient's own genetically modified hematopoietic stem cells to increase ARSA production to 10-15x the normal rate. This super-production in the blood is to offset the reduced number of cells that typically cross the blood brain barrier.

Gene therapy is based on the principle that every illness caused by gene defect can be cured by inserting, through viral vectors, a functional copy of the gene in the sick cells of the patient. In the case of the MLD, it is problematic to insert the functional gene in the sick cells of the central and peripheral nervous system for the inaccessibility of these organs. It is, however, possible, by using appropriate gene transfer systems, to correct in a stable way hematopoietic cells that can transport then the functional enzyme to the affected nervous system.

What is ex vivo gene therapy? Replacing faults in stem cells has been practiced for more than 40 years, in the form of donor hematopoietic stem cell (HSC) transplants (bone marrow transplants). However such transplants rely on stem cells taken from an immune matched, or closely related, donor, which is not always available. There is always a risk of graft rejection but this is particularly high when matched donors cannot be found. This ex vivo gene therapy transfers the corrected gene to the patient's own stem cells. The patient's own HSCs are harvested from their body, 'healthy' copies of the gene are inserted into the cell using a modified viral vector and the cells are re-introduced to the patient.

Because the technique uses the patient's own cells there is much less risk of immune rejection compared to a bone marrow transplant. The reintroduction process is similar to the historical transplantation of hematopoietic cells from healthy donors, but since it uses the patient's own cells - an autologous transplant - it is hoped to be a less risky and more effective alternative.

Click here to see a video interview with Dr. Alessandra Biffi, Principal Investigator for the Clinical Trial.

Trial Status - July 2010
One pre-symptomatic late infantile has been transplanted to date. He is progressing well but it is too soon to know if there are any indications of efficacy..

Trial Center
The study will take place in Milano (Milan) Italy. 8 MLD patients are being recruited. The study is a Phase I /I I with a requirement from the Italian authorities to show efficacy.

The recruitment of the patients is international. All costs of patients and families participating in the study will be paid by HSR-TIGET.

Inclusion Criteria

  • Late infantile MLD in pre-symptomatic phase (usually identified because of an older affected sibling)
  • Early juvenile MLD in pre-symptomatic phase or within the first 6 months from the onset of the symptoms.
  • No prior therapies stem cell transplant, ERT, etc.)

Trial Period & Follow Up
The post-transplant follow-up will be performed at regular intervals for 3 years with 5 more years of formal post-trial study.

Protocol Summary

  • Bone marrow extraction from the patient of the patient
  • Isolation of the stem cells to be submitted to gene transfer
  • Manipulation of the stem cells ARSA production capability with the lentiviral vector
  • Minimal patient conditioning with Busulfan (GVHD is greatly reduced due to re-implantation of patient's own cells)
  • Re-infusion of the manipulated stem cells

Primary efficacy end points are an improvement or stability in the motor performances assessed by the "Gross Motor Function Measure, GMFM" 24 months after the treatment, in comparison to the scores obtained in a cohort of untreated patients of peer age, and a significant increase of the ARSA activity in the patients' hematopoietic cells measured 24 months after the treatment, in comparison to the pre-treatment values.

Principal Investigators

  • Dr. Alessandra Biffi, Project Leader at HSR-TIGET & Staff Pediatrician in Pediatric Immunohematology and Bone Marrow Transplant Unit at HSR.+39-02-2643-4678/4681 FAX:+39-02-2643-4668
  • Dr. Maria Sessa, Project Leader at HSR-TIGET & Staff Neurologist at HSR (also a member of MLD Foundation's Medical & Scientific Advisory Board). +39-02-2643-2755 FAX:+39-02-26432951

HSR-TIGET ... San Raffaele Institute
HSR-TIGET was funded in 1995 as joint- venture among the Scientific Institute San Raffaele and the Telethon Foundation for the research and treatment of rare genetic diseases. Main goal of the Institute is to be a center of excellence in all the phases of the research from basic to clinical gene and cellular therapy, from the experimentation of new therapeutic strategies in the animal models of disease up to their clinical testing in the patients.

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