Lenti-D ALD 104
Research type
Research Study
Full title
A Phase 3 Study of Lenti-D Drug Product After Myeloablative Conditioning Using Busulfan and Fludarabine in Subjects ≤17 Years of Age With Cerebral Adrenoleukodystrophy (CALD)
IRAS ID
254448
Contact name
Laura Whicher
Contact email
Sponsor organisation
bluebird bio inc
Eudract number
2018-001145-14
Duration of Study in the UK
3 years, 9 months, 27 days
Research summary
Research Summary
This is an international, non randomized,open label, multisite,single dose study designed to evaluate the efficacy and safety of Lenti-D drug product after myeloablative conditioning with busulfan and fludarabine in boys with Cerebral AdrenoLeukodystrophy (CALD).
CALD is a rare X-linked genetic disease caused by a malfunctioning gene called ABCD1. The ABCD1 gene is responsible for producing a protein called adrenoleukodystrophy protein (ALDP). Boys with CALD either do not have this protein in their body or have a protein that does not work well. This malfunction leads to the buildup of very long chain fatty acids (VLCFAs) in the body, particularly in the brain. These fatty acids cause severe damage to brain cells.Subjects who have just been diagnosed and do not have any symptoms will be eligible to enter the study. They will undergo Hematopoietic Stem Cells (HSC) mobilization mediated by Granulocyte-Colony Stimulating Factor (G-CSF,either filgrastim or lenograstim) and plerixafor, and stem cells will be harvested by apheresis using institutional practice guidelines. The harvested cells will then be transduced by the lenti-D lentivirus to insert a functioning ABCD1 gene (Lenti-D drug product).
Once the Lenti-D drug product is made available at the clinical site the subject will undergo myeloablation with busulfan IV and fludarabine IV and then Lenti-D Drug Product will be administered by IV infusion through a central venous catheter. During this treatment phase the subjects will be hospitalised until they show engraftment. After the Lenti-D drug product infusion subjects will be followed-up for 2 years. During this follow-up period the subjects will come to the hospitals every 3 months to undergo, when applicable, neurological evaluation, brain MRI, neuropsychological tests and blood tests.The study will be conducted in several hospitals in Europe and in the US and a total of approximately 20 patients will be treated.
This is an international, non randomized,open label, multisite,single dose study designed to evaluate the efficacy and safety of Lenti-D drug product after myeloablative conditioning with busulfan and fludarabine in boys with Cerebral AdrenoLeukodystrophy (CALD).
CALD is a rare X-linked genetic disease caused by a malfunctioning gene called ABCD1. The ABCD1 gene is responsible for producing a protein called adrenoleukodystrophy protein (ALDP). Boys with CALD either do not have this protein in their body or have a protein that does not work well. This malfunction leads to the buildup of very long chain fatty acids (VLCFAs) in the body, particularly in the brain. These fatty acids cause severe damage to brain cells.Subjects who have just been diagnosed and do not have any symptoms will be eligible to enter the study. They will undergo Hematopoietic Stem Cells (HSC) mobilization mediated by Granulocyte-Colony Stimulating Factor (G-CSF,either filgrastim or lenograstim) and plerixafor, and stem cells will be harvested by apheresis using institutional practice guidelines. The harvested cells will then be transduced by the lenti-D lentivirus to insert a functioning ABCD1 gene (Lenti-D drug product).
Once the Lenti-D drug product is made available at the clinical site the subject will undergo myeloablation with busulfan IV and fludarabine IV and then Lenti-D Drug Product will be administered by IV infusion through a central venous catheter. During this treatment phase the subjects will be hospitalised until they show engraftment. After the Lenti-D drug product infusion subjects will be followed-up for 2 years. During this follow-up period the subjects will come to the hospitals every 3 months to undergo, when applicable, neurological evaluation, brain MRI, neuropsychological tests and blood tests.The study will be conducted in several hospitals in Europe and in the US and a total of approximately 20 patients will be treated.
Summary of Results
Clinical Study Results STUDY ALD-104: A 2-year study of eli-cel in boys with Cerebral Adrenoleukodystrophy (CALD) Study conducted by: bluebird bio Medicine studied: elivaldogene autotemcel or eli-cel Is this treatment FDA approved? Yes, while this study was ongoing the FDA (US Food and Drug Administration) approved this medicine. The commercial name for this treatment is SkysonaTM.
Study number: ALD-104
Dates of study: 24 January 2019 to 24 July 2023
Date(s) of this report: 10 June 2024Full title of this study: A Phase 3 Study of Lenti-D Drug Product After Myeloablative Conditioning Using Busulfan and Fludarabine in Subjects ≤ 17 Years of Age with Cerebral Adrenoleukodystrophy (CALD)
Purpose of this summary: This is a summary of key data from this study in an easy-to-understand format intended for the boys in the trial, their families, and friends, as well as for the general public. It is not intended to include all information collected in the study. It is not intended to educate doctors or scientists or to inform treatment decisions.
What disease was being studied?
Cerebral Adrenoleukodystrophy, or CALD, is a genetic disease which can lead to damage to the brain, nervous system and the adrenal glands (that produce hormones). CALD is the most serious form of the disease called Adrenoleukodystrophy (ALD). This is a disease where patients (almost always boys) are born with a problem with a gene (a gene is genetic material made of DNA that helps make a protein). In patients with CALD, errors in a gene, called the ABCD1 gene, result in a protein (called adrenoleukodystrophy protein or ALDP) not being made properly. Not having this working protein results in accumulation of a certain type of fatty acid which can lead to damage to various parts of the body, particularly the brain.What medicine was being tested? What is eli-cel?
Eli-cel (the treatment given in this study) was being tested as a one-time gene therapy treatment for boys with CALD.
This treatment adds working copies of an ABCD1 gene sequence (the piece of DNA that is not working properly in boys with CALD) to the blood cells of these boys. The study was to assess if eli-cel could slow or stop the damage to the brain of boys with CALD.What is gene therapy?
Gene therapy is a type of medical treatment that tries to fix genetic mistakes that cause disease. Gene therapy treatment with eli-cel uses a patient’s own stem cells (not cells from a donor). Working copies of the faulty gene are added to the patient's own stem cells, which becomes eli-cel and is then given back to the patient.
In eli-cel, working copies of the ABCD1 gene are added to a patient’s cells using a “lentiviral vector”. This means scientists in a laboratory use a virus (a special type of virus called a lentivirus) that was changed so the virus can no longer cause disease, but the virus instead delivers the working gene to the patient’s stems cells.
In some ways eli-cel treatment is like traditional bone marrow or stem cell transplant, which is sometimes used to treat CALD. In a traditional transplant, boys with CALD receive blood cells called stem cells from another person (a donor). Unfortunately, many patients don’t have a suitable or a well-matched donor from whom they can get stem cells. Additionally, the donor cells can sometimes attack the patient's body leading to complications (called Graft versus Host disease or GVHD), or the donor cells can also be rejected by the patient’s body. Both problems can be life-threatening in severe cases.
Because eli-cel is made with the patient’s own stem cells (after new copies of the ABCD1 gene have been added), cells from another person are not needed. It is hoped that by using the patient’s own stem cells, many of the medical problems with traditional bone marrow transplants (like rejection of poorly matched donor cells or GVHD) and poor availability of well-matched donor stem cells could be overcome. As such, this treatment would be especially useful to patients who cannot find a suitable and well-matched donor.Who was allowed to be in this study?
Boys aged 17 years and younger with CALD were included in this study. They could be in this study if they were younger than 18 years old and if their disease had not become too severe.What was the purpose of this study?
The purpose of this study was to learn if a one-time eli-cel gene therapy treatment can stop CALD from getting worse and to determine if it is safe for patients to use. Researchers wanted to know:
• How well does eli-cel work at slowing or stopping the progression (worsening) of CALD symptoms?
• How safe was it for boys with CALD in this study to receive this treatment?What happened during the study?
Researchers tested eli-cel in 35 boys between the ages of 5 and 13 years old who had early (meaning their symptoms were not yet considered too severe) CALD.
The main steps involved in eli-cel treatment were:
• Step 1 Mobilization – boys received medicines to make their stem cells move from the bone marrow to the bloodstream (called mobilization) so stems cells could be collected.
• Step 2 Apheresis –stem cells were collected from the bloodstream using a machine in a process called Apheresis.
• Step 3 Transduction (functioning gene is transferred to stem cells) – the stem cells collected in Step 2 were shipped to a factory where they had the functioning ABCD1 genes added to them. These genes were delivered into the cells using a modified virus in a laboratory. The modified stem cells with the new ABCD1 genes in them are the eli-cel medicine (the medicine being tested).
• Step 4 Conditioning with chemotherapy agents – boys to be treated with eli-cel needed to first receive several days of strong chemotherapy drugs (in this study busulfan and fludarabine were used). This step was called “conditioning”. This was done to remove the original blood stem cells that have the faulty copy of the ABCD1 gene in the boy’s bone marrow. This “makes space” for the newly modified stem cells (eli-cel medicine) in the bone marrow where blood stem cells live and develop.
• Step 5 Eli-cel treatment - the eli-cel medicine (the modified stem cells) were shipped from the factory back to the study center and then given to boys through their veins (called intravenously or with an IV).
• Step 6 Engraftment and Step 7 Maintenance follow-up – the boys remained in hospital until their blood cell counts returned to normal or until the study doctor said it was safe for them to leave the hospital. Then each boy's health was monitored for 2 years. This included many doctor visits to test brain function, perform blood tests, take brain images with MRI, and perform other tests to see how the gene therapy worked and what side effects or medical problems occurred.Where and when did this study take place?
The Sponsor ran this study at sites in the USA, UK, France, Italy, Germany, and the Netherlands from 24 January 2019 to 24 July 2023.
Participants from several other countries also came to these study centres to enrol in the study.Who participated in this study?
Only boys with early CALD were included in this study. They were all between the ages of 5 and 13 years of age when they entered the study. Most of the boys were White (59%).How long did the study last?
Study participants were in Study ALD-104 for 2 years of follow-up after receiving eli-cel gene therapy treatment. This 2-year treatment and follow-up period in Study ALD-104 is the focus of this summary.
All 35 participants completed the study, but 3 participants also needed to be treated with traditional bone marrow transplants during the study.
All 35 boys entered a long-term follow-up study (Study LTF-304) in which they will continue to be monitored for 13 more years to gather more information about their health.
Note – in the interest of transparency some key information from this long-term follow-up study is also provided in this summary.What were the results of the study?
How well did eli-cel work at slowing or stopping the worsening of CALD symptoms?
To see if boys’ CALD symptoms got worse, neurological tests were performed at study visits. Based on these tests, researchers noted if boys had one or more problems called major functional disabilities (or MFDs). The 6 MFDs tracked in this study were:
· Difficulty speaking - called loss of communication
· Blindness related to the brain disease (not caused by the eyes themselves) – called cortical blindness
· Difficulty eating (required a tube for feeding) – called tube feeding
· Participant consistently soiled himself – called total incontinence
· Inability to walk – called wheelchair dependence
· Was paralyzed - complete loss of voluntary movement
Researchers tested how well eli-cel worked by seeing how many boys completed 2 years of this study without having these difficulties (were MFD-free) and were still alive. They also noted how many of the boys had to also have a traditional bone marrow transplant during the study.
In this study, 30 of the 35 boys neither developed MFD nor received a traditional transplant.
Five boys had major CALD symptoms (MFDs) or had to have a traditional bone marrow transplant within the 2 years of the study. These were:
• 1 boy developed total incontinence that was thought to be due to disease progression.
• 1 boy developed total incontinence that was perhaps due to a transverse myelitis (a very serious inflammation of the spinal cord).
• 3 boys had a traditional bone marrow transplant during the study: 2 boys due to their CALD symptoms getting worse and one boy due to a form of blood cancer called myelodysplastic syndrome (MDS) (more details below).How safe was this gene therapy treatment?
A short summary of key safety results from this study is provided in the sections below.What medical problems did boys have during the study?
Researchers in this study recorded any medical problems the boys had during the study (from the time of enrolment). This included boys reporting medical problems to their doctor (side effects and other medical problems not due to treatment). Researchers also recorded results of laboratory testing, such as blood tests.
Medical problems could also have been caused by eli-cel or by another medicine the boys were taking as part of this study (for mobilization or conditioning for example) or medicines they were taking for other reasons. Participants could have had medical problems for reasons not related to the study (for example, caused by the CALD disease itself or by chance).
By assessing the possible causes of these medical problems, the researchers tried to understand how treatment in this study impacts a participant’s overall health.Was the stem cell transplant a success?
One especially important measure of success was to make sure the participant’s bone marrow recovered after they got eli-cel treatment. This was important as patients got strong chemotherapy drugs (busulfan and fludarabine) to remove the participant’s own stem cells (that had the faulty ABCD1 gene) leaving them with no bone marrow cells prior to getting the eli-cel stem treatment. But were the new eli-cel stem cells able to survive and remake blood cells in the boy’s body (called engraftment)?
To check this, doctors tested each boy’s blood to make sure they had enough of specific types of white blood cells (especially neutrophils that help fight infections) or platelets (that help blood clot). This is called neutrophil and platelet engraftment. This would show that the modified stem cells got to the bone marrow and started making blood cells. If this was not seen, the patient may have had engraftment failure. This can be classified as primary (just after transplant) or secondary engraftment failure (when initial engraftment was seen but then it failed later).
In this study all 35 boys (100%) achieved neutrophil and platelet engraftment and so were considered to have had a successful stem cell transplant (no boys had primary or secondary graft failure). Therefore, yes, all patient’s bone marrow was considered to have recovered.Overall, what medical problems were seen in this study?
All 35 boys had at least one medical problem during the study (as noted earlier this could be associated with the study (like a side effect of chemotherapy or of a treatment infusion procedure, or of eli-cel itself) or for other reasons (like an accident).
Most of the medical problems seen in this study happened after the Conditioning step (where chemotherapy was given) and were medical problems generally known to occur with such treatment. Participants recovered from these problems as expected.
There were 11 medical problems in 7 boys that were thought by the doctors to be perhaps related to treatment with eli-cel itself (possible eli-cel side effects).
These included 6 eli-cel related serious medical problems (events that were either life threatening, resulted in hospitalization, were an MFD, engraftment failure events, or were medically important in other ways). These 6 eli-cel related serious medical problems were:
• 1 event of a blood cancer called myelodysplastic syndrome (MDS).
MDS is a type of cancer in which the bone marrow fails to produce enough normal blood cells. This can cause anaemia (due to not enough normal red blood cells), frequent infections (due to not enough normal white blood cells) and bleeding (due to not enough normal platelets). This boy received chemotherapy and a traditional transplant and follow-up is continuing in another Study LTF-304 that monitors participants long-term.
• 3 events of pancytopenia (abnormally low levels of all type of blood cells [red blood cells, white blood cells, and platelets] in the boy’s blood). One boy had one serious event of pancytopenia. Another boy had 2 serious events of pancytopenia and during the long-term follow-up Study LTF-304 this boy was eventually diagnosed with MDS, the form of cancer described above. This boy received chemotherapy and a traditional stem cell transplant but unfortunately died 2 years later due to graft versus host disease (GVHD).
• 1 event of disease progression was considered serious in a boy with a total ABCD1 gene deletion. The treating physician was concerned that the eli-cel gene therapy treatment was not working well in a boy with such a gene deletion (based on a drop in the level of cells with eli-cel gene insertions over-time) and alternative treatment was sought (a traditional stem cell transplant), and
• 1 event of cytogenetic abnormality (the boy’s DNA [from the bone marrow] did not look normal in a lab test after the eli-cel treatment)
The other 5 eli-cel related medical problems were less serious:
• 1 event of nausea (feeling sick or having the urge to vomit),
• 1 event of disease progression in a boy. This boy’s CALD symptoms worsened, with total incontinence being reported accompanied by cognitive deterioration (brain function decline) and difficulties communicating),
• 1 event of neutropenia (not enough of an important white blood cell [called neutrophils] in the boy’s blood), and
• 2 events of thrombocytopenia (low platelet levels [needed for blood clotting])
There were no deaths in the study and no boys had any issues related to human immunodeficiency virus (HIV) (a potential concern as the gene transduction used a vector derived from HIV).Important cancer risk Information based on long-term follow-up?
As noted above, one of the boys in this study developed cancer (MDS) during the study. One other boy had issues with his platelet counts during Study ALD-104 and MDS (cancer) was later observed in that boy during the long-term follow-up study and very sadly this boy later died from complications related to a traditional transplant that was performed to treat MDS.
In addition to these 2 boys who had a cancer diagnosis or showed signs of cancer during Study ALD‑104, several other patients also treated with eli-cel in this study later developed blood cancer during the long-term follow-up Study LTF-304. Eli-cel treatment may cause cancer of the blood, which can be life-threatening and lead to death. Blood cancer has resulted because cancer-causing genes have been turned on by the gene therapy. Patients have developed cancer as early as one year after treatment with eli-cel, which is prior to eli-cel having time to potentially help their CALD. Blood cancer can also take years to develop and has been diagnosed as late as 7.5 years after eli-cel treatment, but the maximum timeframe when cancer caused by eli-cel could develop is unknown. The percent of patients who will develop cancer after eli-cel is also unknown.
Because of the risk of cancer following eli-cel treatment, it is important for patients to be monitored lifelong. At a minimum it is recommended that blood tests occur every 3 months for 15 years. Blood tests will look at your blood cell counts and the locations in the blood cells where the gene therapy is inserted. If the blood count is abnormal, additional testing may be recommended. This testing might include more frequent blood tests or even a bone marrow evaluation, which can tell your doctor more than blood tests about the health of a patient’s bone marrow and if there is cancer forming.Where can I learn more about this study?
Participants and their families who took part in this study should contact the staff at their study site with questions about this study or the results presented in this summary.
Other people interested in learning more about this treatment should speak with their physician.
If you would like to find more details on this study, please visit:
https://gbr01.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrials.gov%2F&data=05%7C02%7Cwestlondon.rec%40hra.nhs.uk%7Cdc5f838ff87a494472a208dcab06cf5c%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638573292945246957%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C0%7C%7C%7C&sdata=cPoD1oOKCX%2F%2BuynfG0QocsvrSoOjGLPX3azsEFwuhN8%3D&reserved=0 and search for the study identifier NCT03852498 or
https://gbr01.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrialsregister.eu%2F&data=05%7C02%7Cwestlondon.rec%40hra.nhs.uk%7Cdc5f838ff87a494472a208dcab06cf5c%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638573292945253565%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C0%7C%7C%7C&sdata=SSi0aJq%2FQ%2BHtycyuYHGn1NK%2Bm3gZH2ik1PQ71Cfq50s%3D&reserved=0 and search for the study identifier 2018-001145-14– Thank You –
The sponsor of this study, bluebird bio, would like to thank all the brave boys, their parents and caregivers, and their extended families who participated in this study.
We also thank all the committed study investigators and staff at the study sites for their dedication to this study, these boys, and their families.
Legal Notice
While bluebird is proud to make public this plain language study summary, it is important to keep in mind that this summary pertains to the main objectives and key safety information in the form of an easy-to-understand summary based on a single study (and therefore does not represent the complete set of results from across the eli-cel clinical development program).
Although this single study result summary may provide helpful information to study participants, their families, and other patients and the wider public, the content of this summary may not reflect the overall benefits and risks associated with Skysona and should be read with this in mind.
This is because the overall benefits and risks associated with this medicine are based on information gathered and analysed from the entire research and development program which included other studies. The sponsor would like to remind the reader that only qualified health care professionals can determine if a specific medical treatment is appropriate for a particular patient. If you are a patient or the family member of a patient and have questions regarding any information in this summary, or have questions about CALD, you should consult a qualified health care professional.
Similarly, when making prescribing decisions, health care professionals should always refer to the specific approved medicine labelling information for Skysona, rather than relying upon the information provided in this summary. The information contained in this summary is not intended to promote or otherwise commercialize (directly or indirectly) this medicine or any off-label or unapproved uses.REC name
London - West London & GTAC Research Ethics Committee
REC reference
19/LO/0104
Date of REC Opinion
17 Apr 2019
REC opinion
Further Information Favourable Opinion