SkysonaCerebral adrenoleukodystrophy (CALD) in patients aged <18 years
New molecular entity
Development and Regulatory status
Aug 21bluebird bio announced that the US FDA has placed a clinical hold on studies of elivaldogene autotemcel for CALD. This hold is related to a report of a suspected unexpected serious adverse reaction of myelodysplastic syndrome in a patient treated with elivaldogene over 1 year ago in a PIII trial. The company reported that “Evidence currently available suggests that specific design features of Lenti-D LVV likely contributed to this event”. They do not anticipate any impact on its other gene therapy programs for sickle cell disease (SCD), β-thalassemia or oncology. However, the company do plan to focus on the US market going forward. They plan an orderly wind down of operations in Europe and to explore how to give pts in Europe access to its gene therapies, including potentially out-licensing the ex-U.S. rights to its three lead products to a company with European experience and capabilities. [21,22]
Jul 21A marketing authorisation application for Skysona is currently under review by the MHRA .
Jul 21Approved in EU .
May 21Recommended for EU approval by CHMP on basis of an assessment by the Committee for Advanced Therapies – the full indication is ‘Skysona is indicated for the treatment of early cerebral adrenoleukodystrophy in patients less than 18 years of age, with an ABCD1 genetic mutation, and for whom a human leukocyte antigen (HLA) matched sibling haematopoietic stem cell (HSC) donor is not available’. Skysona will be available as a 2-30 x 10⁶ cells/ml dispersion for infusion .
Oct 20Currently pre-registration in EU .
Jul 18EMA CHMP recommends that elivaldogene tavalentivec is eligible for Priority Medicine (PRIME) status; this gives access to early dialogue with the regulators to optimise development plans, and would be expected to lead to accelerated assessment of the eventual Marketing Authorisation Application (MAA) .
May 18US FDA grants Breakthrough Therapy designation for treatment of cerebral adrenoleukodystrophy based on preliminary data from ongoing PII/III Starbeam Study .
Nov 17Bluebird Bio announced purchase of a manufacturing facility in North Carolina, USA and execution of multiple global (US and Europe) agreements to enhance its ability to deliver gene therapies. The new manufacturing facility will produce lentiviral vector for the company’s gene and cell therapies, including Lenti-D and LentiGlobin .
Oct 12EMA Committee for Advanced Therapies concludes that ´Autologous CD34+ haematopoietic stem cells (HSCs) transduced with lentiviral vector Lenti-D encoding the human ABCD1 cDNA´ falls within the definition of an advanced therapy medicinal product, in particular of a gene therapy medicinal product .
Jun 12Granted orphan drug designation by the US FDA and the EMA .
Lentiviral vector expressing a human ATP-binding cassette, sub-family D, member 1 (ABCD1) gene, transduced with autologous CD34+ haematopoietic stem cells.
Adrenoleukodystrophy (ALD), or Lorenzos Oil disease, is a rare X-linked disorder caused by mutations of ABCD1 . Estimated birth incidence is 1 in 20,000 (male and female) worldwide, global prevalence is between 1 to 9 in 100,000 . Cerebral ALD is the most severe form of the disease and primarily affects boys. Symptoms of CALD usually occur in early childhood and progress rapidly if untreated, leading to severe loss of neurological function and eventual death in most patients .
Cerebral adrenoleukodystrophy (CALD) in patients aged <18 years
Trial or other data
Oct 20Enrolment continues in PIII ALD-104 study designed to assess the efficacy and safety of eli-cel after myeloablative conditioning using busulfan and fludarabine in patients with CALD. Additionally, the long-term safety and efficacy follow-up study (LTF-304) for patients who have been treated with eli-cel for CALD and completed two years of follow-up in bluebird bio-sponsored studies continues. The PII/III Starbeam study (ALD-102) has completed enrolment; this assessed efficacy and safety of eli-cel after myeloablative conditioning using busulfan and cyclopshosphamide in patients with CALD .
Aug 20bluebird bio is currently enrolling patients for ALD-104, a PIII study designed to assess the efficacy and safety of eli-cel in patients with CALD after myeloablative conditioning using busulfan and fludarabine, a different chemotherapy conditioning regimen than what is used in ALD-102 (busulfan and cyclophosphamide). The primary efficacy endpoint is the proportion of patients who are alive and free of MFDs at Month 24, and the primary safety endpoint is the proportion of patients with neutrophil engraftment after eli-cel infusion. All reported data below are as of February 2020. In ALD-104, the 13 patients currently on study have a median of 6.1 months of follow-up to date (min-max: 2.2 – 10.3 months). All 13 patients achieved neutrophil engraftment and 12/13 evaluable patients had platelet engraftment (platelet engraftment pending in one patient as of data cut date). Due to the limited duration of follow-up, only safety data are being presented. No events of acute or chronic GvHD have been reported and there have been no reports of graft failure, graft rejection, cases of insertional oncogenesis, or replication competent lentivirus. The treatment regimen, comprising mobilization/apheresis, conditioning, and eli-cel infusion had a safety and tolerability profile primarily reflective of the known effects of mobilization/apheresis and conditioning. In ALD-104, two AEs of pancytopenia were considered possibly related to eli-cel. These two ongoing AEs were deemed as suspected unexpected serious adverse reactions (SUSARs) by the principal investigator and were diagnosed approximately two months post-eli-cel infusion in two patients (one Grade 2 and one Grade 3). An additional AE was ongoing as of February 2020, a Grade 3 SAE of transverse myelitis that was diagnosed in the presence of viral infection (adenovirus and rhinovirus/enterovirus positivity) approximately six months after eli-cel infusion and deemed unrelated to eli-cel .
Aug 20bluebird bio announces updated results including long-term results from the Phase 2/3 Starbeam study (ALD-102/LTF-304) and data from the Phase 3 ALD-104 study. The ALD-102 study has completed enrollment. All reported data below are as of January 2020 and reflect a total population of 32 patients with a median follow-up time of 30.0 months (9.1 – 70.7 months). Of the 32 patients who have received eli-cel as of January 2020, 20 have completed ALD-102 and enrolled in a long-term follow-up study (LTF-304). Nine additional patients continue to be followed in ALD-102 and have not reached 24 months post-treatment. As previously reported, two patients withdrew from the study at investigator discretion, and one experienced rapid disease progression early on-study resulting in MFDs and death. To date, 104.3 patient-years of follow-up have been reported for ALD-102 and LTF-304. The primary efficacy endpoint in the study is the proportion of patients who are alive and free of MFDs at Month 24. Of those patients who have or would have reached Month 24, 87% have met the primary endpoint and continue to be alive and MFD-free at more than two years of follow-up (N=20/23). Fourteen patients have at least four years of follow-up, including 10 patients who have reached at least their Year 5 follow-up visit. The nine patients from ALD-102 that have not reached Month 24 have shown no evidence of MFDs. Data on several secondary and exploratory efficacy outcomes are reported, including changes in neurologic function score (NFS), a 25-point score used to evaluate the severity of gross neurologic dysfunction across 15 symptoms in six categories; resolution of gadolinium enhancement (GdE), an indicator of active inflammation in the brain; and change in Loes score, an MRI measurement of white matter changes in CALD. Of the 32 patients treated, 31 had stable NFS following treatment with eli-cel, defined as NFS 3 from baseline, and 24 patients maintained an NFS of 0. An NFS of 0 indicates that there are no concerns with the neurologic functions that are assessed on the 25-point scale. Loes scores generally stabilized within 12-24 months and GdE was no longer seen in most patients following eli-cel treatment. The primary safety endpoint is the proportion of patients who experience acute (≥Grade 2) or chronic GvHD by Month 24. GvHD is a condition that may occur after an allo-HSCT, where the donated cells view the recipient’s body as foreign and attack the body. No events of acute or chronic GvHD have been reported post-eli-cel treatment. There have been no reports of graft failure or graft rejection. In addition, there have been no cases of replication competent lentivirus or insertional oncogenesis to date. Integration site analysis (ISA) was conducted to determine the pattern of integration post-eli-cel infusion and assess whether dominant or expanding clones were present. In one patient, now enrolled in LTF-304 for long-term follow up, a case of benign clonal expansion was observed with three separate integrations in the DNA of the cell at ACER3, RFX3, and MECOM. As of the patient’s Month 62 visit in March 2020, the patient remained clinically stable. Bone marrow analyses showed no dysplasia (abnormal cell growth) or molecular abnormalities. The treatment regimen, comprising mobilization/apheresis, conditioning, and eli-cel infusion, had a safety and tolerability profile primarily reflective of the known effects of mobilization/apheresis and conditioning. In ALD-102, as previously reported, three adverse events (AE) were considered possibly related to drug product and include one serious AE (SAE), BK viral cystitis (N=1, SAE, Grade 3), and two non-serious AEs, vomiting (N=2, Grade 1). All three AEs resolved using standard measures .
Dec 19UK trial sites: NCT03852498 UCL 
Dec 19PIII long-term follow-up study (NCT02698579) is enrolling by invitation. 50 patients will be followed for an additional 13 years for a total of 15 years post-drug product infusion .
Jan 19PIII trial (ALD-104; NCT03852498) started. Open-label single group assignment trial intends to enrol 20 participants in the US. The first patient in the trial was dosed in April 2019 
May 18The Starbeam study (NCT01896102) has finished recruiting with 30 participants and estimated primary completion date is now July 2020 .
Oct 17Further interim data from the Starbeam study (NCT01896102) have been published in the NEJM (DOI: 10.1056/NEJMoa1700554). Of the 17 patients treated, 15 remain alive with none experiencing any of the specified MFD. One patient withdrew from the study following radiographic progression and died from complications of a subsequent HSCT, the other had rapidly progressive disease from early in the study that would not have been expected to respond to treatment . The study remains ongoing with a target recruitment of 25 and estimated primary completion date of August 2019 .
Mar 16Interim data released from the PII/III Starbeam study in patients with CCALD in the US (ALD-102; NCT01896102). As of Oct 15, 17 patients, aged up to 17 years, had been treated with a median follow up of nine months. The primary endpoint is the proportion of subjects who have no Major Functional Disabilities (MFDs), as determined by key measures in the Neurological Function Score (NFS), assessed at 24 months post-transplant. All 17 patients were free of major functional disabilities. NFS stabilisation was observed in 16 out of 17 patients with change of <3 points and an absolute NFS = 4. Occurrence of stuttering in one patient and episodic urinary incontinence in another, resulted in NFS of 1. One patient had NFS of 5 as reflected by deficits in speech, vision, difficulty walking and running and episodes of urinary incontinence, thus demonstrating early and rapidly progressive course. Fourteen of 17 patients had a stable Loes score with a change of 5 points (or an absolute Loes score of 9). By month 6, 16 of 17 patients had resolution of gadolinium enhancement, while 5 patients showed re-emergence of diffuse contrast enhancement, at month 12. Two of those 5 patients showed resolution of gadolinium enhancement at month 18, after atleast 18 months of follow up .