Clinical Trials

Date: 2018-09-05

Type of information: Presentation of results at a congress

phase: 2-3

Announcement: presentation of results at the Society for the Study of Inborn Errors of Metabolism (SSIEM) 2018 Symposium in Athens, Greece.

Company: Bluebird bio (USA - MA)

Product: Lenti-D™

Action mechanism:

• gene therapy/stem cell therapy.  Lenti-D™ drug produt is autologous CD34+ cell-enriched population that contains cells transduced with Lenti-D lentiviral vector encoding human adrenoleukodystrophy protein, suspended in a cryopreservative solution. Lenti-D Drug Product is administered by IV infusion following myeloablative conditioning with busulfan and cyclophosphamide.

Disease: childhood cerebral adrenoleukodystrophy (CCALD - X-linked adrenoleukodystrophy cerebral childhood)

Therapeutic area: Rare diseases - Genetic diseases - Hematological diseases

Country: USA

Trial details:

• This trial will assess the efficacy and safety of autologous CD34+ hematopoietic stem cells, transduced ex-vivo with Lenti-D lentiviral vector, for the treatment of childhood cerebral adrenoleukodystrophy (CCALD).  The Starbeam Study is assessing this investigational gene therapy approach in boys up to 17 years of age. It involves transplantation with a patient’s own stem cells, which are modified to contain a functioning copy of the ABCD1 gene. The copy of the gene is intended to allow the body to produce ALDP, a protein critical for the breakdown of very long chain fatty acids (VLCFAs). Buildup of VLCFAs in the central nervous system contributes to neurodegeneration in CALD. The primary efficacy endpoint for the Starbeam Study is the proportion of subjects with no major functional disabilities (MFDs) at 24 months post infusion. MFDs are six specific components of the Neurological Function Score (NFS) that would have a profound negative impact on patients’ lives: loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence and complete loss of voluntary movement. (NCT01896102)

   

Latest news:

• • On September 5, 2018, bluebird bio announced updated results from the Phase 2/3 Starbeam study (ALD-102) of its investigational Lenti-D™ gene therapy in boys 17 years of age and under with cerebral adrenoleukodystrophy (CALD), and initial data from ALD-103, the ongoing observational study of outcomes from allogeneic hematopoietic stem cell transplant (allo-HSCT) in boys 17 years of age and under with CALD. The data were presented at the Society for the Study of Inborn Errors of Metabolism (SSIEM) 2018 Symposium in Athens, Greece. bluebird bio has also reached general agreement with the FDA and the European Medicines Agency (EMA) on the clinical development program to support future marketing applications for Lenti-D in CALD.
• The Phase 2/3 Starbeam study has met its enrollment goal. All reported data are as of April 25, 2018 and reflect a total study population of 31 patients. Of these 31 patients, 29 have received Lenti-D and the median follow-up for all treated patients was 34 months (0.4 – 54 months).
• The primary efficacy endpoint of the Phase 2/3 Starbeam study is the proportion of patients who are alive and free of major functional disabilities (MFD) at month 24. MFDs are six severe disabilities commonly attributed to CALD and thought to have the most profound impact on a patient’s ability to function independently: loss of ability to communicate, cortical blindness, need for tube feeding, total incontinence, wheelchair dependence, and complete loss of voluntary movement.
• As previously reported in the New England Journal of Medicine (October 2017), of the 17 patients treated with Lenti-D who completed 24 months of follow-up, 15 patients (88 percent) were alive and MFD-free. One patient withdrew from the study, and one died following rapid development of MFDs post-treatment. All patients who were MFD-free at 24 months (n=15) continued to be MFD-free. The median follow-up for the initial group (n=17) was 41.4 months (13.4 - 54.0 months).
• An additional 12 patients have received Lenti-D in the Phase 2/3 Starbeam study. While these patients have not reached the primary endpoint of 24-month follow-up, there have been no MFDs reported as of April 25, 2018. The median follow-up for this additional cohort of patients is 4.2 months (0.4 – 11.7 months).
• Secondary efficacy endpoint data for gadolinium-enhancement (GdE) and Neurologic Function Scores (NFS) were also reported. GdE was assessed by magnetic resonance imaging (MRI) every six months following transplant up to 24-months, and then every 12 months. In the 15 patients who completed 24 months of follow-up, 14 were negative for GdE as of their last MRI. Eleven patients in the study had intermittent re-emergence of GdE-positivity at various follow-up assessments, however, post-treatment GdE positivity was markedly reduced in intensity and does not appear to correlate with clinical outcome.
• NFS was used to quantify the severity of neurologic dysfunction based on 15 symptoms. All patients had an NFS of ?1 at time of Lenti-D treatment. In 15 patients who met 24 months of follow up by April 25, 2018; 14 had an NFS score ?1 at their last follow-up visit, and one patient had an increase in NFS from 1 to 2, due to vision impairment and non-febrile seizures. One patient had rapid disease progression beginning early in their participation in the study, resulting in multiple MFDs and an NFS of 17 at last follow-up.
• The primary safety endpoint of the Phase 2/3 Starbeam study is the proportion of patients who experienced grade ?2 acute graft-versus-host disease (GvHD) or chronic GvHD by 24 months post-treatment. No acute or chronic GvHD has been reported post-Lenti-D treatment as of April 25, 2018. There has been no graft failure, insertional oncogenesis or replication competent lentivirus detected. The safety profile of Lenti-D is generally consistent with myeloablative conditioning with busulfan and cyclophosphamide. Three adverse events (AE) have been deemed potentially related to treatment with Lenti-D and include BK-mediated viral cystitis (grade 3), tachycardia (grade 1), and vomiting (grade 1).Initial Results from ALD-103 Study Allo-HSCT has been successfully used to treat CALD but may be associated with adverse immunologic complications. The ongoing observational study ALD-103 is designed to assess safety and efficacy outcomes of this treatment option in boys 17 years of age or younger with CALD. As of April 25, 2018, 41 pediatric patients were enrolled in the ALD-103 study and had undergone allo-HSCT. Thirty-one patients received cells from unrelated donors and 10 received cells from a related donor. The median baseline NFS for the group was 0.0 (min – max, 0.0 - 4.0). The median Loes score, a 34-point scale that measures the location and extent of demyelination through MRI, was 3.0 (min – max, 0.0 - 16.0). Twenty-five patients had early cerebral disease, defined as having evidence of cerebral disease established by GdE positivity or Loes score ?0.5, Loes score ?9.0, and NFS ?1.Initial results were in line with safety and efficacy outcomes reported in the literature for allo-HSCT in patients with CALD. Two-year Kaplan-Meier estimates of MFD-free survival post-allo-HSCT, were 78 percent for patients with early disease (n=25) and 71 percent for all patients (n=41).Transplant-related mortality was defined as death due to any transplantation-related cause other than disease progression. There were six transplant-related deaths at one year (14.6 percent); none of these patients had a matched sibling donor. Engraftment failure was reported in five patients (12 percent); none of these patients had a matched sibling donor and all received a second transplant. Of the 41 patients who received allo-HSCT, 34 percent (n=14) experienced either grade 2 acute GvHD or chronic GvHD.
• • On  October 4, 2017, bluebird bio  announced that interim data from an initial cohort of 17 patients in the ongoing Phase 2/3 Starbeam Study (ALD-102) evaluating Lenti-D™ investigational gene therapy in boys with cerebral adrenoleukodystrophy (CALD) were published in the New England Journal of Medicine (NEJM). As of the April 25, 2017 data cut off for the publication, 16 of the 17 patients had completed the primary analysis period (24 months or discontinuation).
  • Patient 2016 had not experienced an MFD, but withdrew from the study due to radiographic progression of disease and underwent allogeneic hematopoietic stem cell transplantation (HSCT). He subsequently died from complications of the allogeneic transplantation.
    • 15/17 patients maintained NFS ? 1.
    • Loes score has stabilized in 12/17 evaluable patients (71%). Stabilization is characterized as maintaining a Loes score ?9 or not increasing a Loes score by ?6 points.
    • Gadolinium enhancement, positive in all patients at baseline, was negative in 16/17 patients by month 6. Diffuse gadolinium enhancement re-emerged in 6 patients at month 12. Subsequent fluctuations in gadolinium enhancement were observed, with 11/17 patients negative for gadolinium enhancement at their last follow-up. In all patients showing gadolinium re-emergence, the enhancement was less extensive compared to baseline. Initial results suggest that re-emergence of gadolinium enhancement does not correlate with clinical outcome.Patient 2018, as previously reported in April 2016, had rapid disease progression beginning early in his participation in the study, resulting in multiple MFDs and an NFS of 15. The rapidity of his disease progression suggests it would have been difficult to alter his early neurological decline given that Lenti-D treatment takes months to exert a therapeutic effect in CALD.The primary efficacy endpoint for the Starbeam Study is the proportion of patients who are alive and have no major functional disabilities (MFDs) at 24 months post drug product infusion. MFDs are the six severe disabilities commonly attributed to CALD that, if present, would have a profound negative impact on patients’ lives: loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence and complete loss of voluntary movement. The primary safety endpoint is the proportion of patients who experience Grade 2+ acute GVHD or chronic GVHD at 24 months post-treatment. Secondary and exploratory assessments include Neurologic Function Score (NFS; a scoring system of 15 symptoms/signs across multiple domains used to evaluate the severity of gross neurologic dysfunction), gadolinium enhancement on MRI (an indicator of neuroinflammation), MRI Loes score (a method for quantifying brain lesions in patients with CALD using brain MRI), and additional safety assessments.As of the April 25, 2017 data cut-off, 15/17 (88%) (95% confidence interval [CI]: 64% to 99%) of the patients infused with Lenti-D drug product remain alive and free of MFDs, the primary efficacy endpoint of the trial. Median follow-up at the time of data analysis was 29.4 months (range: 21.6 to 42.0 months). This exceeds the pre-defined efficacy success benchmark for the study of 76% MFD-free survival at 24 months for this initial subset of patients. Most adverse events occurred during the 2 weeks post-transplant and most were associated with myeloablative chemotherapy. One possibly drug related serious adverse event occurred (viral cystitis) and resolved with standard measures. There was no engraftment failure, graft versus host disease (GVHD) or life-threatening infections. There was no evidence of insertional oncogenesis.
• • On June 26, 2017, bluebird bio announced topline interim data from the initial cohort of 17 patients in the ongoing Phase 2/3 Starbeam Study (ALD-102) evaluating Lenti-D™ investigational gene therapy in boys under 18 years old with cerebral adrenoleukodystrophy (CALD).As of June 13, 2017, 17 patients with CALD have completed 2 years of follow-up post-Lenti-D treatment, with 15/17 (88%) remaining free of major functional disabilities (MFDs), the primary endpoint of the trial. This exceeds the pre-defined interim efficacy benchmark for the study of MFD-free survival of 76%, derived from the literature and based on clinical data from an earlier observational study describing that natural history of CALD and outcomes from allogeneic HSCT. In the Starbeam Study, the safety profile of Lenti-D was consistent with myeloablative conditioning. No patients treated with Lenti-D had graft versus host disease (GvHD), and there was no graft rejection or clonal dominance.
• In December 2016, bluebird bio announced that the Starbeam study had been expanded to treat eight additional patients at sites in Europe and the US, and the study is currently enrolling the additional patients. The expansion of the study is intended to enable the first manufacture of Lenti-D in Europe, the subsequent treatment of subjects in Europe, and to bolster the overall clinical data package for potential future regulatory filings in the United States and Europe.
• • On April 20, 2016, bluebird bio announced that interim data from the ongoing Phase 2/3 Starbeam Study (ALD-102) evaluating the Lenti-D™ product candidate in pediatric patients with cerebral adrenoleukodystrophy (CALD) will be presented at the American Academy of Neurology (AAN) Annual Meeting during the Clinical Trials Plenary Session. The data will be highlighted in an oral presentation by Florian Eichler, M.D., Director of the Leukodystrophy Service at Massachusetts General Hospital for Children. As of March 31, 2016, 17 patients with CALD had received Lenti-D drug product. All patients had at least six months of follow up, with eight patients having between 12 and 24 months of follow up. Data from these 17 patients as of March 31, 2016, that will be reported today at AAN include: All patients remain free of MFDs. Sixteen of 17 patients had NFS stabilization (change of <3 points and an absolute NFS ? 4). Two patients have an NFS of 1, due to the occurrence of stuttering in one patient, and episodic urinary incontinence in another patient.
• One patient had an early, rapidly progressive course and has an NFS of 5, reflecting deficits in speech, vision, difficulty walking and running, and episodes of urinary incontinence. Fourteen of 17 patients had a stable Loes score (change of ? 5 points or an absolute Loes Score ? 9). Sixteen of 17 had resolution of gadolinium enhancement by month six. Re-emergence of diffuse contrast enhancement was seen in five patients at month 12. Of those five patients, the two with at least 18 months of follow up showed resolution of gadolinium enhancement at month 18.
• The safety profile of Lenti-D treatment appears consistent with myeloablative conditioning with one possibly drug-related serious adverse event (Grade 3 BK-mediated viral cystitis) and one possibly drug-related adverse event (Grade 1 tachycardia). Both resolved with standard measures. Integration site analyses have demonstrated polyclonal reconstitution in all subjects without evidence of clonal dominance to date.
• • On March 3, 2016, bluebird bio announced that interim data from the ongoing Phase 2/3 Starbeam Study (ALD-102) for the treatment of cerebral adrenoleukodystrophy (CALD) will be presented in an oral presentation during the Clinical Trials plenary session on April 20, 2016 at the American Academy of Neurology (AAN) 2016 Annual Meeting, in Vancouver, BC, Canada. The Starbeam (ALD-102) Study is assessing the efficacy and safety of an investigational gene therapy approach in boys up to 17 years of age with CALD. It involves transplantation with a patient’s own stem cells, which are modified to contain a functioning copy of the ABCD1 gene. The copy of the gene is intended to allow the body to produce ALDP, a protein critical for the breakdown of very long chain fatty acids (VLCFAs). Buildup of VLCFAs in the central nervous system contributes to neurodegeneration in CALD. As of October 2015, 17 subjects with CALD have been treated with Lenti-D drug product with median follow-up time of nine months. ALDP expression was observed in leukocytes of all subjects. Reported adverse events were consistent with myeloablative conditioning. One serious adverse event with possible relation to drug product was reported (BK virus cystitis) and resolved with supportive care Integration site analyses have demonstrated polyclonal reconstitution in all subjects without evidence of clonal dominance In the 12 subjects with at least six months of follow-up:
• No major functional disabilities and no NFS worsening were reported
• The median change in Loes score was 1 (range 0-6)
• All subjects experienced resolution of gadolinium enhancement.

Is general: Yes