JEFFERIES
Bluebird (BLUE): Interim Lenti-D Data in CALD Somewhat Mixed, But Expecting Further Improvement
Rating BUY
Price Target $84.00
Price $47.72
Bloomberg NASDAQ: BLUE
Key Takeaway
Interim data of Lenti-D Ph2/3 Starbeam study in CALD were presented at AAN today. We see 16/17 stabilization in the neurological function scores as impressive. While Loes score progression and re-emergence of gadolinium enhancement in some pts at 12mon raise some questions on potential disease stabilization, we expect to see continued improvement at 24mon based on sustained VCN, protein expression and underlying science.
None of 17 cerebral adrenoleukodystrophy (CALD) pts treated with Lenti-D experienced major functional disabilities (MFDs) with 6-24mon follow-up. Recall that Lenti-D (gene therapy for CALD) Ph2/3 Starbeam study enrolled 17 pts with % pts without MFDs at 24mon as the primary endpoint. MFDs include 6 serious symptoms (loss of communication, no voluntary movement, cortical blindness, tube feeding, wheelchair required and total incontinence) as measured in the neurological function scores (NFS, 0 means normal and the higher score, the more severe the symptom). With variable follow-up periods (=6mon for all 17 pts, 12-24mon for 14 pts including 3 pts with full 24mon follow-up), none of the 17 pts experienced MFDs as of Mar 31’16, suggesting the 3 pts with sufficient follow-up have already met the primary endpoint. With further follow-up, we expect to see ~80% pts to meet the primary endpoint at 24mon (link), comparable to current standard of care (allo-HSCT, allogeneic hematopoietic stem cell transplantation).
Stabilization in NFS score appears better vs. natural history study of allo-HSCT treated pts and our KOL expectation. Sixteen of 17 pts (94%) achieved stabilization in NFS score (change of <3 points and an absolute NFS = 4). Two pts had NFS increase of 1 (worsening of disease) and one pt had NFS increase of 5 in 6mon after treatment. The results appear better vs. our KOL expectations (50% disease stabilization in 9-12mon) and the natural history study conducted by the company (ALD-101, 70% NSF stable at 24mon).
While Loes score progression (measuring myelin degeneration using MRI) and re-emergence of gadolinium enhancement (GdE+, indicator of neuroinflammation) in some pts at 12mon raised some questions on potential disease stabilization, we expect to see continued improvement at 24mon. Fourteen of 17 pts achieved stabilization in Loes score (defined as change of <5 points and an absolute Loes score = 9). Note that several pts had Loes score increase of ~3-4 within 12mon follow-up. Although resolution of GdE+ was achieved in 16/17 pts at 6mon, re-emergence of GdE+ was observed in 5/14 pts at 12mon. GdE enhancement was resolved in 2 of 5 pts at 18mon follow up. Although it is unclear if GdE+ would be resolved for the remaining 3 pts, we expect to see continued improvement for both Loes score and GdE at 24mon because: 1) sustained vector copy numbers were observed for nearly every single pt throughout treatment period, 2) ALD protein expression showed steady increase for all pts, 3) natural history of the disease suggests rapid progression upon diagnosis (usually death within 5 yr) while it would require meaningful time (>6-9mon according to our KOL) for stem cells to differentiate to microglia cells in order to prevent the ongoing demyelination. Our KOL feedback also suggests improved disease stabilization over time based on stem cell transplant (70-80% at 24mon vs. 50% at 12mon), 4) one case presented at the meeting suggested Loes score decreased to baseline with longer followup (2 at the baseline, 3 at 12mon and 2 at 24mon).
Safety profile of Lenti-D continues to be consistent with myeloablation treatment with 6mon+ follow-up vs. data in the abstract, highlighting its advantage as autologous transplantation. One possibly treatment-related SAE (grade 3 BK virus cystitis, common in bone marrow transplantation, link) and treatment related AE (grade 1 tachycardia) were reported and resolved with standard measures. Integration site analysis showed no dominant clones. Consistent with autologous transplantation, Lenti-D treatment led to no graft versus host disease (GvHD) vs. 45-75% in allo-HSCT-treated pts.