RE:Denali & Bioasis why notThey might want and need us even more after their latest study results.
https://endpts.com/denali-slips-as-a-snapshot-of-early-data-raises-some-troubling-questions-on-its-pioneering-blood-brain-barrier-neuro-work/ July 26, 2021 07:36 AM EDTUpdated 08:11 AM R&D
Denali slips as a snapshot of early data raises some troubling questions on its pioneering blood-brain barrier neuro work Max Gelman
Editor
Denali Therapeutics had drummed up considerable hype for their blood-brain barrier technology since launching over six years ago, hype that’s only intensified in the last 14 months following the publications of a pair of papers last spring and proof of concept data earlier this year. On Sunday, the South San Francisco-based biotech gave the biopharma world the next look at in-human data for its lead candidate in Hunter syndrome.
But while the interim analysis showed positive signs in affecting biomarkers related specifically to this disease, the results for the highly-scrutinized neurofilament biomarker — spanning a wider breadth of the neurodegenerative spectrum — proved inconclusive at best. And in the eyes of some Wall Street analysts, these data cast a shadow over Denali’s entire drug development effort and raise serious questions over whether the early benefits seen in Hunter syndrome can translate to the biotech’s efforts in bigger targets like Alzheimer’s and Parkinson’s.
Overall, Denali shares $DNLI were down slightly on the news, dropping about 4.5% in pre-market trading Monday morning.
Sunday’s data came from an interim readout of a Phase I/II study of the Hunter syndrome program, known as DNL310, where Denali revealed results from two cohorts. A total of 17 patients have been enrolled, five in Cohort A and 12 in Cohort B, the latter of which is continuing enrollment.
Denali’s data cover up to 24 weeks of follow-up for Cohort A in the biomarker specific to Hunter syndrome in urine and serum, called heparan sulfate, as well as other lysosomal biomarkers measured in the cerebrospinal fluid. In Cohort B, 13 weeks of follow-up were available for 10 patients across these measures. The median age of patients was six years old, all but one of whom had neuronopathic Hunter syndrome.
It’s these results Denali touted as positive. After Cohort A patients switched from the standard of care treatment of enzyme replacement therapy, Denali observed an average 51% reduction of heparan sulfate in patients’ serum and 90% in CSF. And in the evaluable Cohort B patients, mean HS reductions in the CSF ranged from 86% at the low dose to 92% at the high dose.
All 15 evaluable patients saw their CSF heparan sulfate levels normalize, with 12 touted by Denali seeing normalization by Week 7 — quick enough to be described as “rapid” by the biotech. It’s suggestive that Denali’s overall theory of getting large molecules across the blood-brain barrier is working, CEO Ryan Watts told Endpoints News, which involves utilizing the body’s natural ability to transport iron into the brain to sneak past the boundary.
“We’re seeing superior activity relative to standard of care,” Watts told Endpoints. “I do think the data around the low dose having such a robust effect really helps validate the [platform], and now we’re applying it to other enzymes and antibodies.”
Denali also said “most” patients saw normalization in another Hunter syndrome biomarker, dermatan sulfate. In the CSF, Cohort A patients saw an average 75% reduction, while Cohort B patients saw average reductions between 62% and 76% depending on the dosage level.
But Denali also looked at CSF levels of neurofilament, a biomarker that’s been gaining traction to potentially help measure several neurodegenerative diseases. Normally found in nerve cells, neurofilament is a protein that leaks into blood and cerebrospinal fluid when those cells become injured. Elevated neurofilament levels in the CSF is highly suggestive of neuronal cell death.
Several Wall Street analysts were eager to see these results, noting it would be the first look at neurofilament levels in Hunter syndrome patients. Only the 24-week data from the five Cohort A patients were available, with Cohort B assessments still ongoing.
Among these five patients, however, neurofilament levels increased by an average of 15% in serum and 36% in cerebrospinal fluid. That mark came in way under what Evercore’s Josh Schimmer had hoped for, with Schimmer saying a 20% reduction could potentially translate to clinical benefit.
Additionally, there wasn’t even neurofilament benefit for patients with higher baseline levels, the group most likely to see a reduction, Schimmer said. “We would have liked to at least seen something here,” he wrote Sunday.
Stifel’s Paul Matteis, meanwhile, gave Denali credit for their “extensive” research into neurofilament, especially regarding a natural history study conducted for neurofilament levels in serum. Denali looked at three patients’ levels here prior to enrolling them in Cohort A, and found an average 94% increase in the 4.5- to 6-month period before clinicians administered treatment.
Nevertheless, Matteis wrote that the data “look noisy” and are “trending in the wrong direction.” It might be that six months is simply too short of a period to truly evaluate the impact on neurofilament levels, Matteis said, as was seen in the early stages of BioMarin’s development of Brineura, a now-approved enzyme replacement therapy in Batten disease.
But at best, the neurofilament data are “uninterpretable,” he wrote to investors.
“Bottom line, these data are clearly not encouraging, but we don’t disagree with management that it may be too early to see anything as we don’t fully understand the kinetics of NfL changes, especially in a treatment setting,” Matteis wrote.
Jefferies’ Michael Yee struck a more positive note, calling the overall data “mostly strong.” The neurofilament results were “mixed, but fine” in his eyes.
Carole Ho
Denali execs say they’re going to continue investigating whether or not neurofilament can serve as an effective biomarker for Hunter syndrome. Chief medical officer Carole Ho highlighted the fact that there are much fewer neurofilament data in pediatric settings than for adults, given the need to tap into the CSF, which may have led to a significant amount of “variability” in the natural history study.
“It’s hard to make any sort of interpretation,” Ho said. “We feel like there needs to be much more natural history data to use this as a treatment response measurement.”
Watts added that, at this point, there aren’t enough data to conclude if there’s any relationship at all between neurofilament and the Hunter syndrome biomarkers. He also ruled out any relationship between those biomarkers and tau, another measurement evaluated by Denali that saw no change across the Cohort A treatment period.
Though the neurofilament results have likely disappointed investors, Denali is planning to charge ahead with a Phase II/III registrational trial. The biotech is aiming to start the study “as soon as possible,” Ho said, with a launch expected for the first half of next year. Researchers will be attempting to measure efficacy with two patient- and caregiver-reported tests that look at behavioral and cognitive benefits in Hunter syndrome patients, rather than changes in a biomarker.
It will run in parallel to the ongoing Phase I/II, which is yet to enroll the third cohort of patients, Ho added.
The new study will be a “risky” proposition for Denali, Schimmer said, due to the lack of impact on neurofilament levels and the fact that registrational data won’t be available for at least three more years. During that time, it will be difficult to tell whether or not their technology can work for other conditions, he wrote, noting the LRRK2 program for Parkinson’s disease may take a similar amount of time to de-risk.
With reviews likely to continue rolling in, Sunday’s results represent somewhat of a humbling moment for Denali. Launched in 2015 with what was at the time the biggest Series A in biotech history, Denali set its sights on a broad range of neurodegenerative diseases and a mission to succeed where many in biopharma had failed.
But, like its predecessors, Denali is learning there may be bumps along the way.
“Drug development is very rarely linear, and that’s part of when we’re going into a new space like the blood-brain barrier, you have to have very robust biomarkers that link to brain penetration,” Watts said. “That’s why we selected enzymes as really the first path for us to prove the [platform] because it’s a really simple equation … If we can get that enzyme across the blood-brain barrier, we can basically rescue the disease.”
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