Al Sandrock on why neurology might finally be ready to accelerate

From an array of genetic targets to brain-penetrant delivery systems, Voyager CEO sees the pieces finally aligning for neurology-wide progress

Voyager CEO and former head of R&D at Biogen Al Sandrock is more optimistic than ever about the prospect of bringing clinically meaningful solutions to patients with Alzheimer’s disease and other neurodegenerative disorders.

The threads of progress are finally coming together, he said in a special episode of the BioCentury This Week podcast.

From the first disease-modifying therapies for Alzheimer’s disease, to a growing biomarker toolkit, to an expanding set of genetically validated targets in other neurodegenerative conditions — and, crucially, to delivery vehicles capable of broadly and deeply penetrating the brain — neurology drug development may be poised to accelerate.

The first of those threads is Alzheimer’s disease, where anti-amyloid mAbs can slow decline for at least some patients, an important step forward. Those products are now being tested in presymptomatic patients, where Sandrock believes they will prove more powerful, due to amyloid’s early role in a disease process that unfolds over decades. 

Accompanying these developments, he said, is a growing biomarker toolkit. Should anti-amyloid therapies show efficacy in Alzheimer’s prevention, the blood-based biomarkers now reaching the market will be poised for greater adoption in clinical decision-making.

“In the primary care setting you’re going to need a blood test,” Sandrock said. He envisions a future where Alzheimer’s is treated the way cardiology treats cholesterol and blood pressure — intervening before overt events.

And beyond amyloid lies tau, a target that Voyager Therapeutics Inc. (NASDAQ:VYGR) is pursuing both extracellularly, with a mAb, and intracellularly with a vectorized siRNA. Recent studies have raised hopes that either approach could still be effective, despite an initial set of mAbs failing in the clinic.

Important data are coming next year from tau-targeting agents that could read through to Voyager’s programs. If it turns out that effective ways of targeting tau have finally been identified, it could pave the way to multiple disease-modifying treatment options.

Despite the progress, mysteries remain on the precision medicine front, said Sandrock. For example, some patients respond more strongly to anti-amyloid therapy than others, and it’s unclear why. Disease stage may factor in — conventional wisdom says earlier is better with the amyloid mechanism — but “there’s some conflicting data there,” he acknowledged.

Murkier still, he said, is the role that other disease mechanisms, such as neuroinflammation, play in the disease.

Initially, he was skeptical that inflammatory pathways were causal rather than reactive, given that dying neurons can themselves drive inflammatory responses. Human genetic studies have pushed him toward a more causal view, but the biology is multifaceted and difficult to untangle, he said.

Neuroinflammation can be caused by immune cells in the brain — microglia — or immune cells that enter from outside, and microglial cells can adopt various phenotypes that are incompletely understood.

“There are forms of neuroinflammation, or microglial activation, that we think are protective” and others that are harmful, he said. “We’d hate to decrease the protective forms,” he said, adding that “we want to dampen down the harmful ones.” Measuring those states correctly remains a challenge, and one that’s layered on top of target-specific complexities. One of the highest-profile neuroinflammation targets, TREM2, has its own complicated biology, Sandrock noted, including soluble and membrane-bound forms. 

Good targets, better delivery

Two other powerful forces promise transformational progress in neurology: the identification of genetically validated targets and the development of delivery vehicles that can bring drugs to those targets.

“I believe we have a lot of really well-validated targets to go after in the central nervous system,” said Sandrock.

He pointed to SOD1 as proof of concept that intervening in the causal biology of amyotrophic lateral sclerosis can not only slow the disease but reverse it, something he could barely have imagined back when he was neuromuscular physician at Mass General.

“Imagine ALS patients who are putting aside their walker or getting out of the wheelchair; this is happening,” he said. “It’s a great indication of how far we’ve come.”

While SOD1 mutations only account for a tiny fraction of ALS cases, there are now many other targets with genetic validation, and some of them hold promise for broader populations.

A foundational issue limiting access to these targets is the blood-brain barrier, which keeps most biologics, and even some small molecules, out of the CNS. Voyager is among a growing number of companies aiming to solve that problem — and its in-house toolkit is growing.

Founded to develop AAV gene therapies, Voyager has a BBB-penetrant capsid that enables it to create vectorized therapies against validated CNS targets. Having discovered the receptor that its lead capsid uses to enter the brain — tissue non-specific alkaline phosphatase (ALPL) — the company has developed ligands against ALPL and shown in mouse studies that those ligands can transport other types of biologic cargo across the BBB. 

One of Voyager’s shuttle’s key differentiators from leading transferrin (TfR)-based shuttles is its longer CNS half-life, which might be critical for certain targets and enable less frequent dosing. It’s also likely to have a different safety profile: blocking TfR on reticulocytes can cause anemia because of TfR’s role in iron transport.

Sandrock said humans with 50% less ALPL show no obvious adverse effects, although loss of 70% or more can cause bone mineralization issues. 

The goal is not one shuttle to rule them all, but an arsenal of shuttles with different properties suited to different applications.

“Having an array of shuttles against various receptors that give you the characteristics you need for the particular disease is going to be the way to go, and that’s why we’re doing what we’re doing,” he said.