Key takeaways:

• Diranersen targets microtubule-associated protein tau mRNA to reduce tau production.
• Reductions in cerebrospinal fluid total tau ranged from 50% to 65% across doses.
• Adverse events were mild to moderate.

Patients with early Alzheimer’s disease treated with diranersen experienced slower cognitive decline and greater reductions in tau compared with placebo, according to data presented at the Alzheimer’s Association International Conference.

Diranersen (BIIB080, Biogen) is an investigational antisense oligonucleotide therapy that reduces tau production by targeting microtubule-associated protein tau mRNA, including intracellular and extracellular tau, unlike other therapies that only reduce extracellular tau, Biogen said in a press release.

Data derived from press release.

“Addressing intracellular tau is particularly important because tau tangles accumulate inside neurons,” Diana Gallagher, MD, head of immune mediated and neurodegeneration development, Biogen, told Healio.

“Unlike amyloid pathology, which can be present for many years prior to symptom onset, the spreading of tau tangles is known to be more temporally associated with clinical decline in Alzheimer’s,” she said.

In the clinic

The randomized, double-blind, placebo-controlled, dose-ranging phase 2 CELIA study included 416 patients (mean age, 68 years; 51% women), with 60% diagnosed with mild cognitive impairment and 40% with mild Alzheimer’s disease dementia.

Approximately 69% of the patients were APOE e4 carriers, and 23% were homozygotes. Patients intrathecally received 60 mg or 115 mg of diranersen every 6 months or 115 mg of diranersen every 3 months, or placebo, over 18 months.

The group taking 60 mg of diranersen every 6 months (n = 60) experienced the slowest cognitive decline of the treatment groups compared with the placebo group (n = 115), the researchers said.

Differences included 26% in Clinical Dementia Rating Sum of Boxes (CDR-SB), 42% in Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), 50% in Mini Mental State Examination (MMSE), 30% on modified Integrated Alzheimer’s Disease Rating Scale (iADRS) and 23% in Alzheimer’s Disease Composite Score (ADCOMS).

Among patients taking 115 mg every 6 months (n = 115), differences with the placebo group included 14% for CDR-SB, 32% for ADAS-Cog13, 34% for MMSE, 29% for modified iADRS and 21% for ADCOMS.

Differences between the group taking 115 mg every 3 months (n = 116) and the placebo group included 9% for CDR-SB, 29% for ADAS-Cog13, 38% for MMSE, 18% on modified iADRS and 7% on ADCOMS.

Reductions in cerebrospinal fluid total tau from baseline ranged from 50% to 65% across the treatment groups. Tau PET imaging (n = 131) also indicated decreases from baseline in all three treatment groups across all the regions of the brain that were evaluated.

“In CELIA, diranersen became the first tau-directed therapy to demonstrate robust reductions in both cerebrospinal fluid total tau and toxic tau tangles measured by PET scans,” Gallagher said.

Calling the treatment “well-tolerated,” Gallagher and colleagues categorized adverse events as “mild or moderate” as well as “non-serious,” with no treatment discontinuations or study withdrawal for most patients who experienced them.

Procedural pain, post-lumbar puncture syndrome and confusional state were the most common adverse events reported, with most confusional state episodes following doses by a few days and resolving within a week.

More than 90% of patients who completed the placebo-controlled period enrolled in the extension study.

Since diranersen targets tau, the researchers said they do not expect patients to experience amyloid-related imaging abnormalities, and findings from this study were consistent with these projections.

Community response

Along with these reductions in cerebrospinal fluid tau and tau PET, the findings at lower doses raise questions about optimal dosing and how future trials are designed, the Alzheimer’s Drug Discovery Foundation (ADDF) said in a press release.

“These are the first data from a randomized trial to show a tau-targeting drug producing both a robust biomarker effect and a signal of clinical benefit,” Laura Nisenbaum, PhD, interim chief science officer at ADDF, said in the release.

Nisenbaum called tau one of two pathologies that define Alzheimer’s disease as well as difficult to target, making these findings particularly notable. Yet patients in the 115 mg dose groups experienced more tau reduction, while patients in the 60 mg group had the strongest clinical signal, according to the ADDF.

“The dose-response discordance between the biomarker and clinical endpoints raises important questions about the optimal level of tau reduction and the right dose of diranersen to test in subsequent studies,” Nisenbaum said.

Although all three doses yielded clinical effects, Gallagher noted that there was no greater deceleration in clinical decline at 18 months. Still, she said, these results will guide phase 3 of this research.

“It is important to remember that this is the first drug to impact tau tangles and show clinical benefit. This phase 2 was designed to help us determine the optimal dose and dosing frequency, the onset and the magnitude of clinical benefit, and tolerability of this novel agent,” she said.

“We look forward to further evaluating these data with health authorities and external experts to inform dose selection and the optimal design for phase 3,” Gallagher said.

The ADDF also pointed out that Alzheimer’s treatment is moving beyond individual targets like amyloid or tau, with 75% of current trials examining inflammation, neurotransmitters and metabolic dysfunction.

“Drug development is moving in the right direction: beyond a single target and toward a broader arsenal of therapies that address the full pathology,” ADDF chief executive officer Isobel Coleman, DPhil, MPhil, said in the release.

“Tau is one of the core pathologies we will need to tackle if we are going to make combination a therapy,” she said. “Progress like this helps move the field closer to the precision medicine future the ADDF has championed for decades.”

Next steps

“The CELIA data provide some of the clearest evidence to date that reducing tau pathology can translate into clinically meaningful benefit,” Gallagher said.

According to Gallagher, the magnitude of these benefits is among “the most compelling reported” in drug development for Alzheimer’s disease.

“Together, the clinical, biomarker and safety data provide phase 2 proof of concept for diranersen’s novel tau-reduction mechanism and support advancing the program into confirmatory phase 3 development,” she said.

Reducing the rate of clinical decline preserves memory, decision-making abilities and other aspects of daily function, Gallagher said.

“For patients and families, maintaining these abilities for longer is meaningful,” she said. “Larger and longer-term studies will help us understand how the clinical effects observed in CELIA may translate into patients’ everyday lives.”

An ongoing long-term extension study will evaluate diranersen’s safety, tolerability and durability in early Alzheimer’s disease.

“Additional analyses and data from CELIA and the extension study will be presented at future scientific conferences,” Gallagher said.

For more information:

Diana Gallager, MD, Laura Nisenbaum, PhD, and Isobel Coleman, DPhil, MPhil, can be reached at neurology@healio.com.