A Phase 1, Open-Label Study to Determine the Biodistribution, Safety, and Tolerability of a Microdose of Radiolabeled BIIB080 Co-administered With BIIB080 in Healthy Adults

In this study, researchers will learn more about a study drug called BIIB080. BIIB080 is currently a drug under investigation for treatment of Alzheimer's disease. The main question researchers are trying to answer in this study is how radiolabeled BIIB080 distributes in the brain and spinal cord. To help answer this question, researchers will use positron emission tomography (PET) scanner that can detect radiolabeled BIIB080 after a single injection of a small dose of radiolabeled BIIB080 ([89Zr]Zr-DFO-BIIB080) and a dose of BIIB080 together via an intrathecal (IT) injection in healthy volunteers. Researchers will also learn about the safety of injecting radiolabeled BIIB080 and BIIB080 together.

Start Date13 Jun 2024

Sponsor / Collaborator

Biogen, Inc.

NCT05399888 / RecruitingPhase 2

A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the Efficacy, Safety, and Tolerability of BIIB080 in Subjects With Mild Cognitive Impairment Due to Alzheimer's Disease or Mild Alzheimer's Disease Dementia

In this study, researchers will learn more about a study drug called BIIB080. The study will focus on participants with mild cognitive impairment or mild dementia due to AD.
The main question researchers are trying to answer is if BIIB080 can slow the worsening of AD more than placebo. It will focus on what dose of BIIB080 slows worsening of AD the most.
To help answer this question, researchers will use the Clinical Dementia Rating-Sum of Boxes, also known as the CDR-SB.
Clinicians use the CDR-SB to measure several categories of dementia symptoms.
The results for each category are added together for a total score. Lower scores are better.
Researchers will also learn more about the safety of BIIB080.
The study will be split into 2 parts. The 1st part is the Placebo-Controlled Period. The 2nd part is the Long-Term Extension Period. The 2nd part of the study will help researchers learn about the long-term safety of BIIB080, and how it affects the participant's daily life, thinking, and memory abilities in the longer term.
A description of how the study will be done is given below.
After screening, participants will first receive either a low dose or high dose of BIIB080, or a placebo, as an injection into the fluid around the spinal cord (cerebrospinal fluid). A placebo looks like the study drug but contains no real medicine.
Participants will receive BIIB080 or placebo once every 12 weeks or 24 weeks.
After 76 weeks of treatment in the Placebo-Controlled Period, eligible participants will move onto the Extension Treatment period, which will last 96 weeks.
In the extension period, participants who received placebo will be switched to high dose BIIB080 every 12 or 24 weeks.
Participants may be in the study for up to 201 weeks, or about 4 years. This includes the screening and follow-up periods.
Participants can continue to take certain medications for AD. Participants must be on the same dose of medication for at least 8 weeks before the screening period.
After the screening period, most participants will visit the clinic every 6 weeks.

Start Date24 Aug 2022

Sponsor / Collaborator

Biogen, Inc.

NL-OMON55789 / RecruitingNot Applicable

A Randomized, Double-Blind, Placebo-Controlled Study, Followed by an Open-Label Extension, to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Doses of Intrathecally Administered ISIS 814907 in Patients with Mild Alzheimer*s Disease - ISIS 814907-CS1

Start Date04 Jan 2018

Sponsor / Collaborator

Ionis Pharmaceuticals, Inc.

100 Clinical Results associated with ISIS-814907

100 Translational Medicine associated with ISIS-814907

100 Patents (Medical) associated with ISIS-814907

Literatures (Medical) associated with ISIS-814907

01 Dec 2023·JAMA neurology

Exploratory Tau Biomarker Results From a Multiple Ascending-Dose Study of BIIB080 in Alzheimer Disease

Article

Author: Kordasiewicz, Holly ; Martarello, Laurent ; Wu, Shuang ; Mignon, Laurence ; Hutchison, R Matthew ; Ziogas, Nick ; Beaver, John ; Budd Haeberlein, Samantha ; Li, Yumeng ; Collins, Jessica A ; Edwards, Amanda L ; Lin, Lin ; DuBois, Jonathan ; Lane, Roger ; Junge, Candice ; Shulman, Melanie ; Graham, Danielle

Importance:

Accumulation of hyperphosphorylated, tangled microtubule-associated protein tau (MAPT) is a pathological hallmark of Alzheimer disease (AD) associated with disease progression and cognitive decline.

Objective:

To evaluate the effect of tau synthesis reduction on tau biomarkers in patients with mild AD.

Design, Setting, and Participants:

This randomized clinical trial was a double-blind, placebo-controlled 36-week multiple-ascending dose (MAD) phase 1b trial (October 2017 to September 2020), followed by a 64- or 71-week open-label long-term extension (LTE) (October 2019 to May 2022). After being assessed for eligibility at 12 sites in Canada and Europe, participants with mild AD and confirmed amyloid pathology were randomized 3:1 (BIIB080:placebo) in 4 dose cohorts.

Intervention:

Intrathecal administration of BIIB080, a MAPT-targeting antisense oligonucleotide, or placebo. Active dose arms included 10 mg every 4 weeks, 30 mg every 4 weeks, 60 mg every 4 weeks, and 115 mg every 12 weeks during the MAD period and 60 mg every 12 weeks or 115 mg every 12 weeks during the LTE.

Main Outcome and Measures:

The original primary end point was safety. Additionally, BIIB080, total tau (t-tau), and phosphorylated tau 181 (p-tau181) cerebrospinal fluid (CSF) concentrations were evaluated. Tau positron emission tomography (PET) was collected in a substudy, and standard uptake value ratios (SUVRs) were calculated in a priori-defined composite regions of interest.

Results:

Of 102 participants assessed for eligibility, 46 participants with mild AD were enrolled; 23 (50%) were female, and mean (SD) age was 65.8 (5.70) years. BIIB080 was generally well tolerated and was associated with a dose-dependent reduction in CSF t-tau and p-tau181 in the MAD period (56% reduction; 95% CI, 50% to 62%; and 51% reduction; 95% CI, 38% to 63%, of CSF t-tau in the 2 higher-dose cohorts) that continued and/or was maintained through quarterly dosing in the LTE. Tau PET demonstrated reduced accumulation vs placebo at week 25 (n = 13). At week 100, tau PET showed a reduction from baseline across all regions assessed (n = 12), with the largest reductions from baseline observed in the temporal composite (−0.71 SUVR; 95% CI, −1.40 to −0.02). A moderate correlation was observed between model-predicted cumulative CSF drug exposure and tau PET change.

Conclusions and Relevance:

In this randomized clinical trial, BIIB080 reduced tau biomarkers, including CSF t-tau, CSF p-tau181, and tau PET, which is associated with cognitive decline, in participants with mild AD. Effects of BIIB080 on biomarkers and clinical outcomes are being further evaluated in a phase 2 trial.

Trial Registration:

ClinicalTrials.gov Identifier: NCT03186989

04 May 2023·Expert opinion on drug discovery

The development of peptide- and oligonucleotide-based drugs to prevent the formation of abnormal tau in tauopathies

Review

Author: Sardone, Rodolfo ; Dibello, Vittorio ; Castellana, Fabio ; Panza, Francesco ; Lozupone, Madia ; Bellomo, Antonello ; Bortone, Ilaria ; Altamura, Mario ; Solfrizzi, Vincenzo ; Daniele, Antonio ; Zupo, Roberta ; Lampignano, Luisa ; Stallone, Roberta

INTRODUCTION:

Tauopathies represent clinicopathological entities with increased and abnormal glial and/or neuronal inclusions of tau, a microtubule-binding protein. Antisense oligonucleotides (ASOs) are a promising therapeutic approach for treating tauopathies as they can target tau mRNA to reduce total human tau expression or tau exon 10 expression and 4 R tau. Additionally, targeting the tau specifically with peptides may be a unique pharmacological approach, between small molecules and proteins.

AREAS COVERED:

The present review investigates the chemical basis of designing ASOs and peptides currently known to treat tauopathies. Among ASOs targeting tau expression, BIIB080 was the first to enter clinical trial development for treating mild Alzheimer's disease (AD). Furthermore, the therapeutic potential of peptide 021 (P021, Ac-DGGLAG-NH2) in tauopathies is discussed based on preclinical studies.

EXPERT OPINION:

ASOs are a promising therapeutic approach for tauopathies, particularly because ASOs may suppress the expression of harmful genes and are directly delivered to the brain, showing little systemic side effects. However, whether a generalized brain tau decrease will produce positive clinical effects remains unclear. A Phase II trial of BIIB080 is ongoing in mild AD. Neurotrophic and neurogenic peptide mimetic compounds have also shown potential as treatment options for AD and other tauopathies.

News (Medical) associated with ISIS-814907

16 May 2024

·www.biopharmadive.com

Biogen, Ionis shelve ALS drug following study failure

Biogen and Ionis Pharmaceuticals are stopping development of an experimental drug for ALS following new clinical trial results that didnt meet the companies expectations.The trial, which enrolled almost 100 people with the nerve-destroying disorder, found the drug actually worked as intended. Biogen and Ionis had designed it to lower levels of ataxin-2, a protein tied to amyotrophic lateral sclerosis, and on that measure it was successful. High-level results released Thursday showed participants who received the drug, named BIIB105, rather than a placebo experienced significant decreases in the protein over a six-month treatment period.However, the drug didnt appear to change the trajectory of the disease. It didnt impact breathing, strength and overall function key health measures that diminish as ALS progresses. BIIB105 also didnt substantially reduce a different protein, neurofilament light chain, that recently became important across this area of research. Qalsody, another ALS medicine developed by Biogen and Ionis, won marketing approval last year based on its ability to lower that protein.“While BIIB105 lowered ATXN2 protein, it did not reduce neurofilament, which gives us confidence that BIIB105 did not slow the disease process,“ said Stephanie Fradette, head of Biogens Neuromuscular Development Unit, in a statement.In the trial, participants who completed the main six-month treatment period were then offered entry into an open-label extension phase, in which they all could receive BIIB105. Biogen and Ionis said data from that phase were similar what was seen earlier in the study, with sustained reductions in the ataxin-2 protein but no impact on neurofilament or clinical outcome measures.The companies said there was no evidence that any subgroup of drug-treated patients benefited clinically.Analysis of the data remains ongoing. Biogen and Ionis plan to present more detailed study results next month at an ALS research convention in Stockholm.The shelving of BIIB105 is the latest setback for a field of drug development marred by failure. ALS, like many central nervous system disorders, is complex and difficult to combat. Scientists first discovered the disease over a century ago; and yet, just a few medicines have ever been approved to treat it. (The list got even smaller this year, as a once-promising medication from Amylyx Pharmaceuticals is being pulled from the market.)Approved in April 2023, Qalsody is the newest offering, though its for a very small fraction of ALS patients with specific genetic mutations. Biogen and Ionis collaborated on early development of the therapy, using the latters antisense oligonucleotide drugmaking technology.Qalsody essentially gums up the production of an ALS-associated protein called SOD1. The therapy actually failed to hit the central goal of the study that led the Food and Drug Administration to clear it. In that trial, Qalsody wasnt any better than a placebo at slowing disease progression. It was, however, better at lowering neurofilament light chain a biological marker of neurological damage.The FDAs decision effectively created a new route to approval for ALS drugmakers, who, since the Qalsody decision, have prioritized showing an effect on neurofilament in their clinical tests.So far, Qalsody is the only clear victory to come out of Biogen and Ionis ALS research. In 2022, the partners discontinued another antisense drug, code-named BIIB078, after an early-stage trial disappointed. Also on Thursday, Ionis revealed that Biogen has opted against licensing a drug the companies have been working on for Angelman syndrome, despite results Ionis described as positive.The longstanding partnership has been fruitful in other areas, though. Its produced a blockbuster medicine in Spinraza, a treatment for a rare, muscle-wasting illness. And over the past couple years, Biogen has highlighted the potential of another experimental drug, BIIB080, which is in mid-stage testing as a possible treatment for Alzheimers disease. '

Clinical ResultOligonucleotideDrug Approval

24 Apr 2024

·www.fiercebiotech.com

To be better at neuroscience, Biogen will invest outside the therapeutic area

Biogen already signaled a foray into rare disease last year, where CEO Chris Viehbacher said the company has “tremendous commercial capability.” To be a better neuroscience company, Biogen is going to have to diversify—outside of the therapeutic area that has in recent years defined the company. “We always call ourselves a neuroscience company, but the reality of neuroscience is that this is a high-risk area,” CEO Chris Viehbacher said on the drug developer’s first-quarter earnings call Wednesday morning. And so Biogen will be focused on business development outside of the neuroscience arena, which in turn, will support the expensive, lengthy trials required of the beat. “While we remain committed to neuroscience, my personal view is that is not diversified enough for a company of our size,” the CEO said. Biogen already signaled a foray into rare disease last year, where Viehbacher said the company has “tremendous commercial capability.” Thanks to the slow buildout of Leqembi in Alzheimer’s disease, Biogen knows a thing or two about launching medicines in difficult areas where diagnosis is a challenge and hurdles with payers are rampant. Viehbacher also sees further potential for expansion in multiple sclerosis. “We are very well placed in neurology … but the reality is that we sit there with programs that are very difficult to predict, very expensive, very long-running. And when you actually look at the ability to do external deals, that field is also very narrow. There's just not that many people working in the CNS space,” Viehbacher said. “So we're by no means abandoning it. The fact that we go after these really tough diseases is really a source of pride within Biogen.” He continued: “But the reality is we need to have more predictable results out of R&D.” Biogen's industry peers have found plenty to buy in the space. Bristol Myers Squibb bought Karuna Therapeutics and its schizophrenia med KarXT for $14 billion while AbbVie picked up CNS-focused Cerevel Therapeutics for $8.7 billion, all at the end of 2023. Speaking of deals, Biogen is unlikely to take on a huge acquisition this year, given the company’s balance sheet, the CEO said. “If something really extraordinary came along, you’d look at it,” he said. Chief Financial Officer Michael McDonnell said the balance sheet is “in a very good spot” in terms of net debt for the first quarter. He says there’s about $4 billion to $5 billion to play with for an acquisition target. In 2025 or beyond, that number could grow. As for the pipeline, the executives had little to report with respect to concrete data, but Viehbacher promised more to come as three key readouts draw closer. A big one is Biogen’s anti-tau agent for Alzheimer’s disease called BIIB080, followed by phase 3 assets dapirolizumab pegol and litifilimab, both for systemic lupus erythematosus. Biogen has developed some tough go-no-go criteria to ensure those programs are only advanced if they prove promising, said Priya Singhal, M.D., head of development. “I think the next job is really now to build out the pipeline,” Viehbacher said. “We want to diversify our business a little bit more than we have in the past.”

AcquisitionPhase 3

07 Mar 2024

·www.fiercebiotech.com

Tau, anti-inflammation and orals form Biogen's future Alzheimer's pipeline

Biogen has two clinical-stage Alzheimer's disease assets behind Leqembi, both of which target tau proteins or their dysfunction. “What does it mean to be a leader in Alzheimer’s disease?” That’s the question Biogen is asking itself, and the question many of the company’s peers are working fervently to answer as the heated race to differentiate from the first batch of Alzheimer’s treatments turns to a simmer. Adam Keeney, Ph.D., corporate development chief for the Leqembi co-maker, said in an interview with Fierce Biotech that Biogen is "not only just satisfied with [amyloid] beta" and instead "looking at the different pillars of disease." Keeney says the first stop on the portfolio-building circuit is tau. The company’s phase 2 antisense drug, BIIB-080, targets the protein buildup that accompanies amyloid beta in patients with Alzheimer’s. It’s an intrathecal injection—an injection into the spinal cord to bypass the blood-brain barrier— which Keeney described as “not ideal” though probably satisfactory for a first-generation option. But Biogen is planning for and think-tanking easier methods, like IV delivery and even oral compounds. “We're thinking about degraders and molecular glues and different technologies that we can use,” Keeney said. Biogen already has one oral option in the clinic, the O-GlcNACase inhibitor BIIB-131, a small molecule that looks to block the enzyme research has tied to tau’s dysfunction in Alzheimer’s patients. Keeney described oral delivery as a goal that’s on a “longer time horizon” routing the work back to the original question: What does it mean to be a leader in the space? Biogen has experienced the ups and downs of Alzheimer's drug discovery more acutely than probably any company. Its well-documented Aduhelm failure came to a much-expected conclusion earlier this year, when Biogen wound down all work on the approved med. Not only was it made obsolete by Leqembi, but the therapy was a corporate representation of time wasted. Meanwhile, Eli Lilly pressed on from behind, raising up donanemab, which is expected to get an FDA ruling any day now. The amyloid beta battle may not ultimately be an automatic reflection of tomorrow’s tau contest, or other options that may be discovered. Deeper into Biogen’s research work, the company is tinkering with novel anti-inflammatory targets, Keeney says. Targeting rogue tau buildup has proven difficult, just like amyloid. Lilly cut a phase 2 large-molecule zagotenemab in October 2021 after it failed to hit phase 2 endpoints. This followed phase 1 data showing four cases of brain bleeding (ARIA-H) across three patients, representing 19% of treated patients. Kenney says it remains to be seen whether that’s a genuine signal tied to tau-busting treatments—but it's certainly been an issue with Leqembi and donanemab. “I think it's probably too early to say there's a signal or not in that,” he said. “We have no signal that is preventing us to move forward.” Beyond drug development, critical advancements are happening in the Alzheimer’s diagnostic sector, with companies working to improve the tests that could detect amyloid buildup. There’s been such improvement in this area that a working group convened by the Alzheimer’s Association and the National Institute on Aging recently revised its criteria for diagnosing Alzheimer’s to include blood-based biomarkers. Keeney says those tests may not immediately be a primary diagnosis, but a negative result could preclude someone from an additional PET scan. “So we're also investing and working with collaborators because there are blood-brain barrier biomarkers that are out there,” Keeney said, noting they aren’t yet 100% predictive. “We're helping also get the predictive validity improved.” Despite the blood-based tests needing refinement, authors of the new testing criteria made clear that the future is now, and some tests provide “excellent diagnostic performance.” “The field is now in a transition phase during which plasma biomarkers are being integrated with traditional CSF and PET biomarkers,” the guidance states.

Phase 2Phase 1

100 Deals associated with ISIS-814907

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Dementia due to Alzheimer's disease (disorder)	Phase 2	US	Biogen, Inc.	24 Aug 2022
Dementia due to Alzheimer's disease (disorder)	Phase 2	JP	Biogen, Inc.	24 Aug 2022
Dementia due to Alzheimer's disease (disorder)	Phase 2	AU	Biogen, Inc.	24 Aug 2022
Dementia due to Alzheimer's disease (disorder)	Phase 2	BE	Biogen, Inc.	24 Aug 2022
Dementia due to Alzheimer's disease (disorder)	Phase 2	CA	Biogen, Inc.	24 Aug 2022
Dementia due to Alzheimer's disease (disorder)	Phase 2	DK	Biogen, Inc.	24 Aug 2022
Dementia due to Alzheimer's disease (disorder)	Phase 2	DE	Biogen, Inc.	24 Aug 2022
Dementia due to Alzheimer's disease (disorder)	Phase 2	IT	Biogen, Inc.	24 Aug 2022
Dementia due to Alzheimer's disease (disorder)	Phase 2	PL	Biogen, Inc.	24 Aug 2022
Dementia due to Alzheimer's disease (disorder)	Phase 2	ES	Biogen, Inc.	24 Aug 2022

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03186989 (Literature) Manual	Phase 1	Alzheimer Disease Tau protein	46	BIIB080	hmbpdqmwth(qjwblajvpt) = kjpjklylci zjsuowktha (iwbngrsuou, 50 - 62) View more	Positive	30 Oct 2023
NCT03186989 (Literature) Manual	Phase 1	Alzheimer Disease Tau protein	46	placebo	-	Positive	30 Oct 2023
NCT03186989 (NEWS) Manual	Phase 1	Alzheimer Disease	46	BIIB080	nbztkpssmi(bbnslkdutj) = gwckuidilx urgogdbngp (lcgtpgjjda )	Positive	26 Oct 2023
NCT03186989 (PRNewswire) Manual	Phase 1	Alzheimer Disease	46	BIIB080 (low dose group treated every four-weeks)	oorkdzfnkh(itybscaktf) = All adverse events were mild to moderate in severity with no serious adverse events occurring in any patients that received BIIB080. There were no deaths, dose-limiting adverse events or dosing discontinuations. pnobmxkvbc (vxinjtayih ) Met	Positive	16 Aug 2023
NCT03186989 (PRNewswire) Manual	Phase 1	Alzheimer Disease	46	BIIB080 (medium dose group treated every four-weeks)		Positive	16 Aug 2023
NCT03186989 (Ionis-MAPT Rx CS1, AAN2018)	Phase 1/2	Alzheimer Disease	-	IONIS-MAPT Rx	epnrhpihxf(sppfdmlwnq) = pkfxcthmfo ouxhcvphcn (txdkoobwyu )	Positive	10 Apr 2018
ANA2017	Not Applicable	Alzheimer Disease	-	Ionis-MAPTRx	egdrcrfrih(wrgyoixadn) = lhmgyjizab laittgbuxu (qpjefsuwug )	-	15 Oct 2017
Ionis-MAPTRx-CS1 (AAIC2017)	Not Applicable	Alzheimer Disease	-	Ionis-MAPTRx	krtydicjkj(xqbjooxlra) = bhwalzdvsj kfoaxzcpts (hedemxrazj )	-	01 Jul 2017

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