Key Points: – AbbVie acquires Aliada Therapeutics, adding ALIA-1758 and its unique drug-delivery platform. – Expands AbbVie’s neuroscience pipeline with advanced Alzheimer’s treatments. – Aliada’s MODEL platform enhances drug delivery across the blood-brain barrier.
AbbVie has strategically bolstered its Alzheimer’s portfolio by acquiring Boston-based Aliada Therapeutics in a deal valued at $1.4 billion. The acquisition brings AbbVie ALIA-1758, a Phase I anti-amyloid antibody targeting Alzheimer’s disease, along with Aliada’s novel Modular Delivery (MODEL) platform. This technology aims to improve the delivery of therapeutics across the blood-brain barrier (BBB), a significant challenge in developing drugs for the central nervous system.
With Alzheimer’s becoming a critical area for biotech and pharma innovation, AbbVie’s acquisition comes amid heightened interest in anti-amyloid therapies. The recent successes of Biogen and Eisai’s Leqembi and Eli Lilly’s Kisunla, the first FDA-approved disease-modifying treatments for Alzheimer’s, have demonstrated the potential of anti-amyloid treatments, though they come with risks. ALIA-1758 is designed to target pyroglutamate amyloid beta, an epitope similar to that in Kisunla, and leverages Aliada’s MODEL platform to improve therapeutic delivery.
The MODEL platform is engineered to transport therapeutic agents across the BBB by targeting transferrin and CD98 receptors, both of which are abundantly expressed in brain endothelial cells. The technology effectively carries antibodies across the BBB, allowing higher therapeutic concentrations in the brain to address amyloid plaques associated with Alzheimer’s. This targeted approach has the potential to provide superior treatment efficacy compared to previous approaches.
This acquisition aligns with AbbVie’s strategy of expanding its presence in neuroscience. The company already has a robust portfolio that includes experimental therapies like ABBV-916, another anti-amyloid antibody; ABBV-552, which targets nerve terminals to enhance synaptic function; and AL002, an antibody developed in partnership with Alector Therapeutics. With the addition of ALIA-1758, AbbVie strengthens its position in the field and continues to invest in innovation that could transform the treatment landscape for neurodegenerative diseases.
While the Alzheimer’s market is promising, AbbVie’s expansion comes with some caution. Analysts have noted that investor sentiment in anti-amyloid drugs is mixed, given the high cost and developmental challenges. However, AbbVie’s investment signals confidence in the MODEL platform’s potential to enhance drug delivery, particularly in addressing diseases with significant unmet needs like Alzheimer’s. AbbVie is optimistic that Aliada’s technology will complement its existing assets and support long-term growth in the neuroscience sector.
Expected to close by the end of 2024, the acquisition of Aliada Therapeutics is subject to regulatory approvals and standard closing conditions. The deal underscores AbbVie’s ongoing commitment to innovation and its mission to bring novel treatments to patients suffering from Alzheimer’s and other neurological disorders.
Pharmaceutical giant Merck announced Tuesday that it will acquire Caraway Therapeutics, a preclinical biotech company pursuing novel approaches to treating genetically defined neurodegenerative and rare diseases. The deal reflects Merck’s ongoing commitment to developing much-needed disease-modifying therapies for progressive brain conditions.
Under the agreement, Merck will make an upfront payment to obtain Caraway, followed by additional milestone payments contingent upon the progress of certain Caraway pipeline assets. Though financial terms were not disclosed, the total potential consideration could reach up to $610 million.
“Caraway’s multidisciplinary approach has yielded important progress in evaluating novel mechanisms of modulation of lysosomal function with potential for the treatment of progressive neurodegenerative diseases,” said George Addona, Merck’s head of discovery. “We look forward to applying our expertise to build upon this work with the goal of developing much needed disease-modifying therapies for these conditions.”
Unlike symptomatic treatments, disease-modifying therapies aim to directly impact underlying disease processes and ultimately alter the course of a condition’s progression. This has remained an elusive goal for brain diseases like Alzheimer’s and Parkinson’s.
Caraway’s work targets dysfunctions in cellular “recycling” processes that clear toxic materials from the brain. Its treatments stimulate lysosomes, which act as cell disposal units, to boost their activity. Researchers believe a boost in waste clearance could counter neurodegeneration.
Merck has been an investor in Caraway since 2018 through its venture capital arm MRL Ventures Fund. Now, by folding Caraway’s team and portfolio into its research labs, Merck aims to leverage its considerable drug development capabilities to advance lysosomal modulation treatments for neurodegeneration.
“This is a testament to the hard work and dedication of the Caraway team and our mission to develop therapeutics with the potential to alter the progression of devastating neurodegenerative diseases and help patients,” said Caraway CEO Martin D. Williams in a statement. “This acquisition leverages Merck’s industry-leading research and development capabilities to help further advance our discovery and preclinical programs.”
Alongside Merck, Caraway has been backed by several high-profile life sciences investors including SV Health Investors, AbbVie Ventures, Amgen Ventures, and Eisai Innovation.
An Urgent Need for Better Brain Treatments
Currently available medications can only manage symptoms for a period of time for Alzheimer’s, Parkinson’s, and related neurodegenerative diseases. None treat underlying pathologies or substantially slow worsening cognition and functionality.
Alzheimer’s alone impacts more than 6 million Americans and the prevalence is expected to triple in the next 30 years if no new treatments emerge. Experts have emphasized the urgent need for innovations.
Major players in the pharmaceutical industry have confronted disappointed late-stage clinical trial results among proposed Alzheimer’s treatments over the past decade, suffering high-profile setbacks.
Yet Merck’s buy-in suggests promise still exists in Caraway’s early-stage lysosomal modulation approach, even though treatments haven’t advanced to human testing yet. Merck aims to apply its extensive expertise to push potential therapies over the finish line where others have stumbled before.
Continuing a Neuroscience Focus
Alongside this deal, Merck continues to expand its research across neurodegenerative diseases in other ways. Thus far in 2023, Merck has also entered into research collaborations to pursue non-amyloid targets for Alzheimer’s and chiral chemistry for better brain penetrance among compounds targeting neurological conditions.
“The alignment with Caraway’s innovative science and focus on elucidating disease-modifying neurotherapeutics dovetails nicely with our ongoing work,” said Addona.
Overall, Merck’s acquisition of Caraway signals both increasing momentum around emerging theories of neurodegeneration—like waste clearance’s role—and a formidable commitment by the pharma organization to translating the latest science into paradigm-shifting treatments for patients.
Shares of clinical-stage biotech Prothena Corp skyrocketed over 20% on Monday amid reports the company is exploring strategic options including a potential sale. Prothena specializes in developing therapies for neurodegenerative diseases like Alzheimer’s, making it a hot target for larger pharmaceutical firms hungry for new assets in this space.
Based in Ireland and spun off from Elan Corp in 2012, Prothena focuses on protein misfolding disorders. Its pipeline features several promising programs targeting proteins believed to play a key role in Alzheimer’s and other neurological conditions with high unmet need.
Prothena’s lead candidate is birtamimab, an antibody-based therapy for AL amyloidosis in late-stage studies. Results expected later this year or in early 2024 could support regulatory filings. Beyond amyloidosis, the company is going all-in on Alzheimer’s research.
The most advanced Alzheimer’s asset is PRX012, an antibody targeting amyloid beta proteins thought to drive disease progression. Prothena is also developing a dual vaccine dubbed PRX012/PRX123 against amyloid beta and tau proteins. Reducing both proteins simultaneously may provide better clinical benefit.
These programs have already attracted partnership interest. Prothena has neuroscience collaborations with pharmaceutical giants Bristol Myers Squibb, Roche, and Novo Nordisk. Just this month, Bristol Myers exercised an option to license PRX005, Prothena’s anti-tau antibody, for nearly $60 million upfront.
But Prothena may seek an acquirer willing to buy the entire company outright. The potential payoff from Alzheimer’s success is massive given the huge unmet need. With late-stage data upcoming, now may be the optimal time for a sale.
Any acquirer would gain full access to Prothena’s Alzheimer’s pipeline, along with its programs for Parkinson’s disease and other neurodegenerative disorders. Adding these diverse assets to an existing neuroscience portfolio could create exciting synergistic opportunities.
Prothena’s small size also makes it financially digestible for big pharma buyers. The company’s market cap sits around $2.5 billion, presenting a worthwhile gamble for majors like Roche or Bristol Myers with scores of billions in annual revenue.
News of the company exploring strategic options sent Prothena shares surging 25% on nearly 6x normal volume. Investors are betting a buyout could be announced in coming months. Prothena’s pipeline progress makes it an alluring target.
Upcoming clinical results will prove whether Prothena’s Alzheimer’s bet pays off scientifically. But from a business perspective, the stars may be aligning for a near-term acquisition. Cash-rich pharmas need new prospects to bolster aging portfolios, and Prothena boasts some of the most exciting neurological assets out there.
If Prothena’s Alzheimer’s programs demonstrate strong efficacy, bidding wars could drive the buyout price sky-high. With biotech valuations rebounding from lows, management may see now as the perfect time to capitalize on these assets. Whether via sale, partnership or remaining independent, Prothena’s future direction should become clearer soon.
Image credit: National Human Genome research (Flickr)
What the FDA’s Accelerated Approval of a New Alzheimer’s Drug Could Mean for Those with the Disease – 5 Questions Answered about Lecanemab
The U.S. Food and Drug Administration (FDA) approved the medication Lecanemab, sold under the brand name Leqembi, on Jan. 6, 2023, through an “accelerated approval pathway” that fast-tracks promising clinical treatments for diseases in which there are no other currently effective options.
James E. Galvin, a neurologist from the University of Miami School of Medicine, specializes in the study of Alzheimer’s disease and Lewy body dementia. Below he explains the drug’s clinical potential to help ease the suffering of the roughly 6.5 million Americans who live with Alzheimer’s.
How Does Lecanemab Work, Biologically Speaking?
Lecanemab is a monoclonal antibody that targets beta-amyloid, a naturally occurring protein that becomes toxic when it clumps together to form the characteristic plaques that accumulate in the brains of people with Alzheimer’s disease. The drug is given through intravenous infusions every two weeks.
Antibodies are Y-shaped proteins circulating in the blood that recognize and neutralize substances in the body that they see as foreign, such as bacteria and viruses. A monoclonal antibody is produced by cloning, or making a copy of, a single white blood cell so that all the offshoot antibodies are derived from the same cell and bind to one specific target. In this case, lecanemab binds only to beta-amyloid proteins.
Lecanemab binds to a particular form of beta-amyloid as it clumps, called a protofibril. Studies suggest this is the species of beta-amyloid that is both most likely to aggregate into plaques that disrupt cell functioning and to play a role in the development of Alzheimer’s disease.
Earlier trials of other monoclonal antibodies failed to demonstrate a benefit and had more side effects, possibly because they targeted forms of beta-amyloid either too early or too late in the aggregation process.
Image: Misfolded beta-amyloid proteins aggegrate into clumps, called plaques, that form in the brains of people with Alzheimer’s
Could Lecanemab be a Game Changer for Alzheimer’s Treatment?
Potentially, yes, for people with early-stage Alzheimer’s disease. Medications such as lecanemab have the potential to interfere with the progression of Alzheimer’s disease by removing beta-amyloid from the brains of people who are suffering with it.
Two recent publications describe results from two different phases of clinical trials.
One study, published in early January 2023, reported the results of a phase 3 clinical trial that included 1,795 participants, half of whom received lecanemab and another half who didn’t. In that trial, treatment with lecanemab not only met all its clinical outcomes and safety requirements, but it also reduced the amounts of beta-amyloid measured in imaging tests and in the blood.
Researchers also saw reductions in the levels of tau – the protein responsible for the neurofibrillary tangles that accumulate inside the neurons in patient’s with Alzheimer’s. And they found reduced levels of other proteins that measure brain injury and degeneration. This suggests that lecanemab could potentially address the disease by targeting it through both direct and indirect pathways.
A separate study published in December 2022 reported the results of a phase 2 study with 856 participants. Lecanemab treatment also led to significant reductions in amyloid plaques on brain imaging tests, reductions in blood measurements of amyloid and tau protein and slowing of disease progression. These findings provide independent confirmation of the phase 3 findings and support the potential of lecanemab in the treatment of Alzheimer’s disease.
What Were the Results?
After 18 months of treatment in the phase 3 study, lecanemab slowed disease progression by 27% compared with the control group. Compared with those who didn’t receive the treatment, participants treated with lecanemab also showed 26% less decline on cognitive testing and a 36% slower loss of function in everyday activities. The study also found a marked reduction in the amount of beta-amyloid deposits in the brains of those who received the treatment.
These outcomes are the some of the largest effects yet seen in any Alzheimer’s disease clinical trial. While not cures, they provide hope that by significantly slowing physical, cognitive and functional decline while also removing amyloid, the course of disease might be altered in a way to give patients improved quality of life.
It is important to remember that the trial was only carried out over 18 months, so we do not fully know the long-term benefits of lecanemab. Ongoing long-term studies will hopefully bring additional insights. However, some recent simulation models have suggested that lecanemab treatment may provide long-term benefits and improve overall quality of life.
While lecanemab has shown clear benefits, it also comes with some notable potential adverse effects that need to be considered. In this case, the concerns are very specific to treatment with amyloid monoclonal antibodies.
In the phase 3 clinical trial, of the 1,795 participants, 12.6% taking lecanemab experienced swelling of the brain on MRI scans compared to 1.7% of those who received the placebo. Overall, only 2.8% of participants experienced any symptoms – mostly headaches.
In addition, 17.3% of those who received lecanemab had small hemorrhages, or bleeds, of the brain on MRI scans compared to 9% in the placebo group. While few participants experienced complications, at least three deaths due to brain hemorrhage have been reported in individuals enrolled in an ongoing long-term study. But notably, each of these people appear to have had additional risk factors.
How is Lecanemab Different from Other Treatments?
The currently available Alzheimer’s treatments – which include donepezil, rivastigmine, galantamine and memantine – primarily treat symptoms. They do not address the underlying disease processes, and they have modest clinical benefits.
One medication that does treat the disease, aducanumab, sold under the brand name Aduhelm, was approved by the FDA in 2021 under the same accelerated process as lecanemab. But it has not become widely used due to controversy about its efficacy and pricing.
So lecanemab could offer the first disease-modifying medication with undisputed results for people living with the early stages of Alzheimer’s disease. It is important to note that lecanemab was not studied in and was not approved for individuals with moderate or severe stages of Alzheimer’s disease.
When Could Lecanemab Reach Patients Who Could Benefit?
Although lecanemab has received approval from the FDA, it will likely be several months before it is available for clinical use.
Eisai and Biogen, the pharmaceutical companies that developed lecanemab, recently published guidelines on their pricing policy and roll-out plans for the drug. However, the Center for Medicare and Medicaid Services has said that for now, therapies targeting beta-amyloid will not be covered by insurance except for those individuals who are enrolled in clinical trials funded by the National Institutes of Health. And commercial insurance companies generally follow Medicare guidance.
Lecanemab will have an estimated out-of-pocket cost of $26,500 per year. The drugmaker has already filed a supplemental application for traditional FDA approval. If that approval is granted, it is more likely that Medicare and commercial insurance payers will cover most of the cost of lecanemab, which would make the drug much more widely accessible to those living with Alzheimer’s disease.
This article was republished with permission from The Conversation, a news site dedicated to sharing ideas from academic experts. It represents the research-based findings and thoughts of, James E. Galvin, Professor of Neurology, University of Miami.
Harnessing the Brain’s Immune Cells to Stave off Alzheimer’s and Other Neurodegenerative Diseases
Many neurodegenerative diseases, or conditions that result from the loss of function or death of brain cells, remain largely untreatable. Most available treatments target just one of the multiple processes that can lead to neurodegeneration, which may not be effective in completely addressing disease symptoms or progress, if at all.
But what if researchers harnessed the brain’s inherent capabilities to cleanse and heal itself? My colleagues and I in the Lukens Lab at the University of Virginia believe that the brain’s own immune system may hold the key to neurodegenerative disease treatment. In our research, we found a protein that could possibly be leveraged to help the brain’s immune cells, or microglia, stave off Alzheimer’s disease.
This article was republished with permission from The Conversation, a news site dedicated to sharing ideas from academic experts. It represents the research-based findings and thoughts of, Kristine Zengeler, Ph.D. Candidate in Neuroscience, University of Virginia.
Challenges in Treating Neurodegeneration
No available treatments for neurodegenerative diseases stop ongoing neurodegeneration while also helping affected areas in the body heal and recuperate.
In terms of failed treatments, Alzheimer’s disease is perhaps the most infamous of neurodegenerative diseases. Affecting more than 1 in 9 U.S. adults 65 and older, Alzheimer’s results from brain atrophy with the death of neurons and loss of the connections between them. These casualties contribute to memory and cognitive decline. Billions of dollars have been funneled into researching treatments for Alzheimer’s, but nearly every drug tested to date has failed in clinical trials.
Another common neurodegenerative disease in need of improved treatment options is multiple sclerosis. This autoimmune condition is caused by immune cells attacking the protective cover on neurons, known as myelin. Degrading myelin leads to communication difficulties between neurons and their connections with the rest of the body. Current treatments suppress the immune system and can have potentially debilitating side effects. Many of these treatment options fail to address the toxic effects of the myelin debris that accumulate in the nervous system, which can kill cells.
A New Frontier in Treating Neurodegeneration
Microglia are immune cells masquerading as brain cells. In mice, microglia originate in the yolk sac of an embryo and then infiltrate the brain early in development. The origins and migration of microglia in people are still under study.
Microglia play important roles in healthy brain function. Like other immune cells, microglia respond rapidly to pathogens and damage. They help to clear injuries and mend afflicted tissue, and can also take an active role in fighting pathogens. Microglia can also regulate brain inflammation, a normal part of the immune response that can cause swelling and damage if left unchecked.
Microglia also support the health of other brain cells. For instance, they can release molecules that promote resilience, such as the protein BDNF, which is known to be beneficial for neuron survival and function.
But the keystone feature of microglia are their astounding janitorial skills. Of all brain cell types, microglia possess an exquisite ability to clean up gunk in the brain, including the damaged myelin in multiple sclerosis, pieces of dead cells and amyloid beta, a toxic protein that is a hallmark of Alzheimer’s. They accomplish this by consuming and breaking down debris in their environment, effectively eating up the garbage surrounding them and their neighboring cells.
Given the many essential roles microglia serve to maintain brain function, these cells may possess the capacity to address multiple arms of neurodegeneration-related dysfunction. Moreover, as lifelong residents of the brain, microglia are already educated in the best practices of brain protection. These factors put microglia in the perfect position for researchers to leverage their inherent abilities to protect against neurodegeneration.
New data in both animal models and human patients points to a previously underappreciated role microglia also play in the development of neurodegenerative disease. Many genetic risk factors for diseases like Alzheimer’s and multiple sclerosis are strongly linked to abnormal microglia function. These findings support an accumulating number of animal studies suggesting that disruptions to microglial function may contribute to neurologic disease onset and severity.
This raises the next logical question: How can researchers harness microglia to protect the nervous system against neurodegeneration?
Engaging the Magic of Microglia
In our lab’s recent study, we keyed in on a crucial protein called SYK that microglia use to manipulate their response to neurodegeneration.
Our collaborators found that microglia dial up the activity of SYK when they encounter debris in their environment, such as amyloid beta in Alzheimer’s or myelin debris in multiple sclerosis. When we inhibited SYK function in microglia, we found that twice as much amyloid beta accumulated in Alzheimer’s mouse models and six times as much myelin debris in multiple sclerosis mouse models.
Blocking SYK function in the microglia of Alzheimer’s mouse models also worsened neuronal health, indicated by increasing levels of toxic neuronal proteins and a surge in the number of dying neurons. This correlated with hastened cognitive decline, as the mice failed to learn a spatial memory test. Similarly, impairing SYK in multiple sclerosis mouse models exacerbated motor dysfunction and hindered myelin repair. These findings indicate that microglia use SYK to protect the brain from neurodegeneration.
But how does SYK protect the nervous system against damage and degeneration? We found that microglia use SYK to migrate toward debris in the brain. It also helps microglia remove and destroy this debris by stimulating other proteins involved in cleanup processes. These jobs support the idea that SYK helps microglia protect the brain by charging them to remove toxic materials.
Finally, we wanted to figure out if we could leverage SYK to create “super microglia” that could help clean up debris before it makes neurodegeneration worse. When we gave mice a drug that boosted SYK function, we found that Alzheimer’s mouse models had lower levels of plaque accumulation in their brains one week after receiving the drug. This finding points to the potential of increasing microglia activity to treat Alzheimer’s disease.
The Horizon of Microglia Treatments
Future studies will be necessary to see whether creating a super microglia cleanup crew to treat neurodegenerative diseases is beneficial in people. But our results suggest that microglia already play a key role in preventing neurodegenerative diseases by helping to remove toxic waste in the nervous system and promoting the healing of damaged areas.
It’s possible to have too much of a good thing, though. Excessive inflammation driven by microglia could make neurologic disease worse. We believe that equipping microglia with the proper instructions to carry out their beneficial functions without causing further damage could one day help treat and prevent neurodegenerative disease.
