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A next-generation therapeutic approach for patients after spinal cord injuries

NurExone (TSXV:NRX) has created an exosome-based drug-delivery platform and is developing a novel therapy for acute spinal cord injuries.
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NurExone has created ExoTherapy, a cutting-edge exosome-based drug-delivery platform and is developing its lead product, ExoPTEN, as a novel therapy for acute spinal cord injuries.

Over the past two decades, exosomes – small, extracellular vesicles that are naturally released by many cell types and can carry a variety of molecular cargoes – have become the subject of increasingly intense scientific investigation. Studies suggest exosomes are important messengers for cells and organs, with as-yet unexplored diagnostic and therapeutic potential.

Today, NurExone Biologic Inc. (TSXV:NRX), headquartered in Haifa, Israel, is at the forefront of developing exosomes into next-generation nanocarriers for drug delivery. Drawing on deep expertise in exosome biology, NurExone has created the ExoTherapy technology platform, which comprises proprietary methods for the production, isolation and loading of molecules into exosomes for therapeutic purposes. NurExone is applying the ExoTherapy platform to create the company’s lead product, ExoPTEN, an intra-nasally administered exosome-based ExoTherapy to promote neuro-regeneration for the treatment of acute spinal cord injuries.

Harnessing the properties of exosomes for therapeutic applications

Many cells produce extracellular vesicles (EVs), which are organized into subtypes with different sizes and biological functions. EVs generally fall into two categories: ectosomes, which pinch off from the cell membrane by outward budding; and much smaller exosomes, which have an endosomal origin and are created when endocytotic multivesicular bodies fuse with the plasma membrane, releasing the vesicles they contain as exosomes.

Scientific understanding of the origins and functions of exosomes is advancing, but there is widespread recognition that, far from being cellular waste products as once thought, exosomes play an important biological role in intercellular communication and transmission of macromolecules between cells. Further, through their cargo-carrying capacity, exosomes facilitate the spread of proteins, lipids, mRNA, miRNA, and DNA, which can contribute to their general therapeutic effects.

Beyond their normal biological roles, exosomes have increasingly gained attention as vehicles for the delivery of active pharmaceutical ingredients (APIs), from small molecules and peptides to proteins and nucleic acids, as an alternative not only to other kinds of nanocarriers such as lipid vesicles, but also cell-based gene therapies.

Exosomes offer a number of advantages as drug-delivery vehicles. As naturally occurring biological entities harvested from cells, exosomes have completely natural membranes that are better tolerated than many other types of drug-delivery vesicles synthesized from scratch in the laboratory. At the same time, exosomes do not seem to elicit the strong immune responses that often hamper allogeneic cell-based therapies used to deliver therapeutic molecules and genes to patients. In contrast to alternative therapeutic approaches, exosome therapies do not require expensive and time-consuming personalization, but can be used as “off-the-shelf” therapies suitable for all patients.

Exosomes have additional benefits as EV-based delivery vehicles for therapeutic agents. First, exosomes, including those produced by the ExoTherapy platform, can cross the blood–brain barrier (BBB), while other nanoparticles, such as most liposomes, cannot. ExoTherapy opens up the possibility of targeting different cell types – and, by extension, therapeutic indications – that are beyond the reach of non-BBB-crossing EVs1,2. Second, unmodified exosomes, even those carrying no molecular payload, have intrinsic properties that can be therapeutically beneficial, such as anti-inflammatory effects. Finally, exosomes can be administered intra-nasally.

Exosomes originate from many sources. NurExone’s ExoTherapy platform employs exosomes derived from mesenchymal stem cells, which are effective in targeting neuronal cells. The ExoTherapy platform overcomes the many technical challenges involved in producing, purifying, and loading exosomes with APIs of almost any type (Fig. 1). Through its ability to carry a wide variety of therapeutic modalities, ExoTherapy stands as a true platform technology for creating “off-the-shelf” therapies that can be administered non-invasively.

Fig. 1 | From exosome to ExoTherapy: NurExone’s technology platform. NurExone is developing a platform for large-scale production of exosomes and loading of molecular cargo to create biologically guided ExoTherapy. The company’s vision is to restore motor function in patients after a spinal cord injury. siRNA, small interfering RNA. Development of a non-invasive therapy for functional recovery after SCI

The ExoTherapy platform sits at the heart of NurExone’s long-term business plan, providing a tool for creating a rich pipeline of novel therapeutic assets. In the near term, NurExone’s ambitious goal is to bring to market a novel treatment for acute spinal cord injuries (SCIs) derived from the ExoTherapy platform, ExoPTEN.

Globally, an estimated 250,000–500,000 people experience an SCI annually3, with roughly 17,000 new cases in the United States4 and 10,000 in Europe3 each year, bringing the potential market to ~50,000 new cases per year. Vehicular accidents and falls account for the majority of SCIs; sports and recreational accidents are another relatively common cause of SCI. Although the incidence of SCI is low compared with major disease such as cancer or heart disease, the effects are often devastating for patients, irreversible, and expensive to manage.

Depending on the location of the SCI, the consequences can be loss of sensory or motor control of both lower limbs (paraplegia), lower limbs and trunk, or both lower and upper limbs (tetraplegia). SCIs can also affect autonomic regulation of the body, affecting breathing, heart rate, blood pressure, temperature and bowel and bladder function.

Patients with an SCI typically spend almost two weeks in an intensive care unit, followed by a month in a rehabilitation unit. Fewer than 1% of people with an SCI experience full neurological recovery by the time of discharge, and have reduced quality of life and overall life expectancy4. SCI patients are also often frequently re-hospitalized, on average for almost three weeks, principally due to diseases of the genitourinary system, but also resulting from respiratory, circulatory and musculoskeletal problems.

In addition to the enormous physical toll SCIs exert on patients, they are also costly for health service providers. Depending on the location of the SCI, estimates place the cost of managing patients recovering from SCI at between $300,000 and >$1 million, representing a huge burden on health services and the families of new SCI patients.

There are two major obstacles to recovery from SCI. First is the poor innate regenerative capacity of the central nervous system. A major impediment to axonal growth is phosphatase and tensin homolog (PTEN), which downregulates the mammalian target of rapamycin (mTOR) activity and as a result restricts the synthesis of protein required for axonal growth. Second, SCI healing is hampered by the inflammation, myelin-associated inhibitors, glial scar components and compromised blood supply that typically surround SCIs and create a hostile environment for recovery.

ExoPTEN, which comprises exosomes loaded with small interfering RNA (siRNA) that inhibits the production of the PTEN protein, addresses both of these obstacles. The exosome component of ExoPTEN possesses intrinsic anti-inflammatory properties, which helps create a more hospitable recovery environment at the SCI site. Meanwhile, the anti-PTEN siRNA counters the suppressive effects of PTEN, activating downstream pathways necessary for the protein synthesis underlying axonal growth and regeneration (Fig. 2).

Fig. 2 | ExoPTEN for the treatment of acute spinal cord injury. a, ExoPTEN: MSC-derived exosomes are loaded with PTEN siRNA (left). b, Non-invasive delivery. c, Mechanism of action: PTEN siRNA inhibits PTEN, downregulating PTEN-related pathways and promoting cell growth and proliferation. d, NurExone’s ambitious goal for ExoPTEN is to induce at least partial functional recovery in patients with acute spinal cord injuries. MSC, mesenchymal stem cell; PTEN, phosphatase and tensin homolog; siRNA, small interfering RNA.

ExoPTEN has been tested as an intra-nasally administered formulation in an extreme rat model of acute SCI: complete transection of the spinal cord resulting in paraplegia. In an internal preclinical study carried out by NurExone, untreated rats remained almost totally paralyzed eight weeks after surgical transection, whereas rats receiving ExoPTEN for a maximum of two weeks showed significant partial functional recovery. No ExoPTEN human trials have yet taken place but NurExone believes the therapy could translate to improvements in quality of life. (Unloaded exosomes also demonstrated a mild effect on post-operation recovery, highlighting the dual-effect nature of ExoPTEN.) ExoPTEN also partially restored healthy electrophysiological traces, indicative of axonal rewiring and regeneration, and improved sensory recovery and urinary reflex restoration.

ExoTherapy’s applications beyond spinal cord injury

The regenerative effects observed with ExoPTEN in the severe spinal cord transection model suggest it may also have therapeutic applications in situations in which cell regeneration is a limiting factor for recovery. One major potential application of ExoPTEN identified by NurExone is traumatic brain injury, which affects more people than SCI and for which there are no effective pharmacological treatments that reduce mortality or improve functional recovery. Other potential therapeutic areas in which ExoPTEN may have a powerful impact include cardiac ischemia/reperfusion injury and associated disease, wound repair, and infertility.

While ExoPTEN employs exosomes to deliver siRNA, the ExoTherapy platform can just as easily be used to deliver other drug modalities. Moving forward, NurExone is planning to continue the development of in-house candidates such as ExoPTEN, and will also explore licensing possibilities for pharma companies looking for an enhanced delivery system for their drug(s) of various modalities, as well as opportunities to form partnerships and collaborations to jointly develop novel ExoTherapy-based medicines.

References Guo, S., Redenski, I. & Levenberg, S. Cells 10, 1872 (2021). Guo, S. et al. ACS Nano. 13, 10015–10028 (2019). World Health Organization. Factsheet: Spinal cord injury (2013). Available from: https://www.who.int/news-room/fact-sheets/detail/spinal-cord-injury National Spinal Cord Injury Statistical Center, Facts and figures at a glance. Birmingham, AL: University of Birmingham at Alabama (2016).

This is third-party provided content issued on behalf of NurExone Biologic, please see full disclaimer here.

Join the discussion: Find out what everybody’s saying about this stock on the NurExone Biologic Inc. Bullboard investor discussion forum, and check out the rest of Stockhouse’s stock forums and message boards.

The post A next-generation therapeutic approach for patients after spinal cord injuries appeared first on The Market Herald Canada.

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Four burning questions about the future of the $16.5B Novo-Catalent deal

To build or to buy? That’s a classic question for pharma boardrooms, and Novo Nordisk is going with both.
Beyond spending billions of dollars to expand…

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To build or to buy? That’s a classic question for pharma boardrooms, and Novo Nordisk is going with both.

Beyond spending billions of dollars to expand its own production capacity for its weight loss drugs, the Danish drugmaker said Monday it will pay $11 billion to acquire three manufacturing plants from Catalent. It’s part of a broader $16.5 billion deal with Novo Holdings, the investment arm of the pharma’s parent group, which agreed to acquire the contract manufacturer and take it private.

It’s a big deal for all parties, with potential ripple effects across the biotech ecosystem. Here’s a look at some of the most pressing questions to watch after Monday’s announcement.

Why did Novo do this?

Novo Holdings isn’t the most obvious buyer for Catalent, particularly after last year’s on-and-off M&A interest from the serial acquirer Danaher. But the deal could benefit both Novo Holdings and Novo Nordisk.

Novo Nordisk’s biggest challenge has been simply making enough of the weight loss drug Wegovy and diabetes therapy Ozempic. On last week’s earnings call, Novo Nordisk CEO Lars Fruergaard Jørgensen said the company isn’t constrained by capital in its efforts to boost manufacturing. Rather, the main challenge is the limited amount of capabilities out there, he said.

“Most pharmaceutical companies in the world would be shopping among the same manufacturers,” he said. “There’s not an unlimited amount of machinery and people to build it.”

While Novo was already one of Catalent’s major customers, the manufacturer has been hamstrung by its own balance sheet. With roughly $5 billion in debt on its books, it’s had to juggle paying down debt with sufficiently investing in its facilities. That’s been particularly challenging in keeping pace with soaring demand for GLP-1 drugs.

Novo, on the other hand, has the balance sheet to funnel as much money as needed into the plants in Italy, Belgium, and Indiana. It’s also struggled to make enough of its popular GLP-1 drugs to meet their soaring demand, with documented shortages of both Ozempic and Wegovy.

The impact won’t be immediate. The parties expect the deal to close near the end of 2024. Novo Nordisk said it expects the three new sites to “gradually increase Novo Nordisk’s filling capacity from 2026 and onwards.”

As for the rest of Catalent — nearly 50 other sites employing thousands of workers — Novo Holdings will take control. The group previously acquired Altasciences in 2021 and Ritedose in 2022, so the Catalent deal builds on a core investing interest in biopharma services, Novo Holdings CEO Kasim Kutay told Endpoints News.

Kasim Kutay

When asked about possible site closures or layoffs, Kutay said the team hasn’t thought about that.

“That’s not our track record. Our track record is to invest in quality businesses and help them grow,” he said. “There’s always stuff to do with any asset you own, but we haven’t bought this company to do some of the stuff you’re talking about.”

What does it mean for Catalent’s customers? 

Until the deal closes, Catalent will operate as a standalone business. After it closes, Novo Nordisk said it will honor its customer obligations at the three sites, a spokesperson said. But they didn’t answer a question about what happens when those contracts expire.

The wrinkle is the long-term future of the three plants that Novo Nordisk is paying for. Those sites don’t exclusively pump out Wegovy, but that could be the logical long-term aim for the Danish drugmaker.

The ideal scenario is that pricing and timelines remain the same for customers, said Nicole Paulk, CEO of the gene therapy startup Siren Biotechnology.

Nicole Paulk

“The name of the group that you’re going to send your check to is now going to be Novo Holdings instead of Catalent, but otherwise everything remains the same,” Paulk told Endpoints. “That’s the best-case scenario.”

In a worst case, Paulk said she feared the new owners could wind up closing sites or laying off Catalent groups. That could create some uncertainty for customers looking for a long-term manufacturing partner.

Are shareholders and regulators happy? 

The pandemic was a wild ride for Catalent’s stock, with shares surging from about $40 to $140 and then crashing back to earth. The $63.50 share price for the takeover is a happy ending depending on the investor.

On that point, the investing giant Elliott Investment Management is satisfied. Marc Steinberg, a partner at Elliott, called the agreement “an outstanding outcome” that “clearly maximizes value for Catalent stockholders” in a statement.

Elliott helped kick off a strategic review last August that culminated in the sale agreement. Compared to Catalent’s stock price before that review started, the deal pays a nearly 40% premium.

Alessandro Maselli

But this is hardly a victory lap for CEO Alessandro Maselli, who took over in July 2022 when Catalent’s stock price was north of $100. Novo’s takeover is a tacit acknowledgment that Maselli could never fully right the ship, as operational problems plagued the company throughout 2023 while it was limited by its debt.

Additional regulatory filings in the next few weeks could give insight into just how competitive the sale process was. William Blair analysts said they don’t expect a competing bidder “given the organic investments already being pursued at other leading CDMOs and the breadth and scale of Catalent’s operations.”

The Blair analysts also noted the companies likely “expect to spend some time educating relevant government agencies” about the deal, given the lengthy closing timeline. Given Novo Nordisk’s ascent — it’s now one of Europe’s most valuable companies — paired with the limited number of large contract manufacturers, antitrust regulators could be interested in taking a close look.

Are Catalent’s problems finally a thing of the past?

Catalent ran into a mix of financial and operational problems over the past year that played no small part in attracting the interest of an activist like Elliott.

Now with a deal in place, how quickly can Novo rectify those problems? Some of the challenges were driven by the demands of being a publicly traded company, like failing to meet investors’ revenue expectations or even filing earnings reports on time.

But Catalent also struggled with its business at times, with a range of manufacturing delays, inspection reports and occasionally writing down acquisitions that didn’t pan out. Novo’s deep pockets will go a long way to a turnaround, but only the future will tell if all these issues are fixed.

Kutay said his team is excited by the opportunity and was satisfied with the due diligence it did on the company.

“We believe we’re buying a strong company with a good management team and good prospects,” Kutay said. “If that wasn’t the case, I don’t think we’d be here.”

Amber Tong and Reynald Castañeda contributed reporting.

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Petrina Kamya, Ph.D., Head of AI Platforms at Insilico Medicine, presents at BIO CEO & Investor Conference

Petrina Kamya, PhD, Head of AI Platforms and President of Insilico Medicine Canada, will present at the BIO CEO & Investor Conference happening Feb….

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Petrina Kamya, PhD, Head of AI Platforms and President of Insilico Medicine Canada, will present at the BIO CEO & Investor Conference happening Feb. 26-27 at the New York Marriott Marquis in New York City. Dr. Kamya will speak as part of the panel “AI within Biopharma: Separating Value from Hype,” on Feb. 27, 1pm ET along with Michael Nally, CEO of Generate: Biomedicines and Liz Schwarzbach, PhD, CBO of BigHat Biosciences.

Credit: Insilico Medicine

Petrina Kamya, PhD, Head of AI Platforms and President of Insilico Medicine Canada, will present at the BIO CEO & Investor Conference happening Feb. 26-27 at the New York Marriott Marquis in New York City. Dr. Kamya will speak as part of the panel “AI within Biopharma: Separating Value from Hype,” on Feb. 27, 1pm ET along with Michael Nally, CEO of Generate: Biomedicines and Liz Schwarzbach, PhD, CBO of BigHat Biosciences.

The session will look at how the latest artificial intelligence (AI) tools – including generative AI and large language models – are currently being used to advance the discovery and design of new drugs, and which technologies are still in development. 

The BIO CEO & Investor Conference brings together over 1,000 attendees and more than 700 companies across industry and institutional investment to discuss the future investment landscape of biotechnology. Sessions focus on topics such as therapeutic advancements, market outlook, and policy priorities.

Insilico Medicine is a leading, clinical stage AI-driven drug discovery company that has raised over $400m in investments since it was founded in 2014. Dr. Kamya leads the development of the Company’s end-to-end generative AI platform, Pharma.AI from Insilico’s AI R&D Center in Montreal. Using modern machine learning techniques in the context of chemistry and biology, the platform has driven the discovery and design of 30+ new therapies, with five in clinical stages – for cancer, fibrosis, inflammatory bowel disease (IBD), and COVID-19. The Company’s lead drug, for the chronic, rare lung condition idiopathic pulmonary fibrosis, is the first AI-designed drug for an AI-discovered target to reach Phase II clinical trials with patients. Nine of the top 20 pharmaceutical companies have used Insilico’s AI platform to advance their programs, and the Company has a number of major strategic licensing deals around its AI-designed therapeutic assets, including with Sanofi, Exelixis and Menarini. 

 

About Insilico Medicine

Insilico Medicine, a global clinical stage biotechnology company powered by generative AI, is connecting biology, chemistry, and clinical trials analysis using next-generation AI systems. The company has developed AI platforms that utilize deep generative models, reinforcement learning, transformers, and other modern machine learning techniques for novel target discovery and the generation of novel molecular structures with desired properties. Insilico Medicine is developing breakthrough solutions to discover and develop innovative drugs for cancer, fibrosis, immunity, central nervous system diseases, infectious diseases, autoimmune diseases, and aging-related diseases. www.insilico.com 


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Another country is getting ready to launch a visa for digital nomads

Early reports are saying Japan will soon have a digital nomad visa for high-earning foreigners.

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Over the last decade, the explosion of remote work that came as a result of improved technology and the pandemic has allowed an increasing number of people to become digital nomads. 

When looked at more broadly as anyone not required to come into a fixed office but instead moves between different locations such as the home and the coffee shop, the latest estimate shows that there were more than 35 million such workers in the world by the end of 2023 while over half of those come from the United States.

Related: There is a new list of cities that are best for digital nomads

While remote work has also allowed many to move to cheaper places and travel around the world while still bringing in income, working outside of one's home country requires either dual citizenship or work authorization — the global shift toward remote work has pushed many countries to launch specific digital nomad visas to boost their economies and bring in new residents.

Japan is a very popular destination for U.S. tourists. 

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This popular vacation destination will soon have a nomad visa

Spain, Portugal, Indonesia, Malaysia, Costa Rica, Brazil, Latvia and Malta are some of the countries currently offering specific visas for foreigners who want to live there while bringing in income from abroad.

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With the exception of a few, Asian countries generally have stricter immigration laws and were much slower to launch these types of visas that some of the countries with weaker economies had as far back as 2015. As first reported by the Japan Times, the country's Immigration Services Agency ended up making the leap toward a visa for those who can earn more than ¥10 million ($68,300 USD) with income from another country.

The Japanese government has not yet worked out the specifics of how long the visa will be valid for or how much it will cost — public comment on the proposal is being accepted throughout next week. 

That said, early reports say the visa will be shorter than the typical digital nomad option that allows foreigners to live in a country for several years. The visa will reportedly be valid for six months or slightly longer but still no more than a year — along with the ability to work, this allows some to stay beyond the 90-day tourist period typically afforded to those from countries with visa-free agreements.

'Not be given a residence card of residence certificate'

While one will be able to reapply for the visa after the time runs out, this can only be done by exiting the country and being away for six months before coming back again — becoming a permanent resident on the pathway to citizenship is an entirely different process with much more strict requirements.

"Those living in Japan with the digital nomad visa will not be given a residence card or a residence certificate, which provide access to certain government benefits," reports the news outlet. "The visa cannot be renewed and must be reapplied for, with this only possible six months after leaving the countr

The visa will reportedly start in March and also allow holders to bring their spouses and families with them. To start using the visa, holders will also need to purchase private health insurance from their home country while taxes on any money one earns will also need to be paid through one's home country.

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