Feliza Mirasol is the science editor for 

Feliza Mirasol

Novartis has entered into a global license and collaboration agreement with PTC Therapeutics (PTC) under which Novartis gets access to PTC’s PTC518 Huntington's disease program, which includes related molecules, the two companies announced on Dec. 2, 2024 (1,2). PTC518 is a huntingtin (HTT) messenger RNA (mRNA) splice modulator. It has the potential to become the first oral disease-modifying therapy for Huntington's disease, according to the Novartis press release (1).

Under the agreement, Novartis will pay an upfront payment of $1 billion and up to $1.9 billion in development, regulatory, and sales milestones. Both companies will share in profits and losses in the United States on a 40/60 basis (40% PTC and 60% Novartis) (2). Novartis will also pay PTC tiered royalties on sales outside the US (1). The transaction is subject to customary closing conditions, including regulatory clearance, and is expected to close in the first quarter of 2025 (2).

Novartis will assume responsibility for the development, manufacturing, and commercialization of PTC518 following completion of the placebo-controlled portion of an ongoing Phase II study (PIVOT-HD), which is expected in the first half of 2025. The agreement bolsters Novartis’ neuroscience pipeline and as the company focuses its efforts on neurodegenerative diseases with high unmet needs.

"PTC518 is the leading oral disease-modifying therapy in development for Huntington's disease and the economics of this agreement are consistent with the promise of this treatment," said Matthew B. Klein, MD, chief executive officer, PTC Therapeutics, in that company’s press release (2). "This collaboration combines PTC's expertise in developing small-molecule splicing therapies with Novartis's expertise in global development and commercialization of neuroscience therapies. We are excited to collaborate with Novartis to accelerate the potential of PTC518 for the hundreds of thousands of HD patients worldwide in need of a therapy designed to be well-tolerated and an effective disease-modifying therapy. PTC will use the proceeds of this transaction to expand our splicing platform as well as to support commercial and development portfolio activities."

PTC discovered PTC518 through its validated splicing platform. Interim results reported in June 2024 (3) from the ongoing Phase II study demonstrated that treatment with PTC518 resulted in durable, dose-dependent reduction in blood and cerebrospinal fluid mutant HTT levels. The interim results also showed early signals of a dose-dependent benefit on key clinical measurements at 12 months. More importantly, according to PTC, PTC518 has continued to demonstrate a favorable safety and tolerability profile (3).

"Huntington's [d]isease is a devastating, fatal, familial disease. This agreement with PTC is intended to bolster our neuroscience pipeline and reflects our strategic focus and commitment to explore new and potentially transformative approaches for neurodegenerative diseases with high unmet needs," said Vas Narasimhan, CEO of Novartis, in PTC’s company press release (2). "We look forward to building on our expertise in neurodegenerative diseases and experience in [Huntington's disease] with the intention to advance this potential first-in-class oral therapy for the [Huntington's disease] community."

1. Novartis. Novartis Bolsters Neuroscience Pipeline with In-Licensing of PTC518 for Huntington’s Disease. Press Release. Dec. 2, 2024.
2. PTC Therapeutics. PTC Therapeutics Enters into a Global License and Collaboration Agreement with Novartis for PTC518 Huntington's Disease Program. Press Release. Dec. 2, 2024.
3. PTC Therapeutics. Interim PIVOT-HD Results Demonstrate Evidence of Favorable CNS Biomarker and Clinical Effects at Month 12 in Huntington's Disease Patients. Press Release. June 20, 2024.

Articles

Novartis will in-license PTC's PTC518 program, which has the potential become the first oral disease-modifying therapy for Huntington's disease.

Novartis Enters $2.9 Billion License Agreement with PTC Therapeutics for Huntington’s Disease Development Program

Lipid nanoparticles (LNPs) have been gaining traction as a primary formulation and drug delivery tool in the manufacture of messenger RNA (mRNA)-based therapeutics, having proven their utility in the development of mRNA COVID-19 vaccines. As the development of LNP-enveloped mRNA therapeutics advances, what other nanoparticle technologies offer the opportunity for optimizing the formulation of mRNA—and potentially other nucleotide-based—therapeutics? This article explores the advancement of LNP formulations as well as additional nanoparticle technologies in this space.

Developing an mRNA therapeutic involves both the manufacture of the mRNA molecule itself and combining that molecule into some sort of delivery technology, whether that delivery technology is a LNP or other platform, says Colin McKinlay, PhD, senior director, Chemistry and Delivery Technologies, at Nutcracker Therapeutics. One of the challenges McKinlay points out is the type of approach a developer must take in manufacturing these types of drugs, which are unique in that they are personalized therapies, where every patient, each therapy, and the drug components are basically different.

“I think one of the lessons learned from the whole COVID-19 pandemic and putting together the mRNA-based vaccines for COVID-19 was that we could actually scale these [vaccines] up to worldwide scales, and that we were able to do that fairly effectively,” said McKinlay. “But starting to think about distributing and manufacturing mRNA drugs, where every patient has a different type of formulation, I think that starts to be a different type of challenge.”

Somewhat related to the logistics of distribution, McKinlay goes on to explain that many of the challenges associated with mRNA drug manufacturing are tied into having the ability to bridge smaller-scale companies—that is, their research work—into Phase I, Phase II, clinical-trial scale, and get these companies the materials they need for conducting those trials. “There are [many] commercial suppliers that are available for research-grade mRNA and for making mRNA at that small scale when [companies] are doing [their] discovery work. And obviously, if [a company] wants to invest a large amount of money into manufacturing, there are [many] opportunities available for large-scale commercialization, but getting strategies that are suited for … small clinical-trial stage where it is not too cost prohibitive upfront is something [where] there is a definite need in the market for,” McKinlay says.

With personal background experience in academia and moving up to a small startup and eventually to a mid-size startup, McKinlay relates the lessons learned in dealing with LNP manufacturing. “One of the things I’ve found throughout my career is that when you’re doing those initial discovery experiments and early stage experiments, you really want to be able to run high-throughput type experiments—screening different formulation chemistries, different combinations of components, or even different mRNA cargo types. However, at that small [of a] scale, [many] commercial options for making LNPs are not really tailored towards that small scale,” he explains.

In the course of his work, McKinlay noted that, although there are production systems available from various different suppliers, these systems generally have a rather large minimum volume or minimum scale at which they can operate. “What [many] people end up doing is to just pipette-mix or hand-mix their components, which means that the LNPs you’re making are very different than the LNPs you’re going to be making farther down in your development process during scale up,” he says.

One of the ways that a company can address this problem is by having its own engineering team in-house, McKinlay emphasizes. With this in-house capability, the company can have the team think about the challenges and ways to design LNPs on both a manufacturing level and at a system level. The results of the engineering team’s work can be used in research that is applied to much of the same core technologies. This gives the company the advantage of having information that can be translatable at every stage of development. “I think there are other companies that are starting to pick up on that importance,” McKinlay says, “but if you don’t think about that early on, you might end up optimizing for something that doesn’t end up being quite as good later on [and further] into your manufacturing process.”

Looking beyond the manufacturing challenges, innovations are in development to address these hurdles. McKinlay notes that some of those innovations are just starting to kick off. “The first wave [of innovation] has [involved the use of] a lot of the existing manufacturing technologies in the biologic space for these mRNA molecules. Now, [the industry is] actually starting to get different companies that are thinking about: how do we actually pursue this workflow for an mRNA specific platform? Not just pushing ourselves across the finish line, but really trying to adapt things to the advantages of mRNA and the unique challenges associated with mRNA?” he states.

McKinlay has also observed that some of the larger mRNA companies are starting to consider the problems in the mRNA space much more deeply with an aim to innovate in this space in a more mRNA-centric way. “For instance, one of the things I brought up earlier is the personalized medicines aspect. One of the exciting things about mRNA is some of the personalized therapies and personalized vaccines [that have come out of this space],” he remarks.

With a growing number of personalized medicines coming onto the scene, the industry is now looking at unique manufacturing challenges associated with them. “I think those are areas where we’re going to continue to see different types of innovation in the field,” McKinlay adds.

Broadly speaking, McKinlay considers the fact that not everybody is going in the same direction with mRNA therapeutic development an exciting trend. “There are a lot of different places that mRNA can be applied. In some cases, moving past the early stages of this field, one of the things that people are going to have to do is start specializing in different areas and saying, ‘Okay, this company is going to take mRNA in this direction.’ ‘This company is going to take it in a different direction.’ I think [this attitude] is one of the great things about a broad field like mRNA,” McKinlay says.

Vaccine development is an area where mRNA has truly demonstrated its effectiveness. But McKinlay points out the importance of not pigeonholing that platform technology such that mRNA is only thought of as a vaccine technology. Moving beyond infectious disease vaccines, or even COVID-19 vaccines, is going to be crucial to the growth of the mRNA field, McKinlay believes.

In terms of the LNP side of this field, McKinlay emphasizes that a number of LNP technologies exist that will focus on expression in the liver and that are directed towards the liver. “One of the [notions] that a lot of folks in the field are really focusing on is, ‘how do we actually direct these lipid nanoparticles to other organs in the body so that we can address other types of disease areas?’,” he says. Many companies are on this train of thought as well as researchers in academia, McKinlay explains. However, there has not been large-scale clinical successes in this area yet, he notes. “I think that’s definitely a place where more development is going to be taking place, and there’s going to be a lot of kind of handoffs between academia and industry in finding some strategies to address that,” he states.

Exploring other delivery vehicles and opportunities

In terms of non-viral RNA delivery, LNPS have largely dominated this field in terms of clinical approvals and later-stage development, according to McKinlay. However, he cautions against the industry getting stuck in these local maxima, “where the field does a lot of optimization, and [players] are able to climb in efficacy, but then [they] reach a point where there’s not too much [left] that [they] can really optimize anymore.”

Nutcracker’s exploration of alternative delivery vehicles has resulted in the company’s peptoid-based platform. According to McKinlay, these peptoids can be used in a traditional LNP-type formulation. “We’re able to branch away from traditional LNP type particles and have particles that are a little bit more unique to the chemistry of these peptoid molecules. We think that [this technology] is pushing us over, a little bit away from where the rest of the field is working; there may be a little bit more room to grow and a little bit more room to improve,” he states. McKinlay also believes that, with more and more people in the field exploring different respective local maxima, the industry as a whole can net benefit together by improving the overall safety and efficacy of the mRNA delivery vehicles that it has available to it.

Meanwhile, in academia there is also focus on using LNPs for other types of genetic cargo, such as other types of RNA or even DNA. “Beyond nucleic acids, there is also significant opportunities for using LNPs in, maybe, combination therapies, where you may have an mRNA molecule, but you also have a lipophilic, small molecule that you can incorporate into the LNP. By combining those two together, you can [potentially] see increased efficacy,” McKinlay says. “Regardless of what the future holds for mRNA therapeutics, a tight handshake between therapeutics discovery and manufacturing will be necessary for its success.”

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Vol. 48, No. 12
December 2024
Pages: 20–21

When referring to this article, please cite it Mirasol, F. Exploring Opportunities for LNP Delivery in mRNA. 

LNPs have gained solid ground as a drug delivery system for mRNA due to their success in the vaccines arena.

Exploring Opportunities for LNP Delivery in mRNA

On Dec. 5, 2024 both Eli Lilly and Company (Lilly) and Amgen announced their plans to expand their manufacturing facilities in Kenosha County, Wis., and Holly Springs, NC, respectively. Lilly said it is investing $3 billion to expand the Kenosha County manufacturing facility it acquired earlier in 2024 (1), while Amgen said it will invest $1 billion to establish a second drug substance manufacturing facility at its site in Holly Springs, which brings Amgen’s total planned investment in Holly Springs to more than $1.5 billion (2).

Lilly’s investment aims to extend the company’s global parenteral product manufacturing network to meet growing demand for its diabetes and obesity therapies as well as future pipeline medicines across therapeutic areas. Construction for the expansion is expected to begin in 2025. Lilly expects to add 750 highly skilled jobs to the current approximately 100-person workforce at the Kenosha County location. The new highly skilled jobs will include operators, technicians, engineers, and scientists and will be in addition to the more than 2000 construction jobs that will open up during the construction phase.

"Today's announcement represents our single largest US manufacturing investment outside our home state of Indiana and will add to our ability to expand capacity to make both our existing and future pipeline of medicines right here in the Midwest," said Edgardo Hernandez, executive vice-president and president of Lilly Manufacturing Operations, in a company press release (1). "We look forward to bringing high-wage, advanced manufacturing, engineering, and science jobs to people in Wisconsin, a state that is becoming a critical geography in our global manufacturing operations."

Lilly plans to use advanced automation—including guided vehicles, robotics, and production equipment—to accelerate injectable medicine production. Digital automation will be embedded throughout the site for data management to operations to accelerate processes and increase accuracy.

Lilly aims to foster partnerships with local higher education institutions and support various community initiatives in Wisconsin to advance innovation in pharmaceutical manufacturing.

Amgen grows drug substance manufacturing capacity

Amgen’s investment in its Holly Springs site will build a new manufacturing facility for drug substance production. As part of the expansion, the company will incorporate cutting-edge technologies and sustainable practices. Together with the already existing facility at the site, the company’s investments will create 370 new jobs in the region and will support a robust biomanufacturing hub (2).

"This expansion underscores our unwavering focus on bringing transformative medicines to patients around the world," said Robert A. Bradway, chairman and chief executive officer at Amgen, in a company press release (2). "North Carolina will be an important part of our global manufacturing network as we continue to meet the growing demand for our innovative therapies while generating significant local economic impact."

Amgen chose North Carolina, which has grown a reputation as a premier life sciences destination, for the state’s ecosystem of life sciences innovation and skilled workforce. “This expansion enhances the company's global biomanufacturing network, leveraging decades of operational expertise and technological advancements to ensure the reliable and efficient delivery of high-quality medicines to patients worldwide,” the company stated in its release (2).

1. Eli Lilly and Company. Lilly Announces $3 Billion Expansion of its Recently Acquired Manufacturing Facility in Wisconsin. Press Release. Dec. 5, 2024.
2. Amgen. Amgen Announces $1 Billion Manufacturing Expansion in North Carolina. Press Release. Dec. 5, 2024.

Lilly is investing $3 billion to expand its recently acquired manufacturing facility in Wisconsin, while Amgen is investing $1 billion to expand its facility in North Carolina.

Lilly and Amgen Each Announce Major Expansions of US Manufacturing Sites

Cambrex, a contract development and manufacturing organization, announced on Dec. 5, 2024 that it has entered into an agreement with Eli Lilly and Company (Lilly) aimed at Cambrex providing accelerated access to clinical development capabilities for Lilly's biotech collaborators.

Under the agreement, Cambrex will partner with Lilly's early external innovation and collaboration arm, Lilly Catalyze360-ExploR&D. Cambrex will provide drug substance, drug product, analytical service labs, and R&D expertise to biotech collaborators teamed with Lilly Catalyze360.

"We are excited to support Lilly's mission to enable external biotech collaborators to expedite their product development," said Brandon Fincher, president of Early Stage Development & Testing at Cambrex, in a company press release (1). "Our Longmont [Colorado] facility offers all services required to advance early stage small molecules into the clinic with speed, flexibility, and scientific excellence. We look forward to propelling Lilly Cataylze360 collaborators forward on an efficient path to success with their products."

Lilly Catalyze360 focuses on advancing science and supporting emerging medicines via investment and through its three pillars—Lilly Ventures, Lilly Gateway Labs, and Lilly ExploR&D. Under the agreement, Cambrex will partner with ExploR&D, which brings enterprise learning, scientific know-how, and best-in-class research and development capabilities to accelerate partner science, according to the company press release.

Primary services offered through the agreement will be conducted in the Longmont, Colo., facility. Additional support will be provided by Cambrex's network, as needed. Cambrex's Longmont facility specializes in the early development of investigational new drugs, from process development and drug substance manufacturing through to formulation development and drug product manufacturing. The facility houses capacity for non-good manufacturing practice (GMP) and current good manufacturing practice (CGMP) production. The site simultaneously provides full analytical development and CGMP testing support.

Cambrex also recently strengthened its process development capabilities when it formed a strategic collaboration with Atinary Technologies in September 2024 (2). Under this collaboration, Snapdragon Chemistry, a Cambrex company, will integrate Atinary’s AI-driven and automated process optimization technology with its own state-of-the-art laboratories and process development capabilities, which will allow Snapdragon to tackle complex challenges in drug development. Snapdragon specializes in API process development, with a focus on continuous flow process development, lab automation, and complex synthetic APIs.

Under the collaboration with Atinary, Snapdragon has integrated its proprietary LabOS software platform with Atinary’s SDLabs platform to build a fully automated and AI-driven, medium-throughput Solid-Phase Oligonucleotide Synthesizer (SPOS). The purpose of the SPOS is to enable autonomous multi-objective process optimizations. Atinary’s AI platform has enhanced Snapdragon’s process optimization campaign with significant improvements across tested applications. Snapdragon was able to demonstrate up to an 18% increase in product yield and a 22% reduction in cost compared to processes previously optimized by an experienced scientist (2).

“Atinary is committed to accelerating innovation and delivering cutting-edge solutions to our customers,” said Hermann Tribukait, PhD, co-founder and CEO of Atinary Technologies, in a company press release issued in September (2). “Our work with Snapdragon showcases the power of our AI and data-driven process to solve complex chemistry and molecular discovery challenges in the pharmaceutical and biotech industry, orders of magnitude faster than traditional methods.”

1. Cambrex. Cambrex Announces Strategic Agreement with Lilly to Support Biotech Collaborator Manufacturing. Press Release. Dec. 5, 2024.
2. Cambrex. Atinary Technologies Announces Strategic Collaboration with Snapdragon Chemistry, a Cambrex Company. Press Release. Sept. 26, 2024.to Support Biotech Collaborator Manufacturing. Press Release. Dec. 5, 2024.
2. Cambrex. Atinary Technologies Announces Strategic Collaboration with Snapdragon Chemistry, a Cambrex Company. Press Release. Sept. 26, 2024.

Through the agreement, Cambrex will provide accelerated access to clinical development capabilities to Lilly’s biotech collaborators.

Cambrex Enters Agreement with Lilly to Support Biotech Collaborator Manufacturing 

Belgium-based EXO Biologics and its contract development and manufacturing organization (CDMO) subsidiary, ExoXpert, both innovators in exosome-based therapeutics and drug delivery solutions, announced on Dec. 2, 2024,  that ExoXpert has received good manufacturing practice (GMP) certification for its Liège, Belgium, manufacturing facility. At the same time, EXO Biologics achieved the loading of GMP-grade exosomes with messenger RNA (mRNA) and DNA payloads. Both achievements mark significant milestones for the development of exosome-based therapeutics (1).

According to a company press release, ExoXpert is the first European CDMO specializing in exosomes that has received GMP certification (1). The certification was awarded by the Belgian Federal Agency for Medicines and Health Products. Both BioWin, the Health Cluster of Wallonia, Belgium, and the Public Service of Wallonia have been strong supporters of EXO Biologics’ and ExoXpert’s growth, according to the press release.

“We have now achieved two critical strategic milestones by the end of 2024, which extends our continued progress in developing scalable, GMP-compliant solutions for exosome as therapeutic and drug delivery system. This extends our market leading position in the development of exosome-based technologies, unlocking new possibilities for drug delivery, gene therapy, and immunotherapy,” said Hugues Wallemacq, CEO of EXO Biologics, in the press release.

The importance of the GMP certification lays in the official status it gives to ExoXpert’s ability to produce exosomes according to the highest industry standards. The GMP-certified facilities enable EXO Biologics to internalize production of EXOB-001, currently in Phase I clinical development and the first global European Medicines Agency-approved mesenchymal stem cell-based exosome therapeutic in clinical trials. The certification also enables ExoXpert to offer exosome-specialized GMP capabilities internationally, including to current clients in the United States and European Union markets as well as future partners. ExoXpert also has the ability to activate additional cleanroom on demand. The greatest demand for exosomes currently is their use as a safe and non-viral drug delivery system for cell and gene therapy applications, according to the company press release (1).

The second achievement, the successful loading of mRNA and DNA payloads into GMP-grade exosomes, represents a critical step toward developing safe, efficient, and scalable exosome-based therapies for genetic material delivery. While small molecules and short nucleic acids (e.g., small interfering RNA and microRNA) have already been validated in an end-to-end GMP-like setting (2), EXO Biologics’ achievement demonstrates significant progress in the loading of larger molecules (i.e., mRNA and DNA) into GMP-grade exosomes that can then be used for third-party non-viral drug delivery applications. The company’s preliminary trials data have shown a retention rate up to 80% of the loaded DNA cargo upon exosome loading (1).

“The GMP certification of ExoXpert’s Liège manufacturing facility and the successful loading by EXO Biologics of mRNA and DNA into exosomes are major steps in bringing safe and effective exosome-based therapies to patients worldwide. We are now working on optimizing the loading technology to further reduce the manufacturing cost and strengthen the attractiveness of exosome therapeutics and manufacturing compared to alternative classical technologies. This will revolutionize the treatment of complex diseases, including cancer, genetic disorders, and viral infections,” Wallemacq said in the release (1).

1. EXO Biologics. EXO Biologics & ExoXpert Achieve Two Critical Industry-First Milestones for the Exosome Field. Press Release. Dec. 2, 2024.
2. Bhome, R.; Del Vecchio, F.; Lee, G-H.; et al. Exosomal MicroRNAs (exomiRs): Small Molecules with a Big Role in Cancer. 

, 228–235. DOI: 10.1016/j.canlet.2018.02.002

EXO Biologics and ExoXpert, an EXO Biologics subsidiary, have received GMP certification of a European manufacturing facility for exosomes and have successfully loaded mRNA and DNA payloads into GMP-grade exosomes for drug delivery.

Exosomes Field Advances with Milestones Achieved by EXO Biologics and ExoXpert

Lonza has expanded its services to support smart capsule companies developing orally delivered biologics. Oral biologics have unique development and manufacturing requirements, Lonza stated in a Dec. 3, 2024 company press release (1).

Smart capsules are designed to enhance precision, efficacy, and control. They use electronic or mechanical elements to deliver drugs to the stomach or intestine, and their mode of action has the potential to revolutionize the market for oral biologics, Lonza stated in its release (1). There are promising applications for smart capsules in diabetes, obesity, and other therapeutic fields.

To meet the needs of companies developing smart capsule-based therapeutics, Lonza has expanded its offering with a bespoke development and manufacturing service that is focused on the specific needs of smart capsules companies. Through this offering, Lonza leverages its expertise in highly customized capsule solutions that can be tailored to specific requirements, such as size, design, and lock mechanisms. The service also offers a variety of functionalities, including targeted release using a bi-layer manufacturing technology, which can be adjusted to the needs of the respective API.

“The strong market interest in this bespoke offering for smart capsules, marked by the first customer already on board and additional discussions in progress, reinforces the value of our approach,” said Bart Pelgrims, vice-president, R&D, Capsules & Health Ingredients, Lonza, in the release (1). “By ensuring every detail of development, which goes beyond formulation, we are confident in our ability to support smart capsule innovators to help shape the future of healthcare.”

Oral delivery of APIs has traditionally been the route of administration preferred by most patients worldwide. Oral administration has led to improved patient compliance and adherence as well as drug accessibility. Delivering biologics through an oral administration route represents a growing market, and one that is expected to exhibit a 35% compound annual growth rate from 2023–2028, according to Lonza in the press release (1,2). “Since most new drug entities face bioavailability challenges, exploring innovative delivery solutions to mitigate these challenges is of great value to drug developers and their patients,” Lonza stated in the release (1).

Meanwhile, Lonza has also expanded its bioconjugation capabilities at its Visp, Switzerland, site with the addition of two new manufacturing suites (3). In November 2024, the company announced that the new suites will provide additional manufacturing capacity for launch and commercial supply to address growing market demand.

The two new multipurpose 1200-L manufacturing suites and manufacturing-related infrastructure will be added to the site’s existing bioconjugation facility and will double capacity for the launch and commercial supply of bioconjugates. The company expects that the new capacity will be operational starting in 2028 and will generate approximately 200 new jobs (3).

1. Lonza. Lonza Launches Tailored Offering for Smart Capsules Companies Developing Oral Delivery Solutions for Biologic Drugs. Press Release. Dec. 3, 2024.
2. Market Report Manav AI. 

. Lonza Market Intelligence, 2023.
3. Lonza. Lonza to Expand Bioconjugation in Visp (CH) with Two Additional Manufacturing Suites. Press Release. Nov. 12, 2024.

With its new offering, Lonza can tailor services to support smart capsule companies with its bi-layer capsule manufacturing technology.