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Feliza Mirasol

Monte Rosa Therapeutics, a Boston, Mass.-headquartered clinical-stage biotechnology company specializing in novel molecular glue degrader (MGD)-based medicines, announced on Oct. 28, 2024,  that it entered into a global exclusive development and commercialization license agreement with Novartis. The agreement is worth potentially up to $2.1 billion and aims to advance vav guanine nucleotide exchange factor 1 (VAV1) MGDs, including MRT-6160, a drug candidate being evaluated in an ongoing Phase I single ascending dose (SAD)/multiple ascending dose (MAD) healthy volunteer study for immune-mediated conditions.

Under the agreement, Novartis will pay Monte Rosa $150 million up front in exchange for exclusive worldwide rights to develop, manufacture, and commercialize MRT-6160 and other VAV1 MGDs. Monte Rosa is eligible to receive up to $2.1 billion in development, regulatory, and sales milestones, starting with the initiation of Phase II clinical studies of MRT-6160. Monte Rosa is also eligible to receive tiered royalties on ex-US net sales.

Novartis will be responsible for all clinical development and commercialization of MRT-6160, starting at the Phase II clinical phase. Monte Rosa, meanwhile, will remain responsible for completing the ongoing Phase I clinical study for the drug candidate. In addition, Monte Rosa will co-fund any Phase III clinical development. The company will also share any profits and losses associated with the manufacturing and commercialization of MRT-6160 in the United States.

“We are thrilled to announce this agreement with Novartis, a key player in immune-mediated conditions, and we are excited about the transformative potential it provides for Monte Rosa and MRT-6160. We expect this will accelerate and broaden the scope of clinical development of MRT-6160 to advance this unique, orally bioavailable modality while retaining substantial value for Monte Rosa. We believe the transaction validates our unique and industry leading QuEEN discovery engine, and it further increases our conviction to rationally design and develop highly selective and safe MGDs for undruggable targets, including in the areas of immunology and inflammation, metabolism, and genetic diseases,” said Markus Warmuth, MD, chief executive officer, Monte Rosa Therapeutics, in a company press release. “The financial resources provided by this agreement are expected to extend our operational runway, enable us to advance our pipeline to potential value-creating milestones and anticipated proof-of-concept readouts, and further leverage our QuEEN discovery engine.”

MRT-6160 is a potent, highly selective, and orally bioavailable investigational degrader of VAV1, which is known as a key signaling protein found downstream of both T- and B-cell receptors. According to preclinical studies, MRT-6160 demonstrated deep degradation of VAV1, which resulted in a significant decrease in cytokines linked to immune-mediated conditions. It also showed no detectable effects on other proteins. The candidate has shown promising activity in preclinical models of multiple immune-mediated conditions (1,2).

"Novartis has had a long-standing interest in molecular glue degraders, which offer the potential to tackle challenging biological targets. We are excited about their application in immunology and the early progress we have seen by Monte Rosa in this space and with MRT-6160. We look forward to advancing MRT-6160 and learning more about its potential to provide a new therapeutic option for people living with a range of immune-mediated conditions,” said Fiona Marshall, president, Biomedical Research, Novartis, in the press release. “Novartis is committed to bringing forward new therapeutic options for these patients, and we are happy to be working with Monte Rosa to harness the potential of this approach to address unmet medical needs.”

1. Cartwright, A.; Desai, F.; Vora, S.; et al. MRT-6160, a VAV1-Directed Molecular Glue Degrader, Reduces Joint Inflammation and Autoantibody Production in a Collagen-Induced Arthritis Autoimmune Disease Model. Poster presented at Digestive Disease Week 2024, Washington, DC, May 21, 2024.
2.Cartwright, A.; Vora, S.; Gyger, L.; et al. MRT-6160, a VAV1-Directed Molecular Glue Degrader, Inhibits Disease Progression in a T-cell Transfer Mediated Colitis Model Concomitant with Reduced Calprotectin Expression. Poster presented at EULAR 2024—Annual European Congress of Rheumatology, Vienna, Austria, June 14, 2024.

Articles

The collaboration aims to advance clinical development of a Phase I drug candidate, MRT-6160, and to explore other therapeutic opportunities across multiple indications.

Novartis and Monte Rosa Therapeutics Form $2.1 Billion Global License Agreement for MGD-based Therapeutics

Shawn Li, principal scientist at Merck & Co., known as MSD outside the Unites States and Canada, talked about the importance of properly characterizing HCPs in the biomanufacturing process.

AAPS PharmSci 360: The Importance of HCP Analysis in Biomanufacturing

® spoke with Xuanwen (Shawn) Li, PhD, Principal Scientist at Merck & Co., known as MSD outside of the United States and Canada, during AAPS PharmSci 360 about the importance of properly analyzing host cell proteins (HCPs) during the biomanufacturing process.

“Host cell proteins are process-related impurities in biopharmaceutical manufacturing. The identification and control of a high-risk host cell protein in biopharmaceutical development is critical to ensure biopharmaceutical product quality and shelf life,” Li stated. For example, he explained, certain HCPs can have direct biological effect, and some HCPs can degrade the drug product or formulation excipients such as polysorbate. “The host cell protein issue can lead to significant delay or product withdrawal … Therefore, it's extremely important to understand how to properly analyze host cell proteins in biopharmaceutical manufacturing,” Li said.

, scheduled on Wednesday, Oct. 23, at 3:45 pm MT (2:45 pm PT, 5:45 pm ET), he focuses on the identification and control for one of a group of high-risk HCPs called the polysorbate-degradative enzyme. With an analytical toolbox developed at Merck, the company can better understand polysorbate degradation in biologics. One assay Li highlights in his talk is activity-based protein profiling (ABPP). “In short, ABPP can overcome the dynamic range issue of trace levels of high-risk host cell protein to drug substance and really enable the identification of those low abundance enzymes, while also providing activity information,” he said.

Attendees can visit Merck at Booth #3344. AAPS PharmSci 360 is taking place Oct. 21–23 at Salt Lake City, Utah.

Xuanwen (Shawn) Li, PhD, Principal Scientist, Merck & Co.

Shawn Li is a principal scientist and scientific supervisor in the Analytical Research & Development, Mass Spectrometry group at Merck & Co. Inc. His research is focused on mass spectrometry-based biologics and vaccine characterization for chemistry, manufacturing, and controls (CMC) development and regulatory submission. Prior to joining Merck in 2018, Li worked as a research scientist at Eli Lilly and Company on protein characterization. Before his industry career, Li was a director of the mass spectrometry facility at the Institute for Translational Medicine and Therapeutics at the University of Pennsylvania. Li received a PhD in proteomics at the Hunan Normal University in China and completed his post-doctoral training in clinical pharmacology and bioanalysis at the University of Pennsylvania.

Videos

At AAPS PharmSci 360, Karunakar Sukuru, global vice-president, Catalent Pharma Solutions, discussed lipid-based formulations and tackling bioavailability challenges for oral biologics.

AAPS PharmSci 360: LBFs and Tackling Oral Biologic Formulations

® spoke with Karunakar Sukuru, RPh, PhD, global vice president of Rx Product Development, Pharma and Consumer Health, at Catalent Pharma Solutions, about the advantages and new challenges with lipid-based formulations (LBFs). Sukuru also discussed the challenges of addressing bioavailability in the search for developing oral formulations for biologics.

“Lipid-based drug delivery systems are not new,” Sukuru said, noting, though, that although lipid-based drug delivery systems exist, there is, today, an increased need for them, particularly considering that of the almost 8500 or so molecules—small molecular entities—in development, 70% of them are poorly bioavailable. “Because [these small molecules] are either poorly soluble, or poorly soluble and poorly absorbed, [that] is where the lipid-based formulation comes into play … they have a very demonstrated and valuable utility,” he stated. LBFs enhance bioavailability, so that a molecule may not necessarily need to have aqueous solubility.

Meanwhile, delivering biologics or proteins through an oral route is very challenging because of their high molecular weight. “[There] [are] certain limitations; the body does not allow absorb[tion of] these high molecular weights … with most monoclonal antibodies or biologics, they are in the hundreds of 1000s of Daltons [in size],” Sukuru pointed out. “However, there are a lot of efforts going on, and novel formation and answers are showing good promise, where they open the tight junctions, facilitating the absorption of the molecules,” he added. Another challenge he emphasized is stabilizing the biologic molecule once it is delivered to the intestine, where it would otherwise be destroyed by an acidic environment.

Attendees can visit Catalent at Booth #1141 at AAPS PharmSci 360, which is taking place on Oct. 20–23, 2024 in Salt Lake City, Utah.

Karunakar (Karu) Sukuru, RPh, PhD, Global Vice President, Rx Product Development, Pharma and Consumer Health, Catalent Pharma Solutions

Karunakar Sukuru (Karu) RPh, PhD is the global vice president of Rx Product Development, Pharma and Consumer Health, at Catalent Pharma Solutions. With over 29 years of experience in the pharmaceutical industry, he has led the development and manufacturing of various drug delivery systems and technologies and has been responsible for product development and execution of projects globally. Sukuru had technical oversight of more than a dozen contract development and manufacturing organizations worldwide while working at Endo Pharma. In his current role at Catalent, he works with hundreds of pharmaceutical clients, including leading biopharma companies, globally. He has developed innovative controlled-release platform technologies in softgel form (three granted patents) and has over 27 pending patent applications in the field of modified shell and fill suitable for capsules for enteric and colonic delivery and lyophilization. After completing his PhD in Pharmaceutics from IIT-BHU, India, in 1995, Sukuru began his career at Natco Pharma in India, where he developed a variety of oral dosage forms for two years. He then joined Banner Pharmacaps in India, and later in Banner Pharmacaps USA, he worked on softgel and gel enrobed tablets. Sukuru joined Endo Pharma in 2006 and Catalent in 2016 as the vice president of Product Development. He is also a registered pharmacist.

At AAPS PharmSci 360, Karunakar Sukuru, RPh, PhD, the global vice-president-Rx Product Development, Pharma and Consumer Health, at Catalent Pharma Solutions, discussed lipid-based formulations and tackling bioavailability challenges for oral biologics.

Karunakar Sukuru, RPh, PhD, the global vice-president-Rx Product Development, Pharma and Consumer Health, at Catalent Pharma Solutions, spoke on recent challenges and trends in softgel formulations. 

AAPS PharmSci 360: Challenges and Trends in Softgel Formulations

® spoke with Karunakar Sukuru, RPh, PhD, the global vice-president-Rx Product Development, Pharma and Consumer Health, at Catalent Pharma Solutions, during AAPS PharmSci 360 to discuss recent challenges and trends in softgel formulations.

“Recent challenges are mostly related to enhancing the solubility and making those solubilized molecules stabilized in the systems, particularly in softgels, and enhancing the bioavailability,” Sukuru said. He noted that there is an increasing demand for non-animal products by the industry, particularly in Europe where gelatin, an animal byproduct, is used as a shell component. Although gelatin is a good material to use in terms of its ability to make robust, subgenerative capsules, it also has some disadvantages, such as cross-linking challenges, Sukuru pointed out. “That is where [there is need] to address both the non-animal byproduct need, using plant-based materials, as well as … the cross linking issues,” he stated.

, which is on Monday, Oct. 21, at 3:30 pm MT (2:30 pm PT, 5:30 pm ET), centers around the missed opportunity for superior bioavailability and the ability to develop moderated drug release products using softgels. “Softgel is one of the most versatile dosage forms, and you could deliver [a] drug through any orifice in the body, literally,” Sukuru said. “There are products that we manufacture commercially to deliver through oral route, ophthalmic route, nasal, otic, vaginal, and every route of delivery, but it's very underutilized. [Futhermore] there are a lot of myths and misconceptions about softgels being very expensive. No, they are not. In fact … compared to spray drying and some other bioavailability enhancing technologies, they are not.”

Attendees can visit Catalent at Booth #1141 at AAPS PharmSci 360, which is taking place on Oct. 20–23 in Salt Lake City, Utah.

Karunakar (Karu) Sukuru, RPh, PhD, Global Vice-President-Rx Product Development, Pharma and Consumer Health, Catalent Pharma Solutions

Karunakar Sukuru (Karu) RPh, PhD is the global vice-president of Rx Product Development, Pharma and Consumer Health, at Catalent Pharma Solutions. With over 29 years of experience in the pharmaceutical industry, he has led the development and manufacturing of various drug delivery systems and technologies and has been responsible for product development and execution of projects globally. Sukuru had technical oversight of more than a dozen contract development and manufacturing organizations worldwide while working at Endo Pharma. In his current role at Catalent, he works with hundreds of pharmaceutical clients, including leading biopharma companies, globally. He has developed innovative controlled release platform technologies in softgel form (three granted patents) and has over 27 pending patent applications in the field of modified shell and fill suitable for capsules for enteric and colonic delivery and lyophilization. After completing his PhD in Pharmaceutics from IIT-BHU, India, in 1995, Sukuru began his career at Natco Pharma in India, where he developed a variety of oral dosage forms for two years. He then joined Banner Pharmacaps in India, and later in Banner Pharmacaps USA, he worked on softgel and gel enrobed tablets. Sukuru joined Endo Pharma in 2006 and Catalent in 2016 as the vice-president of Product Development. He is also a registered pharmacist.

Bala Addepalli, PhD, Director, R&D New Modalities Portfolio, Waters Corporation, discussed trends in new analytical tools for RNA characterization and gave highlights of his talk at AAPS PharmSci 360.

AAPS PharmSci 306: Trends in New Analytical Tools for RNA Characterization 

® at AAPS PharmSci 360,Bala Addepalli, PhD, Director, R&D New Modalities Portfolio, Waters Corporation, discussed some major trends in the development of new analytical tools for RNA characterization. Addepalli pointed to DNA sequencing technologies, which have pushed the sequencing of RNA too.

“Those technologies are referred to as next-generation sequencing; the problem with the next-generation sequencing is that it's an indirect sequencing method,” Addepalli stated. “That means the RNA is converted into DNA, so … you would lose some information during this conversion process. We need to do direct sequencing of RNA, [and] that's what people have realized while analyzing these RNA drugs and RNA therapeutics.”

“There are a lot of ambiguities in the sequence interpretation and data accuracy, so that's where … new tools and software can come into the picture,” Addepalli also said. “Having … enzymes that would improve the sequence coverage, and … a simple sample preparation method can help reveal the full information. That's where the trends are being focused, on analytical characterization [and on] how to simplify the process of RNA characterization through direct methods. [Those are] the major trend[s] that's been going on currently.”

Addepalli also highlighted some key points in his presentation at AAPS PharmSci 360, which is on 

Oligo Mapping of Large RNA Therapeutics by Novel Enzyme Specificities

: “I'm going to talk about … enzymes, [their] properties and their applications in characteriz[ing] large RNA therapeutic drugs, [such as] single guide RNA that is used in genome editing, and mRNA [messenger RNA] as part of the LNPs [lipid nanoparticles] that are used for vaccinations, or cancer therapies, or protein replacements,” he said.

Attendees can visit Waters Corp. at Booth #2438 at AAPS PharmSci 360, which is being held on Oct. 20–23, 2024 in Salt Lake City, UT.

Bala Addepalli, PhD, Director, R&D New Modalities Portfolio, Waters Corporation

Bala Addepalli, Bala_Addepalli@waters.com, is currently working as director of the Evaluations and Application Science Team under New Modalities (Cell and Gene Therapy product analysis) portfolio of Waters Corporation. His interests include development of simpler but efficient approaches for cell and gene therapy products such as messenger RNA (mRNA), lipid nanoparticle (LNP), and adeno-associated virus (AAV) analysis through liquid chromatography coupled with light scattering and mass spectrometry-based detection techniques.Prior to joining Waters, Addepalli developed novel enzymes and analytical methods for characterization of cellular RNA and modified oligonucleotides through mass spectrometry at University of Cincinnati. Before that he worked on RNA processing events including mRNA polyadenylation at University of Kentucky, and viral RNA characterization through mRNA translation for his graduate studies at Indian Agricultural Research Institute, New Delhi, India. Bala has authoredover 60 publications in peer-reviewed scientific journals and has delivered oral presentations at scientific meetings.

AAPS PharmSci 306: Trends in New Analytical Tools for RNA Characterization

Bala Addepalli, PhD, Director, R&D New Modalities Portfolio, Waters Corporation, discussed recent advancements and current challenges in the development of large RNA therapeutics.

AAPS PharmSci 360: Advancements and Challenges in Large RNA Therapeutics

® sat with Bala Addepalli, PhD, director, R&D New Modalities Portfolio, Waters Corporation, at AAPS PharmSci 360, which is taking place Oct. 20–23, 2024 in Salt Lake City, UT, to discuss the challenges seen in large RNA therapeutics as well as their challenges.

Addepalli pointed out that there is much interest by industry in developing RNA-based drugs for treating genetic disorders, especially after the success of messenger RNA (mRNA), which was used to develop COVID-19 vaccines. He also noted that pharmaceutical vendors and companies are developing mRNA vaccines for other viral diseases such as influenza or as a combination of COVID and influenza vaccines. Furthermore, mRNA vaccines are also part of protein replacement therapies for patients who have deficiency in enzymes or proteins.

Meanwhile, challenges in the large RNA therapeutic space include inadequate analytical tools, Addepalli said. “The analytical tools that are currently available are inadequate, in a sense; they would provide only incomplete or partial information, so the purity and identity of the molecule is not fully revealed. And it also necessitates development of complex procedures in order to get such information,” he stated. And, he further explained, when specialized procedures and complex techniques are employed, the cost of development and manufacturing goes up, “and that leads to accessibility issues,” Addepalli added.

Attendees can visit Waters Corp. at Booth #2438 at AAPS PharmSci 360.