A $2.25 Billion Bet: Unpacking Novartis's VAV1 Molecular Glue and its Market Potential

 Information

On October 28, 2024, Monte Rosa Therapeutics announced a global exclusive development and commercialization licensing agreement with Novartis to advance VAV1 MGD, including MRT-6160. MRT-6160 is currently undergoing a Phase 1 single ascending dose (SAD)/multiple ascending dose (MAD) study in healthy volunteers for immune-mediated diseases. Under the terms of the agreement, Novartis will receive global exclusive rights for the development, manufacturing, and commercialization of MRT-6160 and other VAV1 MGDs, and will be responsible for all clinical development and commercialization starting from Phase 2 clinical studies. Monte Rosa remains responsible for completing the ongoing Phase 1 clinical study of MRT-6160.

MRT-6160 is an effective, highly selective, orally bioavailable investigational VAV1 degrader, VAV1 is a key signaling protein downstream of T cell and B cell receptors. Preclinical studies have shown that VAV1 is deeply degraded, leading to a significant reduction in cytokines associated with immune-mediated conditions, with no detectable impact on other proteins. MRT-6160 has shown promising activity in various preclinical models of immune-mediated diseases.

According to the terms of the agreement, Novartis agrees to pay Monte Rosa an upfront payment of $150 million. Starting from the second phase of research, Monte Rosa is eligible to receive up to $2.1 billion in development, regulatory, and sales milestones, as well as tiered royalties on net sales outside the United States. Monte Rosa will co-fund any Phase 3 clinical development and will share any profits and losses related to the manufacturing and commercialization of MRT-6160 in the United States.

The Phase 1 SAD/MAD study of MRT-6160 is currently ongoing, with clinical data expected to be available in the first quarter of 2025.

Relevant background information on VAV1 molecular glue has been previously introduced. This year's summary report on the molecular glue industry has also briefly introduced this. However, there has not been a detailed report on this, so here is a summary and supplement.

 Background on the biology of VAV1

As early as August of this year, Monte Rosa published a report in Trends in Immunology regarding the biological background of VAV1 (DOI: 10.1016/j.it.2024.06.004), indicating that the transcription factor VAV1, as an "undruggable" protein, is a key positive regulator of T cell receptor (TCR) activation and cytokine production in primary human CD4+ and CD8+ T cells; data indicate that the loss/inhibition of VAV1 regulates autoimmunity and inflammation; and promising preclinical data from T and T/B cell-mediated arthritis and colitis disease models show the effectiveness of selectively targeting VAV1 through protein degradation.

 VAV1 plays a key role in antigen receptor signal transduction

The core guanine nucleotide exchange factor (GEF) dependent function of VAV1

VAV1 is a validated key scaffold protein and signaling molecule downstream of T cell and B cell receptors. VAV1 knockout can block T cell-mediated B cell activity (IL-17A, IL-17F, IL-6, IL-2, TNF, sIgG).

 The commercial value of VAV1 molecular glue

In recent years, the emergence of targeted therapies has brought breakthroughs in the treatment of autoimmune diseases and chronic inflammatory diseases, such as inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, and psoriasis, but there are still many unmet clinical needs. Currently, treatment strategies for autoimmune diseases and chronic inflammatory diseases mainly include biologics and oral small molecule drugs; however, issues such as treatment failure, poor drug tolerance, dependence on glucocorticoids, and lack of targeted therapies for certain diseases remain unresolved.

Existing treatment options, such as biologics, are effective in treating certain diseases, but they are often injectable and have issues such as immunogenicity. Oral small molecule drugs, while easy to administer, are limited in their scope of action because their targets are usually located intracellularly. Additionally, existing targeted therapeutic drugs often only inhibit a single protein or signaling pathway, leading to suboptimal efficacy. Therefore, developing more novel drugs targeting autoimmune diseases and chronic inflammatory diseases, especially those that can target multiple important signaling pathways and have safety and efficacy, remains an important direction for future research.

Compared to the shortcomings of the aforementioned therapies, the advantages of VAV1 molecular glue are mainly reflected in the following aspects:

1. Strong targeting: VAV1 is primarily expressed in hematopoietic cells, including T cells and B cells, so molecular glue targeting VAV1 can more effectively suppress immune responses and reduce damage to other organs and tissues.
   
2. Multiple mechanisms of action: VAV1, as a bifunctional protein, has both GEF activity and scaffold protein function. VAV1 molecular glue can simultaneously inhibit its GEF activity and scaffold protein function by degrading VAV1 protein, thereby blocking various important signaling pathways in T cells and B cells, more comprehensively suppressing immune responses.
   
3. High efficacy: Studies have shown that VAV1 molecular glue exhibits good therapeutic effects in various animal models of autoimmune diseases, such as arthritis and colitis models, where VAV1 molecular glue can significantly reduce inflammation and improve tissue damage.
   

In summary, VAV1 molecular glue, as a novel targeted therapeutic drug, has three major advantages: strong targeting, multiple mechanisms of action, and high efficacy, and is expected to become a new hope for the treatment of autoimmune diseases and chronic inflammatory diseases.

Monte Rosa also listed the relevant mechanisms and drug development trends of existing autoimmune therapies in the article, VAV1 molecular glue has a unique mechanism and broad potential applications, which can address various autoimmune diseases through safe oral treatment.

Experimental research has also shown that the VAV1 molecular glue has a more selective and more efficient blocking activity for T cell-mediated B cell activation.

 As for the in vivo efficacy of VAV1:

MRT-6160 improves T cell transfer-induced colitis better than standard therapy.

MRT-6160 reduces inflammation-mediated colonic damage and cytokine production in a model of T cell transfer in ulcerative colitis.

MRT-6160 inhibits disease progression, joint inflammation, and autoantibody production in a model of rheumatoid arthritis, also outperforming standard therapy.

MRT-6160 induces dose-dependent activity in a model of T cell-mediated multiple sclerosis autoimmune disease.

Monte Rosa therefore has high expectations for this project, believing it to be a potential oral alternative therapy for various autoimmune diseases, likely to have a strong impact on the current billion-dollar autoimmune drug market.

 What does MRT-6160 look like?

At the most critical stage, what does the specific structure of Monte Rosa's VAV1 molecular glue MRT-6160 look like?

In fact, by combining publicly available poster information and patents (WO2024151547A1), it is easy to guess.

First, the degradation activity of MRT-6160: DC50 = 7 nM, Dmax = 97%.

What is the situation in the patent? Here, I will lazily borrow content from previous reports; it is evident that through activity data, simple SAR analysis, and drugability assessment, Cpd.185 is very likely the specific structure of MRT-6160.

 Epilogue

It was previously mentioned that VAV1 is a target with a high similarity to the G-loop surface of GSPT1. The discovery of VAV1 molecular glue relies on the QUEEN platform from Monte Rosa, developed based on AI and structural biology, and is a true AIDD drug.

Even more astonishingly, the great benefactor has open-sourced this project on GitHub. Those interested can run it to help discover new VAV1 molecular glue.

The first attention to the VAV1 molecular glue began last July. The project, which has long been promising, has finally received preliminary confirmation through this deal with Novartis, which is quite delighting. I look forward to future clinical results further confirming this. The writing is rushed, and the content is a bit hurried, so please forgive any mistakes.

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 Disclaimer: This article only represents personal views and does not represent the company's position.

The Future of PROTACs/Molecular Glues: A Look at E3 Ligand Discovery - The unique approach of HitGen

 The story continues from the last time【What is the future of PROTAC/molecular glue? Current status of new E3 ligase and E3 new ligand development】

This time, let me introduce a leader in the development of new E3 ligands in China: HitGen.

According to HitGen's earlier introduction:

The targeted protein degradation platform of HitGen utilizes the company's trillion-level DNA-encoded compound library to screen certain E3 ligases, validate the binding of novel ligand molecules to E3 ligases, and demonstrate that these ligands have good degradation capability for popular protein degradation targets.

 The DEL screening platform based on trimeric complexes originates from the official website of HitGen

This includes the newly structured CRBN (pan-tissue expression) ligand with stronger degradation capability, the first discovery of the specific TRIM21 (high expression in tumor tissue) ligand, the BIRC7 (melanoma-specific) ligand, the MDM2 (high expression in tumor tissue) ligand, and the ABTB1 (high expression in lymphatic and thyroid tissue) ligand, among others.

The representative E3 ligase of differentially expressed genes, but the reliability of the data seems questionable (CRBN expression profile)

Talk is cheap; facts speak for themselves. Recently, HitGen publicly released a series of patents related to E3 ligase ligands, including the three E3 ligases CRBN, BIRC7, and TRIM21. Based on publicly available information and patents, let's analyze this briefly.

CRBN

 First is CRBN, involving 4 patents.

It can be seen that HitGen indeed obtained a new skeleton CRBN ligand through DEL and structural modification. Compared to the key group of thalidomide derivatives, the key group of this type of ligand is clearly the spirocyclic structure containing succinimide (red box in the image above).

Currently, the Kd values of the three commonly used amide compounds are all above 100 nM. In comparison, HitGen's new scaffold CRBN ligand has improved the affinity to about 10 nM.

HitGen also provided comparative data, with its representative ligand mostly being A3 from WO2024051664A1. It also presented a BRD4 PROTAC designed based on A3, which has better degradation activity compared to dBET1, consistent with its promotional claims.

 However, this comparative data clearly involves some sleight of hand, turning cause into effect.

Firstly, the conformational changes of the E3 ligands and the linker will affect the degradation activity of PROTACs. The design of thalidomide-based PROTACs can also achieve excellent degradation activity through optimization (see the right side of the figure below). It is difficult to intuitively compare the degradation activities of PROTACs based on the two, not to mention that the formation of the ternary complex mediated by PROTACs does not have high requirements for the affinity of the E3 ligands.

However, what can be intuitively evaluated is the drug-like properties of the two. It is well known that currently, medicinal chemists are focusing on optimizing PROTAC by reducing molecular weight and finding a fine-tuning balance between activity and overall pharmacokinetic properties, while the molecular weight of A3 molecule 354 has no advantage compared to the current new generation of thalidomide-like CRBN ligands (the molecular weight of PG is only 189). Based on this, the overall molecular weight of PROTAC is too large, which can lead to potential solubility, metabolic absorption, and many other drug-like property issues. Personally, I am not optimistic about this.

The above viewpoint also applies to molecular adhesives, as seen from the patents published by Monte Rosa, which also choose to reduce molecular weight in drug-like optimization.

Of course, the new skeleton CRBN ligands led by HitGen are not without merit, and the new skeletal structure is bound to lead to new protein binding conformations. This may enable the design of molecular glues to recruit new targets.At the same time, these new spirocyclic structures containing succinimide may also be the core group for future rational design of molecular glues..This point can also be glimpsed from a recent article featuring many experts (https://doi.org/10.1101/2024.09.30.615685). The article reports on the ENL molecular glue dHTC1, whose CRBN recruiting fragment is the spirocyclic structure containing succinimide.

BIRC7

First, let's discuss the tissue distribution of BIRC7.

From the database, BIRC7 is indeed a very tissue-specific E3 ligase, highly expressed only in SKCM (skin melanoma) and UVM (uveal melanoma) in tumors, which is consistent with the  introduction of HitGen.

In normal tissues, BIRC7 is also highly expressed in the skin, with expression levels second only to the placenta.

The data provided by HitGen also indicates that BIRC7 is highly expressed in the skin. The BRAF PROTAC designed based on BIRC7 ligands only shows BRAF degradation in cell lines with high BIRC7 expression, while it has poor degradation capability in cells with low BIRC7 expression.

These features indicate that for BIRC7 high-expressing melanoma, BIRC7-based PROTACs may have better safety and tolerability.

 So, what does the BIRC7 ligand look like?

From the recently published patent by HitGen WO2024165017A1, the patent discloses a series of compounds, some of which have good BIRC7 affinity activity (0.1 ~ 1 μM). There is not much information revealed, and some representative structures are as follows.

TRIM21

TRIM21 is a broadly expressed E3 ligase, but according to HitGen's materials, TRIM21 has a higher expression level in tumors than in normal tissues, while CRBN has similar expression levels in tumors and normal tissues. This also suggests that TRIM21-based PROTACs may have better safety compared to CRBN PROTACs.

As for the statement that TRIM21 PROTAC has better degradation activity than CRBN PROTAC, I still hold a reserved attitude.

In addition, it is worth noting that TRIM21 ligand 652-NX-1 exhibits anti-tumor activity in certain tumor cell lines, which also indicates its potential molecular glue properties.

According to patent WO2024179572A1, the representative embodiment has excellent TRIM21 affinity activity (KD = 1~10 nM), as shown in the figure below.

From the database, TRIM21 has PPI with many proteins, and this type of compound has a relatively simple structure and a wide range of development directions, making TRIM21 a potential high-value E3 ligase for molecular glue development.

However, if there are readers interested in this, the primary difficulty in developing TRIM21 lies in the fact that HitGen has not provided the binding conformation of 652-NX-1 with TRIM21, as well as the specific cell lines that exhibit anti-tumor activity.

Of course, the solution is also simple: either contact HitGen to seek joint development cooperation to obtain this key information, or you can only conduct a co-crystal analysis, followed by high-throughput screening, high-resolution mass spectrometry, and proteomics analysis, which will provide some insights.

 Epilogue

The currently published results from HitGen are indeed impressive, which may also be attributed to its powerful DEL screening platform. Looking forward to more outstanding progress in the future.

After all, compared to some domestic companies that are limited to targets like IKZF1/3 and GSPT1, being able to focus on basic research in the TPD field is quite rare.

In addition, according to its statement, other patents such as MDM2 (high expression in tumor tissues) ligands and ABTB1 (high expression in lymphatic and thyroid tissues) ligands have not yet been disclosed, and these can only await further reports.

Finally, I would like to clarify that this article is merely a summary of the latest advancements in E3 ligands, and HitGen has not provided any funding support for this article (since we are already at this point...).

If you’re exploring new E3 ligase binders, DEL could be the game-changer you’re looking for. We can connect you with a well-established, cost-effective DEL provider to accelerate your research. Feel free to reach out – we’re here to help.

you can comment at bottom of the article or contact the author (https://www.linkedin.com/in/haixiang-pei-1a40b82b0/) on LinkedIn

 As for other developments in this field, stay tuned for the next installment.

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Welcome to forward, share, and make reasonable citations. When citing, please indicate the source prominently;If you need to reprint, please leave a message or send a message to the WeChat public account backend, and indicate the public account name and ID.Original articles may not be reproduced without authorization, and violators will be held legally responsible.
Disclaimer: This article only represents personal views and does not reflect the company's position