VDP-117 Magnaetus Therapeutics

[Ageless_Partners]

One liner: Magnaeutus Therapeutics is developing a first-in-class agent for weight loss and metabolic disease.

Longevity Dealflow WG team

Scientific evaluation: 2 biotech managers, 2 scientists, 1 pharma consultant

Shepherd: Jason C. Mercurio

Other squad members: Eleanor Davies, Maria Marinova, Rhys Anderson

Sourced by: Jason C. Mercurio

Project PI: Guy Barry, Paul Baldock

Summary

Magnaetus Therapeutics aims to reverse age-related metabolic decline through the development of an exercise mimetic. They intend to develop a therapeutic that will have the effect of weight loss and targeting obesity as well as extending healthspan.

Problem

Obesity and metabolic syndrome have reached crisis levels with almost no effective, patient supported interventions. By 2035, an estimated 50% of the world’s population will be overweight or obese (4.5 billion people).

Currently, patients are offered ozempic, although this is associated with severe side effects including pancreatitis, hypoglycemia and kidney failure amongst others. Alternatively, there are extreme bariatric surgery measures such as gastric banding.

Solution

Magnaeutus Therapeutics is developing a peptide therapy, based on an endogenous protein that mimics the beneficial effects of calorie restriction and exercise. This peptide is thought to reduce fat mass whilst preserving lean tissue.

Opportunity

The weight loss and weight management diet market size was valued at $192 billion in 2019, and is projected to reach $295 billion by 2027. Ozempic (Novo Nordisk) alone had 2022 sales of $8.56 billion.

Following 15 years of research, Magnaetus Therapeutics has identified an endogenous protein that stimulates energy release and consumption, rather than conservation.

Serum levels of this protein are suppressed by obesity, but stimulated by calorie restriction and exercise.

Classified as an extracellular matrix molecule secreted into the extracellular space, it acts via interaction with cell surface receptors, and has a wide range of activities. Importantly, it also circulates, consistent with inter-organ actions and metabolic responses. Multiple repeat loops provide specific binding activities.

Elevated levels are thought to be responsible for the downstream health benefits of exercise and dieting including: increased fat burning, reduced food intake, improved insulin sensitivity and secretion, and improved nutrient signalling.

Relevance to longevity

The therapeutic being developed targets metabolism systems thereby directly impacting longevity.

IP Roadmap

The team is working towards a composition of matter patent. The aim is to file a PCT after lead isolation studies with Dominique Bridon and then apply for a full RCT after healthspan and metabolic studies with Brian Kennedy are complete (7-9 months).

The protein is not heavily studied (86 papers with protein in title, 256 total), cancer/cardiac function dominates literature and thus do not anticipate being challenged for priority date.

Experimental Plan

Year 1

Synthesis of proteins (12 weeks)

Solid phase synthesis (SPPS) for production, HPLC and MS for characterisation to deliver 2-3 core proteins and their analogues (about 3-5 for each core protein) that mimic protein structure.

In-vitro screening (12 weeks)

Cell-based assays to define critical aspects of protein activity profile: weight loss and longevity mTOR/AKT (MCF7, MIN6): Insulin (MIN6): Lipolysis (3T3-E1): Glucose, AMPK (C2C12).

In-vivo screening (20 weeks)

Acute murine studies in HFD to define critical aspects of protein activity profile: weight loss and longevity. Weight loss, fat mass, food intake, GTT, ITT, energy expenditure, muscle + adipose (mTOR, AKT, AMPK), serum.

They have worked through the generation of data on animal studies to determine how their protein of interest operates in the body. They looked at mice.

They also have determined that their protein of interest is in adipose tissue, muscle and bone. It is not found in the pancreas.

Budget

Year 1 go/no go milestone: 500,000 USD

• Incorporated
• Past rounds: They have not raised capital for this company before.
• We have yet to decide on an exact valuation although it may be around a 3M - 5M post-money valuation.

Financing and VitaDAO Terms

• VitaDAO would fund 100K and the lead investor would fund 400K.
• Equity deal

Team

Guy Barry, PhD — CEO

25 years experience with 11 in biotech with an emphasis on metabolic, neural and cardiovascular mechanisms. Worked in academia where he performed research on IPS cells, long non-coding RNA, cancer, G-Protein Coupled Receptors, and bioinformatics.

Paul Baldock, PhD — CSO

25 years experience with extensive time in academia — researcher with an emphasis on in-vivo models, metabolic, musculoskeletal, glycaemic, neural, endocrine, and cancer. Identified the unique protein that serves as a longevity target through metabolism optimization.

Brian Kennady, PhD — Advisor

Dominique Bridon, PhD — Advisor

Additional information

• Deck: Magnaetus Therapeutics Presentation.pdf - Google Drive

(Newer deck available if needed with NDA)

Highlights

As above

Risks

Customer Risks

The potential for causing more harm than benefit or adversely affecting daily life is low. This is largely because the protein in question is naturally occurring in the human body. Interestingly, the high cost is not seen as a risk. Insurance companies are generally willing to cover the costs of medications that benefit patients, and the FDA often grants exclusive rights to newly approved drugs.

Product Risks

There could be side effects from the developed drug although this is minimal since the body already contains the protein and it’s natural.

Go-To-Market & Business Model Risks

There could be competing products when going to market with an exercise mimetic and weight loss drug.

Team Risks

The founders have been working together for many years. There is a risk of getting more team members efficiently as their organization grows.

External Factor Risks

There are known risks as well as unknown risks.

Bibliography

Links

Lilly to Acquire Versanis to Improve Patient Outcomes in Cardiometabolic...

Senior Review Digest - Quantitative

Below is the average scores out of 5 per category from 5 reviewers, who all recommended that the project should be advanced for community feedback.

Average Scores:

• Novelty & Impact 3.6
• Feasibility & Data 3.6
• Relevance 4
• Science Team 3.8
• Market Advantage 3
• IP Potential 3.25
• General Conviction Score 3.6

Senior Review Digest - Qualitative

Reviewer 1

My questions have been answered very well, and took away some of the worries I had on IP and general approach. I think the team has provided quite some convincing data in one of the hottest fields of pharma at the moment, which is also one of those fields that is relevant for longevity. There are 2 major points that I’d like the community to be aware of for the voting:

1. It is a serious problem the receptor is not identified. Pharmacological modelling will be practically impossible, making dose-predictions etc a true headache. In pharma companies, this would be an early kill for the project and will make your partnering possibility at early stage very challenging. I would advise to include a biopharmaceutical pharmacologist very early onwards in the project to work on this.

2. To me, the mTOR effect is still a serious worry for this project. Although I think the experiment they’ve done is interesting, perhaps just doing a prolonged treatment in elderly mice and monitoring pmTOR in leukocytes (as a proxy) would be a good way to address this?

Reviewer 2

Although no direct relationship or direct mechanistic action with aging, I am enthusiastic about their idea to use parts of the ECM and the protein of interest to target obesity (and metabolic dysregulation), which definitely will have a big impact on the aging society. Also, if they succeed, Novo Nordisk or Eli Lilly is likely to acquire them.

Reviewer 3

After reevaluating the data based on the company’s answers, they do indeed look promising and would allow VitaDAO to enter the weight-loss market. From a commercial perspective, my key concerns are the limited knowledge by the team of what is being developed outside of the two weight-loss drugs that are already commercialized and the lack of a Target Product Profile to be presented to physicians for feedback. I would also recommend as soon as it is feasible to generate head-to-head data vs semaglutide (Novo Nordisk) and tirzepatide (Eli Lilly). Also, given the size of the market, this is not a drug that can be developed and sold on its own, and Business Development activities targeted at Big Pharma must be initiated as soon as possible

Reviewer 4

All of my questions are answered thoroughly and satisfactorily. I believe the approach Magnaetus Therapeutics is taking and experiments planned together with their research collaborators is very well designed and will be helpful to gain a lot of insights during the study. Fast IP protection should be considered in this project. I would further recommend providing funding to this project by VitaDAO given its direct application on longevity and age related diseases.

Reviewer 5

Magnaetus is proposing a very diligent approach to identify the most promising elements to achieve the intended functionality. A step-by-step program is proposed and one may question if some work could be speeded-up by a more intertwined planning and execution. In fact, the team agreed during the Q&A session that shortening of the plans is feasible. It is noted that it took the team fairly long to provide answers to the questions raised by the VitaDAO team. Execution speed is a concern.

The team has a strong background in research, medicinal chemistry and early stage drug development. The team would benefit from entrepreneurial expertise and speed to ensure that research efforts are well aligned with business needs to attract further funding and build the company for success towards an exit strategy. At this stage, limited information is available. The team is currently planning for a 6 monthly implant, which is a demanding pharmaceutical presentation. Except for the TPP, appropriate responses to my questions were provided. In summary, I recommend funding of this project by VitaDAO.

• Agree
• Disagree
• Revisions Requested [Details in Comments]

[bowtiedshrike]

Are the initial set of figures in cell lines? What’s the protein amount for the GTT and insulin tests? The preliminary data are KO mice lacking the ECM protein or just the cleaved part of the peptide? Or is there a transgenic overexpressing mouse? Translating from genetic systems to injectables can be a challenge, though it looks like Dr Bridon does a lot of the ‘conjugate it to HSA’ chemistry, and there may be linker regions amenable to the chemistry.

Are the repeats involved in each of the proposed functions unknown? And that’s what is expected to allow the peptide combos to be patented? Or the protein analogues going to be what does it? Or is the plan to introduce things like cysteines into the linker that allow conjugation to HSA or other things?

The cell based assays all use mouse cell lines (except the MCF7). And do you mean 3T3-L1 or E1? Usually the L1 are used as pre-adipocytes. Mouse lines may help for the mouse end, but the end goal is human.

If there’s a lot of cancer/cardio literature, what potential complications are there from those domains with this protein? For example, cardiac hypertrophy? Is it a cancer target, or sold as ‘anti-cancer’?

No proposed experiments to look at immunogenicity?

This sounds similar to the irisin stories, but there have been some concerns about irisin results being antibody artifacts. I am concerned there may be some risk of artifact if it’s part of a protein that does a lot of other things, or if it tickles a receptor that has many ligands.

At 256 papers, I would not be complacent in PCT/RCT filing. That’s more than enough groups to stumble on a potential metabolism play and quietly move to protect it. I know people working on proteins with fewer publications that have multiple companies and groups moving protect their variants.

[Ageless_Partners]

Are the initial set of figures in cell lines?

Panel 1 from data slide 2 is in vitro (MIN6 cells). All other data is in vivo.

What’s the protein amount for the GTT and insulin tests?

3ug bolus

The preliminary data are KO mice lacking the ECM protein or just the cleaved part of the peptide?

We made the mouse using Crispr targeting Exon 2 (created 21 bp deletion, including start codon). It was, however, not a full KO, protein levels were ~50%. This was a predetermined requirements, as full KO mice have very weakened skin (weakened collagen), and we wished to avoid handling issues.

Or is there a transgenic overexpressing mouse?

No, increased protein was studied in mice with a bone specific deletion of raptor (reducing mTOR). These mice displayed an increase in serum protein secretion. Both germline and conditional models were examined, and were found to have consistent changes. Data shown is from conditional mice.

Translating from genetic systems to injectables can be a challenge, though it looks like Dr Bridon does a lot of the ‘conjugate it to HSA’ chemistry, and there may be linker regions amenable to the chemistry.

One consideration for modification is the relatively simple repeat-loop structure of the parent protein. This lends itself to scenarios whereby functional segments of the parent (a loop with a beta sheet ‘signaling’ region on each concave surface of the loop) may retain their simple structure/function in the face of other, PK-mediated modifications. Moreover, we will determine the extent to which individual loops can be artificially joined to produce chimera-like functional pairs that enable specified functional characteristics of each pair to be matched to patient requirements.

Functional aspects are the focus of Year1. PK etc. will be the focus of Year 2.

Are the repeats involved in each of the proposed functions unknown?

Correct. Delineating the potential for repeat specific function is the principle aim of the first phase of development. This has dual purpose,

to identify said functional specificity

to identify functional candidates that are ~50 amino acids in length, thereby enabling synthetic, not recombinant production methodology.

And that’s what is expected to allow the peptide combos to be patented?

Composition of Matter patenting is obviously vital for any successful development. It is conceivable that combinations of loop-specific pairs would be considered to go some way toward being sufficient in this requirement. Additional modifications for stability, immunogenicity, etc. would further strengthen these claims. At 50 aa, the 2 loop pairs would be half the size of any naturally occurring variant of the parent protein.

Or the protein analogues going to be what does it?

See above

Or is the plan to introduce things like cysteines into the linker that allow conjugation to HSA or other things?

That is one possibility. The specifics of our lead development will be finalized following our analysis of the characteristics of the peptides in year 1.

The cell based assays all use mouse cell lines (except the MCF7). And do you mean 3T3-L1 or E1? Usually the L1 are used as pre-adipocytes. Mouse lines may help for the mouse end, but the end goal is human.

Correct L1, typo, apologies. Protein amino sequence is near identical between mouse and human across the entire region of our focus, enabling confidence that responses will be similar. Our therapeutic studies in vitro and in vivo used human sequence for all mouse studies, and functional responses were consistent. The main resone for using the murine cell lines is that they are standard usage, gaining confidence in those viewing the data that results gained are in line with standard studies in the field. But we take your point under advisement.

If there’s a lot of cancer/cardio literature, what potential complications are there from those domains with this protein?

The beneficial effects of the protein in these two areas comes from increased levels. So any unforeseen ‘side effect’ of therapy would be advantageous. However, in the case of cardiac effects, these are a result of the ECM activities, which involve for example optimization of collagen strength (allowing high pressure hearts to continue to function adequately, or to maximize healing capacity after an infarct). Our therapeutic design specifically circumvents the ECM binding, attenuating these effects.

In the case of anti-cancer activities, these have been associated with metabolic changes, most markedly mTOR inhibition. Thus our design will produce agents with the potential to act in this manner.

For example, cardiac hypertrophy?

As above, the parent protein has been shown to inhibit cardiac hypertrophy.

Is it a cancer target, or sold as ‘anti-cancer’?

The promoter has a p53 binding element, and reduced levels have been identified in many tumour types. Over expression/treatment studies have been shown to inhibit multiple aspects of cancer activity, from cell growth, invasion and EMT transition.

No proposed experiments to look at immunogenicity?

The parent protein shows no immune responses, however, this will be a component of lead development studies in year 2.

This sounds similar to the irisin stories, but there have been some concerns about irisin results being antibody artifacts. I am concerned there may be some risk of artifact if it’s part of a protein that does a lot of other things, or if it tickles a receptor that has many ligands.

We need to increase levels, so no antibodies.

Our confidence regarding artifacts lies in the potential for repeat-specific activities. In this manner, we aim to focus the functionality of our agents to specific pathways, and avoid the broader, and inherently more risk-bound actions of the parent.

In addition, the physiological regulation of serum levels appears to follow specific contextual patterns, reinforcing the likelihood that the protein acts within a well-adapted, integrated response. Increased levels inducing the beneficial responses of exercise and calorie restriction, reduced levels compounding the challenges of inactivity, weight gain and aging.

Indeed, it is our aim to produce the advantages of these beneficial responses in patients, through induction of key aspects of the diet/exercise behaviors, without the necessity of the inherently patient aversive efforts normally required.

At 256 papers, I would not be complacent in PCT/RCT filing. That’s more than enough groups to stumble on a potential metabolism play and quietly move to protect it. I know people working on proteins with fewer publications that have multiple companies and groups moving protect their variants.

We hear you loud and clear and appreciate the sound advice. We have a provisional patent written and ready to go. It is an issue that we are constantly debating.