VDP-106 [Governance] Proposal eligibility criteria to enter the VitaDAO deal-flow funnel

[Paolo]

Motivation

The resources of VitaDAO and applicants are precious. Both should invest time in a proposal only if it has reasonable chances to get funded, which ultimately requires a positive vote by token holders. It is therefore important to provide clear guidelines to applicants and reviewers as to what we like to pursue.

While VDP 26.1 [3] and its references [4, 8] already contain some indications, after almost two years of operations and an overwhelming number of applications received, it becomes necessary to provide more stringent guidelines.

A set of draft evaluation criteria are available in “Major drug project evaluation” [5], but these are mainly designed to thoroughly evaluate proposals that are already in the funnel, as clarified in “Implementation discussion for drug project evaluation” [6], rather than to quickly filter proposals before they enter the funnel, which is the scope of this document.

Preparing this document was one of the improvement actions decided at the VitaDAO offsite workshop that took place in May 2023 in Zuzalu.

Rationale

The mission of VitaDAO is to fund longevity science that can improve people’s life [2] in a self-sustainable manner. Therefore all funded projects should accelerate R&D aimed at ultimately delivering concrete solutions to increase healthy lifespan [1], while providing economic returns that can be used to fund more projects and support the organization without needing to permanently raise funds from external sources, in an attempt to maximize long-term impact with limited resources.

The criteria proposed in the next section are designed to perform a quick screen of proposals by assessing the alignment with this mission.

Introduction

The proposed pass/fail criteria are split into the following categories, covered in the next sub-sections:

• Longevity fit
• Team expertise
• Scientific viability
• Commercial potential
• Budget feasibility
• Application completeness

Because these criteria contain some degree of subjectivity, they should be taken as guidelines.
Some of these criteria are inspired to “Major drug project evaluation DRAFT 2. 2 March 2023” [5].
Some of these criteria are inspired to the evaluation grid of Capital Cell [7], a biotech crowd-equity.

These criteria have already been through a round of internal review with the participants of VitaDAO offsite workshop of May 2023, but further comments to these criteria are welcome and will be used to reach consensus on a final version to be voted on chain as an update of VDP 26.1 section 2.

Longevity fit

The proposal should have the potential to:

• modulate one or more mechanisms of aging [8, 10]
  • including those in [9] and other ones with reasonable scientific consensus
• treat or prevent multiple age-related diseases [8]
• extend healthspan or lifespan of healthy individuals
  • this should be documented with in-vivo data in humans or model-organisms produced by the applicant’s research or other data from peer-reviewed literature.

Any intervention that does not fulfill all three criteria is not an ideal fit for VitaDAO. However, we realize that there are different opinions as to what truly qualifies as longevity, including among our reviewers.

We recognize meeting each of the three criteria is highly subjective. Nevertheless, please do your best to explain how your therapy might fit each of them.

Team Expertise

The team should include at least one person with a background relevant for the proposal.

Ideally the team should include more than one person, except in cases of exceptional background of the solo founder.

Scientific viability

At the time of the application, the proposed intervention shall at least be at TRL3 (technology readiness level): experimental and/or analytical proof of concept. This includes in-vitro results and/or strong bioinformatics or machine learning evidence.

The results should be encouraging.

Commercial potential

The proposal should include one or more reasonable routes to market [4]. To fulfill this requirement it is sufficient to:

• identify one or more candidate indications with a market potential for which the intervention could be useful
• provide a rough state of the art and competitive landscape, providing arguments in support of the novelty and competitiveness of the proposed intervention

It is OK if indication selection has not been finalized: in fact, the proposed use of the proceeds could include experiments to advance in the indication selection process.

Budget feasibility

The budget required should:

• not exceed 200 k$
  • this is based on VitaDAO’s current runway, and may evolve
• be sufficient to reach an inflexion point that enables to raise further funding or exit
  • if the requested budget is part of a larger round, the applicant should give us confidence that it can be closed

This requirement typically implies the need to produce defensible intellectual property (IP) at the end of the project.

Proposals that can reach an inflexion point with a budget of less than 100k will be preferred.

Application completeness

The application submission form on VitaDAO internet site [10] should be filled in most of its parts with sufficient information.

Importantly, the application should contain information on the use of the proceeds.

It should also include a short video pitch with the founder(s).

If this proposal is approved, the application submission form [10] and the accompanying instructions and Q&A webpage will be updated accordingly, potentially including tutorials and references.

References

1. VitaDAO White Paper

2. VitaDAO homepage

3. VDP26.1 – Section 2

4. Sourcing Projects for VitaDAO

5. Major drug project evaluation DRAFT 2. 2 March 2023

6. Implementation discussion for drug project evaluation. DRAFT. 3 March 2023

7. Capital Cell evaluation grid

8. What counts as aging

9. Hallmarks of aging: An expanding universe

10. Application submission form

Note: some of these references are internal, access available upon request.

• Agree
• Revisions Requested (Detail in Comments)
• Disagree

[Jack_Scannell]

This strikes me as good and I have just one comment / question.

I have looked at a number of applications across various DAOs and I also led the drafting of Major drug project evaluation materials (reference [5]). I would like to highlight what strikes me as a general problem: applications may contain a core of great science but the large majority that I have seen are not readily translatable and therefore not fundable in the form in which they arrive BUT might become fundable with substantial work and input from experts in the DAO, from reviewers, etc.

I therefore raise the following question: should applicants be asked up-front, very early in the process, whether they are prepared to work collaboratively with experts in a way that might very substantially alter the initial proposal? Of course, they may all say “yes.” But asking this question up-front will, at least, set expectations for later. It may reduce the amount of time wasted on evaluating projects that applicants are unwilling to modify in the light of good advice. It may also make it easier to work with projects that miss some of the other criteria but where there is the core of something very promising.

[timrpeterson]

Thanks @Paolo !

In terms of longevity fit, I want to emphasize that it’s unlikely someone would have demonstrated their therapy works in multiple disease models in advance of submitting their proposal.

Having a suggestion that manipulation of a gene or pathway would affect multiple diseases is increasingly shown for many cases. Meaning, it’s not that special anymore. Related is that many, many genes or pathways could be said to fit a mechanism of aging. Therefore, as the proposal says it’s highly subjective how one might best fit this criteria.

Also, most biotech investors won’t be requiring lifespan experiments. Longevity is still a very small % of biotech investment. There is no regulatory path where lifespan experiments help get a drug approved. Therefore, though yes we want to push people in this direction, one could argue spending funds on lifespan experiments is not advised.

I’d like to see these caveats incorporated into the final version so that applicants are aware that we are aware how subjective the “longevity fit” requirement is.

[Paolo]

Thank you for the feedback and for the project evaluation document, @Jack_Scannell!

Your question touches upon an important point: some projects would benefit from incubation before evaluation, and that’s one aspect where VitaDAO community can add significant value, on top of funding. We already provide this support, which does require both parties to be onboard, so it makes sense to ask upfront if applicants are open to it.

In fact, when we start working with founders at the beginning of our process, it is important to explain it, and tell them whether we think some incubation is needed in order to reach a point where the project stands a good chance of getting a positive evaluation, in comparison with projects that we have funded in the past.

[EliMo]

@Paolo

extend healthspan or lifespan of healthy individuals

• this should be documented with in-vivo data in humans or model-organisms produced by the applicant’s research or other data from peer-reviewed literature.

Just to clarify - the in vivo data should eventually be produced by the applicant, i.e. the application should include a path to it, correct? (Rather than the applicant already possessing this data)

[timrpeterson]

Yes @EliMo ideally the applicant already has the in vivo data, but certainly they should have figured out a path to it.

[Paolo]

Thank you for your comments @timrpeterson. I did not answer right away because the points you raise are difficult to address, at least for me. Let me give it a shot, making it clear that this is just my attempt, and I am curious to have others’ opinions too.

Concerning the first point, the proposed longevity criterion on diseases does not require applicants to demonstrate their therapy works in multiple disease models in advance of submitting their proposal, but to argue that it has the potential to work. As you point out, one way way to do so is to provide evidence causally linking manipulation of the target with multiple diseases. It is true that many targets would fulfill this criterion: for example, according to Ageing-related disease analysis, there are about 300 genes linked to cardiovascular diseases and about 200 linked to nervous system diseases. However, only about 60 are linked to both. If on top of the disease criterion, you require a link with a molecular mechanism of aging, such as senescence, the number goes down: for example only 13 genes are related to both cardiovascular diseases and cellular senescence, according to the same resources above. Therefore, in order to address your point, I propose to add to the disease criterion an explanatory sub-bullet going like “providing evidence that manipulation of a target gene or pathway would affect multiple diseases is one way to show potential”.

Concerning your second point, the proposed longevity criterion on disease does not require applicants to have carried out experiments themselves: the evidence can come from literature. Furthermore, because most biotech investors do not require a lifespan study, I have not included in the proposal a requirement to spend funds on lifespan experiments. This is probably a point where there are different opinions in the community, and I encourage others to express their views. For example, longevity aside, can a lifespan study be useful to include in order to generate data that reassure on safety, therefore facilitating a follow-up investment decision?

[EliMo]

OK so there is a straight disagree vote. It would be good to know why… Do you disagree with having clearer criteria? Do you disagree with the content? Do you just not like the font of the proposal?

Of course, I joke, but it would be good to get more clarity on why someone would just straight disagree - it does not help us learn from it. Please help us improve!

[bowtiedshrike]

I would propose to condense some of these categories. Otherwise there is a tendency to give all the categories equal weight, which will bias towards complete applications with strong team expertise and commercial “potential” at the cost of longevity fit and scientific viability.

I propose condensing to 3 criteria:

-Longevity fit
-Scientific viability
-Business plan

Team expertise and budget would fit into each aspect of those criteria as needed (eg Team has the needed expertise to pursue the indicated conditions/commercialize the IP), and application completeness can be gated by a bot at time of submission.

How many of the proposals that VitaDAO has passed meet all 3 criteria for longevity fit?

I’m not convinced there should be an emphasis on “multiple” aging related diseases. If you can treat one well, that’s still a winner. Similarly, I think there should be more allowance for chronic disease work because most of those tie in to lifespan and healthspan. Or to ask more provocatively, ‘what makes someone a healthy individual?’ (follow-up Q: ‘what % of the population fits your definition’)

I would also suggest that the scientific viability be more rigorous than “encouraging” results. Instead: Explain the current preliminary data, and the future experiments needed to test the proposed effect and mechanism. Note the controls planned and already performed. Note key experiments that would provide ‘go/no-go’ for the next step.

In my opinion, the science is the make-or-break for project success, and the weakest part of many proposals that make it to discourse.

For business plan/commercial potential, it might be clarified that the indication does not need to match the long-term longevity fit. Things like pre-existing IP/produced IP would fit here instead of a separate ‘budget’ section. Also team ability to commercialize would fit in here. Most academics have no clue how to commercialize, so making this section a checklist (eg pre-writing the business plan) or fill-in-the-blank would be helpful. For example, something along these lines (or likely more streamlined down to the key points):

What IP is expected to be created by the end of the proposed work?

Do you currently own any IP related to this proposal?

What is the candidate indication(s) with market potential?

How is the current indication treated (state of the art)?

What is the current competitive landscape?

What makes your idea stand out (what is the competitive advantage?)

Who in your team will manage the business aspects?

What is your budget for IP protection and business development?

Do you have a Tech Transfer Office or other entity that must sign off?

Are you willing/able to generate IP-NFTs to represent IP generated by this project?

Please include a video sales letter that pitches your solution by your founders.

[Paolo]

@bowtiedshrike, thank you for your post. Please allow some time for me to reply to the various points.

[Paolo]

@bowtiedshrike, thank you again for taking the time to read this long proposal and providing comments. Here are some answers.

• Condensing to 3 criteria. First ,I would like to clarify that the proposed criteria are pass/fail, there is not a notion of weight, because these are screening criteria, not scoring criteria like those that are used for project evaluation. Although project evaluation is out of the scope of this proposal, I would still like to address here your suggestion of condensing the criteria. I actually think that providing higher score granularity to voters gives them a better information to help them vote according to what they think is a great venture, which is subjective. For example, for some people team is the most important thing, for others it is the commercial potential, and yet for others it is the research plan. By condensing these into a single criterion (with one-size-fits-all weights), this diversity is lost. The limit to this is that too many criteria could overwhelm voters, but 5-10 should be manageable.

• Retrospective analysis of longevity fit of funded proposals. This is an interesting exercise which could also be useful for mapping our portfolio according to variables like “hallmarks of aging” and “life extension” potential. I quickly went through the last 5 funded proposals: in my opinion they tick the boxes, but there is some degree of subjectivity, as stated twice (!) in the “Longevity fit” section of this proposal

• Emphasis on “multiple” aging-related diseases. Indeed, a therapy that can treat even a single type of cancer and only that is a winner, but that’s pure oncology not longevity, IMHO. However, the idea is not to ask applicants to go after multiple aging related diseases, but to have the potential to do so because their intervention addresses a mechanism upstream of several diseases. For chronic diseases and diseases in general, please see my answer below on the commercial potential.

• More rigorous “scientific viability” criterion: agreed. I propose the following:

  • Replace “The results should be encouraging” with “The results should be encouraging and clearly explained”
  • Add “A research plan including key experiments that would provide ‘go/no-go’ for the next step should be available.”

• Commercial potential:

  • I propose to add that “Candidate indications do no need to be aging-related.”
  • Thank you for your checklist, it’s a good input for reviewing our application form once this proposal is approved

[bowtiedshrike]

@Paolo

the proposed criteria are pass/fail

This was not clear from the proposal, and I would recommend making it clear at the start. If they’re all pass/fail, it makes sense to not condense the criteria.

However, if the criteria are all pass/fail, that may cause some challenges with the subjective nature of certain criteria. Perhaps the subjective aspects of ‘longevity fit’ and ‘scientific viability’ should be re-written like the ‘aims and scope’ of a journal-- give examples of what is in-scope and examples of what is out-of-scope. That way applicants have an idea and can cite that language when making a case that their project is in-scope, and community members/reviewers can use that language as a guideline for deciding if something is in-scope.

If the community is split on what is ‘in-scope’ vs ‘out-of-scope’ for longevity, that needs to be decided. Otherwise, it will depend on who reviews the proposal, which is not fair to applicants or to VitaDAO.

For scientific viability, I think the timeline/GANTT chart for key experiments would be helpful. For the scope, I would not use ‘encouraging’ and ‘clearly explained’ because those are too subjective. State something more like ‘For new/repurposed drugs and biologics, minimum preliminary data required are in vitro data showing proof of concept, with appropriate controls and statistics. Additional data (eg in vivo) with high rigor is helpful, but not required. For behavioral interventions, minimum preliminary data required are XXX. Computational-only data, or bioinformatics analysis without follow up testing are out of scope for this funding mechanism.’

I’m not a behavior person, which is why I left that XXX, but am thinking about what prelim data would be needed for some of the apps and lifestyle modification approaches that don’t requrie drugs, but could have a big impact on longevity.

Also, if this is pass/fail, I disagree with a requirement for hitting ‘multiple’ aging processes/diseases. That should be part of significance/impact later on in the review. On one hand, it will discourage people with great ideas for targeting one specific mechanism that could have a transformative impact on aging. On the other hand, everything is so interconnected that everything has the potential to hit “multiple” diseases/processes, so I don’t know requiring that will add much to a proposal. For example, many groups are turning the anti-CD19 CAR T cells used in cancers against lupus now.

Here’s an example of why I think ‘multiple disease mechanisms’ should be removed : If someone has a target and encouraging prelim data for going after age-related macular degeneration, would that be in-scope or out of scope? By definition, this is a disease of aging, fixing that would extend healthspan, but if it’s something like regenerating retinal epithelia or implanting something in the eye, it is unlikely to apply to other aging diseases. While it’s only one disease, if there was a way to stall or reverse it, that would be huge. Why should a team with expertise in ARMD have to worry about ‘can this apply to other aging diseases’? (and if you let them split hairs with “multiple diseases” by citing different genetic bases for the same disease as ‘multiple diseases’, what’s the point of this criterion?).

It just seems better to remove that, especially if it’s pass/fail at the top of the funnel.

[SB23]

What makes longevity biotech different from traditional pharma (which has been ineffective at curing age-related diseases, despite enormous amounts of capital spent/wasted)?

LongBio targets the root cause of most disease – which is aging – rather than the myriad manifestations of aging (specific diseases). Like cutting of the heads of the Hydra.

If we fund drugs that can only work for a single indication, but there’s no evidence of slowing or reversing the pace of aging – that’s a deviation from the mission of VitaDAO – which is longevity.

Targeting narrow single diseases makes us no different from the traditional pharma model. Trying to treat an age-related disease at a late stage or in already aged people is like re-arranging deck chairs on the Titanic.

We need drugs that both: 1) treat some existing disease, in order to get approval by regulatory monopolies, and 2) can be used as a preventive therapy in otherwise healthy people to slow aging. Rapamycin is a good example. It does both.

We need to quickly rule out projects that do not have evidence of targeting the core mechanisms of aging for lifespan extension.

It’s not very difficult to determine if a therapeutic is a real geroprotector.

1. It should extend lifespan (median lifespan of preferably multiple species)
   OR
2. The MoA or target in question has been firmly linked to slowing the pace of aging (autophagy, mTOR, cellular senescence…)

Importantly, the drug must be extremely safe – so safe that healthy people can take it to slow and reverse aging. This is a high bar – and mouse lifespan extension data is highly supportive of being a low toxicity molecule.

The Hallmarks of Aging and Seven Deadly SENS are pretty good frameworks as well.

Here are some more ideas:

[bowtiedshrike]

This is why I think we need to clearly lay out what we think is in-scope and what is out of scope.

Would a treatment for age-related macular degeneration be out of scope to you?

Would a regenerative that restores muscle mass be out of scope to you? (For that matter, would a hormone that boosts muscle mass be out of scope?)

Inflammation… all in scope, none in scope, or depends?

Safety is also downstream of proof-of-concept. I do not think that should be top of the funnel for early-stage research. Maybe ask that it be tested in the project, but that usually requires in vivo.

[SB23]

Agreed – the more explicit the criteria, the better the signal/noise ratio and respecting everyone’s time.

The basic premise of LongBio is that targeting the molecular biology of aging is most likely to work in the clinic when targeting age-driven diseases. Pharma fails mostly because they target symptoms of disease rather than root causes, and their animal models of disease are contrived (relative to wildtype aging across species).

Specific cases:

AMD – if the MoA is a hallmark of aging, then yes. For example, autophagy enhancement works in some AMD models.

If it’s a therapy like growing iPS-derived RPE cells to transplant in the macula, then no. That’s regenerative medicine but it’s not LongBio. It won’t extend lifespan and act systemically, because the cells remain local to the eye.

Generally speaking, a drug that could only be used for AMD is not a geroprotector, because it cannot be used prophylactically to slow aging in healthy people.

Muscle regeneration: Depends on the MoA. If it’s dosing with testosterone, no.

If it’s transplanting muscle stem cells (satellite cells), it’s a harder sell, but I could make the case that having more functional muscles is sufficiently convincing as a geroprotective MoA, because of the systemic effects of muscle mass (and myokines).

Inflammation: if there is lifespan extension data, including functional improvement (cognitive function, physical performance, resistance to multiple age-related pathologies, slowing of epigenetic clock, multiple lines of evidence for slowing aging) – then yes.

There are many therapeutics which seem to mediate their geroprotective effects by resolving inflammation (generally more at the root cause, like senolysis, rather than just masking/silencing the inflammatory signal which indicates damage or pathology – like turning off your ‘check engine light’ in your car.

That said, there’s a high bar with general inflammation blocking in the brute force way that say, anti-TNF therapies or corticosteroids work. All else equal, these drugs will shorten your lifespan when used chronically.

We are looking for pharmaceuticals that are actually good for you when taken long-term. (Or at least have lasting benefits when dosed transiently, like senolytics)

---

The devil is often in the details, but requiring lifespan and healthspan data (with the drug itself, or the target, or the broader MoA) is a pretty clear-cut criterion for ‘longevity.’

If there’s no reason to believe that a drug will slow aging, rejuvenate, and extend lifespan, it’s not a geroprotector.

We may decide to allocate (x)% of our total budget annually to projects which lack this fundamental sine qua non – essential quality of a geroprotective therapy (rejuvenation data) – in the interest of diversifying the portfolio and keeping active.

Truly novel geroprotectors are rare, at the current pace of geroscience, they don’t come around very often. So when they do, you want to double down and invest heavily. This is the model of Thiel and Druckenmiller – and consistent with the Power Law distribution in venture returns.

[bowtiedshrike]

I disagree with you on many of these points, which is why I think the DAO needs to decide how broad aging research should be-- for example, I would consider all of my examples in scope.

I think Pharma has failed not because they target symptoms, but because fixing diseases is hard. Aging diseases are hard because it takes decades to test hypotheses in humans, and no one wants a 10-year model system, much less a 20-50-year model.

One problem with restricting to “geroprotectors” is that I am not convinced “geroprotection” is real, or that a single drug will ‘slow aging’ or even ‘reverse aging’. Does autophagy/rapamycin extend life by prolonging the lifetime of only the weakest part or two of an organism, or does it globally help all organ systems? If it helps everything, why only a 10% boost? While 10% is 7-8 years for a person and not trivial, it’s nowhere near our long-term goals. We already have the tech to add 10-20 years to most people’s life-- diet, exercise, sleep, steps, CAC scans, cancer screening, hormone therapy. The near term goal should be a 2-10x for life/healthspan. We won’t get that from taking rapamycin and optimizing health, even with elite genetics.

To hit a 2-10x, we’re going to have to make sure each organ system is optimized to continue running for another 100 years or more. While organ-organ crosstalk is important, I think work prolonging any organ system is in scope. If iPS RPE cells reverse AMD to keep eyes functioning in that timeline, I would argue that is aging-related research. Technically they would even “reset” the epigenetic clock in the eye by virtue of their iPSC reprogramming.

I’m not convinced we know enough about aging to say ‘these areas are the best ones to look in’. Sure, there’s something going on with autophagy, and with senescent cells (though killing them still doesn’t hit the root cause-- can we keep them from forming in the first place?), and those mechanisms are expected to be part of the aging solution. But we’re going to need more than that. I think limiting scope to known MoAs will limit the innovation we fund. And for crossing the Valley of Death, we should be looking at innovative solutions.

The last challenge with a narrow view of longevity is that you miss related tech and advancements that can be a game-changer for the area. siRNA in humans came out of studying a system we knew didn’t work in mammals. I think a broader approach that includes rigorous science will be more likely to produce a winner (both $$wise and longevity wise).

[timrpeterson]

@SB23 @bowtiedshrike VitaDAO has had these “what’s in scope?” discussions for a long time now. Good news is it’s a democracy. The community votes to decide what’s in scope. We don’t need to tell the community what’s in scope in this VDP, rather provide some guidelines and make the audience aware that we are aware they are loose. Strong opinions, loosely held.

[EliMo]

Do you not think we should establish what’s in scope at least for a certain time period? IMHO it would resolve so many of these discussions and disagreements (a la let’s agree to disagree) that really do not bring value.

[timrpeterson]

Loose guidelines as @Paolo has done. Beyond that community vote decides.

[proofofsteve]

I am still reading through the comments but have read through the OP and wanted to ask, what challenges is Vita currently primarily facing with the early stages of its funnel?

Are you seeing a lot of submissions which you don’t think fit in the DAO’s purview? Are you seeing a lot of low quality submissions, or submissions which are perhaps high quality science but not potentially profitable investments? Or something else? In simple terms I’d like to better understand what the pain points are with sourcing rn.