[refurb]

What is in this set of "thousands of FDA-approved drugs"? Just oncolytics? Or more broad than that?

A few potential challenges:

1. Just because a combination of drugs works on a cell culture, doesn't mean it works in a human body; there are just so many more variables in vivo

2. You're just testing for efficacy, not safety; what happens if one drug potentiates the other and results in the patients getting very sick or dying? Likely a small risk since most drugs list contraindications, but a few problems might slip through

3. How are you planning on dealing with reimbursement? Insurance companies (Medicare/Medicaid included), won't pay for cancer drugs unless there is proof that they work; that proof is usually a clinical trial or at least some published data supporting it; there may be some pushback if insurance companies either don't believe your data or just don't know how to interpret it

Not trying to shit on your company, just curious if you've looked at these issues yet. It's definitely a cool idea!

[M_NotableLabs]

Thanks for your questions! We are testing both cancer and non-cancer drugs.

1. We agree, the reason we are using cell culture is because it is very fast and allows us to test many combinations at once. We have improved standard cell culture conditions and continue to do so to mimic the patient's brain as much as possible.

We confirm our results using in vivo mouse models where we have injected a patient's brain tumor cells into the mouse's brain.

2. Another great question, we prioritize the results based on safety first, then efficacy. Since these are exclusively approved therapies there is existing software that can predict toxicity interactions. We will also have a group of pharmacists that will validate the safety of the combinations.

3. This was one of the first hurdles we encountered after we started the company. The drugs we are testing are mostly off-patent generic drugs that are cheap for patients to buy directly without reimbursement from their insurance company.

If it is a more expensive drug, we can help the patient and their doctor appeal to get reimbursement on the rationale that the standard of care for grade 4 brain cancer is ineffective.

We will be starting a feasibility clinical trial as soon as we can for the purpose of publishing data on the safety and feasibility of this approach.

[tgokh]

If you're using mouse models to confirm cell culture results, roughly how long does it take to go from receiving the tissue sample to sending out a report to the patient's physician?

What type of responses to your reports have you gotten from practicing oncologists?

[vobios]

> You're just testing for efficacy, not safety

The drugs being tested are all already approved, so safety would not be really a concern.

> Insurance companies (Medicare/Medicaid included), won't pay for cancer drugs unless there is proof

After some time to collect the data, you could fairly easily compare outcomes of patients who undergo this test versus those who do not.

[refurb]

The drugs being tested are all already approved, so safety would not be really a concern.

Not true at all. Two drugs could be very safe on their own, but in combination could cause serious adverse events or even lead to death (combining some drugs with grapefruit juice can be bad). When drugs are approved by the FDA, the obvious combinations are sometimes tested for (or theoretical interactions are called out). New combinations are basically an unknown.

After some time to collect the data, you could fairly easily compare outcomes of patients who undergo this test versus those who do not.

Unless you are running a controlled clinical trial, I'm not sure anyone would trust the data. There is too much variability among patients, that if not controlled for, could seriously skew results. Sure it might indicate a promising lead, but I doubt that's enough for insurance companies to start paying for it.

[vobios]

> Two drugs could be very safe on their own, but in combination could cause serious adverse events

That is true. My assumption was that only single compounds or previously tested combinations are suggested.

> Unless you are running a controlled clinical trial, I'm not sure anyone would trust the data.

I agree. I just meant it would be relatively easy to collect enough preliminary data to have a reasonable idea of how a proper clinical trial would go. It's not like going from an animal model to human trials or from a tiny cohort of late-stage patients to a larger more heterogenous group.

[refurb]

It's not like going from an animal model to human trials or from a tiny cohort of late-stage patients to a larger more heterogenous group.

Fair point. A retrospective analysis would provide some data. The problem is insurance companies have pretty high standards (at least for cancer drug that cost a lot)!

[ejstronge]

> The drugs being tested are all already approved, so safety would not be really a concern

I think the problem is that Notable Labs would be testing combinations of FDA-approved drugs:

  Step 2: We use lab robotics to apply thousands of combinations of FDA-approved drugs...

> After some time to collect the data, you could fairly easily compare outcomes of patients who undergo this test versus those who do not

Until then, this won't be broadly available. I do think such a comparison would be interesting.

I guess you'd need to compare the expected benefit of using the Notable Labs-suggested combination to using the standard of care. You'd need to have cells from patients who did not use the Notable Labs-suggestion. This requirement could turn an 'easy comparison' into a lengthy clinical trial.

[M_NotableLabs]

Thanks for your questions!

Yes we'll be testing combinations, as this brain cancer has not responded historically to single agent therapy for decades.

With combinations of existing drugs it is possible to affect multiple driver pathways in the tumor at once. Similar to the dramatic improvement of AIDS therapy and infectious disease treatment with cocktails, tumors could respond much differently to combinations instead of a "one at a time approach" that has resulted in very small survival gains in this disease.

Please see this paper for more detail on the scientific approach to mutli-agent combinations to target many pathways at once. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226667/

Patients have been taking the CUSP-9 protocol without any serious adverse affects on a compassionate use basis. This has now moved into a prospective clinical trial for recurrent glioblastoma patients in Germany http://www.anticancerfund.org/projects/cusp9-a-combination-o...

Personalized medicine services like this could allow clinicians to move beyond traditional randomized controlled trials. Commercial services such as Foundation Medicine provide test results to oncologists who then use their discretion to treat the patient outside of a clinical trial with scientific rationale based on the test itself as opposed to a standard of care.

In a severe disease like Glioblastoma where average survival is 15 months, if the majority of patients using a system like Notable Labs live substantially longer, is a control arm necessary? The HAART cocktail for AIDS treatment never went through a phase 3 trial, so there is precedent in high need diseases.

I also would like provide a link to a recent documentary that highlights the combination approach in brain cancer by telling the story of a 20 year survivor of Glioblastoma, Ben Williams. Other patients who safely used combinations of existing drugs are featured as well. http://www.survivingterminalcancer.com/

[newman8r]

I have not looked into your company - but what's your opinion on crowdsourcing some of this? Some of these devices are remarkably similar to 3d printers and not so tough for the hobbyist to assemble.

If you do that then the community can start banding together to test formulations and then send the promising ones to you for further analysis.

Good luck. I love the idea and I personally have a few ideas of my own in the field that I want to start in 2016/2017

Edit * of course everyday people won't necessarily have access to approved therapies - but perhaps they can test other compounds and environmental conditions (or get the FDA to somehow approve tiny little test pellets for different drugs that would be legal for hobbyists to use in testing)

[vobios]

> I think the problem is that Notable Labs would be testing combinations of FDA-approved drugs

I assume that only previously used combinations are suggested.

> This requirement could turn an 'easy comparison' into a lengthy clinical trial.

But at least you would have a fairly reasonable idea of how a clinical trial would go. It's not like going from an animal model to human trials. I assume they can get a large enough sample size as they can probably recruit patients easily for what can be viewed as a second opinion.