A Framework for Ideation in Early-Stage Biotech

Ideate — what do you want to work on?

Often, biotech companies are founded by a scientist that has an insight in their laboratory - however, it is absolutely possible to start from zero and iterate to a viable concept - sometimes being naive to a field can actually be a competitive advantage. This article gives a subset of questions to help you along this process.

Ideation & Understanding the Basic Biology

1. Keyword search a particular area or look at all the recent articles in high-quality journals. Pick a few areas of interest and dive deeper. May I recommend the field of aging? :)

2. Download every article relevant to the target. Skim them and understand the general current top-line opinions and players in the space. You’ll start to see patterns.

3. Who are the big players (academics, biotechs, Pharma) in the space? How has their work evolved over the years? What ideas have they rejected? Why have they not spun out a company around this already?

4. What labs are working on this protein? Sniff out incipient ideas from projects, lab websites, abstracts, patents etc.

5. Build a historical picture of the field — how did we get to today? What were the key discoveries?

6. Build a full map of the pathway/protein and every biomolecular interaction and function within it. Understand the biochemistry relevant to it — the protein’s structure, how is its size relevant to the surrounding area. Build a picture in your head of what happens.

7. How is your protein distributed across tissue, organs, developmental periods? How does it change over the course of a minute, hour, day, month, year?

8. What is the gene behind the protein? What regulates its expression positively or negatively?

9. Is it involved in any feedback loops?

10. Other pathways the target may be relevant in? In what diseases/states is it up- or down-regulated?

11. Who else has tried to drug this target? What happened? What about other proteins within this pathway?

12. How do molecules bind your protein? What is the structure? What is it homologous to, within humans? What is it orthologous to?

13. What patents have been filed around this target? How old are they? Are they still active? Who owns the patents? Has anyone licensed them?

14. Is there freedom-to-operate? Would you need to license a patent to pursue this?

15. Are there other ways to protect your position or idea?

Modality Selection (what type of drug will you develop?)

1. What are your options? What can feasibly drug this target? Not every modality works on every target!

2. How many active sites are there? Allosteric sites? Structural details?

3. How can you tell if you have found a drug that modifies your target (a hit)?

4. How can you efficiently determine whether your molecule is inhibiting/activating your target? Can you make this high throughput? What would be the positive and negative control?

5. How does this type of drug enter and exit the body? Are there any inherent toxicities of this modality? How would it be excreted? Can it break down into toxic compounds?

6. How will patients take the drug? What’s the best way to take it? What is the sphere of possible ways?

7. Will patients want to take the drug this way? What are the non-biological unintended consequences of this delivery? Could there be adherence issues?

8. What kinds of off-target effects are predictable? Are most worrisome?

9. Manufacturing challenges?

10. PK/PD considerations?

11. What is the concentration of the target in the blood/cell membrane/intracellular space, etc.? Does the target refurbish or cycle? Half-life?

12. Are there any drugs, antibodies, markers etc. for your target? How and where do they bind? How strongly do they bind? Who owns the IP?

Indication Selection (what diseases could this work for?)

1. What disease(s) is this pathway relevant to?

2. What is the incidence? Does this vary across different countries? What is the profile of a typical patient? What are the stages of the disease and how does the biology differ across them? Is there a certain point from which the pathological phenotype is not rescuable?

3. How is your target population changing over time? Do you expect this disease to become more or less prevalent with time?

4. Clinical trials

   1. What is currently in clinical trials? What was previously in clinical trials? What was the clinical trial design?

   2. How long of a clinical trial is necessary to determine efficacy over standard of care (SOC)?

   3. Size of clinical trial necessary? How large were previous clinical trials for this indication?

   4. What is the safety bar? How severe is the disease, how large the unmet need?

   5. How are patients sub-grouped?

   6. What are the endpoints for previous clinical trials trials?

   7. What biomarkers exist? How easy are they to measure? How well are they tied to the biological benefit you are targeting?

   8. Are there any potential surrogate endpoints? How well are they characterized?

   9. How many trials are currently underway, relevant to the number of patients? Have any trials been cancelled or delayed due to recruitment issues?

   10. What clinical trials have failed for this disease? Why did they fail? What happened to the lead molecule?

5. What is the cause of the disease?

6. Common co-morbidities?

7. What predisposes a patient to developing this disease?

8. Modeling the disease pre-clinically

   1. What are the model organisms?

   2. How good are the animal models, really?

   3. How is the model organism designed to mimic the disease? Is this phenotypic or genotypic simulation? Does it mimic the underlying biology? Would you expect a response from your drug in this model?

   4. Success rate of animal model benefit to human benefit?

9. Current therapies

   1. What is the current SOC?

   2. What is the patent protection around the SOC?

   3. Are there any generics/biosimilars upcoming?

   4. What is the cost of the current therapy? What is the total market penetrance and sales?

   5. How well does the SOC meet patient need? What is the duration of response? Is there a group of non-responders? Is there a subgroup which responds exceptionally well?

   6. Are there any long-term cures or preventatives in the pipeline or available on the market?

10. Are there any regulatory advantages or programs available?

11. What is the market for this drug? What other diseases could this drug segue into?

12. Would this drug be cost-effective? How cost-effective is the current SOC? How price-sensitive will healthcare providers be for a drug for this indication?