Successful New Drug Development for Small Companies

Not to know is bad; not to wish to know is worse (African proverb)

Spend Your Project $$Wisely

New Drug Development is Risky Business

Source: PhRMA Pharmaceutical Industry Profile 2006

Pitfalls: Why Drugs Fail to Reach Patients

Toxicity

PK / Formulation

Clinical Safety

Efficacy

Funding

What does this refer to?

Preclinical or long-term tox

Drug interaction, CYP induction, variable PK

Low incidence adverse events most difficult

More novel target, less known here

Low projected sales, high COGs, indication determined “non-strategic”, multiple compounds with same target

When? Early or late (carc

studies)

Usually in Phase 1

Anytime Phase 1

Anytime Phase 1 More novel target, higher risk

Anytime – Phase 3 funding a real issue for small companies

Further Observations

First-in-Class compounds have a high attrition rate Large companies still structured to focus on

compounds with high commercial potential ~25% of post IND program terminations for low

commercial value/portfolio reasons Undertreated diseases: HIV-AIDS in Africa, Malaria, TB,

Lupus, Childhood genetic diseases

Trends Dose selection will remain the single most important

scientific decision to be made Drug delivery nanotechnologies creating a new paradigm

for development – miRNA, oncology, neurology

Understand your drug Strengths / Weaknesses Knowledge gaps

Step 1

Learn from competitor drugs Strengths / Weaknesses Knowledge gaps

Have we / others been this way before?

If yes, what worked, what didn’t?

Step 2

Practice Rigorous Dose Selection Science Early1. Demonstrated Preclinical Efficacy

validated model? (biomarker predictive of clinical efficacy?)

validated target? Sufficient animal model exploration?

2. Favorable MAP profile CYP450 substrate / inhibition profile active metabolites / enantiomers? Allometric scaling CYP induction signal (PXR, HHA)? dose proportional PK? Toxicokinetics for preclinical tox

3. Formulation / Drug solubility Any limits to ability to evaluate preclinical

toxicology across the intended tox dose range via the intended route of admin in humans?

4. Select preliminary Phase I dose range and doses for IND tox studies

5. IND tox studies Are MTD and dose-limiting toxicities

sufficiently characterized in rodent and non-rodent species?

Selectivity - any unwanted secondary pharmacology?

If metabolism-related, would potential for tox increase in man due to drug-drug interactions?

Species sensitivity? Chemotype or target-related specific toxicities?

class liabilities? Nature of toxicity vs. target patient population

evaluated (risk/benefit)

Safety/exposure multiples support Phase-I dose range as is? Pre-IND meeting needed?

6. Finalize Phase I dose range

The person who knows everything has a lot to learn (anonymous)

Recommendations for Small Companies

Learn from “first in class” compounds Get earlier and better patient and standard of care

information Critically evaluate all the data to understand what

safety and efficacy biomarkers may be predictive – what are not

Focus clinical development plan on efficacy biomarkers with real potential, not exploratory

Utilize a rigorous approach for dose selection that provides a defendable risk-benefit for the patient

If the efficacy-safety problem warrants it, consider partnerships with drug delivery technology company

Advice for Business People Interested in Advancing Medicine

Finding an effective new drug treatment is a Marathon not a Mile run!

Don’t oversell the science until it is proven!