“JUST RIGHT” PROCESS FROM DRUG - Crystal Pharmatech … · Lead candidate profile, chronic efficacy study, target engagement biomarker, GLP tox study Inform safety and clinical

“JUST RIGHT” PROCESS FROM DRUG

DISCOVERY TO DEVELOPMENT

Elizabeth Kwong , Ph.D.

Robert Wenslow, Ph.D.

1

Target Validation

In-vivo POC studies

Lead Identification Hit finding, development of in vivo efficacy

model, comparator compound, specificity,

selectivity, PK screen (%F), metabolism, tissue

delivery, target engagement studies and tox

screen

Lead Optimization Lead candidate profile, chronic

efficacy study, target

engagement biomarker, GLP

tox study

Inform safety and clinical studies of candidate

And differentiation to comparator

Drug Discovery Process-Pre-development

2

Focus is in vitro potency and ADME properties

― Allowing highly active but poorly soluble compounds to progress through primary and follow up screens

― Traditional lead series with slight increase in logP, molecular mass and complexity

Un-optimized lead

― Poor or unknown oral exposure

― Uncharacterized physico-chemical properties

• Changing form/phase

• Chemical instability

Material availability

Inflexible timeline

Limited resources

Need to develop a formulation fit for the animal efficacy model which may not apply to preclinical tox studies

Discovery scientists not familiar with development space which can contribute to the disconnect in activities from discovery to development

Challenges in early drug discovery

3

DISCOVERY/DEVELOPMENT

Low productivity

Not due to available budget but to high attrition of drug candidates

Difficulties to find new drugs

Or commercial pressure driving towards a preferred strategy

Might be due to mismanagement of already difficult R&D process

Outcome of inefficiencies of drug

4

Current success rate by phase may not be ideal and can contribute to increase in cost 5

OUTCOME OF INEFFICIENCIES OF DRUG


• TIME

6

Source: Di Masi JA, Grabowski HG and Vernon J, R&D Costs and Returns by Therapeutic

Category. Drug Information Journal 38, pp 211-223 (2004) 7

OUTCOME OF INEFFICIENCIES OF DRUG


• COST

8

According to recent literature, it may now costs an average

of $2.5 billion to get a novel drug to market. Further, very

few products ever hit blockbuster status - $1 billion in

annual sales – making the investment for R&D increasingly

costly for companies.

9

http://www.bostonglobe.com/business/2014/11/18/cost-bringing-prescription-drug-market-tops-billion-tufts-research-center-estimates/6mPph8maRxzcvftWjr7HUN/story.htmlhttp://www.bostonglobe.com/business/2014/11/18/cost-bringing-prescription-drug-market-tops-billion-tufts-research-center-estimates/6mPph8maRxzcvftWjr7HUN/story.htmlhttp://www.nytimes.com/2014/11/16/magazine/why-are-there-so-few-new-drugs-invented-today.html?_r=1

Startups Productivity

Small startups are now becoming

the “New” innovative machines,

that offer the high risk, high

reward paradigm. According to

surveys, last year, 64% of the

approved phase I studies

originated at a smaller startups.

from: E. Kwong (2017). Oral Formulation Roadmap

from Early Drug Discovery to Development Ed

Elizabeth Kwong, 2017 John Wiley & Sons, Inc.

Published 2017. pp 1-2

10

11

Source: Czerepak E.A. and S. Ryser (2005), Drug approvals and failures: Implications for alliances, Nature

Reviews Drug Discovery, Vol 7 pp197-198.

11

Pharmaceutical Industry showed low productivity in proportion to the total

number of drugs approved while biotech industry showed higher approval by

FDA, the rate of failure is still extremely high (~50%).

Collaborations could lead to a better productivity and smaller failure rate in

phase III.

Collaborations or acquisitions

11

“GREAT DISCOVERIES AND

IMPROVEMENTS INVARIABLY INVOLVE

THE COOPERATION OF MANY MINDS”.

JUST RIGHT PROCESS

Alexander Graham Bell

12

Borderless Discovery team

Closer collaboration between functional areas are key to success

Co-location or smaller team groups will be beneficial

Team needed to understand the development space to minimize risks and liabilities of the candidates

Resources can be shared with other projects but needed to be committed to solving issues

Must make disciplined decisions to select quality candidates that can deliver a safe and effective commercializable drug that is differentiated from current therapy

13

Truly integrated nimble team with

infrastructures to support team, eg

CROs, academia, consultants and

“right people on the bus” ie., strong

leadership, ownership of projects,

knowlegeable and had discovery/

development scientists mindset.

14

Candidate Selection

Lead

optimization

Lead ID

Lead Identification

Lead Optimization

Candidate Selection

Right amount of work at the Right time to

make the Right decisions

Complexity of Discovery Space

15

E. Kwong. Advancing Drug Discovery: A Pharmaceutics Perspective. J. Pharm Sci 2015, 104, 865-871

Activities in a staged Approach

16

HT solubility

― Diagnose bioassay problems

― SAR- guides structural modification to improve solubility

― Address ADME issues

Multivariate optimization

― Affinity

― Selectivity

― Activity

― Properties

― PK

Formulation and route of administration to support in vivo efficacy or PD

model

― DMSO alone is not a formulation

― Excipients needed to be innocuous in the model

― Observe precipitation in vehicle of the Active ingredient due to un-optimized phase

― Alternate route of administration can be used to target delivery to site of action, also

can address issues of compound eg. Metabolized by oral route

Lead Identification Lead ID/Target Validation Space

17

Lead Optimization/ Structure-property-based design

Use of In Silico solubility models for real NCE

― Needed to consider the crystal packing to get good accuracy in prediction

Use of drug-likeness or efficiency scoring

Historical Cross functional Data capturing to be shared with the expanded team

― Oral preclinical PK (AUC, Cmax, T1/2, Tmax)

― Solubility (kinetic vs equilibrium)-[Medium throughput for LO space]

• pH range- pH dependency of solubility, salt formation

• organic solvents- solid form screening, purification, formulation

development, process development, analytical chemistry, manufacturing,

cleaning validation

• biorelevant media ie., SGF, SIF

― BCS class

API synthesis scaled up to ~1-10g

Identification of a preclinical tox formulation that will be safe and no background

effect

DRF to GLP 14 day Tox studies in 2 preclinical species

Salt screen/identification of crystalline form (may not be a full polymorph screen)

Lead Optimization

18

Critical Compound information


19

High level view of formulation choices

Palucki M.,Higgins JD, Kwong E and Templeton AC. Strategies at the Interface of Drug Discovery and Development: Early Optimization

Of the solid state Phase and Preclinical Toxicology Formulation for Potential Drug Candidate. J Med Chem. 53,5897-5905 (2010)

20

Key Developability attributes Candidate Selection

Solubility

― Poor in vivo exposure leading to marginal efficacy

― Narrow therapeutic index caused by limited exposure in tox studies

― Expensive or unstable formulation

― Food effect

“Fit” molecule [Obese molecule- too large and too lipophilic

for their own good]

― Promiscuity

― Toxicity

― Permeability

Formulatability

― Simple homogeneous stable suspension that provide the required bioavailability (ie., BCS I or II) is preferred to support a dry blend in

capsule 21

Phase and formulation activities



22

Important considerations for candidate selection

Physico-chemical properties in small molecule drug discovery are completely

under the control of medicinal chemists and can easily be calculated before

chemical synthesis.

During optimization med chemists should constantly monitor physical

properties especially lipophilicity to help alleviate the appalling attrition rate in

clinical drug development

Exploring chemical space in drug discovery such as quantitative estimates

of drug-likeness (QED) or Preclinical Safety Pharmacology (PSP) or adverse drug

reactions (ADR) models to link targets and adverse effects should be encourage

to decrease late stage attrition.

23

Phase and formulation Definition



24

Concluding Remarks

This presentation focussed on “must do” laundry lists per phase of discovery to

development

The lists helps progress drug discovery candidates to development

Helps determine the low risk that provided a balance of speed and quality of the

selected candidate

For drug discovery, continue to swing from biology-directed chemical synthesis

to computational predictive methodologies for hit ID. Partnership with

companies specializing in hit/lead generations should be encouraged.

25

References

Elizabeth Kwong ed. Oral Formulation Roadmap from Early Drug Discovery to Development. New Jersey: John Wiley & Sons, Inc. 2017.

Hann MM. Molecular Obesity, potency and other addictions in drug discovery. Med Chem. Comm. 2011,2, 349-355.

Di L, Fish PV and Mano T. Bridging solubility between drug discovery and development. Drug Discovery Today. 2012, 17,486-495.


Palucki M.,Higgins JD, Kwong E and Templeton AC. Strategies at the Interface of Drug Discovery and Development: Early Optimization of the solid state Phase and Preclinical Toxicology Formulation for Potential Drug Candidate. J Med Chem. 53,5897-5905 (2010)

26

BACK UP SLIDES

27

HIGH THROUGH PHASE SCREENING

30

Phase selection cycle

Information can be

generated throughout the

lead selection

Historical data can help

with this cycle



31

REASONS FOR ATTRITION FROM 1991- 2000

Source: Kola I & Landis J. Can the pharmaceutical industry reduce attrition rates. Nature Reviews Drug

Discovery. 3 pp711-715 (2004)

32

R&D MODELLING

Source: Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg R and Schacht AL. How to improve R&D

productivity” The pharmaceutical industry’s grand challenge. Nature Reviews Drug Discovery 9, 203-214 (2010)

33

SIGN OF THE TIMES

Recent publication in Fortune entitled “Big Pharma Innovation in Small Places”3(Fortune, May 13,2016)quoted several big pharma executives as to the current nature of big pharmaceutical companies where the focus of R&D is diminished to sorting out changes in the company and reprioritizing programs. Furthermore, with investor money flooding in, and shift of drug pipelines from internal R&D to startups licensing opportunities, Big Pharma are acquiring small companies at faster pace than before.

Small startups are now becoming the “New” innovative machines, that offer the high risk, high reward paradigm. According to surveys, last year, 64% of the approved phase I studies originated at a smaller startups.

from: E. Kwong (2017). Oral Formulation Roadmap from Early Drug Discovery to Development Ed Elizabeth Kwong, 2017 John Wiley & Sons, Inc. Published 2017. pp 1-2

34

Information needed for Candidate Nomination

LT equilibrium solubility

― With crystalline materials

Developability risk assessment

― Aqueous solubility- biorelevant medium (Fassif/SGF)

― Chemical stability

― Form selected

― Discovery tox formulation development

― Dose number (efficacious dose, Fassif solubility)

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Documents

“JUST RIGHT” PROCESS FROM DRUG - Crystal Pharmatech … · Lead candidate profile, chronic efficacy study, target engagement biomarker, GLP tox study Inform safety and clinical