Return on Investment in Discovery Chiral Separations

Transcription

1 Return on Investment in Discovery Chiral Separations Averica Discovery Services 260 Cedar Hill Street Marlborough MA

2 What Should I Spend? Understanding ROI There are entire business school courses on this subject, but there are four easier methods: 1. Changing Value Method 2. Negative Impact of Gantt Chart Slippage 3. Rough Calculation of Running Costs 4. Relative Costs of Alternatives These are fast and simple no complex value metrics or calculations. Each can be conceptually represented by scribbling on a cocktail napkin. Which method you use depends on both your goals and on your program s progress.

3 Nomination: Frequent R&D Choke Point Rapid assessment and decision-making keeps a program moving

4 De-Risking and Profiling: Supply is Critical Best Practice List for Pre-GLP Safety Assessment Average Phys. Chem. prop prediction 94% Genotox pilot (e.g. mini-ames) 87% Off-target assays (e.g. CEREP) 87% herg inhibition (e.g. auto patch clamp) 85% Reactive metabolite detection 85% 1-2 week pilot tox in rodent 82% Genotox prediction (e.g. DEREK) 79% General tox & ADME prediction (e.g. MCASE, TOPKAT) 74% Mouse micronucleus (gene tox) 72% Ames (normal Ames) 68% 3-4 day mini-tox in rodent 68% Safety pharmacology core battery 66% Safety pharmacology telemetry 62% 1-2 week pilot tox in large species 60% herg screening (e.g. Rb efflux) 57% Transporter binding/inhibition 57% Percentage of programs requiring specific assay prior to full development - Source: Drug Safety Executive Council (DSEC) survey of 20 Directors of safety assessment at major pharmaceutical companies, 2011

5 Changing Value Method Changing value = changing impact on cost/benefit of delays, successes, disruptions

6 Changing Value Method In hit-to-lead or lead optimization: How fast is the program moving impact of delay? Are there ancillary benefits: validation of mechanism? Better assay results? In candidate selection: How much material is needed to finalize lead selection? How many compounds are potential candidates? Can you source the active enantiomer in increasing amounts? What are the costs of a delay or quality problem? Averica has a >95% success rate with chiral separations

7 Gantt Chart Slippage Overall timeline tracks the critical path. If a non-cp task is delayed, the critical path can shift and the timeline increase In Discovery, assays are generally on the critical path and supply is not

8 Gantt Charts Discovery vs. Development Discovery Compound profiling determines timeline - supply should not slow things down Chromatography is the fastest source for chirally pure material Validate mechanism, improve assay signal/noise, and speed decision making Development Availability of supply keeps things progressing prior to development of a scaled synthesis Take advantage of scalable supply: Averica can deliver 10s-100s of grams in days

9 Calculating Program Run Costs Simple assumptions can lead to a fairly accurate calculation of running costs This method is useful in assessing cost of options according to their time cost or their consumption of additional resource

10 Cost Calculation: Common Conclusions Weekly Discovery program costs are in the tens of thousands of $, increasing as the program progresses Even if you shift chemists off the program, overhead costs continue to escalate No matter what your absolute costs, the DIY approach makes sense only when outsourcing = delays Averica s industry leading success rate and rapid turnaround can lower costs and shorten timelines

11 Decisions Based on Relative Costs Suppose you want 50 grams of 98% ee material for assays. Put alternatives into time and resource terms, and use the Program Run Cost Model. Then figure the chances of success: 1-6 weeks of chemist effort to develop an asymmetric synthesis (90% chance of success) 2-4 weeks of chemist effort to develop a diastereomeric crystallization (75% chance of success) 1-2 weeks to resolve material chromatographically (100% chance of success)

12 Relative Cost Scenarios Imagine a program exploring three chiral late stage leads. To nominate any one requires 200 grams for profiling and de-risking. Internal medicinal chemistry can make racemic at the 50 gram scale. Choices: 1. Develop an asymmetric process and transfer it to CRO. Have them make grams of each compound. 2. Beg, borrow or steal internal Process Chemistry resources. Have them do it. 3. Have medicinal chemist make 50 g at a time, and resolve it chromatographically. Choice 3 has limited chance of delay, and is less wasteful it s unlikely that 200 grams will be needed for all three compounds

13 Relative Cost Models Compare spending on the three choices over time Averica helps ensure steady supply as needed, when needed

14 Averica Discovery Services, Inc. A boutique CRO: Contract chemistry services, small molecule pharmaceutical sector, non-gmp focus Specialized separations technology to provide scalable supply for lead advancement, chiral compounds, reference standards, accurate assay results Accelerated Development: Assessing lead candidates at pre-nomination stage Massachusetts corporation established 2007 Newly expanded, 4400 ft 2 laboratories in Marlborough, MA Over 150 clients in pharma, agricultural chemicals, veterinary medicine, and flavor/fragrance industry

15 What You Get with Averica Averica has a >95% success rate with chiral and other difficult separations Scalable assay supply fast: 10s- 100s of grams in 3-5 days Key intermediate supply to 1 kg Method development can be scaled further for CTM production Preformulation services facilitate accelerated candidate nomination and development Stress degradation and HPLC method development for preliminary stability assessment

16 Detailed List of Services Purification High efficiency SFC purification, chiral separations Absolute configuration, Certificate of Analysis Labile or sensitive compounds Scalable supply: 5 mg to 1 kg LCMS, ELSD detection NMR, thermal analysis DEA Controlled substance license (all Schedules) Impurity Isolation Batch impurities isolated to 0.01% of bulk Stress degradation studies Full structure elucidation using 2D NMR and accurate mass MS/MS Reference standards Multiple components from one sample Consultation with project team and downstream CROs Pre-formulation Services Discovery phase-appropriate salt selection Phase-appropriate solid state work Preliminary stability HPLC method Kinetic and equilibrium solubility, pka, logp/logd

17 Contact Averica Averica Discovery Services 260 Cedar Hill Street Marlborough MA Jeffrey Kiplinger, President