TARGET PRODUCT PROFILE:HOW TO DEVELOP SUCCESSFUL

STRATEGY FOR PHARMACEUTICAL

PRODUCTS

Yosyong Surakitbanharn, Ph.D.

YS PharmTech

People First

Boonsri Ongpipattanakul, Ph.D.

Puree Anantachoti, PhD.

Rungpetch Sakulbumrungsil, Ph.D.

Conference organizers and audiences

Success & Failure

Success: the accomplishment of an aim or purpose

Failure: the state or condition of not meeting a

desirable or intended objective

Big Pharma Strategy

Unmet medical needs

IP protections: API, formulation, process & device etc.

Market exclusivity: FDA insentives

Short development time line: FDA fast track

Minimum $ investment untill approval

Approvable: NDA 505(b)1

Marketable with high profit margin (>$1B sale annually)

Small Pharma & Biotech Strategy

Unmet medical needs

IP protections: API, formulation, process & device etc.

Market exclusivity: FDA insentives

Short development time line: FDA fast track

Minimum $ investment of each milestone

Approvable: NDA 505(b)2 or ANDA

Deal, license, joint venture or acquisition etc.

Transaction Trending

Drug Application Types

NDA (New Drug Application) – full reports of safety and

efficacy studies

ANDA (Abbreviated New Drug Application) – generic

duplicate of NDA products

Borrows safety and efficacy studies from NDA

Must have identical active ingredient, administrating route, dosage form,

strength, labeling and intended use

Must demonstrate bioequivalent

NDA 505(b)2

NDA modification of an approved drug

New active ingredient (e.g. salt, active moiety etc.)

New formulation (e.g. excipients)

New dosage form

New dosing regiment & strength

New administrating route

New indication

Rely on published safety/efficacy studies of approved drug

Must contain sufficient data to support the safety/efficacy of

the modification

Marketing Applications

NDA Filling Process

Intellectual Property (US Patent)

Provisional patent application

File first not invent first policy since 2013

No review for 1 year

Non-provisional patent application

Within a year of provisional app, must file a non-provisional or utility patent via a global PCT (including US, excluding Taiwan) or US directly

Within 18 months prior to filing targeted countries

~6 months for application publication

2-3 years for approval or denial process

Prioritized non-provisional patent application

Extra fee ($2500)

Yay or Ney results within 12 months

Market Protection Strategy

Patent – 20 year protection

FDA exclusivity

FDA cannot approve any ANDA application within exclusivity period

NDA 505(b)2 application: 3 years

NDA 505(b)2 with new chemical entity: 5 years

Orphan drug (<200,000 patients per year) application: 7 years

Additional for pediatric drug: 6 months

Patent Restoration

Design to restore the patent term lost during regulatory approval

Restoration time = ½ clinical trial period (IND effective date till NDA filing) +

entire FDA review period

Not exceed 5 years and total patent life not >15 years after approval

Patent & Market Exclusivity

Effective Patent Life

Qualified Infectious Disease Product

2012 – Congress passed Generating Antibiotic Incentives Now

(GAIN) act

50,000 patients die each year from antimicrobial-resistant infections

Encouraged pharma companies to develop antimicrobials

2012 – FDA offered qualified infectious disease product

(QIDP) designation

Expedited review & 5 year market exclusivity

After 2years, FDA granted 46 QIDP covering 32 compounds (some

compounds for multiple indications)

QIDP Strategy

May 2013 – FDA approved 1st QIDP drug, Dalvance (dalbavancin) by Durata Therapeutics (Chicago, IL)

Treat acute bacterial skin & skin structure infections (ABSSSI) by Staphylococcus or Streptococcus bacteria.

Both bacteria are GRAM positive and listed as “serious” threats by US Center of Disease Control and Prevention in 2013

Clinical study showed:

Dalbavancin worked as well as vancomycin for Gram-positive skin infections

Unlike daily dose of vancomycin, dalbavancin is once a week therapy

Ref: Nature Medicine 20, 690–691 (2014)

Fast Track & Orphan Drug Strategy

Cidara Therapeutics (San Diego, CA) developed an antifungal

drug (CD101 IV) for treatment of systemic Candida infections

CD101 IV prolongs half-life targeting once-weekly IV therapy

compared to other drugs of once daily IV infusions

FDA status:

Approved for fast track application

Approved for Qualified Infectious Disease Product (QIDP) with 5 year

market exclusivity

Approved for orphan drug classification with 7 year market exclusivity

Total potential 12 year market exclusivity after FDA approval

PK & PROLONGED HALF-LIFE

CD101 IV prolongs half life >80 hours in human for once-

weekly IV therapy

Two doses in 14 days of treatment post-clearance of active

infection

Another Orphan Drug Strategy

Meritage (San Diego, CA) licensed budesonide formulation for treatment of Eosinophilic Esophagitis (EoE) from UCSD

Currently no FDA approved drug for EoE tretment

Found in 2008 and raised $30.5M from virtual capitals

Developed new formulation of oral suspension budesonide (US patents: 9050368, 9119863)

Designed to coat esophagus for local absorption and providing patient’s symptomatic relief (US patents: 8865692, 8497258)

Qualified for orphan drug with 7 year market exclusivity

Completed clinical Phase IIB with positive results

Shire acquired Meritage in 2015

$70M (upfront) and $175M (milestone)

Citizen Petition Strategy

A strategy to delay a competitor’s approval

Citizen Petition Denial

Citizen Petition Action

Disease Strategy

Business leads science

Target medications for consumer diseases like eating disorder

e.g. ulcer, high cholesterol, acid reflux etc.

Tagamet (SKB) and Zantac (Glaxo) for ulcer treatment breaking >$1B

sales in 1986 and 1987, respectively

Lipitor (Warner Lambert & Pfizer) for high cholesterol treatment passing

highest ever sale (>$13B) in 2006

Nexium (AstraZeneca) for treatment of acid reflux disease with $5.3B

sale in 2014

US Top Ten Drug Sales 2015

Drug Company Disease Sale (Billion

US$)

Lyrica Pfizer Neuropathic pains 3.4

Januvia Merck Diabetes 3.8

Nexium AstraZeneca Acid reflux 4.7

Advair Diskus GlaxoSmithKline Asthma 4.8

Sovaldi Gilead Science Hepatitis C 4.9

Lantus Solostar Sanofi-Aventis Diabetes 5.0

Crestor AstraZeneca Cholesterol 6.1

Enbrel Amgen Rheumatoid arthritis 6.1

Abilify Otsuka Schizophrenia 7.2

Humira Abbott Crohn’s disease 8.6

Strategy Adjustment

1985 – Sildenafil citrate developed by Pfizer (Sandwich, UK)

for heart failure & hypertension

Found unusual side effect of erection in male subjects (1991)

Changed disease strategy to erectile dysfunction, Viagra

Costed £600M & 13 years to receive approval in 1998

2.9 million prescriptions in 1st quarter sale (currently >$1.2B/yr)

Patent expiry 2020, but ANDA drugs with licensing fees available 2017

2003 – Levitra (Verdenafil) and Cialis (Tadanafil) approved

Anticipated Disease

Aeolus Pharma developed a catalytic antioxidant drug for

acute radiation syndrome (ARS) disease.

A medication for countermeasure against chemical and radiological

weapons

Funded by Biomedical Advanced Research and Development Authority

(BARDA) with options, at up to $118M (received $30M)

Potential customers: US Strategic National Stockpile and other foreign

governments i.e. Israel, Japan, South Korea

Orphan drug with 7 years market exclusivity

Acute Radiation Syndrome

Who is BARDA

U.S. Department of Health & Human Services

Budgets:

2014 ($414M), 2015 ($473M) and 2016 ($522M)

Manages $2.8B Special Reserve Fund for procurements of

Strategic National Stockpile

2014 ($255M), 2015 ($255M) and 2016 ($646M)

Procurements for ARS drugs:

Neuprogen (Amgen), a leukocyte growth factor ($157.5M)

Leukine (Sanofi-Aventis), a leukocyte growth factor ($36.5M)

Device Strategy

Medication to replace injectable insulin to a non-invasive administration i.e. inhalation

Device patent (US6257233 B1) in 1999

Niche strategy with sale projection $1-4B per year

After 11 years & $2.8B investment, Exubera (Nektar/Pfizer) successfully approved in 2006*

$175M licensing fee (one time payment) paid to Nektar

After 9 month sale of $12M in 2007, Exubera was terminated as a historical pharma’s biggest flops

* Nature Biotechnology 25, 1331 - 1332 (2007)

Size is Matter

Human factor played a key role of product failure

Not secretive, but extremely large delivery device

Name calling: flashlight, a can of tennis ball & marijuana bong

Big No Good, Make It Small

Afrezza (Mannkind), inhaled insulin with a small delivery

device approved in 2014

Sanofi licensed $150M (upfront), $775M (milestone) and

65/35 profit share

After 9 month sale of $5.4M in 2015, Sanofi terminated the

collaboration*

*http://www.reuters.com/article/us-sanofi-mannkind-idUSKBN0UJ1KO20160105

Small No Good, What Went Wrong

Sanofi Study: 6,000 patients who wanted the inhaled product,

only 35% stayed on the drug*

MannKind's CEO “We think we know what went wrong in Sanofi's hands,

and we think we can fix that” (www.mmm-online.com)

Identify new patient populations to target

Evaluate new pricing tactics, and

Reopen discussions with payer

*www.fiercepharma.com by Tracy Staton (Feb 10, 2016)

Another Device Strategy

Anaphylaxis – anaphylactic shock symptom

Treatment: Epinephrine Injection (1:1000)

EpiPen

Epinephrine auto injector (1:1000)

FDA approved in 1987 (Day Laboratory)

~30 year old sulfite formulation and never changed

Mylan acquired & introduced new patented device in 2008

Monopolize $1.2B market (95%) w/o any significant

competitors

EpiPen Market Size

Auvi-Q (Sanofi)

A talking credit card size device: compressed CO2 gas instead

of spring for delivering the medication

Developed by Intelliject (YS consultant) from 2008-2012

Licensed $230M to Sanofi ($25M upfront & $205M approval)

Commercial launch in 2013

2015 (1/2 year) Worldwide sale ~€52 million prior to total product

recall due to inaccurate dosage delivery

2016 Auvi-Q is returned to Intelliject (Kaleo)

Vibex™ (Teva)

Developed by Antares and licensed to Teva for ANDA for

ANDA filing of generic EpiPen in 2014

Mylan’s “Citizen Petition” to block Vibex™ becoming generic

due to device operational differences

FDA rejected ANDA in 2016

Teva’s new strategy to file NDA 505(b)2

Mylan Citizen Petition

Differences in design and operating principles

Twinject & Adrenaclick

30% anaphylactic treatments require 2nd dose

Auto & manual single injection in one device

Rejected by patients as preferred to have two auto devices

Change strategy back to 1 injection per device (Adrenaclick)

Adrenaclick (twin packs) <5% market share

Prefilled Syringe (Adamis)

Adamis (San Diego, CA) developed of a prefilled syringe epi

injection under NDA 505(b)2

2015 (Mar) - FDA rejected (volume accuracy)

2016 (Jan) - Resubmitted NDA

Early June, licensed $35M (milestone base) to Watson

Mid June, FDA rejected (unreliable human factor uses)

Early July, Watson broke deal to avoid non refundable fees

Need >1 year prior to new filing

Why Device, Not Formulation

Product = Device + Formulation

All products use bisulfite or metabisulfite as antioxidant

Sulfite + epi generates epi sulfonic acid (ESA) ~15% at expiry

date (18 months)

Short shelf life is good for pharma company, not patients

New formulation development

may need clinical study

Device modification (i.e. retractable needle, compressed CO2

for plunger etc.):

may not need clinical study with 20 year patent protection

New Epi Formulation

Patent App US 20080269347 A1 (Rejected)

Antioxidant combo: ascorbic acid, EDTA, cysteine, citric acid etc.

Patent App US 20120029085 A1 (Rejected)

Antioxidant: thiol agent e.g. N-acetylcysteine, cysteine etc.

Patent App US 20120129944 A1 (Rejected)

Antioxidant: Na bisulfite 0.7-1.3 mg/mL

Patent App US20150246009 A1 (Pending)

Antioxidant: Na bisulfite 0.005-1.5 mg/mL

Patent App US20150374832 A1 (Pending)

Antioxidant: modified ß-cyclodextrin

Alternative Epi Administration

Sublingual Delivery

U of Manitoba, Canada (patent US 20070202163 A1)

Pro & Con

Better stability of epi salt (bitartrate) dry powder

Larger dose of >30mg epi sublingual vs. 0.3 mg IM injection

Rely on saliva for drug dissolution prior to absorption

Limited absorption due to epi vasoconstriction property

Complicated clinical study: cannot recruit anaphylatic shock patients to

volunteer during an emergency of life/death situation

Hard to find and convince investors

Epi Sublingual Model

Epinephrine bitartrate in rabbit model in patent (US 20070202163 A1)

Opioid Overdose

Pharmaceutical opioids: hydrocodone, oxycodone, morphine,

codiene, buprenorphine, pentazocine etc.

CNS drugs for pain relief

Drug Delivery Strategy

Naloxone HCl >45 years for life-threatening opioid overdose

Evzio (Kaleo Pharma)

Naloxone HCl Injection, 0.4 mg auto-injector (Auvi-Q device)

FDA approved in 2014

Price “soared from $575 to $3,750 per two-dose package in just two

years” (www.politico.com)

NARCAN® (Adapt Pharma)

Naloxone HCl Nasal Spray, 4 mg (needle free & ready to use)

FDA granted fast-track, priority review and approved in 2015

Price: US$140 per unit

Naxolone Nasal Spray vs. IM Injection

Clinical: one nostril spray (4mg) ≧ than one IM injection (0.4mg)

Evzio vs. Narcan

US$3,750 US$140Recalled Recalled

Evzio Pricing

2014 - $575; 2015 - $750 and 2016 - $3,750

Manufacturing Strategy

Viracept (Nelfinavir Mesylate), an protease inhibitor for

HIV/AIDS treatment with a dose of 2.5g BID

1997: Under a fast track NDA, launched 250mg tablet

including oral powder for pediatric patients

2003: FDA approved 625 mg tablets

Patent WO 03/063837 A1 (Pfizer for US)

Conventional granulation process

Patent WO 02/089835 A2 (Hoffmann-La Roach for EU)

Hot melt granulation

Viracept Process

Bulky light substance (<0.2 g/mL)

Glue like substance when wetting with water

Need anti-caking agent like CaSiO3 or SiO2

Need unusual pausing granulation process

Need unusually high levels of disintegrant and moisture to

improve disintegration and dissolution etc.

Large coated tablet ~1.2g with drug loaded ~0.73g

DOE study led to a unique patented granulation process

Viracept Recall

2007 – Patients complained strange

odor in Viracept bottles in EU

Roche recalled Viracept throughout

EU market due to high impurity level

of ethyl mesylate, a genotoxin

causing cancer (found >2300 ppm)

No recall on US Viracept as using

different API sources, processes and

manufacturing sites

Pricing Strategy

2011 KV Pharmaceuticals

Acquired Makena (hydroxyprogesterone caproate) a preterm labor treatment approved in 1956

Raised the price from $15/dose to $1450/dose or $29,000 (full course)

FDA not pursue pharmacies filing prescriptions with compounded equivalent

2015 Turing Pharmaceuticals

Acquired Daraprim (pyrimethamine), a treatment of rare disease (toxoplasmosis). Patent expiry in 1953 & no generic competition.

Raised the price from $13.50/tablet to $750/tablet

US congress hearing in March 2016, public angry but no effect

Replaced new CEO, but no change on drug price

Daraprim Pricing

Valient Pricing Scandals

2015 - CEO (Michael Pearson) with new drug model

Too much R&D spending from pharma & going nowhere

Created drug giant, focus on distribution & let others doing R&D

Bought rival drug companies, fired staff and slashed R&D

Increased prices same day of acquisition, and steadily kept increasing

Boost stock price ($260 max) with a short live

Left the company with $9M severance package

Valient’s Wellbutrin XL

Old antidepressant drug (once daily) with generic competitors

Transformed into a top seller via a specialty pharmacy

Declined prescriptions, but increased $ sale due to 11 times

price increase

$1400 a month supply vs. $30 generic version

$150M sale in 2013 vs. $300M sale in 2015

Valient’s Drug

Other Valient’s Drug

2015 – Increased 54 drug prices ~65.6% for instance:

Isuprel (Isoproterenol) Injection (537% Increase)

$45/dose (Hospira), $218/dose (Marathon) & $1,200/dose (Valient)

Nitropress (Na Nitroprusside) Injection (237% Increase)

Glumetza – 550% Increase

$896 (2013) to $10,020 (2015) for 90 tablets

Zegerid – 530% Increase

Cuprimine – 330% Increase

Etc.

Price Time Line

Mylan Pricing News (CNN)

Mylan Pricing News (CNBC)

Mylan Pricing Scandal

August 22nd – MN senator asked Senate Judiciary Committee

& Federal Trade Commission (FTC) investigating Mylan on

EpiPen price increase

40% Mylan revenue from $1.2B EpiPen

Heather Bresch, Mylan CEO annual salary increase from

$2.4M (2007) to $18.9M (2015)

You can complain, but you can’t control