Dr. Milind Biyani-Innovative Strategies to increase ...aspire-advisors.net/Innovative generics dev strategies to increase... · ASPIRE Super-generics account for 3 out of the 4 major

ASPIRE

Aspire Advisors

Dr. Milind Biyani

Director, Aspire Advisors Private Limited

Innovation strategies to increase commercial value for the next generation Indian generic manufacturer s

ASPIRE 2

Four key areas covered in this presentation

Why pursue super-generics?

How to approach development of super-generics?

What are the recent examples of super-generics deve loped by different companies?

How have companies benefited commercially from purs uing super-generics?

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Why pursue super-generics?

ASPIRE

Super-generics account for 3 out of the 4 major rou tes to develop branded products

NCENew drug discovered , 505(b)(1) NDA, Type 1 for US

• Patetnt protection for 20 years and data exclusivity in EU 6 to 10 years

Orphan DrugAilment has a patient population of < 200, 000

• Exclusivity of 7 years in US; 10 years in EU

NMENew ester, salt, etc

• Exclusivity of 5 years

Innovation in formulations

Change of dosage, form, strength, route of administ ration, etc. Exclusivity of 3 years, 505(b)(2) type NDA for US

Super-generics are innovative formulations obtained by tweaking existing formulations for therapeutic bene fit

Super-generics

1

2

3

4

ASPIRE 5

Annual approvals of super-generics have out-paced approvals for NCE

2421

1720

31

15 15 16

21 20

15

57

3

8 9

16

10

21 22

26

5356

11

0

10

20

30

40

50

60

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

NC E T ype1

NDA b2

Approvals per year

Annual approvals of NCE v/s super-genericsAnnual approvals of NCE v/s super-generics

Super-generics

Source: USFDA; Orange book; Aspire analysis

ASPIRE 6

New formulations and combinations are leading in re cent approvals of super-generics

Category 2010 2011

12 months 3 months

Formulations 35 6

Combinations 15 3

Indication 3 -

Old drugs 3 1

OTC - 1

Total 56 11

Break-up of super-generics approvalsBreak-up of super-generics approvals


ASPIRE 7

Oral dosage forms still constitute major area for i nnovations

Break-up of total approvals of super-generics betwe en 2000 to 2010Break-up of total approvals of super-generics betwe en 2000 to 2010

Total approvals


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How to approach development of super-generics?

ASPIRE 9

Need Speed of action

Instant action

Delayed, extended action

Time target delivery/Chronopharmacology

Ability to stop the action

Ability to initiate actionwhen desired/ at the timeof acute attack

Compliance/ administration

Convenience of route ofadministration

Better compliance

To qualify as an innovation in formulation atleast one of several criteria need to be met

Effect

Reduced side effects

Improved efficacy

Controlled effect

Synergistic effect bycombinations

Unmet medical need

New indication

Rx to OTC switch

ASPIRE

Several routes available for innovating in formulat ions

Innovations valid under US FDA 505(b)(2)

Innovations valid under US FDA 505(b)(2)

1. New Molecular Entity (NME)

2. New ester, New salt or other non-covalent derivative

3. New formulation

4. New combination

5. New manufacture

6. New indication

7. Drug already marketed, but without an approved NDA

8. OTC (over-the-counter) switch

Possible ways to innovate in formulations

Possible ways to innovate in formulations

1. New useful polymorph / isomer /salt

2. Changes in dosage form

3. Strength change

4. Change in route of administration

5. Substitution of an active ingredient in a combination product

6. Naturally derived recombinant active ingredient

7. Difference in bioequivalence

ASPIRE 11

Innovations are happening in relatively high tech a reas in quest for deriving increased commercial value

1. Extended Release formulations

2. Sustained Release

3. Controlled Release

4. Sublingual

5. Buccal

6. Transmucosal

7. Target drug delivery

8. Extrusion

9. Pellet coating, tangential/powder layering

ASPIRE 12

Key factors determining success for generic manufac turers embarking on the super-generics path

Having a guaranteed source of API

Experience in controlled release products

Scalability for high tech products from lab to pilo t plant to commercial plant

Early tie-ups with marketing partners, for which fi ve possibilities exist • At the time of product selection• After patent application, pilot BE and proof of concept studies• After pre-IND meeting with FDA• After IND submission• Before BA, clinical studies and NDA filing

Note: BE-Bioequivalence; BA-Bioavailability; IND-Investigational new drug; NDA-New drug application

ASPIRE 13

Recent examples of super-generics developed and com mercialized

ASPIRE

Companies may use different approaches for innovati on depending on their context

Forward integrating around own API, to explore innovative formulation possibilities

Simple incremental changes• Simple solution, great indication• Oral to topical

Sophisticated changes• Expertise in technology• Sublingual tablets• Buccal soluble film• Use of platform technology• ER/OD/XL tablets• Targeted release pellets

Supplying to new geography

Meeting unmet therapeutic need

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Illustrative approaches adopted by companiesIllustrative approaches adopted by companies

ASPIRE

Forward integrating around own API, to explore inno vative formulation possibilities

Rifaximin is a gut-selective antibiotic for travell ers diarrhoea due to E. Coli

It has been used in Italy for 26 years and is appro ved in 33 countries

Lupin agreed to supply API and ER tablets to Saliz exclusively for US in Oct, 2009; Received $5 million as first milestone p ayment.

Lupin granted worldwide rights to Salix except for India in April 2011; Received $10 million as further payment

Will get quarterly payment for product development and other activities

Also regulatory milestone payments plus royalties o n sales

Super-generics commercialization exampleSuper-generics commercialization example

Drug

Commercializationexample

Rifaximin

1

ASPIRE

Forward integrating around own API, to explore inno vative formulation possibilities; Early partner identifica tion

Drug


Levetiracetam is an anti-epileptic patent scheduled to expire in Sept 2011

Alembic applied for patent in Aug 2005 for ER table ts and assigned to UCB; UCB launched Keppra ER tablets in Sept 2008

•Patent granted in Sept 2010•Exclusivity expiry in Sept 2011•Patent expiry in Sept 2028

Alembic benefited with milestone payments of $11 mi llionand low to medium single-digit royalties on worldwi de sales

Keppra XR sales in 2009, Euro 55 million


Levetiracetam

1

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Simple incremental changes: Simple solution, great indication

Drug


A novel, water-soluble, buffered diclofenac potassi um powder,Cambia is the only prescription Non-steroidal anti- inflammatorydrug (NSAID) available for the acute treatment of m igraine

Cambia enters the bloodstream quickly and readily a chievespeak plasma concentrations, providing rapid onset o f painrelief via oral therapy without increasing the pati ent’s total exposure to diclofenac

Cambia was approved by the US FDA in June 2009

100 mn USD milestone payments earned by Nautilus Ne urosciences from Cavidien


Diclofenac Potassium

2

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Expertise in technology

Drug


Azelastine is an antihistamine and fluticasone a co rticosteroid; both are indicated for nasal treatment of allergic rhinitis

Meda and Cipla agreed to collaborate in markets suc h asEurope, Japan, Brazil, South Korea and Australia.

Meda will pay Cipla USD 5 mn upon regulatory approv al in thefirst market and up to USD 10 mn as other milestone payments;

Cipla will manufacture the product


Azelastine fluticasone

3

ASPIRE

Expertise in technology: Sub-lingual tablet

Drug


Used for the short-term treatment of insomnia, as w ell as some brain disorders

Brand name: Intermezzo

Purdue agreed to pay Transcept near-term milestones that include an upfront cash payment of $25 million and an addition al payment of up to $30 million based upon the timing of an FDA approva l of Intermezzo

Transcept is eligible to receive up to an additiona l $90 million upon reaching future milestones related to achievement o f intellectual property and US net sales targets.

Purdue will pay double-digit royalties to Transcept ranging up to the mid-twenty percent level on US net sales of Intermezzo


Zolpidem tartrate

3

ASPIRE

Expertise in technology: Fast dissolving sublingual tablets

Drug


A fast-dissolving tablet for sub-lingual administra tion of fentanyl, intended for the management of breakthrough cancer pain in patients who are already receiving opioid analgesics

Brand name: AbstralApproval date: Jan 2011Patent expiry: 2019

The filing of Abstral will generate a milestone pay ment to Orexo as part of the agreement with ProStrakan for North America

Orexo could receive upto USD27 million in certain r egulatory and sales milestone payments in addition to royalties on prod uct sales


Fentanyl Citrate

3

ASPIRE

Expertise in technology: Buccal soluble Film

Drug


Onsolis consists of a small, dissolvable, polymer f ilm, formulatedwith the opioid narcotic fentanyl for application t o the buccalmucosa (inner lining of the cheek) to manage breakt hrough pain in cancer patients

Approval date July 2009, Exclusivity expiry July 20 12, Patents 2016/19

BioDelivery Sciences (BDSI) will receive an aggreg ate of approximately$27 million in milestone payments

In addition, BDSI will receive a double-digit royal ty on net sales as well as the potential for up to another $30 million in mile stone payments upon the achievement of certain sales thresholds


Onsolis

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Expertise in technology: Use of platform technology

Drug


Diabetes management

Extended release technology for fixed dosage combin ations of sitagliptin and metformin

Depomed, Inc has provided a license to certain pate nts directedto metformin extended release technology to Merck & Co, Incto be used in developing FDCs of sitagliptin and ex tended release metformin

Depomed will receive a $10 million upfront fee; Dep omed is also eligible to receive a milestone for NDA covering Depomed's G lumetza (extended release metformin hydrochloride tablets) product in Merck's regulatory filings covering fixed dose combinations of sitagli ptin and extended release metformin

Depomed has no development obligations under the ag reement


Metformin ER

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ASPIRE

Expertise in technology: Extended release

Drug


Exalgo (hydromorphone HCl) extended-release tablets , for themanagement of moderate to severe pain in opioid tol erant patientsrequiring continuous, around-the-clock opioid analg esia for anextended period of time

CombinatoRx will receive a US$ 40 million milestone payment fromCovidien based on Exalgo approval and is eligible t o receive tieredroyalties on Exalgo net sales


Hydromorphone HCl ER

3

ASPIRE

Expertise in technology: Extended release

Drug


Extended Release tablets as a potential treatment f or moderate-to-severe primary Restless Legs Syndrome (RLS)

Brand name: Solzira

XenoPort has collaboration agreements with GSK and Astellas Pharma Inc

The FDA's acceptance of the NDA triggers milestone payments toXenoPort of $23 million in the aggregate


Gabapentin Enacarbil

3

ASPIRE

Expertise in technology: Once a day

Drug


Arthritis pain relief

Brand name: Ryzolt

Approval date -Dec 2008Exclusivity - Dec 2011; Patents 2014/2020

Labopharm was to receive a special royalty payment from Purdue of US$4.8 million and a one-time payment of US$ 500,00 0

In addition, Labopharm is eligible to receive two a dditional special royalty payments

• US$ 1 million upon net sales of Ryzolt exceeding US$ 20 million in any calendar year until 2020; and

• US$ 2 million upon net sales of Ryzolt exceeding US$ 40 million in any calendar year until 2020


Tramadol OD

3

ASPIRE

Expertise in technology: IR and XL

Drug


Treatment of Attention Deficit Hyperactivity Disord er (ADHD)

Brand name: Equasym

Shire plc, has signed an agreement with UCB to acqu ire the worldwide rights to Equasym (excluding the USA, Canada and Barbados)

Shire will make a cash payment to UCB of €55 millio n for the same

In addition, small milestone payments may become pa yable in 2009 and 2010 if certain net sales targets are met


Methylphenidate HCl IR and XL

3

ASPIRE

Expertise in technology: Once a day

Drug


Aplenzin (bupropion hydrobromide) extended-release tabletsat dosage strengths of 174mg, 348mg and 522mg for t he treatment of major depressive disorder (MDD)

Biovail entered into a supply-and-distribution agre ement with sanofi-aventis US, which is now marketing the produ ct in theUS and Puerto Rico

Biovail's supply price will range from 25 to 35 per cent of net sales, depending on the level of net sales of Aplenzin


Bupropion Hydrobromide OD

3

ASPIRE

Expertise in technology: Targeted release pellets

Drug


Targeted release pellets in sachet form

Indicated for the treatment of ulcerative colitis

Brand name: Rowasa

Ethypharm India, a subsidiary of leading French dru g delivery company Ethypharm SA

Supply agreement with Solvay Pharma India Limited


Mesalazine

3

ASPIRE

Supplying to new geography

Drug


Indicated mainly for LRTI and pre-post surgical inf ections caused by wide range of ESBL producing cephalosporin resistant str ains

Venus Remedies outlicensed to one of the top 10 pha rma companies in South Korea; Product will be supplied from Venus' B addi unit

Sulbactomax will have a significant market share ou t of the present cephalosporin market size of US$585 million in Sout h Korea, growing at 10 per cent per annum


Sulbactomax

4

ASPIRE

Unmet therapeutic need

Drug


Indicated to treat moderate to severe hot flashes i n menopausal women

Brand name: Elestrin

Antares Pharma, Inc received a milestone payment of $450,000from BioSante Pharmaceuticals, Inc related to an ag reementwith Azur Pharma for the marketing of Elestrin (est radiol gel)

BioSante received $3.325 million on signing with Az ur

Antares is entitled to 25 per cent of any upfront a nd milestonepayments as well as a percentage of product royalti es


Estradiol gel

5

ASPIRE


Drug


Indicated for erectile dysfunction

Rights are sold to Warner Chilcott Co. Inc by Nexma de for $2.5 million upfront and will receive additional $2.5 million af ter 505(b)(2) NDA approval


Alprostadil

5

ASPIRE


Drug


Diclofenac sodium for injection

Javelin Pharmaceuticals, Inc has entered into an ex clusive European marketing partnership for Dyloject with Therabel Ph arma NV (Therabel), worth up to $71 million in upfront


Dyloject

5

ASPIRE 33

Summary

ASPIRE 34

Summary of examples of licensing deals for new formulations (I)

# Drug Licensor Licensee Benefit for the licensor

1Dyloject (diclofenac sodium for injection) Javelin Therabel US$71 mn upfront sales

2 Formulating ODT Eurand GSK Euro 1 mn

3 Ondasetron oral spray Novadel HanaMilestone payments and royalties (25% to 15% of sale)

4Mesalazine targeted release pellets in sachet for ulcerative colitis Ethypharm Solvay Outlicensing and manufacturing deal

5Alprostadil topical for erectile dysfunction Nexmade

Warner Chilcott

US$ 2.5 million upfront ; Additional US$ 2.5 million after FDA approval

6Keppra (levetiracetam), leading epilepsy drug Alembic UCB

Milestone payments of $11 million and low to medium single-digit royalties on worldwide sales

7 Gabapentin enacarbil ER tablets XenoPort GSKMilestone payments of US$23 million in the aggregate

8

Coreg CR (carvedilol phosphate extended release microparticles capsules) for cardiovascular

Flamel Technologies GSK Additional $4 million milestone payment

Source: Secondary research; Aspire analysis

ASPIRE 35

Summary of examples of licensing deals for new formulations (II)

# Drug Licensor Licensee Benefit for the licensor

9 Estradiol gel Antares BioSante US$ 1.7 mn upfront, plus royalties

10 Methylphenidate ER UCB Shire Euro 55 mn for global rights except US/Canada

11 Bupropion ER tab Biovail SanofiLicensing fee built into supply price (at 25 – 35% of final sales price)

12 Hydromorphone OD Neuromed MallincrodtUpfront US$15 mn, US$16 mn on launch, plus US$30-40 mn linked to future sales volumes

13 Gyrohaler combination Vectura Sandoz Euro 2.5 mn plus royalties

14 Fenatnyl buccal soluble film BDIS MedaUpfront of US$27 mn with milestone payments upto US$30 mn, linked to future sales volumes

15Zolpidam tartarate sublingual tablets Transcept

Purdue pharma

Upfront of US$25 mn + US$30 mn at FDA approval; upto US$90 mn linked to future sales volumes

16Fentanyl fast dissolving tablet for sub-lingual administration Orexo

Prostrakan Group

US$27 mn on achievement of certain regulatory and sales milestones; In addition royalty on product sales


ASPIRE 36

# Product Licensor Licensee Benefit for the licensor

17 Azelastine Fluticason Cipla Meda5m USD in first market and 10m USD as other milestone payments

18 Hydromorphe ER Tab Combinato Rx Covidien 40 million USD

19 Metformin ER Depomed Merds 10 million up front

20 Ranibizumabinj Sumodics Roche 3-5 million up fnt

21 Diclofenac pot soln Nivo Covidien 100 m USD milestones

22 Rifaximin ER tablets Lupin Salix 5 m USD

23 Prednisporin;Cyclosporin Combinato RX Fovea USD 40 mn


Summary of examples of licensing deals for new formulations (III)

ASPIRE

Summary: Super-generics opportunity is for real! Ar e Indian companies ready?

Super-generics are outpacing NCEs in FDA approvals for innovative formulations

Several companies globally have taken advantage of the super-generics opportunity

Companies have used multiple routes to success in s uper-generics:• Forward integrating around own API, to explore innovative formulation possibilities• Simple incremental changes• Sophisticated changes based on expertise in technology• Supplying to new geography• Meeting unmet therapeutic need

However, very few Indian companies have leveraged t his opportunity, considering India’s strengths in R&D and product development

Indian companies need to move fast to take advantag e of the Super-generics opportunity

ASPIRE

How can Aspire help in development of super-generic s?

ASPIRE 39

We offer complete support to companies embarking on the super-generics path: Three key areas of support

Mapping of company product expertise (current

and planned)

Mapping of drugs going off-patent

Prioritized list of products to target for development

Recommended pipeline of

formulations to target under

505(b)(2)

Cross-check with patents already filed

by competitors

Target set of formulations to be pursued under this

opportunity

Identification of formulations to be targeted

Execution of regulatory pathway

Develop planned formulations for product launch

1

2

3

Pre-IND meeting with FDA

Pre-NDA meeting

Pre-IND Information

package

Submission of IND with clinical protocol(s)

Bio-availability and Clinical

studies

NDA submissio

n

NDA approval

Stability studies

Product launch

Pha

se I

Formulation development

Pha

se II

ASPIRE

Thank you

Documents

Dr. Milind Biyani-Innovative Strategies to increase ...aspire-advisors.net/Innovative generics dev strategies to increase... · ASPIRE Super-generics account for 3 out of the 4 major