Market Insight - Rich pickings from reformulations?

In recent years, drug reformulation has emerged as a popular defence strategy among pharmaceutical companies seeking to prolong the life cycles of their best-selling products. It has also attracted growing interest from specialist companies developing novel formulations of off-patent drugs and which either launch them as replacements for the originator products, or reposition them for new indications.

The popularity of reformulation as a strategy is reflected in the fact that, between 2002 and 2005, almost 40% of the total product launches by the top 50 manufacturers were reformulations.

Apart from trying to fend off generic competition, there are a number of reasons why pharma companies pursue reformulated products. Sometimes products are reformulated in an attempt to increase sales by differentiating them from their competitors. Others seek to expand sales by developing a formulation that can address additional patient populations or treatment settings.

A recent Datamonitor report identified four types of reformulation strategy:

• The "generic defence" model;
• The "switch and grow" model, in which patients are switched from an original formulation to a new and competitively differentiated version, at the same time repositioning the product and creating an opportunity to grow sales;
• The "expand and grow" model, where a new formulation is used to expand the indications, and therefore potential market, for a particular product; and
• The "market grab" strategy, where a company develops a new formulation of an off-patent molecule in order to grab market share from the product's originator company and from generics manufacturers.

Reformulated products have generally been successfully deployed in the past, but growing payer scrutiny is starting to cast a shadow over their future. Increasingly, only those products that offer significant advantages over the original therapy will succeed. It will no longer be sufficient simply to offer improved patient compliance or convenience: products will need to offer advantages in terms of addressing unmet therapeutic needs if they are to achieve the pricing and reimbursement terms their manufacturers are looking for.

While interest in the reformulation of products currently still under patent protection will decline, the "market grab" strategy, which does not suffer from this downside, should continue to be popular with pharma companies.

This view is supported by an analysis of reformulated products currently in late-stage development. As can be seen from the following tables, which are broken down according to the type of formulation, the number of off-patent molecules being reformulated, either for the original indication or a new one, is considerably higher than the number of products being reformulated as a generic defence strategy.

Table 1: Inhalable reformulations of existing products in late-stage development

Source: Citeline Drug Intelligence

Product	Originator	Indication	Status	Original product
Clickhaler formulation of budesonide	Innovata Biomed (Vectura)	asthma	approved in the EU, where it is licensed to Merck KGaA	AstraZeneca's Pulmicort
AI (inhalable formulation of aztreonam lysine)	Gilead Sciences in collaboration with PARI Pharma	gram-negative respiratory infections, specifically Pseudomonas aeruginosa in patients with cystic fibrosis	filed for approval in the US	Bristol-Myers Squibb's Azactam
Viveta (inhalable formulation of treprostinil sodium)	United Therapeutics	pulmonary hypertension	filed for approval in the US	United Therapeutics' Remodulin
Afresa (Technosphere formulation of insulin)	Mannkind	type 1 and 2 diabetes	filed for approval in the US	N/A
IsoCrom (inhalable formulation of disodium cromoglycate)	PARI Pharma	asthma	filed for approval in Germany	Fisons' Cromolyn; many generics
Pulminiq (inhalable formulation of ciclosporin)	Novartis	prevention of rejection following lung transplant	Phase III	Novartis's Sandimmun
once-daily inhalable formulation of glycopyrrolate	Sosei in collaboration with Vectura; licensed to Novartis	COPD (formerly marketed as an anti-ulcer)	Phase III	Wyeth's Robinul
tobramycin inhalation powder	Novartis	Pseudomonas aeruginosa in patients with cystic fibrosis	Phase III	generic
Taifun dry powder inhalable formulation of fentanyl	Akela Pharma	breakthrough pain in cancer patients	Phase III	Janssen; many generics
inhalable dry powder formulation of mometasone furoate and formoterol	Schering-Plough jointly with Novartis	asthma and COPD	Phase III	Schering-Plough's Elocon/Yamanouchi's (Astellas's) Atock
Nanocrystal formulation of budesonide	MAP Pharmaceuticals in collaboration with Elan; worldwide rights (except US) licensed to AstraZeneca	acute and chronic paediatric asthma	Phase III	AstraZeneca's Pulmicort
Tempo pressurised metered dose inhaler formulation of dihydroergotamine mesylate	MAP Pharmaceuticals; licensed to Nektar Therapeutics	migraine	Phase III	generic
Staccato formulation of loxapine	Alexza	acute agitation in schizophrenia	Phase III	Watson's Loxitane
once-daily inhalation powder combination of salmeterol and tiotropium	Boehringer Ingelheim	COPD	Phase III	Boehringer Ingelheim's Spiriva
Easyhaler formulation of budesonide and formoterol	Orion Pharma	asthma and COPD	Phase III	AstraZeneca/Yamanouchi (Astellas)
eFlow inhalable formulation of salbutamol	PARI Pharma	asthma	Phase III	GSK's Ventolin

Out of 16 inhalable formulations in late-stage development, only two, United Therapeutics' Viveta and Novartis's Pulminiq, are being developed by the company that launched the original product. Viveta is an inhalable version of Remodulin, which was first launched in 2002, while Pulminiq is an inhalable version of Novartis's anti-rejection product, Sandimmun, which has been on the market since 1983. A few are new combination products, but most are inhalable formulations of older, off-patent products.

Table 2: Transdermal reformulations of existing products in late-stage development

Source: Citeline Drug Intelligence

Product	Originator	Indication	Status	Original product
once-weekly transdermal patch formulation of estradiol and levonorgestrel	Labtec	hormone replacement therapy	approved in Sweden	various
transdermal Tranfersome gel formulation of ketoprofen	IDEA	osteoarthritis symptoms	approved in Switzerland	Sanofi-Aventis's Orudis
transdermal extended-release formulation of oxybutynin	Johnson & Johnson (Alza)	urge incontinence and overactive bladder	approved in the EU	Sanofi-Aventis's Ditropan
once-daily patch formulation of ketoprofen	Applied Pharma Research	tendonitis	MAA filed for approval in France	Sanofi-Aventis's Orudis
once-daily fentanyl citrate tape preparation based on Hisamitsu's transdermal drug delivery system technology	Hisamitsu	cancer pain	awaiting registration in Japan	Janssen; many generics
androgen replacement film	Auxilium	hypogonadism	Phase III	N/A
transdermal patch formulation of granisetron	Abeille Pharmaceuticals (widely out-licensed)	chemotherapy-induced nausea and vomiting	Phase III	Roche's Kytril
transdermal patch formulation of sumatriptan succinate	NuPathe	migraine	Phase III	GSK's Imigran
transdermal patch formulation of huperzine A	Neuro-Hitech and Xel Herbaceuticals	Alzheimer's disease	Phase III	launched in China
transdermal controlled-release formulation of lisuride hydrogen maleate	Axxonis (licensed to Biovail)	restless legs syndrome	Phase III	Bayer Schering Pharma's Dopergin
once-daily transdermal formulation of oxybutynin	Antares Pharma	overactive bladder	Phase III	Sanofi-Aventis's Ditropan
topical cream combination of amitriptyline and ketamine	EpiCept	neuropathic pain	Phase III	N/A
once daily gel formulation of testosterone	Antares Pharma	hormone replacement therapy	Phase III	N/A
diclofenac sodium, Fidia	Fidia jointly with Applied Pharma Research	acute pain due to minor strains, sprains and contusions	Phase III	Ciba-Geigy's (Novartis's) Voltaren/Voltarol
testosterone lotion applied to axilla	Acrux	hypogonadism	Phase III	N/A
diclofenac patch	Cerimon	osteoarthritic pain	Phase III	Ciba-Geigy's (Novartis's) Voltaren/Voltarol
once-weekly patch containing gestodene and ethinylestradiol	Bayer	female contraceptive	Phase III	various
subcutaneous formulation of Gammagard Liquid based on Halozyme's Enhanze delivery technology	Baxter International	immunodeficiency	Phase III	Baxter's Gammagard
Ketotransdel, a cream-based transdermal ketoprofen formulation	Transdel Pharmaceuticals	acute pain	Phase III	Sanofi-Aventis's Orudis
5% gel formulation of acyclovir	Transport Pharmaceuticals	Herpes labialis	Phase III	GSK's Zovirax

Of the 20 transdermal formulations in late-stage development, only Baxter's subcutaneous formulation of its human immunoglobulin product Gammagard is being developed by the product's originator. The new formulation employs Halozyme's proprietary Enhanze delivery technology to enhance dermal penetration, and is intended for monthly administration.

Table 3: Modified-release reformulations of existing products in late-stage development

Source: Citeline Drug Intelligence

Generic name	Originator	Indication	Status	Original product
Cycloset (fast pulse-release formulation of bromocriptine)	VeroScience	type 2 diabetes	approved in the US	generic
Geomatrix once-daily oral controlled-release formulation of ropinirole hydrochloride	GlaxoSmithKline with SkyePharma	Parkinson's disease	approved in the EU, Canada and the US	GSK's ReQuip
Lamictal XR (once-daily formulation of lamotrigine)	GlaxoSmithKline	add-on therapy for the treatment of partial epileptic seizures	approved in the US	GSK's Lamictal
OraDisc A (biodegradable polymer disc formulation of amlexanox)	Uluru	aphthous ulcer	approved in the US	Discus Dental's Aphthasol
Moapar (three-month extended-release formulation of triptorelin)	Debiopharm	sexual deviations	approved in Sweden	Ipsen's Decapeptyl/Watson's Trelstar
once-daily baclofen GRS capsule	Sun Pharma Advanced Research Centre	muscle spasticity	approved in India	Novartis's Lioresal
Remoxy (long-acting bid formulation of oxycodone)	Pain Therapeutics	moderate-to-severe chronic pain	NDA accepted in the US	generic
controlled-release nisoldipine	SkyePharma	hypertension	US sNDA filing submitted	Bayer's Nisocor/Syscor
Zipsor (ProSorb-D oral, immediate-release formulation of diclofenac potassium)	Xanodyne	pain	awaiting US registration	Novartis's Voltaren
exenatide once-weekly	Amylin	type 2 diabetes	awaiting US registration	Amylin's Byetta
extended-duration formulation of Adderall	Shire	attention deficit hyperactivity disorder	US NDA filed for ADHD in adults (approvable letter received)	Shire's Adderall
controlled-release formulation of granisetron	AP Pharma	chemotherapy-induced nausea and vomiting	US NDA filed	Roche's Kytril
once-daily formulation of tramadol using Cipher's oral controlled-release bead technology	Cipher Pharmaceuticals	moderate-to-moderately severe pain	US NDA submitted	Gruenenthal's Tramal
Intuniv (extended-release formulation of guanfacine)	Shire	attention deficit hyperactivity disorder	US NDA filing – approvable	Novartis's Estulic
Onsolis (buccal controlled-release formulation of fentanyl)	QLT	breakthrough cancer pain	awaiting registration in the US	Janssen; many generics
Vicodin CR (extended release formulation of hydrocodone and paracetamol)	Abbott	severe chronic lower back pain	awaiting approval in the US	Abbott's Vicodin
Acurox (orally-active, immediate-release formulation of oxycodone hydrochloride and niacin using Acurox's Aversion (abuse deterrent) Technology)	Acura Pharmaceuticals	moderate-to-severe pain	US NDA has been filed	Purdue Pharma's Oxycontin
CloniBID/ (12hr sustained-release formulation of clonidine hydrochloride)	Addrenex Pharmaceuticals	hypertension	US NDA filing accepted	Boehringer Ingelheim's Catapres
once-daily formulation of trazodone	Labopharm	depression	US NDA accepted	Angelini's Trittico
Soma SR (sustained-release formulation of carisoprodol)	Meda	lower back pain	Phase III	generic
Epliga (once-daily formulation of oxcarbazepine)	Supernus Pharmaceuticals	epilepsy	Phase III	Novartis's Trileptal
modified-release formulation of oxcarbazepine	Desitin	partial epilepsy	Phase III	Novartis's Trileptal
oral formulation of prednisolone metasulfobenzoate sodium based on Alizyme's COLAL colon delivery system	Alizyme	inflammatory bowel disease	Phase III	generic
Exparel (sustained-release formulation of bupivacaine)	Pacira Pharmaceuticals	anaesthesia	Phase III	generic
orBec (oral dual-release formulation of beclometasone dipropionate)	DOR BioPharma	intestinal graft-vs-host disease, Crohn's disease, radiation enteritis, inflammatory bowel disease, ulcerative colitis, prevention of GvHD following bone marrow transplants and irritable bowel syndrome	Phase III	generic
extended-release formulation of baclofen	IMPAX Laboratories	spasticity in multiple sclerosis	Phase III	Novartis's Lioresal
slow-release formulation of interferon-alpha	LG Life Sciences	viral infections such as hepatitis-B and –C	Phase III	N/A
Bioadhesive tablet of aciclovir using BioAlliance's Lauriad delivery system	BioAlliance Pharma	oral herpes	Phase III	GSK's Zovirax
sustained-release formulation of donepezil hydrochloride	Eisai	Alzheimer's disease	Phase III	Eisai's Aricept
extended-release formulation of rabeprazole sodium	Eisai	gastro-oesophageal reflux	Phase III	Eisai's Pariet
transdermal patch formulation of granisetron	Abeille Pharmaceuticals	chemotherapy-induced nausea and vomiting	Phase III	Roche's Kytril
Misopess (a second-generation cervical ripening vaginal insert containing misoprostol)	BTG	induction of labour	Phase III	Pfizer's Cytotec
Hyphanox (enhanced tablet formulation of itraconazole)	Stiefel Laboratories	infection, onychomycosis	Phase III	J&J's Sporanox
Avandamet XR (extended-release formulation of Avandamet fixed-dose combination of rosiglitazone maleate and metformin HCl)	GlaxoSmithKline	type 2 diabetes	Phase III	GSK's Avandamet
Pramipexole-ER (extended-release once-daily formulation of pramipexole)	Boehringer Ingelheim	Parkinson's disease	Phase III	Boehringer Ingelheim's Mirapex
once-daily extended-release formulation of nevirapine	Boehringer Ingelheim	HIV/AIDS	Phase III	Boehringer Ingelheim's Viramune
oral, rapid-release formulation of diclofenac potassium	Applied Pharma Research	acute pain	Phase III	Novartis's Voltaren
once-daily tablet formulation of hydrocortisone	DuoCort	Addison's disease	Phase III	generic
modified release formulation of lercanidipine	Recordati	hypertension	Phase III	Recordati's Zanidip/Lercadip

The picture looks slightly different for the modified-release formulations. These are formulations designed to release their active ingredient over a certain period of time, such as within 24 hours, or formulations that contain two or more layers of active substances, which degrade at different rates, resulting in a multiple dosing schedule through a single administration.

Of the 39 modified-release formulations in late-stage development, no fewer than 11 are being developed by the company that developed the original molecule. They include GSK's antiparkinsonian ropinirole hydrochloride (originally launched in 1996 as ReQuip), GSK's anticonvulsant lamotrigine (first launched in 1991 as Lamictal), Abbott's Vicodin CR (an extended-release formulation of hydrocodone and paracetamol, a combination originally introduced as Vicodin), and Boehringer Ingelheim's once-daily extended-release formulation of its antiretroviral nevirapine (Viramune).

It seems, therefore, that pharma is showing more interest in improving the release characteristics of its products than in developing novel routes of administration.

Table 4: Optimised reformulations of existing products in late-stage development

Source: Citeline Drug Intelligence

Generic name	Originator	Indication	Status	Original product
Lipoplatin (liposomal cisplatin)	Regulon	non-small cell lung cancer	approved in Bulgaria	generic
Asacard (controlled-release Micropump microencapsulation formulation of aspirin)	Flamel Technologies	prevention of myocardial infarction	approved in the EU	N/A
Invega Sustenna (palmitate salt long-acting im formulation of paliperidone)	Johnson & Johnson	schizophrenia	US NDA filed	J&J's Invega
Decapeptyl (six-month sustained-release formulation of triptorelin using Debiopharm's proprietary triptorelin-loaded poly(D,L-lactide-co-glycolide) microparticles	Debiopharm	prostate cancer	awaiting approval in the EU	Debiopharm's Trelstar
Isotretinoin formulation using Cipher's Lidose delivery system	Cipher Pharmaceuticals	acne	awaiting approval in the US	Roche's Accutane
Certriad (fenofibrate plus rosuvastatin)	Abbott in partnership with AstraZeneca	mixed dyslipidemia	US NDA filing submitted	N/A
Paclical (nanoparticle formulation of paclitaxel)	Oasmia	ovarian cancer	Phase III	Bristol-Myers Squibb's Taxol
C2L (prolonged-release microsphere formulation of octreotide)	Ambrilia Biopharma	acromegaly	Phase III	Novartis's Sandostatin
Vekacia (topical cationic emulsion of ciclosporin A)	Novagali Pharma	keratoconjunctivitis	Phase III	Novartis's Sandimmun
BF-200 (nanocolloid formulation of aminolevulinic acid)	Biofrontera	photodynamic therapy of cancerous and precancerous skin lesions	Phase III	N/A
SinuNase (intranasal, encochleated formulation of amphotericin B)	BioDelivery Sciences	chronic rhinosinusitis	Phase III	generic
ThermoDox (formulation of doxorubicin encapsulated in heat-sensitive liposomes)	Celsion	liver cancer	Phase III	generic
once monthly and three times monthly depot injection formulations of leuprolide using GP Pharm's POLITRATE technology	GP Pharm	prostate cancer	Phase III	generic
Marqibo (iv liposomal formulation of vincristine)	Tekmira Pharmaceuticals	relapsed aggressive non-Hodgkin's lymphoma	Phase III	generic

Optimised formulations are designed to enhance the solubility of a molecule or increase its delivery to a specified site in the body. Of the 14 optimised formulations currently in advanced development, only two are reformulations of existing products: Johnson & Johnson's Invega Sustenna, a long-acting formulation of the antipsychotic paliperidone, and Decapeptyl, Debiopharm's six-month depot formulation of its prostate cancer medicine, triptorelin.

Dr Peter Charlish is a principal analyst. Email: peter.char[email protected].