ARE THERE SUITABLE MACROFILARIACIDAL AGENTS OUT
THERE?
• WHAT IS THERE, ALREADY “AVAILABLE”, THAT HAS THE RIGHT CHARACTERISTICS?– MACROFILARIACIDAL EFFECTS IN ANIMALS?
– MIGHT BE ALREADY AVAILABLE FOR USE IN HUMANS FOR OTHER REASONS?
– IS THERE ANYTHING THAT EVEN APPROACHES THE CHARACTERISTICS WE NEED?
DOLF PROPOSAL
Objective 3 Early steps to develop Flubendazoleas a macrofilaricide: “Teaching an
old drug new tricks”
DOLF PROPOSAL PI – Gary Weil
Jim Kazura & Charles Mackenzie
Peter Fischer, Tim Geary, Chris King
OBJECTIVE 3.
FLUBENDAZOLE AS A MACROFILARIACIDE FOR FIELD USE
AIM
• OVERALL: IS FLUBENDAZOLE (FLZ) A CANDIDATE FOR DEVELOPMENT?
• TO EXAMINE PUBLISHED STUDIES AND COLLECT UNPUBLISHED EXPERIENCE WITH FLZ
• SEEK ANY MAJOR REASONS FOR FLZ NOT TO BE DEVELOPED AS A MACROFILARIACIDE FOR FIELD USE (MFU)
• PREPARE A PROPOSAL FOR ITS DEVELOPMENT TO THE IND STAGE
IND ?
• Investigational New Drug Application
• FDA or European routes The FDA reviews the IND application for safety to assure that
research subjects will not be subjected to unreasonable risk.
• The European equivalent of the FDA – European Agency for the Evaluation of Medicinal Products (EMEA)
• “QUICK” ROUTES– FDA - Emergency Use IND– FOR “NEGLECTED DISEASES”
OUTLINE TODAY
• YEAR 1 ACTIVITIES
– TIM GEARY & CDM
– REVIEW AND PROPOSAL PREPARATION
– BACKGROUND
• THE NEW PROPOSAL FOR DEVELOPMENT
– GATHERING A DEVELOPMENT TEAM
– EARLY PLANS
BACKGROUND
THE NEED
• There is no usable macrofilariacidal (anti-adult worm) drug
• Some 150 million people have filarial infections
• Current control programs are based on essentially anti-microfilarial drugs
• A macrofilariacide would shorten the elimination efforts by 10-20 years
• Need to increase cost effectiveness
• Perhaps avoid the problems associated with microfilarial death (e.g. LOA ISSUES
FILARIAL DISEASES
• ONCHOCERCIASIS (River Blindness)
• LYMPHATIC FILARIASIS• (“Elephantiasis”)
• LOAISIS
• HEART WORM IN DOGS
ONCHOCERCA VASCULAR SUPPLY
A LATEX “CAST” OF VESSELSA VASCULAR “STALK”
POTENTIAL COST BENEFITS
• COSTS FOR A MILLION PEOPLE FOR 8 YEARS • IF REDUCED FROM 8 YEARS TO 2 YEARS • IT REDUCES COST FROM $980,000 TO $250,000
(BASED ON TANZANIAN LF PROGRAM FIGURES)
• FOR A COUNTRY WITH 20 MILLION PEOPLE SAVES $14,000,000*
• NOT INCLUDING THE DRUG COSTS
• FREES UP $ AND PERSONNEL FOR OTHER HEALTH GOALS
• OTHER BENEFITS
CHARACTERISTICS OF A SUCCESSFUL MACROFILARIACIDE
• IS RAPIDLY EFFECTIVE or ACTS AFTER ONE (OR VERY FEW DOSES)
• IS SAFE and LACKS DISTASTEFUL SIDE EFFECTS
• ORAL (OR AT LEAST “SIMPLY” ADMINISTERED)
• IS STABLE
• IS INEXPENSIVE
“PREVENT” MICROFILARIAL PRODUCTION - MACROLACTONES
GUT
TARGET REPRODUCTIVE SYSTEM -MACROLACTONES ?
TARGETING WOLBACHIA
FEMALE OVMALE OV
DRUGS AFFECTING ADULT FILARIAL WORMS
• VARIES WITH INFECTION TYPE
• OLDER AGENTS– SURAMIN
– DIETHYLCARBAZINE
– OTHERS
• WOLBACHIA KILLING AGENTS
• BENZIMIDAZOLES
• EMODEPSIDE
• MOXIDECTIN
THE PROPOSAL
• Parenteral Flubendazole is active against human, canine and rodent adult filariae
• Flubendazole:
• Reformulate flubendazole for oral dosage
Background
• Flubendazole (R17889) is an anthelmintic marketed for both human and animal use
• The compound is poorly soluble and has its actions in the gastrointestinal tract
• Formulations include those intended for live stock, companion animals and man
• Formulations include a tablet (100 mg), chewable tablet (500 mg), syrup and an emulsion-suspension (Solubenol)
• The oral bioavailability of flubendazole from these formulation is low
FLUBENDAZOLE
• Binds tubulin
• A benzimidazole – a group that overall had a good track record for safety…..e.g. albendazole, etc.
• Recently shown to be effective against tissue parasites in mice (cystic echinococcosis –Lanusse group) i.e. solution>suspension
WHY FLUBENDAZOLE?
• ANIMAL STUDIES– Brugia in jirds – effective in a single dose
– Dirofilaria – “the most effective macrofilariacide tested” John McCall
– Has poor/no microfilariacidal effect
– Maybe has some prophylactic action (in Brugia)
• HUMAN STUDIES– Registered for use as an intestinal anthelminthic
– Mexico 1982 studies
(1983) An unpublished additional study – Mackenzie and Martinez-Palomo
FLUBENDAZOLE STUDIES IN CHIAPAS MEXICO 1981-1983
MEAN NUMBER OF FORMS PER WORM AT 2 MONTHS AFTER START OF THERAPY
FORM DEC DEC FLUBENDAZOLE FLUBENDAZOLE
NORMAL FORMS
ABNORMAL FORMS
NORMAL FORMS ABNORMAL FORMS
OOCYTE 14,400 8620 9560 3670
EARLY MORULAE
1390 2560 0 130
LATE MORULAE 2300 2560 0 920
EARLY EMBRYOS 1850 840 0 30
LATE EMBRYOS 3800 5160 0 350
MICROFILARIAE 3960 7440 20 1630
SAUSAGE FORMS
- 3000 0 400
EMPTY CAPSULE - 260 0 20
WORMS IN NODULES EXCISED 2 MONTHS AFTER START
DECFemale worms
DECMale worms
FLUBENDAZOLEFemale worms
FLUBENDAZOLEMale worms
DEAD 11 1 9 1
ALIVE 33 11 11 0
EMPTY UTERUS 6 - 1 -
OOCYTES ONLY 8 - 6 -
3 months after FLUBENDAZOLE treatment - FEMALE WORMS
DIETHYLCARBAMAZINE
FLUBENDAZOLE
DEAD 12 27
LIVING 16 0
EMPTY UTERI 5 0
OOCYTES ONLY 14 0
MACKENZIE & MARTINEZ-PALOMO, unpublished
EFFECT ON MICROFILARIAEDominguez et al, 1983
MONTH 0 0.25 1 2 3 6 9 12
DEC 101 1 2 4 8 9 3 9
FLUB 21 31 35 31 4 >1 >1 0
MAJOR OPHTHALMOLOGIC COMPLICATIONS DURING THERAPY
DIETHYLCARBAMAZINE(n=9)
FLUBENDAZOLE(n=8)
LIMBITIS 8 0
PUNCTATEKERATITIS
9 1
UVEITIS 5 0
RETINAL PIGMENT EPITH ATROPHY
1 0
SOLUBILITY STUDIESPFIZER-MSU STUDY 2008
• COMPARED A STANDARD RANGE OF SOLUBILIZING EXCIPIENTS
• THE OPTIMAL SOLUBILIZING AGENT WAS PROPYLENE GLYCOL 40:60
DOMINOWSKI & MACKENZIE 2008
Formulation Possibilities
• HPbCD
• HPbCD + Precipitation Inhibitor at Elevated Temperature (i.e., RWJxxx)
• Liquid Formulation Screen
• Miconization/Nanonization (Nanomill Screen)
• Amorphous DP
• Amorphous Dispersion-Based Systems (Automated Screen)
HYDROXYPROPYL-B-CYCLODEXTRIN
Formulation Possibilities
• HPbCD
Formulation Possibilities
• Micronized
WHY HAS BEEN SO DIFFICULT?
• “IF WE KNEW WE MIGHT BE AHEAD ALREADY”
• PLASTICITY OF FILARIAL ADULT WORMS
– BIOCHEMICAL ADAPTABILITY
• UNKNOWN BIOLOGICAL PROPERTIES
PHASE 1
• PUT TOGETHER A PROPOSAL
• TEAM
• DOCUMENT
• BEGIN DATA COLLECTION– REVIEW, CONTACT
– CARRY OUT PRELIMINARY INVESTIGATIONS• LANUSSE
• McCall
SCIENTIFIC OVERSIGHT/EFFICACY
TIM GEARY
MICHIGAN STATE UNIVERSITY MACKENZIE
FILARIAL DISEASES LABORATORY
WITH
DRUGS FOR NEGLECTED initiative- GENEVA -
FLUBENDAZOLE PROGRAM
MANAGEMENT
A DNDi SUCCESS !
A NEW HAT DRUG
PHARMA PARTNER
JOHNSON & JOHNSON
DEVELOPMENT PHASE
• OVERALL AIM
– SUBMIT AN IND APPLICATION
• CONTINUE TO MOVE FORWARD CAREFULLY
– GO/NO GO POINTS
THE CHALLENGES
• The drug
– Benzimidazoles have a short half life
– They require a relatively long action time for effectiveness as an anthelmintic
• The formulation
– Optimally it should be an oral (hopefully single) dose
– Flubendazole is registered for use in intestinal parasite treatment
TOXICITY
• They are tubulin inhibitors
• Differential effect on worm v mammal
• Breakdown products ? Needs testing
• Pro-drugs ?
DEADLINES – GO/NO, GO POINTS
• CAN WE GET EFFECTIVE AND SAFE BLOOD LEVELS?
• EMBRYOTOXICITY?
• SAFETY PACKAGE SUCCESS?
• STABILITY?
• ACCEPTABILITY IN THE FIELD?
SUMMARY POINTS
• A strong development team
• Time is of the essence
• There are major hurdles to jump (GO/NO GO)
• The class of drugs has a good history
• Animal studies support a tissue parasite effect
– Registered for humans already (needs re registering)
• Optimal formulation debatable
