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• TO EXAMINE PUBLISHED STUDIES AND COLLECT UNPUBLISHED EXPERIENCE WITH FLZ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