The Vagina is a Great Place

K Doody

Disclaimer

• INVO Bioscience (IVOB) is a publicly traded stock• A small amount of shares (<1% of the company) were provided by INVO Bioscience in lieu of financial remuneration to aid in

generation of required sterility data for INVOcell de novo application to FDA• Recently purchased a small amount of shares (<1% of the company)

Access to IVF services

• Widely available in first world urban areas• Access to services limited by• Cost

• Monetary• Time

• Geography• Cultural / religious attitudes

Assumption

• ART utilization per capita increases with decreased burden to patient• Decreased cost• Proximity of provider

Factors impacting cost

• Embryology laboratory• Laboratory personnel

Embryology laboratory

• Air handling system needed for clean air (particles and VOC’s)• Expensive to build and maintain

• Micromanipulation expense• Micromanipulation equipment• Laser• Highly skilled human resource requirement

• Incubators• Expensive electromechanical devices

• Daily QC checks• Gas analyzers / calibration• Temperature / calibrated thermometers• Record / document

• Alarm systems• 24/7 availability required for response to alarms

• Back-up power• Equipment / maintenance expense

• Require expensive supply of high purity gas• CO2• Nitrogen

Effortless IVF

• Simplified IVF with a reduced cost and potential to increase geographic access• Must be safe and effective• Must be applicable to a large portion of patients that require ART• Culturally acceptable

• Study conducted with internal funding (no sponsor)

Hypotheses

• AMH and body weight can be used to determine a safe and effective starting dose for patients at low risk of OHSS (AMH <3.4ng/ml)• GnRH agonist and lower than standard dose of gonadotropins

• Micro-management of gonadotropin dose during stimulation is largely unnecessary• A large proportion of ART patients can be adequately treated without

micromanipulation procedures• Inseminated eggs can be cultured for 5 days without the need for

expensive embryology laboratory and electromechanical incubator systems• Intra-vaginal culture system (IVC)

CP-005 Bacterial Assessment (n=9, n=5)

• Sterility is maintained over 5 days of intra vaginal culture• Incubated with sperm only

Aerobic

Anareobic

CP-005 Osmolarity (n=10 INVO, n=9 IVF)

• Osmolarity of 5 day INVO culture equals 5 days continuous culture IVF• Incubated with sperm only

CP-005 pH (n=16 INVO, n=16 IVF)

• pH of 5 day INVO culture equals 5 days continuous culture IVF

CP-005 Comfort & Retention (n=9)

• 100% retention, 0% dislodging

Discomfort

Dislodging

Retention

CP-005 Tolerability (n=9)

• Vaginal itch 0%, 11% spotting, 11% vaginal discharge

INVOcell Toxicity Assay (n=23 INVO, n=24 IVF)

• Human Sperm Survival is reduced by 64% in INVO vs IVF• Suggests toxicity in INVOcell system• Mild bio-toxicity was observed not related to vaginal culture directly, off

gassing, residue in inner chamber, and is not lot specific (data on file)• Toxicity observed in all three components of inner chamber (data on file)• Toxicity 100% REVERSED by incubating with 0.3 cc Oil for Embryo Culture from

Irvine Scientific (data on file)

CP-005 Conclusions

• 5 day continuous intra vaginal culture is possible with INVOcell• No contamination observed• Generally well tolerated• pH and osmolality matches IVF control• Sperm survival is normalized by inclusion of 0.3cc oil in inner chamber• Proceed to CP-006

CP-006

Randomized Controlled Open-Label Non-Inferiority Trial Comparing Day 5 Embryos Derived from Intravaginal Culture using the Medical Device INVOcell to Traditional In Vitro Fertilization

CP-006 Inclusion criteria

• Age 18-38• Normal FSH and E2 on Day 3• Normal AMH >1 or <3• Normal pelvic U/S• Normal uterine cavity• Negative STD screen• Male partner with normal or only mildly or moderately abnormal

sperm

CP-006 Exclusion criteria

• BMI >36• Donor oocytes, donor sperm• AFC (antral follicle count) < 6 or > 20• AMH Anti-Mullerian Hormone <1 or >3• Previously responded poorly to ovarian stimulation High responder to

ovarian stimulation• > 2 previously failed IVF (neg βhCG)• Previously failed fertilization of all oocytes previous IVF cycle• Smoke or abuse drugs and alcohol• Partner with vasectomy reversal

CP-006 Stimulation / Monitoring Protocol

• Management by sonographic assessment only• Blood drawn for archival only

• Programming with oral contraceptives• Down regulation GnRH agonist• HP-HMG at a preset dose determined by AMH and body

weight• 225 IU per day• 225 IU step down to 150 IU per day• 150 IU per day

CP-006 Stimulation / Monitoring Protocol

• Sonogram after oral contraceptives have been initiated and before start of leuprolide acetate• Sonogram after 7-10 days of leuprolide and before initiation of

gonadotropins• Sonogram after 9 doses of gonadotropin (10th day of

stimulation) to determine day of trigger• Trigger allowable on 10th, 11th, or 12th day of stimulation only• No additional sonograms done if not triggered on day of

sonogram

CP-006 Randomization

40 Subjects

20 IVC

20 IVF

Summary of Patient Profiles

IVC IVF

Age (years) 33.1 32.4

Weight (pounds) 148 161

AMH (ng/ml) 1.87 1.84

FSH utilization (IU) 1849 1882

Endometrial thickness day 10 9.61 9.04

Lead follicle day 10 16.65 16.91

Eggs collected / used 6.8 / 6.4 9.0 / 7.8Number of embryos transferred 1.65 1.80

Fertilization Rates(n=135 IVC, n=179 IVF)

Other Data Embryo Distribution By Grade(n=117 IVC, n=131 IVF)

% of Embryo >2BB for Transferred EmbryosTotal blastocyst transferred > 2BB (n= 29 IVC, n=35 IVF) as a function of total embryo transferred (n=33 IVC, n=36 IVF)

*Not significant at p<0.05 p=0.09

Secondary EndpointEmbryo Transfer Rates• Both IVC and IVF had 100% transfer rates.• All cycles went to transfer

Secondary EndpointPatient Acceptability (combination of 005 & 006 n=27)

INVOcell

Vaginal Discharge 33% (9)

Spotting 11% (3)

Itch 11% (3)

Loss of INVOcell 0% (0)

Importance of conception occurring in the body ? 1-10

5.1

Union of egg and sperm was occurring naturally without mechanical intervention? 1-10

4.6

Pregnancy outcome per cycle start

*IVC all cycles to live birth, IVF 2 cycles ongoing.

*

Birth Data

IVC IVF

Deliveries 11 10

Babies 16 13

Weight (pounds) 5.84 5.67

Summary - Intravaginal culture of eggs /embryos• Safe and well tolerated• Allows extended culture of embryos without need for expensive

embryology laboratories (clean air, alarm systems etc.)• Implementation of this or similar simple culture systems will likely

improve affordability and access to ART services

Our Team

• Kathy Doody• Jason Broome• Physicians

• Anna Nackley• Robin Thomas

• Research coordinators• LeeAnn Hoffman• Chrissy Ayala

• Embryologists• Martin Langley• Raeanna Shetron• Cassie Wiggins• Laurie Wieand