21 st Century Herpes Solutions. William Halford, PhD RVx, Chief Science Officer

Transcription

1 21 st Century Herpes Solutions William Halford, PhD RVx, Chief Science Officer

2 Scope of Herpes Problem: by the numbers A major public health concern HSV-1 and/or HSV-2 HSV-2 infections ~100 million recurrent herpes severe disease intermediate asymptomatic 3.2 billion Need effective vaccines to prevent HSV-driven disease

3 Depth of Herpes Problem: high-level complications Complications doctors know : neonatal herpes herpes encephalitis ocular herpes genital herpes raises risk of HIV / AIDs by 3-fold Complications herpes sufferers know : chronic neuropathic pain (like shingles, but >200 days per year) depression and isolation pushes many towards suicide

4 Real Herpes Solutions RVx s Mission RVx s Technology: a suite of 21 st Century Solutions Preliminary results of a Phase I Clinical Trial RVx s Theravax HSV-2 vaccine (April - Aug 2016)

5 Team RVx William Halford, PhD Agustin Fernandez III Ashley Mihalich, MS Joshua Geltz, PhD Aziz Friedrich

6 Why was RVx formed? The standard-of-care delivered to herpes patients has been inadequate for 20 years. Over 100 million suffer with chronic herpetic disease. Too often, antiviral drugs do not alleviate symptoms.

7 So what s the problem? Approaches doctors use to manage herpes today were proposed 40 years ago. HSV-2 subunit vaccines (1976) main approach in 2016 acyclovir-based drugs (1977) main approach in 2016 HSV antibody-capture ELISA (1977) common approach in 2000s

8 So what s the problem? Theoretical Problem for Scientists 1970s-era solutions offered before HSV s complex biology understood. Practical Problem for Patients Herpes diagnostic tests error-prone HSV-2 vaccines all have failed in U.S. trials Acyclovir-derived antivirals marginally effective

9 How do RVx s Technologies Compare? RVx s New Technologies are x more efficient This is difference between: failure based on outdated assumptions & technology vs success based on 21 st -century information & technology

10 Real Herpes Solutions RVx s Mission RVx s Technology: a suite of 21 st Century Solutions 1. Better Diagnostic Tests HSV ABVIC Test

11 Herpes Diagnostic Testing: the original concept HSV-antibody capture ELISA (1977) Limitations of Original Approach n=1 or 2 measurements per test qualitative test line between (+) vs (-) is fuzzy no internal background control 4-5% of ELISAs yield false (+) results original test was not HSV-2-type-specific HSV (++) HSV-2 (++) HSV (+) HSV-2 (+) HSV (-) sero (-) Cutoff calibrator +/- cutoff (defines +/- line)

12 Herpes Diagnostic Testing: gg-ab capture ELISA (1992) HerpeSelect = current standard of care Logic: gg of HSV-1 vs -2 differ enough to offer type-specific test 0% a.a. homology HSV-2 (++) HSV-2 (+) sero (-) Cutoff calibrator (defines +/- line) gg-2 HerpeSelect

13 UI cells Focus HSV-2 + Serum HSV-1 cells HSV-2 cells Herpes Diagnostic Testing: gg-ab capture ELISA (1992) HerpeSelect = current standard of care Logic: gg-1 and gg-2 differ enough to offer type-specific test Problem: <1% of HSV-specific antibodies target gg-1 or gg kda 130 kda gg-2 (91 kda) > = 1.8% 50 kda 35 kda

14 Is gg-ab capture ELISA really that bad? U.S. Preventive Task Force s findings: offered the lowest rating they assign to diagnostic tests Potential harms outweigh the benefits of these tests due to 4% false (+) rate that misleads patients to believe they are infected with HSV-2 and pose a risk to others August 2016 HSV-2 (++) HSV-2 (+) sero (-) Cutoff calibrator (defines +/- line) = 1.8% gg-2 HerpeSelect

15 RVx: 21 st Century Tools HSV ABVIC Test (2015 Patent) = 1.8%

16 RVx: 21 st Century Tools ABVIC = Antibody-binding to virus-infected cells (contain 100% of HSV antigens)

17 RVx: 21 st Century Tools ABVIC = Antibody-binding to virus-infected cells Technical Advantages n > 30,000 measurements per test highly quantitative test statistical analysis draws +/- cutoff lines internally controlled test fewer false-positive test results 50x greater Ag breadth fewer false-negative results

18 Real Herpes Solutions RVx s Mission RVx s Technology: a suite of 21 st Century Solutions 1. Better Diagnostic Tests HSV ABVIC Test 2. Better Preventative Vaccines Profavax HSV-2

19 HSV-2 Subunit Vaccines: 30 years of failures DNA-free HSV subunit vaccine (1976) Assumption 1. HSV-2 genital herpes causes cervical cancer. Proven wrong by 1983 Assumption 2. DNA-free glycoprotein vaccine will prevent herpes. Prediction has failed in 8 clinical trials spanning 28 years Failed clinical trials of HSV-2 glycoprotein subunit vaccines Mertz, et al, 1990 Straus, et al, 1994 Straus, et al, 1997 Corey, et al, 1999 Stanberry, et al, 2002 Belshe, et al, 2012 Vaxfectin Trial (2015) GEN-003 Trial (2016)

20 HSV-2 Subunit Vaccines: limited Antigenic Breadth Antigenic Breadth B- and T-cell % of HSV-2 proteins Cooperation present in vaccine Subunit vaccines (>40,000 trial participants) Ag Breadth Herpevac = gd 0.8% GEN-003 = gd + ICP4 2% Vical = gd + UL46 3% Admedus = HSV-2 peptides 2% Agenus HerpV = 32 T-cell peptides 3%

21 Profavax HSV-2 : 50 to 100x more Antigenic Breadth Whole HSV-2 ICP0 - virus vaccines (0 trial participants) Ag Breadth Profavax HSV-2 vaccine (ICP0 - ) 99.3%

22 Does Antigenic Breadth matter? Total virus-specific antibody HSV-2 gd subunit vaccine vs live Profavax HSV-2 vaccine

23 Does Antigenic Breadth matter? Protection against herpes HSV-2 gd + alum/mpl naïve survival: 0 / 5 gd-2 survival: 1 / 4 0 NLS survival: 5 / 5 naïve survival: 0 / 5 Profavax HSV-2 vaccine vs gd-2 survival: 1 / 4 0 NLS survival: 5 / 5 Halford, et al, 2010 Halford, et al, 2011 Halford, et al, 2013 Halford, 2014 Geltz, et al, 2015 Halford, et al, 2015

24 RVx: 21 st Century Tools Live HSV ICP0 - vaccines 2010 Patent 2014 Patent Halford, et al, 2006 Halford, 2007 Halford, et al, 2010 Halford, et al, 2011 Halford, et al, 2013 Halford, 2014 Geltz, et al, 2015 Halford, et al, 2015 Royer, et al, 2016

25 Real Herpes Solutions RVx s Mission RVx s Technology: a suite of 21 st Century Solutions 1. Better Diagnostic Tests HSV ABVIC Test 2. Better Preventative Vaccines Profavax HSV-2 3. Better Herpes Treatment? Theravax HSV-2

26 Prophylactic valacyclovir: standard of care for 20 yrs Acyclic guanosine inhibits HSV DNA synthesis (1977) Promise: Acyclovir is potent HSV inhibitor in the lab (300 mm) Problem: Limited bioavailability in vivo (~1 mm) Slightly more soluble acyclovir-like drugs developed by 1990s - valacyclovir - penciclovir - famciclovir Bottom line on prophylactic valacyclovir: has not slowed the epidemic spread of genital herpes does not alleviate all herpes symptoms for all patients annual revenues $2 billion per year

27 Would a therapeutic HSV-2 vaccine be more effective? Therapeutic HSV-2 subunit vaccines: Weakness: HSV-2 subunit vaccines failing for 30 years Live Theravax HSV-2 vaccine to manage GH? 50-fold increase in antigenic breadth 100x more protective than gd-2 vaccines in animal models

28 Theravax HSV-2 Vaccine Trial: Experimental Design 20 pre-screened participants flown to St Kitts in two groups: Group 1 (n=10) 3 shots of Theravax HSV-2 (March - June, 2016) Group 2 (n=10) 3 shots of Theravax HSV-2 (June - August, 2016) At each visit: Blood drawn Intradermal immunization in calf with 150 x 10 6 infectious units Follow-up 2 days later with Administering Physician St Kitts Trial Site Luisa Veloz, MD

29 Theravax HSV-2 Vaccine Trial: Vaccination Site Reactions 20 participants received 2 or 3 shots of Theravax HSV-2 Shot 1 (Day 2) Shot 2 (Day 42) Shot 3 (Day 72)

30 Theravax HSV-2 Vaccine Trial: Safety & Tolerability 20 participants received 2 or 3 shots of Theravax HSV-2 (n=10) (n=10)

31 Theravax HSV-2 Vaccine Trial: Participant-Reported Efficacy 17 participants completed 3 shot-vaccination series Yes, Definitely Yes, Partly No

32 Theravax HSV-2 Trial: four patient sub-populations HSV-2-induced neuropathic pain Menstrual-cycle HSV-2 OBs Recurrent HSV-2 GH Recurrent HSV-1 GH

33 H-Symptomatic Days H-Symptomatic Days H-Symptomatic Days H-Symptomatic Days Theravax HSV-2 Trial: Pre-Vax Symptomatic Days pre-vax + antivirals HSV-2-induced neuropathic pain Menstrual-cycle HSV-2 OBs Recurrent HSV-2 GH Recurrent HSV-1 GH

34 H-Symptomatic Days H-Symptomatic Days H-Symptomatic Days H-Symptomatic Days Theravax HSV-2 Trial: Pre- vs Post-Vax Symptomatic Days pre-vax + antivirals post-theravax HSV-2 HSV-2-induced neuropathic pain Menstrual-cycle HSV-2 OBs Recurrent HSV-2 GH Recurrent HSV-1 GH

35 H-Symptomatic Days H-Symptomatic Days H-Symptomatic Days H-Symptomatic Days Theravax HSV-2 Trial: Pre- vs Post-Vax Symptomatic Days pre-vax + antivirals post-theravax HSV-2 HSV-2-induced neuropathic pain Menstrual-cycle HSV-2 OBs Recurrent HSV-2 GH Recurrent HSV-1 GH

36 H-Symptomatic Days H-Symptomatic Days H-Symptomatic Days H-Symptomatic Days Theravax HSV-2 Trial: Pre- vs Post-Vax Symptomatic Days pre-vax + antivirals post-theravax HSV-2 HSV-2-induced neuropathic pain Menstrual-cycle HSV-2 OBs Recurrent HSV-2 GH Recurrent HSV-1 GH

37 H-Symptomatic Days H-Symptomatic Days H-Symptomatic Days H-Symptomatic Days Theravax HSV-2 Trial: Pre- vs Post-Vax Symptomatic Days pre-vax + antivirals post-theravax HSV-2 HSV-2-induced neuropathic pain Menstrual-cycle HSV-2 OBs Recurrent HSV-2 GH Recurrent HSV-1 GH

38 Herpes Symptomatic Days Theravax HSV-2 Trial: Pre- vs Pre-Vax Symptomatic Days pre-vax + antivirals Herpes neuralgia Menstrual HSV-2 OBs HSV-2 GH HSV-1 GH

39 Herpes Symptomatic Days Theravax HSV-2 Trial: Pre- vs Post-Vax Symptomatic Days pre-vax + antivirals post-theravax HSV-2 p = Herpes neuralgia Menstrual HSV-2 OBs HSV-2 GH HSV-1 GH

40 Herpes Symptomatic Days Theravax HSV-2 Trial: Pre- vs Post-Vax Symptomatic Days pre-vax + antivirals post-theravax HSV-2 p = Herpes neuralgia Menstrual HSV-2 OBs HSV-2 GH HSV-1 GH

41 Theravax HSV-2 Trial: CE-27 Vaccination Site Reactions 60 cm 2 40 cm 2 9 cm 2 Shot 1 (Day 2) Shot 2 (Day 42) Shot 3 (Day 72)

42 Theravax HSV-2 Trial: CE-27 HSV Western Blots

43 Conclusion Genital herpes is an infinitely solvable problem. 1970s-era herpes treatments are not working. RVx s 21 st century solutions are x more effective.

44 RVx Technology Financial Upside for Investors Annual Revenue Potential HSV ABVIC Test $0.1-1 billion per year Quest Diagnostics generated $7.5 billion revenue in 2015 Theravax HSV-2 Vaccine over $5 billion per year Global HSV Treatment Market $4.8 billion per year in 2017 Profavax HSV-2 Vaccine over $10 billion per year market for Profavax HSV-2 is 10x greater than any herpes treatment

45 Acknowledgements