r&d day june 18, 2008 -...
TRANSCRIPT
Safe Harbor StatementSafe Harbor Statement
Except for the historical information contained herein, the matters discussed are forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements involve risks and uncertainties, such as the progress of clinical development of bevirimat and the timing of results of clinical trials, the execution of the Company's financing plans, the timely availability of new products, market acceptance of the Company'sproducts, the impacts of competitive products and pricing, government regulation of the Company's products, the Company's ability to complete product development collaborations and other strategic transactions and other risks and uncertainties set forth in the Company's filings with the Securities and Exchange Commission. These risks and uncertainties could cause actual results to differ materially from any forward-looking statements made herein.
2
Advancing a pipeline of novel HIV drug candidatesAdvancing a pipeline of novel HIV drug candidates
Steady stream of near-term milestones
Highly experienced team in place
– Track record of successfully developing and commercializing drugs
Bevirimat
HIV Fusion Inhibitor
Second-generation HIV Maturation Inhibitor
Research Preclinical Phase 1 Phase 2 Phase 3
Third-generation HIV Maturation Inhibitor
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Experienced team leading Panacos forwardExperienced team leading Panacos forwardAlan W. Dunton, M.D.President & CEO
Johnson & Johnson; Roche; Ciba-Geigy; Metaphore
Graham P. Allaway, Ph.D. Chief Operating Officer
Progenics Pharm.; Manchester Biotech; NIH; Panacos Co-founder
Jane P. HendersonChief Financial and Business Officer
HSBC; CIBC; Lehman Brothers; Citigroup
Scott McCallister, M.D. Chief Medical Officer
Bristol-Myers Squibb; BoehringerIngelheim
Frederick Schmid, D.V.M., M.B.A.SVP, Commercial Operations & Business Development Roche; GlaxoSmithKline
David E. Martin, Pharm.D., M.B.A.SVP, Drug Development
DuPont Pharma; PharmaResearch; SmithKline Beecham
Tom Lategan, D.Phil.VP, Regulatory Affairs
Actelion Pharmaceuticals; The Medicines Company; Roche
John D. Richards, D.Phil. VP, Manufacturing Operations
The Medicines Company; Immulogic; Zeneca PLC
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Board of Directors committed to Panacos’successBoard of Directors committed to Panacos’success
Alan W. Dunton, M.D.Johnson & Johnson; Roche; Ciba-Geigy; Metaphore; Director: Adams Respiratory, MediciNova, Targacept
President & CEO, Director
Jeremy Hayward-SurryFormer President, Pall Corporation
Chairman of the Board
Laurent Fischer, M.D.CEO, Ocera Therapeutics; Dupont Pharma; Roche; Director, AIDS Healthcare Foundation
Director
R. John Fletcher, M.B.A. CEO, Fletcher Spaght; BCG; Director, AutoImmune, Spectranetics, Axcelis
Director
Irwin LernerFormer Chairman & CEO, Roche Inc.; Director & Chairman, Medarex; Director, Covance, Nektar
Director
Joseph M. LimberCEO, Prometheus Labs; ACLARA; Syntex; Ciba-Geigy; SEQUUS
Director
Robert G. SavagePharmacia; Johnson & Johnson; Director, Noven Pharma; Lead Director, The Medicines Company; Chairman, EpiCept
Director
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Our goals for hosting this R&D DayOur goals for hosting this R&D Day
Provide detailed insight into Panacos’ pipeline– Bevirimat:
• Gag polymorphisms and bevirimat efficacy• Formulation status• Next steps for development program
– Maturation inhibitors next generations: strategy– Small molecule oral fusion inhibitors: significance
Articulate the significant market potential of bevirimat– Continued need for novel mechanism HIV drugs
Outline the short-term value-creating events for PanacosIntroduce you to the Panacos team – Express our commitment– Give confidence in our expertise
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Key highlights from today’s meetingKey highlights from today’s meeting
Changes in patient care benefit bevirimat
Study 203 (prospective extension) results confirm predictors of response
Identification of Gag polymorphisms and their impact on bevirimat efficacy and market potential – An attractive market opportunity
– Physicians treat patients based upon viral profiling (genotyping)
– Genotyping is not expected to have a negative impact on a successful bevirimat launch
Significant upside in oral fusion program
Panacos is on the road to success
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Our Key Opinion LeadersOur Key Opinion Leaders
Calvin J. Cohen, MD, MScDirector, Community Research, Community Research Initiative of New England Director, Research, Harvard Vanguard Medical Associates
Joseph J. Eron, MDProfessor, Division of Infectious Diseases Principal Investigator, AIDS Clinical Trials Unit Associate Director, General Clinical Research Center University Of North Carolina at Chapel Hill AIDS Clinical Trials Unit, Department of Medicine , Division of Infectious Diseases
Richard Harrigan, PhDDirector, Research Labs, BC Centre for Excellence in HIV/AIDS Vancouver BCAssociate Professor, Division of AIDS, University of British Columbia
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HIV and AIDSThe Shifting Treatment Landscape
Calvin Cohen, MDCommunity Research Initiative New England
Harvard Medical SchoolBoston, MA
Topics
HIV: epidemiology of the pandemic
2008 treatment options
Limitations of treatment
Future of HIV treatment 2010 and beyond
Estimated global number of people living with HIV: 1990–2007
This bar indicates the rangeYear
1990 1995 1998
Mill
ions
1993 1996 20042000 2002 2006
0
10
20
30
40
1991 19991992 1994 1997 20052001 2003 2007
2007 AIDS epidemic update figure
The HIV-1 replication cycle
Entry Inhibitors
RT Inhibitors
IntegraseInhibitors
Protease Inhibitors
Maturation Inhibitors
Fusion Inhibitors
Entry Inhibitors
Integrase Inhibitors
Protease InhibitorsNRTIs
• Zidovudine
NNRTIs
Available antiretroviral drugs 1990
Fusion Inhibitors
Entry Inhibitors
Integrase Inhibitors
Protease Inhibitors
• Saquinavir
NRTIs• Didanosine
• Lamivudine
• Stavudine
• Zalcitabine
• Zidovudine
NNRTIs
• Nevirapine
Available antiretroviral drugs 1995
Fusion Inhibitors
Entry Inhibitors
Integrase Inhibitors
Protease Inhibitors• Amprenavir
• Indinavir
• Lopinavir
• Nelfinavir
• Ritonavir
• Saquinavir
NRTIs• Abacavir
• Didanosine
• Lamivudine
• Stavudine
• Zalcitabine
• Zidovudine
NNRTIs• Delavirdine
• Efavirenz
• Nevirapine
Available antiretroviral drugs 2000
Fusion Inhibitors
• Enfuvirtide
Entry Inhibitors
• Maraviroc
Integrase Inhibitors
• Raltegravir
Maturation Inhibitors
• None
Protease Inhibitors• Amprenavir
• Atazanavir
• Darunavir
• Fos-Amprenavir
• Indinavir
• Lopinavir
• Nelfinavir
• Ritonavir
• Saquinavir
• Tipranavir
NRTIs• Abacavir
• Didanosine
• Emtricitabine
• Lamivudine
• Stavudine
• Tenofovir
• Zalcitabine
• Zidovudine
NNRTIs• Delavirdine
• Efavirenz
• Nevirapine
• Etravirine
Available antiretroviral drugs 2008
CD4 cell count and plasma HIV-1 RNA level—the impact of HAART
150
100
50
0
-50
-100
-150
-200
CD
4+C
ell C
ount
Plasma H
IV-1 RN
A
1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997
Years MonotherapyDouble RTI CombinationsHighly Active Antiretroviral Therapy
Rates of virologic failure in patients starting triple therapy (resistance)
J. Hopkins: all patients starting 3-drug HAART 1996-2002 (n=1255)
% with <400 copies/mLat 6 mos.:- 1996 43.8- 1997-8 54.2- 1999-2000 70.3- 2001-2 72.4
Moore RD, et al, J AIDS 2005;39:195-8; Lampe F, et al. Arch Int Med 2006;166:521-8.
Virologic failure from 5 observational cohorts; % > 500 copies (n=4,143)
(p<0.001 for trend)
25%30%31%
34%39%
42%40%
0
10
20
30
40
50
1996 1997 1998 1999 2000 2001 2002
Patie
nts
(%)
2008 DHHS guidelines When to start: a shift to earlier treatment?
Available at: http://aidsinfo.nih.gov/Default.aspx. Revision January 29, 2008.
Clinical Conditions and/or CD4 Count Recommendations
CD4 count <350 cells/mm3
History of AIDS-defining IllnessPregnant womenPersons with HIV-associated nephropathyPersons coinfected with HBV, when HBV treatment is indicated
Initiate ARV Therapy
Patients with CD4 > 350 cells/mm3Optimal time to initiate ARV therapy not well defined
Consider patient scenarios and comorbidities
ARV-naïve treatment (“gold standard”) TDF / 3TC / EFV long-term follow-up
▬N=86; Longer term extension in Latin America
% HIV RNA <50 c/mL through Week 192
Enejosa J, et al. 10th EACS; November 17–20, 2005; Dublin, Ireland, Abstract PE7.3/13.
% P
atie
nts
with
H
IV R
NA
<50
c/m
L
0
20
40
60
80
100
0 24 48 72 96 120 144 168 192
ITT M = F
ITT M = Excluded
92%87%
Week
Gilead 903E
DHHS 2008 guidelinesRecommended regimens for treatment-naïve patients
Select 1 Component From Column A and 1 From Column B
Column A Column B
NNRTI or PI NRTIs
Preferred componentsEFV ATV/r
FPV/r (BID*)LPV/r (BID*)
TDF/FTC -or-
ABC/3TC
[HLA-B*5701 negative only]
Alternative components
NVP ATV FPVFPV/r (QD*)
LPV/r (QD*)SQV/r
ZDV/3TC
-or-
DDI + (FTC or 3TC)
Available at: http://aidsinfo.nih.gov/Default.aspx. Revision January 29, 2008.
*BID = Twice daily; QD = Once daily
Treatment options: key points
23 individual drug options and 6 fixed dose combinations are approved in the US—and 2 novel MOA drugs approved in last 18 months
Due to ongoing resistance and tolerability challenges, new drugs (also novel MOA) continue to be needed
Local and international therapeutic guidelines have shifted to recommend earlier start of treatment
Long-term gold standard treatment regimen for naïve or experienced patients are 2 NRTIs + NNRTI or PI (HAART)– New treatment paradigm possible?
0
0.5
1
1.50 2 4 8 12 16 20 24
Weeks
Med
ian
decr
ease
H
IVR
NA
log
copi
es/m
L
lamivudine monotherapy
Kuritzkes D, et al. AIDS. 1996;10:975-981.
(n = 14)
Resistance to individual ARV drugs can occur quickly
- Lamivudine (3TC) monotherapy linked to resistance and virologicfailure within 2 weeks
- Other NRTIs also maintain M184V (e.g. FTC)
- Single dose nevirapine(primarily used for MTCT) also leads to rapid resistance development
Virologic activity and resistance: with NRTIs(and some NNRTIs) this happens rapidly
Raltegravir: the development of resistance
Hazuda DJ, et al. 16th International HIV Drug Resistance Workshop, Barbados 2007
-100 0 100 200 300 400 500 600 700Days in study
22.5
33.5
44.5
55.5
6
Log
[vRN
A]
400cp/ml
Patient B
N155HN155H, L74L/M, T97A
+DVR
-100 0 100 200 300 400 500 600 700Days in study
22.5
33.5
44.5
55.5
6
Log
[vRN
A]
400cp/ml
Patient C
N155H
+ ENF, DRV/r
-100 0 100 200 300 400 500 600 700Days in study
22.5
33.5
44.5
55.5
6
Log
[vRN
A]
400cp/ml
Patient A
Q148HG140SE138E/K
N155H
-100 0 100 200 300 400 500 600 700Days in study
22.5
33.5
44.5
55.5
6
Log
[vRN
A]
400cp/ml
Patient DQ148H, G140S (pop)
G140G/S, Q148Q/H, N155N/H (pop)Q148H and N155H unlinked (clonal)
Short- and long-term safety and tolerability
Short-term safety/tolerability challenges
- Diarrhea, nausea/vomiting: most PIs - Hypersensitivity reactions: abacavir, nevirapine- Elevated bilirubin (+/- jaundice): atazanavir- Elevated liver function tests: NNRTIs, PIs
Long-term safety/tolerability challenges
- Lipodystrophy, body habitus changes: some PIs, some NRTIs- Increased MI risk: some PIs, some NRTIs- Reduced kidney function: tenofovir- Peripheral neuropathy: stavudine- Anemia, leukopenia: zidovudine
Recent use of ddI or ABC increased risk of MI: a limitation of chronic NRTI use?
* Recent = still using or stopped within last 6 months
Stratified by recent* abacavir use
Overall Low Moderate High Not known
Observed Rates of MI for Recent* Use of Abacavir by Predicted 10-year Coronary Heart Disease (CHD) Risk
D:A:D Study
35302520151050
Rat
e (p
er 1
000
PY
Predicted 10-year CHD risk
No recent abacavirRecent abacavir
16
32
D:A:D Study Group. Lancet. April 2 2008, Epub.
Limitations of treatment: key points
Patients need convenient, easy-to-tolerate regimens that have persistent long-term virologic suppression
All treatment regimens require lifelong adherence
Even the most potent drugs must be combined with other active agents for optimal virologic suppression
Resistance development occurs at different rates for each drug
All drugs have at least some relevant side effects: - Some just a nuisance, some may be significant
Newest ARV class: Raltegravir vs. EFV + TDF/3TC HIV RNA <50 copies/mL [NC=Failure]
Markowitz M, et al. IAS 2007; Abstract TUAB104.
0 2 4 8 12 16 24 32 40 48Week
0
20
40
60
80
100
Per
cent
of P
atie
nts
with
HIV
RN
A <5
0 co
pies
/mL
Raltegravir 100 mg b.i.d. (n=39)
Raltegravir 200 mg b.i.d. (n=40)
Raltegravir 400 mg b.i.d. (n=41)
Raltegravir 600 mg b.i.d. (n=40)
Efavirenz 600 mg q.d. (n=38)
Speed to <50 copies/mL for EFV slower than RAL
Raltegravir: the W48 virologic benefit is impacted by the use of specific ARVs in OBR
0 20 40 60 80 100
34
68
57
47
20
64
89
80
69
60
443
44
45
75
191
228
22
23
47
90
Enfuvirtide Darunavir
+
+
+
+
-
-
+ : First use in OBT- : Not used in OBT
Virologic failures carried forward.
TotalSubgroup
-
-
Raltegravir + OBT Placebo + OBT
Cooper D and Steigbigel R, et al. 15th CROI; Boston, MA (2008); Absts. 788 and 789.
Add >2 (preferably 3) fully active agents to an optimized background regimen
Consider RTV-boosted PIs, new MOA drug, and optimized background
Don’t add just 1 active drug to a new regimen as resistance is likely to develop quickly
For patients with extensive prior treatment and drug resistance:- Goal: re-suppress HIV RNA to <50 copies/mL- If complete suppression not possible, preserve immune function and
prevent progression
1/08
2008 DHHS guidelines for experienced patients: general principles
Fusion Inhibitor• Enfuvirtide
CCR5 Antagonists• Maraviroc
• Vicriviroc
IntegraseInhibitors
• Raltegravir
• Elvitegravir
Maturation Inhibitors• Bevirimat
PIs - Protease Inhibitors
• Atazanavir
• Darunavir
• Fos-amprenavir
• Indinavir
• Lopinavir
• Nelfinavir
• Ritonavir
• Saquinavir
• Tipranavir
NRTIs• Abacavir
• Didanosine
• Emtricitabine
• Lamivudine
• Stavudine
• Tenofovir
• Zidovudine
• Apricitabine
NNRTIs• Delavirdine
• Efavirenz
• Nevirapine
• Etravirine
• Rilpivirine
Increasing ARV options: five late-stage clinical drug candidates, four in existing classes, one novel MOA
*In Phase III development: the final stage of evaluation prior to possible FDA drug approval
The future of treatment: key points
Nearly all new agents in development will not be oral or are from existing classes
Despite great advances in HIV treatment, the population of patients with resistance or intolerance to existing treatment options increases, new drugs continue to be needed
Long term treatment may be linked to long term toxicities
In 2010 and beyond:- More people around the world will be on treatment than ever before- Resistance to the newest classes of approved drugs may increase- New classes of drugs will be important components of regimens for
experienced patients (and possibly naïve patients)
HIV and AIDSThe Shifting Treatment Landscape
Calvin Cohen, MDCommunity Research Initiative New England
Harvard Medical SchoolBoston, MA
Bevirimat Bevirimat Novel AntiNovel Anti--HIV HIV
Maturation InhibitorMaturation Inhibitor
36
Joseph Eron, MDUniversity of North Carolina
Bevirimat Clinical Data TopicsBevirimat Clinical Data Topics
Continued need for new oral anti-HIV agents with novel mechanism of action to partner with existing potent drugs
Study 201: 10 days monotherapy in naïve and experienced patients
Study 203: 14 days functional monotherapy in highly experienced patients
Predictors of bevirimat treatment response– Retrospective analysis discovers importance of Gag polymorphisms
– Prospective trial confirms Gag polymorphisms as predictors
Genotype is a simple, common assay to test of Gag sequence
Clinical resistance data 37
Bevirimat Targets Gag at the CA-SP1 Cleavage SiteBevirimat Targets Gag at the CA-SP1 Cleavage Site
38
P6
GAG polyprotein
CA MA NC
P6 CA MA NC
protease
protease
Untreated
BEVIRIMATbudding HIV particle
Treated
SP-1
CD4cell
CA‐SP1 cleavage site between Gag codons 363‐364
Bevirimat Study 201:10D Monotherapy in Naïve/Experienced PatientsBevirimat Study 201:10D Monotherapy in Naïve/Experienced Patients
o Tested doses up to 200mg
oMean VL reduction ~1 log through 10 days (top dose only)
o Target blood level for optimal response not yet established
o Placebo‐like safety profile through 10 days
o Based on these data, modeling suggested Emax90 was 360mg QD
39
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
0.2
0.4
0 5 10 15 20 25
Placebo25 mg50 mg100 mg200 mg
1/3 ARV‐experienced; 2/3 ARV‐naïve
QD for 10 days
Liquid bevirimat solution
Primary endpoint: VL reduction at D11
Treatment Day
Viral Load Re
duction
Bevirimat Study 203 DemographicsBevirimat Study 203 Demographics
41
BEVIRIMAT-TREATED PATIENTS
PLACEBO-TREATED PATIENTS
N 46 13
Age 48.0 (27-70) 47.1 (34-63)
Gender 45M, 1F 12M, 1F
Symptomatic HIV or AIDS
74% 67%
Mean Baseline CD4 (copies/mm3)
277 (30-562) 393 (172-859)
Baseline Viral Load (log10 copies/mL)
4.2 (2.7-5.3) 4.1 (3.7-5.2)
Bevirimat Study 203 Safety Data:Adverse Events (all grades)Bevirimat Study 203 Safety Data:Adverse Events (all grades)
BEVIRIMAT-TREATED PLACEBO-TREATED# % # %
N 46 13TOTAL WITH ANY ADVERSE EVENTS
32 70% 10 77%
GI-RELATEDDIARRHEA 10 22% 5 39%NAUSEA 9 20% 4 31%FLATULENCE 4 9% 1 8%VOMITING 3 7% 2 15%
CNS-RELATEDHEADACHE 9 20% 3 23%DIZZINESS 3 7% 1 8%ABNORMAL DREAMS 5 11% 0 0%
RASH 3 7% 3 23%42
Bevirimat Study 203 Safety Data:Lab Abnormalities (grades 2-4)Bevirimat Study 203 Safety Data:Lab Abnormalities (grades 2-4)
43
Patients with baseline abnormalities excluded unless worsened on treatment.
‐2‐1.8‐1.6‐1.4‐1.2‐1
‐0.8‐0.6‐0.4‐0.2
00.20.4
0 10 20 30 40 50 60 70 80 90 100 110 120
Bevirimat Trough Level (ug/mL)
Viral Loa
d Red
uction
(lo
g copies/m
L)
44
RespondersNon-responders
Bevirimat Study 203: Viral Load Reduction and Trough Data Clearly Demonstrate 2 Patient GroupsBevirimat Study 203: Viral Load Reduction and Trough Data Clearly Demonstrate 2 Patient Groups
NON‐RESPONDERS
RESPONDERS
Bevirimat Study 203: Bi-Modal Efficacy DistributionBevirimat Study 203: Bi-Modal Efficacy Distribution
Responders (definition: > 0.5 log viral load reduction)– N=20– 19 had bevirimat plasma level > 20ug/mL– Mean 1.26 log VLR at Day 14
Non-responders (definition: < 0.5 log viral load reduction)– N=24– 19 had bevirimat plasma level > 20µg/mL– Mean 0.05 log VLR at Day 14
While responders had clinically meaningful VL changes, particularly for such heavily experienced patients,
why don’t all patients respond?45
Bevirimat Study 203: Responder Non-Responder ComparisonBevirimat Study 203: Responder Non-Responder Comparison
Non-Responders Responders Sig.
N 24 20 --
Mean Baseline VL (log copies/mL)
4.23 3.99 NS
Mean Day 15 VLR -0.05 -1.26 <0.0001
Mean Baseline CD4 (copies/mm3)
233 342 <0.01
Mean No. Primary PR mutations
3.7 2.8 NS
Mean No. Gag Polymorphisms (positions 320-400)
7.3 5.9 NS
369 21% 5%
370 54% 15%
371 33% 20%46
Optimal Bevirimat Treatment Response Requires:Optimal Bevirimat Treatment Response Requires:
Bevirimat plasma trough levels > 20 µg/mL– Achieved in all patients in Study 203 at liquid doses ≥ 250 mg
– Twice daily tablet dose now being studied
and
The baseline Gag genotype sequence must be free of changes at positions 369, 370 or 371– Gag amino acid sequence tested easily with a genotype: the most
commonly used resistance test
Registration studies likely will focus on this Phase 3 Profile patient population
47
Bevirimat Study 203: Overall Viral Load Reduction DataBevirimat Study 203: Overall Viral Load Reduction Data
‐0.6
‐1.26
All Patients Phase 3 Profile Patients
1344
48
% patients with >0.5 log VLR45% 92%
All Patients on Bevirimat: ‐‐With/without 369‐371 polymorphisms‐‐Any trough level
Phase 3 Profile Patients on Bevirimat:‐‐No 369‐371 polymorphisms‐‐All with trough level >20 µg/mL
Bevirimat Study 203: VLR Reduced in Patients with Gag Polymorphisms at 369, 370 or 371Bevirimat Study 203: VLR Reduced in Patients with Gag Polymorphisms at 369, 370 or 371
‐0.16‐0.24
‐0.32
‐1.08
‐1.26
369 370 371 No 369‐371 No PM & Cmin>20
49
7 patients had 2 Gag polymorphisms (none had 3):‐‐3 with 369 + 370: mean VLR: ‐0.31 log‐‐4 with 370 + 371: mean VLR: +0.04 log
131712166
Bevirimat Study 203:Specific Amino Acid Changes at 369, 370 or 371Bevirimat Study 203:Specific Amino Acid Changes at 369, 370 or 371
50
GAG POSITION POLYMORPHISM
NUMBER HAVING (OUT OF 59 TOTAL
PATIENTS)Q369 H 9
V370 AM
DELETION
1543
T371 ASN
DELETION
4214
‐‐ Baseline Gag polymorphisms in 59 patients on either bevirimat or placebo
‐‐ 29 (49.2%) had at least one polymorphism at 369, 370 or 371
Bevirimat: Key Gag Polymorphisms at 369, 370 or 371 are Different than in vitro Selected MutationsBevirimat: Key Gag Polymorphisms at 369, 370 or 371 are Different than in vitro Selected Mutations
…G H K A R V L A E A M S Q V T N S A T I M
RED: in vitro resistance mutations1,2
GREEN: key polymorphisms3
*References:
1.Li et al. 2003, PNAS 100:13555–13560
2.Adamson et al. 2006, J. Virol. 80:10957-10971
3.Sitges abstracts
358 363 364 366 369 370 371
CA SP1
51
Gag and Protease Changes Rarely Observed During Bevirimat TreatmentGag and Protease Changes Rarely Observed During Bevirimat Treatment
Gag-related mutations or polymorphismsStudy 201 (true monotherapy)– Through 10 days of bevirimat treatment, 0 patients developed
bevirimat-related resistance mutations or polymorphisms at Gag positions 369, 370 or 371
Study 203 (functional monotherapy)– 2/46 patients on bevirimat had a resistance mutation at A364V
• 1 during extended tablet dosing (transient) likely related to non-adherence
• 1 developed A364A/V mixture; no virologic rebound occurred – 5/46 (11%) of patients on bevirimat and 1/13 (8%) on placebo
developed a new polymorphism at Gag positions 369, 370 or 371
PR-related mutationsStudy 203 (functional monotherapy)– 2 patients developed a new primary PR mutation that was not
present at baseline (both mixed populations likely present at baseline)
52
‹#›
Gag Genotype Fits into Existing Practice and Reimbursement Patterns (www.vircolab.com)
Gag Genotype Fits into Existing Practice and Reimbursement Patterns (www.vircolab.com)
Summary of Bevirimat Clinical DataSummary of Bevirimat Clinical Data
Mean VLR of 1.26 log through 14 days in experienced patients with no 369-371 PMs and trough >20 µg/ML– Same population likely to be studied in Phase 3
Predictors of treatment response (baseline Gag sequence) are established
Bevirimat trough level needed for response is known and achievable with both current formulations
Placebo-like safety profile through 14 days
2 ongoing studies: prospective trial to confirm key Gag polymorphisms (now complete) and controlled trial of twice daily tablets (enrolling)
55
Bevirimat Bevirimat Novel AntiNovel Anti--HIV HIV
Maturation InhibitorMaturation Inhibitor
56
Joseph Eron, MDUniversity of North Carolina
Prospective Study of Gag PolymorphismsProspective Study of Prospective Study of Gag PolymorphismsGag Polymorphisms
Scott McCallister, MDChief Medical Officer
57
Bevirimat Prospective Study of Gag PolymorphismsBevirimat Prospective Study of Gag Polymorphisms
Prospective trial design
Data– Safety– Pharmacokinetics– Viral Load Reduction– Gag Polymorphisms Present
Aggregate data (original Study 203 combined with Prospective Study)– All patients with Gag polymorphisms at 369, 370 or 371 vs.
all patients without Gag polymorphisms
Implications for Phase 3 registration studies
58
Bevirimat Prospective Study of Gag Polymorphisms:DemographicsBevirimat Prospective Study of Gag Polymorphisms:Demographics
60
NAÏVE PATIENTS
EXPERIENCED PATIENTSWITHOUT
POLYMORPHISMS
EXPERIENCED PATIENTS WITH
POLYMORPHISMS
N 9* 10 8
MEAN AGE (RANGE) 40.3 (25‐54) 43.2 (28‐54) 45.1 (31‐60)
GENDER (M, F) 9M 8M, 2F 7M, 1F
MEAN BASELINE CD4 (CELLS/MM3)
366 (132‐708) 380 (156‐962) 341 (190‐612)
MEAN BASELINE VIRAL LOAD (LOG10 COPIES/ML)
4.5 (4.1‐5.1) 4.4 (3.3‐5.1) 4.0 (3.1‐5.2)
*A total of 9 naïve patients completed 14 days of BVM treatment; 2 additional patients received BVM for only 2 days.
Bevirimat Prospective Study of Gag Polymorphisms:Treatment-related Adverse EventsBevirimat Prospective Study of Gag Polymorphisms:Treatment-related Adverse Events
61
NAÏVE PATIENTS
EXPERIENCED PATIENTSWITHOUT
POLYMORPHISMS
EXPERIENCED PATIENTSWITH
POLYMORPHISMS
All events of mild intensity (Grade 1)
N 11 10 8
GI EVENTS
DIARRHEA 2 (18%) 6* (60%) 2 (25%)
NAUSEA 2 (18%) 1 (10%) 0 (0%)
STOMACH DISCOMFORT 0 (0%) 2 (20%) 1 (13%)
VOMITING 1 (9%) 1 (10%) 0 (0%)
CNS EVENTS
HEADACHE 0 (0%) 1 (10%) 0 (0%)
* Overall diarrhea rate for 100 bevirimat‐treated HIV+ patients = 26%
Bevirimat Prospective Study of Gag Polymorphisms:Lab Abnormalities* (> Grade 2)Bevirimat Prospective Study of Gag Polymorphisms:Lab Abnormalities* (> Grade 2)
62
* Patients with baseline abnormalities excluded, unless worsened on treatment.
NAÏVE PATIENTS
EXPERIENCED PATIENTSWITHOUT
POLYMORPHISMS
EXPERIENCED PATIENTS WITH
POLYMORPHISMS
LIPIDS
TOTAL CHOLESTEROL 0 0 1 (G2)
TRIGLYCERIDES 0 0 1 (G3)
LDL 0 1 (G3) 0
HEPATIC
ALT 0 1 (G2) 0
AST 0 1 (G3) 0
PANCREAS
GLUCOSE 2 (G2) 0 1 (G2)
LIPASE 0 0 1 (G2)
HEMATOLOGY
NEUTROPENIA 0 1 (G2) 0
PLATELETS 0 1 (G2) 0
PTT 0 0 2 (G2)
Bevirimat Prospective Study of Gag Polymorphisms:PharmacokineticsBevirimat Prospective Study of Gag Polymorphisms:Pharmacokinetics
63
Bevirimat Trough Level
67
Bevirimat Prospective Study of Gag Polymorphisms:Baseline Gag Positions 369, 370 or 371Bevirimat Prospective Study of Gag Polymorphisms:Baseline Gag Positions 369, 370 or 371
9 ARV-naïve patients– 8/9 had no baseline Gag changes– 1/9 had V370M
10 ARV-experienced patients without Gag polymorphisms– 10/10 had no baseline Gag changes
8 ARV-experienced with Gag polymorphisms– 8/8 had baseline Gag changes– 3/8 had mixed populations– 1/8 had V370M– 0/8 had Q369H and 0/8 had V370A
64
Bevirimat Prospective Study:VLR in Patients With/Without Gag PolymorphismsBevirimat Prospective Study:VLR in Patients With/Without Gag Polymorphisms
PATIENTS WITH RESPONSE PREDICTORS
(NO POLYMORPHISMS AT GAG CODONS 369, 370 OR 371)
PATIENTS WITHOUT RESPONSE PREDICTORS
(ANY POLYMORPHISM AT GAG CODONS369, 370 OR 371) SIGNIFICANCE
N 18 9 ‐‐
MEAN VIRAL LOAD REDUCTION (LOG10 COPIES/ML)
‐1.13 ‐0.59 P < 0.04
65
Bevirimat Prospective StudyVLR in Naïve vs. Experienced PatientsBevirimat Prospective StudyVLR in Naïve vs. Experienced Patients
NAÏVE PATIENTS
EXPERIENCED PATIENTS WITHOUT
POLYMORPHISMS
EXPERIENCED PATIENTSWITH
POLYMORPHISMS
N 9 10 8
MEAN VIRAL LOAD REDUCTION (LOG10 COPIES/ML) ON DAY 15
‐1.04 ‐1.10 ‐0.65
66
– For the 8 naïve patients without baseline polymorphisms, mean VLR was ‐1.16 log copies/mL.
Bevirimat Prospective Study of Gag Polymorphisms:ConclusionsBevirimat Prospective Study of Gag Polymorphisms:Conclusions
Efficacy data confirm the retrospective analysis
Patients free of Gag polymorphisms at positions 369, 370 or 371 are likely to have an optimal treatment response to bevirimat
– The -1.13 VLR for patients without baseline polymorphisms was statistically significant relative to those with polymorphisms
100% of patients in this prospective study had bevirimat plasma levels above the 20 µg/mL trough threshold
Bevirimat continued to have an encouraging safety profile
67
Bevirimat Aggregate DataOriginal Study 203 Combined with Prospective TrialBevirimat Aggregate DataOriginal Study 203 Combined with Prospective Trial
ALL PATIENTSWITH NO
POLYMORPHISMS
ALL PATIENTS WITH ANY
POLYMORPHISM AT 369, 370 OR 371
All patients with available baseline Gag data and with bevirimat trough level >20 µg/mL
N 32 30
NO. PATIENTS (%) WITH > 0.5 VLR (LOG10 COPIES/ML)
28 (88%) 11 (37%)
MEAN VIRAL LOAD REDUCTION (LOG10 COPIES/ML)
‐1.16 ‐0.45
68
Bevirimat Aggregate DataPhase 3 Registration Study PlansBevirimat Aggregate DataPhase 3 Registration Study Plans
Phase 3 Registration Studies (subject to regulatory concurrence)
– All patients to be screened with genotype for Gag, RT and PR
– Patients without polymorphisms at Gag positions 369, 370 or 371 will be randomized to BVM or comparator arms
– Patients with polymorphisms who otherwise qualify will be offered BVM treatment in a separate investigative arm for 7 days
• Patients with > 0.5 VLR by Day 7 continue BVM with an optimized background regimen
• Patients with < 0.5 VLR by Day 7 discontinue BVM
69
Prospective Study of Gag PolymorphismsProspective Study of Prospective Study of Gag PolymorphismsGag Polymorphisms
Scott McCallister, MDChief Medical Officer
70
Scott McCallister, MDChief Medical Officer
Bevirimat Bevirimat Development ProgramDevelopment Program
Bevirimat Development ProgramPhase 2 and 3 ProgramBevirimat Development ProgramPhase 2 and 3 Program
73
Study 203 extension (prospective test of Gag)Study 203 extension (prospective test of Gag)
Objective: – Prospective assessment of Gag polymorphisms at positions 369,
370, 371 in patients with and without treatment experienceDesign:– Gag genotype tested at screening visit– Bevirimat 300mg QD (liquid formulation)– Viral load reduction on Day 14– 24 patients planned
• ARV-naïve patients• ARV-experienced patients without Gag polymorphisms• ARV-experienced patients with Gag polymorphisms
– 12 sites in U.S.Status:– Fully enrolled 15 May – Data available June 2008
74
Study 204 (trial of twice-daily tablets)Study 204 (trial of twice-daily tablets)Objective:– Study tablet formulation BID with extension phase for those with
virologic benefitDesign:– Gag genotype not used to filter patients at screening visit– Bevirimat 200 or 300mg BID (tablet formulation)– Viral load reduction on Day 14– 32 patients
• ARV-naïve patients• ARV-experienced patients
– Patients with > 0.5 log VLR by Week 2 may continue to Week 24 (beyond?)
– Multiple sites in Australia, New Zealand, Belgium, PolandStatus:– Screening began April 08 – 14-day data expected 2H08
75
Study 205 (extended duration trial with Phase 3 dose)Study 205 (extended duration trial with Phase 3 dose)
Objective: – Controlled Phase 2b definitive dose confirmation in Phase 3 Profile
patients with extended duration• Safety and persistence of virologic benefit
Design:– Gag genotype tested at screening visit– Proportion with VL <50 copies/mL at Week 16– 120 ARV-experienced patients (GSS 2-4 only)
• 80 receive bevirimat + 2-3 drug OBR• 40 receive placebo + 2-3 drug OBR
– Patients continue treatment after Week 16 to ~3 years– Sites in North America and Australia
Status:– Patient screening begins 4Q08/1Q09
76
Phase 3 regulatory changes: EMEA and FDAPhase 3 regulatory changes: EMEA and FDA
1. All primary endpoints must be < 50 copies/mL
2. All comparative studies must have 2+ active drugs in comparator arm.
3. Can divide experienced patients into those with GSS of 2+ or GSS of 0, 1
a) Low GSS patients (0, 1) must not be studied in a 2-arm comparative design, since they might randomize to an arm with 0-1 active agents
b) Low GSS patients may be studied in a 1-arm activity trial of less than 24W
c) Such 1-arm designs are inadequate to demonstrate safety
4. Traditional 2-arm design for high GSS patients unlikely to show a superiority at 24W, so should use a non-inferiority endpoint at 48W
5. For naïve studies: 48W minimum for a superiority design (and against SOC comparator) and 96W minimum for a non-inferiority design
77
Phase 3 registration studies: 301 and 302Phase 3 registration studies: 301 and 302Objective: – Demonstrate safety and efficacy of bevirimat against standard of
care in treatment-experienced patients
Design:– 48-week non-inferiority comparison of bevirimat vs. standard of care– Primary endpoint: <50 copies/mL– All patients screened for Gag polymorphisms at baseline
• Those without polymorphisms at 369, 370 or 371 may randomize• Those with polymorphisms may enter 3rd arm with bevirimat for 7 days
before reassessment– Final dose to be decided– N=800-1000 across 2 studies (2:1 bevirimat: SOC)– Multinational study
Status:– Patient screening to begin 2009
78
79
Phase 1 Phase 2 Phase 3
Clinical Studies in HIV+ Patients
PediatricsEAP
ARV‐experienced (X 2)ARV‐naïve
Regulatory Requirements
QTc Prolongation, Hepatic Insufficiency, ADME
ARV Drug‐Drug Interactions
Raltegravir*Tenofovir
Non‐ARV Drug‐Drug Interactions
RifampinOral contraceptiveMethadoneProton Pump Inhibitor
Bevirimat: Longer-term study plansBevirimat: Longer-term study plans
* In vitro drug-drug interactions unremarkable
‹#›
Gag genotype fits into existing practice and reimbursement patterns (www.vircolab.com)
Gag genotype fits into existing practice and reimbursement patterns (www.vircolab.com)
Genotype assays: most common resistance testGenotype assays: most common resistance test
Patients have a resistance test before starting treatment for the first time and whenever changing treatment
Individual patient genotype testing is the most common resistance test used by clinicians
Genotypes are simple to perform, widely available, and fully reimbursed
Genotype testing: cost $200-400; results in 7-14 days
Interpretation of results differ by testing company but are evidence-based simplifications for clinicians
Test development at resistance companies currently in discussions
81
Scott McCallister, MDChief Medical Officer
Bevirimat Bevirimat Development ProgramDevelopment Program
Graham P. Allaway, Ph.D.Chief Operating Officer
Bevirimat: Bevirimat: Understanding Understanding PolymorphismsPolymorphisms
Presentation highlightsPresentation highlights
Laboratory studies confirm effect of polymorphisms at Gag 369, 370, 371 on bevirimat activity
Polymorphisms are distinct from resistance mutations
How do the polymorphisms affect bevirimat activity?
84
Laboratory studies confirm importance of polymorphisms at Gag 369, 370, 371Laboratory studies confirm importance of polymorphisms at Gag 369, 370, 371
Effect of polymorphisms confirmed in different assay formats using:– Patient isolates
– Site-directed mutants
Studies conducted by several groups: InPheno, Virco, Southern Research, and Panacos – Data presented by InPheno, Virco, and Panacos at
Sitges
Patent filing around polymorphism analysis
85
Viruses with “wild-type” 369-371 are more sensitive to bevirimat (InPheno assay)Viruses with “wild-type” 369-371 are more sensitive to bevirimat (InPheno assay)
86
More sensitive (<2X wild-type)
Less sensitive(>3X wild-type)
In vitro sensitivity to bevirimat(IC50 relative to wild-type )
CA-SP1 Sequence
0.57 GHKARVL-AEAMSQVTKSATMM0.84 GHKARVL-AEAMSQVTNPPTIM0.87 GHKARVL-AEAMSQVTNSATIM1.00 (wild-type control) GHKARVL-AEAMSQVTNPATIM1.02 GHKARVL-AEAMSQVTGSAAVM1.14 GHKARVL-AEAMSQVTNSATVM1.16 GHKARVL-AEAMSQVTNPATIM1.51 GHKARVL-AEAMSQVTPSATVM1.69 GHKARVL-AEAMSQVTNPSNIM1.79 SHKARIL-AEAMSQVTGPANIM
3.60 GHKARVL-AEAMSQMTNSAAIM4.25 GHKARVL-AEAMSQMTNSAAIM4.60 GHKARVL-AEAMSQMTNPATIM4.61 SHKARVL-AEAMSQV-NPTNIM4.85 NHKARIL-AEAMCHVTNSATVM12.8 GHKARVL-AEAMSQMTNSATTM14.5 SHKARVL-AEAMCQA-NSTTVM15.3 GHKARVL-AEAMSQATASNVIM
17.4 GHKARVL-AEAMSQA-NSSSIM22.2 GHKARVL-AEAMSQATASNVIM32.3 GHKARVL-AEAMSQATNSAAIM
Bevirimat blocks CA-SP1 processing in “wild-type” but not in polymorphic virusBevirimat blocks CA-SP1 processing in “wild-type” but not in polymorphic virus
369 370 371
…G H K A R V L A E A M S Q V T N S A T I M…G H K A R V L A E A M S Q A T A S N V I M…G H K A R V L A E A M S Q V T G S A A V M…G H K A R V L A E A M S Q M T N S A A I M
CA SP1Wild-type
Patient #125Patient #126Patient #127
Wild-type#125
V370A#126None
#127V370M
─ + ─ + ─ + ─ +Bevirimat:CA-SP1CA
87
Isabelle Malet, Marc Wirden, Anne Derache, Anne Simon, Christine Katlama, Vincent Calvez and Anne-Genevie`ve Marcelin
88
Study of PI-treated patients: > 68% had wild-type QVT at 369-371; changes at 370 most frequent
Each patient may have multiple polymorphisms, so the % of patients with polymorphisms may be less than
the frequency of polymorphisms
357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377
↓
Determinants of bevirimat clinical response: polymorphisms in SP1, not resistance mutationsDeterminants of bevirimat clinical response: polymorphisms in SP1, not resistance mutations
…G H K A R V L A E A M S Q V T N S A T I M
RED: location of in vitro resistance mutations1,2
GREEN: location of key polymorphisms3
*References:
1. Li et al. 2003, PNAS 100:13555–13560
2. Adamson et al. 2006, J. Virol. 80:10957-10971
3. Sitges abstracts
358 363 364 366 369 370 371
CA SP1
89
Polymorphisms behave differently than resistance mutationsPolymorphisms behave differently than resistance mutations
Polymorphisms have not appeared in extensive in vitro resistance selection experiments by several independent groups– Perhaps because bevirimat is active against polymorphic viruses
at low levels of viral replication
– Will this translate to lack of in vivo selection of polymorphisms by bevirimat?
• Further studies necessary
Why do the polymorphisms exist in some patients and not others?– Treatment experience/immune response?
90
How do polymorphisms affect bevirimat activity?How do polymorphisms affect bevirimat activity?Bevirimat competes with protease for binding to the CA-SP1 cleavage site:
91
Bevirimat
Bevirimat targets CA-SP1, not proteaseBevirimat targets CA-SP1, not proteaseBevirimat has no effect on protease activity in cell-free systems1,2
Bevirimat resistance mutations generated in cell culture experiments occur only near the CA-SP1 cleavage site, not in protease or elsewhere in the genome1,2,3
SIV is insensitive to bevirimat – Its CA-SP1 sequence differs from that of HIV-1– SIV acquires bevirimat sensitivity when its CA-SP1 sequence is
replaced by the HIV-1 sequence4
All PI-resistant viruses tested to date are sensitive to bevirimat1,2
Bevirimat is synergistic with protease inhibitors5
References:1. Li et al. (2003) PNAS 100:13555-135602. Zhou et al. (2004) J. Virol. 78:922-93. Adamson et al. 2006, J. Virol. 80:10957-109714 Zhou et al. (2004), Retrovirology 1:15 5. Kilgore et al. (2006), CROI, Denver, Co.
Predicted structure of CA-SP1 cleavage site indicates bevirimat binds to a helical region in Gag Predicted structure of CA-SP1 cleavage site indicates bevirimat binds to a helical region in Gag
… G H K A R V L A E A M S Q V T N S A T I M …
SP1CA NC
93
Model suggests bevirimat binding site forms helical bundle structure: this may be perturbed by SP1 polymorphisms Model suggests bevirimat binding site forms helical bundle structure: this may be perturbed by SP1 polymorphisms
94Wright et al. EMBO J. (2007) 26:2218-26
SP1
CA
Panacos confirms polymorphisms affecting bevirimatPanacos confirms polymorphisms affecting bevirimat
Laboratory studies confirm effect of polymorphisms at Gag 369, 370, 371 on bevirimat activity
Polymorphisms are distinct from resistance mutations
Polymorphisms likely affect bevirimat activity by altering the CA-SP1 helix conformation
95
Graham P. Allaway, Ph.D.Chief Operating Officer
Bevirimat: Bevirimat: Understanding Understanding PolymorphismsPolymorphisms
Richard Harrigan, PhDBC Centre for Excellence in HIV/AIDS
University of British Columbia
97
Gag: A Structural Protein of HIVGag: A Structural Protein of HIVThe Viral Target for BevirimatThe Viral Target for Bevirimat
Presentation topicsPresentation topics
Structure and function of Gag
Development of polymorphisms
Prevalence of polymorphisms at 369, 370 or 371
Genotypic testing for Gag
98
The HIV genome: function and ARV drug targetThe HIV genome: function and ARV drug target
HIV Component Function ARV Drug
GagSynthesizes major structural and core proteinsCapsid-SP1 cleavage site is the target of bevirimat Bevirimat
Pol Yields viral enzymes RT, PR, and integrase
PIs: ATV, RTV, LPV, DRV, othersNRTIs: ZDV, ABC, DDI, othersNNRTIs: EFV, NVP, ETVNTRTI: TDFInt Inh: RAL, ELV
Env Synthesizes surface protein subunits of the virus Fusion Inh: T20R5 Antag: MVC, VCVPA-161
Others Nef, Rev, Tat, VIF, VPR, VPU Discovery stages
99
The HIV-1 replication cycleThe HIV-1 replication cycle
Entry Inhibitors
RT Inhibitors
IntegraseInhibitors
Protease Inhibitors
Maturation Inhibitors
100
Bevirimat targets Gag at the CA-SP1 cleavage siteBevirimat targets Gag at the CA-SP1 cleavage site
101
P6
GAG polyprotein
CA MA NC
P6 CA MA NC
protease
protease
Untreated
BEVIRIMAT
budding HIV particle
Treated
SP-1
CD4cell
CA‐SP1 cleavage site between Gag codons 363‐364
SP1MA CA p6 PR INTSP2NC
LTRgag pol env
PROTEASE
P51 (RT) P66 (RT)
LTR
NEF
HIV-1 genome: proximity of Gag and Pol and capsid-SP1 cleavage siteHIV-1 genome: proximity of Gag and Pol and capsid-SP1 cleavage site
Key Points:1. Gag and Pol are adjacent genes2. Gag has 6 component subunits and 500 amino acids3. Protease mutations may lead to compensatory changes on Gag
(at cleavage sites)
102
Gag: the development of polymorphismsGag: the development of polymorphisms
Gag polymorphisms– Compensatory change to evade immune pressure – Compensatory change to allow cleavage by protease that has mutations
due to protease inhibitor use
Gag polymorphisms due to CTL-based immune pressure often have an association with an HLA epitopeIn a review of heavily treatment-experienced patients at UBC, compensatory Gag polymorphisms occurred at multiple Gag locations:– NC-SP1 cleavage site: 52% of patients– SP2-P6 cleavage site: 43%– SP2-NC cleavage site: 39%–– CA-SP1 cleavage site: 4%
103
…
% of treatment experienced patients with cleavage site mutations
**50%**36%
21%14%
7%
4%PITreated
SP1MA CA p6 PR P51(RT) INTSP2NC
4%
NRTI 11% 11% 4%
P66(RT) NEF
4%19% 16%
11%
7%
** = p <0.05
HIV-1 genome: locations of compensatory Gag polymorphisms that follow protease mutationsHIV-1 genome: locations of compensatory Gag polymorphisms that follow protease mutations
Most common sites of Gag compensatory changes due to protease mutations
(from database of experienced patients)
104
Gag positions near CA-SP1 cleavageHLA epitope associationGag positions near CA-SP1 cleavageHLA epitope association
Gag is a common target of the immune system (CTL: cytotoxic T-lymphocytes) in trying to control HIV infection, even in the absence of anti-HIV drugs
Multiple HLA epitopes are known that map to specific positions on Gag
HLA epitopes near the CA-SP1 cleavage site on Gag are known– None yet identified that specifically target Gag positions 369, 370
or 371
105
0
20
40
60
80
0 50 100 150 200 250 300 350 400 450 500HIV GAG Codon
% a
a va
riatio
n
p17 p2/p7/p1/p6p24
Selection pressure from the human immune system results in Gag polymorphisms
• HIV-HLA associations observed at 51/500 (10%) Gag codons
Brumme et al., PLoS Pathogens July 2007
Prevalence of Gag polymorphisms in patients at academic databasePrevalence of Gag polymorphisms in patients at academic database
At UBC cohort of J. Montaner and colleagues, HIV-positive adults had samples collected for genotype assay 1996-2005
Samples not part of a clinical trial
567 ARV-naïve patients were assessed with Gag genotype– Standard DNA primers used to determine amino acid sequence
– Mean CD4: 280 copies/mm3
– Mean Viral Load: 5.0 log copies/mL
114 ARV-experienced patients were assessed with Gag genotype (standard primers)
107
Prevalence of Gag polymorphisms at 369, 370 or 371 (UBC patient database)Prevalence of Gag polymorphisms at 369, 370 or 371 (UBC patient database)
Patient Population N
Proportion without polymorphisms at 369, 370 or 371
ARV‐naïve 567 60.2%
ARV‐experienced 114 59.7%
108
Malet et al: 68.3% of PI‐experienced patients were free of polymorphisms at 369, 370 or 371 (AIDS 2007, 21[7]:783)
Prevalence in ARV-naïve vs. experienced patients (UBC patient database)Prevalence in ARV-naïve vs. experienced patients (UBC patient database)
Patients free of polymorphisms at individual positions 369, 370 or 371 in two clinical databases at UBC
109
ARV‐naïve Patients (N=567)
ARV‐experienced Patients(N=114)
Q369 95.4% 93.8%
V370 72.3% 75.4%
T371 92.0% 90.4%
Individual amino acid changes at 369, 370 or 371 (UBC ARV-naïve patient database)Individual amino acid changes at 369, 370 or 371 (UBC ARV-naïve patient database)
110
Gag codon with Clade B consensus
amino acidAmino acid
polymorphismProportion of patients without polymorphism
V370 AV/A
DeletionMIL
81.4%96.8%97.9%98.6%98.8%98.8%
T371 DeletionAN
94.8%98.4%98.8%
Q369 HQ/H
97.7%97.7%
0.00
10.00
20.00
30.00
40.00
50.00
60.00
<25 25-49 50-99 100-199 200-499 >=500
CD4
%
No Mutation Mutation
CD4 count distribution is similar for patients with and without mutations
Source: 2008 UBC patient clinical database (Harrigan)
Gag polymorphisms: summary conclusionGag polymorphisms: summary conclusionCA-SP1 cleavage site on Gag is the target of bevirimat
Gag polymorphisms are compensatory, due either to immune pressure or protease mutations
Patients free of 369-371 polymorphisms in external databases
– 60.2% in 567 ARV-naïve patients (Harrigan, UBC)
– 59.7% in 114 ARV-experienced patients (Harrigan, UBC)
– 68.3% in 82 PI-experienced patients (Malet, Paris)
Amino acid changes at individual codons are variable, and some may not have an impact on bevirimat activity
Gag genotype can be assessed with a well-standardized and widely used assay that is rapid and relatively simple to perform
112
Richard Harrigan, PhDBC Centre for Excellence in HIV/AIDS
University of British Columbia
113
Gag: A Structural Protein of HIVGag: A Structural Protein of HIVThe Viral Target for BevirimatThe Viral Target for Bevirimat
114
David E. Martin, Pharm.D., MBASenior Vice President
Drug Development
PK/PD Profile andPK/PD Profile andFormulation ProgressFormulation Progress
Bevirimat PK/PD and formulation highlightsBevirimat PK/PD and formulation highlights
Predictable pharmacokinetics
Limited potential for drug-drug interactions
Achieved top of the dose-response curve
Identified target plasma concentration
Developing tablet and liquid formulations
115
Bevirimat demonstrates predictable human pharmacokineticsBevirimat demonstrates predictable human pharmacokinetics
Long terminal elimination half-life: ~60 hours
Linear and predictable pharmacokinetics
Glucuronidated and excreted through the bile
No renal clearance, and no circulating glucuronidemetabolites
No significant gender differences
No significant differences between HIV-infected patients and uninfected patients
Well absorbed throughout the small intestine
116
Bevirimat demonstrates lack of clinically relevant interactionsBevirimat demonstrates lack of clinically relevant interactions
No metabolically based interaction with raltegravir
– In vitro drug-drug interaction study
No effect on atazanavir pharmacokinetics or atazanavir-induced hyperbilirubinemia– Atazanavir is a substrate for CYP3A
– Indicates no clinically relevant interactions with other CYP3A substrates
Minimal effect of ritonavir on bevirimat pharmacokinetics– Ritonavir 100mg BID: ~17% decrease in bevirimat exposure
• Most commonly used boosting dose
117
Maximal viral load reduction achieved in Study 203Maximal viral load reduction achieved in Study 203
118
PK/PD Response in Patients without Polymorphisms*
0.0
0.4
0.8
1.2
1.6
2.0
0 10 20 30 40 50 60 70 80 90 100Average Cmin on Day 14 and Day 15 (μg/mL)
Mea
n H
IV R
NA
Red
uctio
n fr
om B
asel
ine
on D
ay 1
5(L
og10
/mL)
PredictedObserved
EC50 = 21.2 μg/mL
Emax = 1.27 Log10/mL
EC90 = 27.0 mg/mL
*Excludes patients 106 and 47
Bevirimat target trough concentration identifiedBevirimat target trough concentration identified
119
100% of responders had trough concentrations > 20 µg/mL
60% of non-responders had trough concentrations < 20 µg/mL
* Excludes patients 106 and 47
PK/PD Response in Patients without Polymorphisms*
0.0
0.4
0.8
1.2
1.6
2.0
0 10 20 30 40 50 60 70 80 90 100
Average Cmin on Day 14 and Day 15 (µg/mL)
Mea
n H
IV R
NA
Red
uctio
n fr
om B
asel
ine
on D
ay 1
5(L
og10
/mL)
PredictedObserved
EC50 = 21.2 µg/mL
Emax = 1.27 Log10/mL
EC90 = 27.0 mg/mL
PK/PD highlightsPK/PD highlights
120
Observed maximal antiviral effect in Study 203– No further dose escalation required
Identified minimal trough concentration of 20 µg/mL
Target trough concentration achievable with doses > 250 mg/day
Solid and liquid formulations in developmentSolid and liquid formulations in development
Tablets– 100mg tablets developed: 2 distinct formulations
– Manufacturing for clinical use in 3Q08
– Expected for use in Study 205
Liquid– Multi-component formulation under development
• Key issue: long-term stability
– Powder for dispersion under development• Patients disperse stable powder in water prior to administration
• Combines the advantages of a solid (stability) with the advantages of a liquid (bioavailability)
– Proof-of-concept demonstrated for both formulations
121
Tablet formulation: monkeyTablet formulation: monkey
122
* Administered dose of 100 mg (n=3-6/dose)
AUC values are normalized (mg/kg) and converted to percent with the reference 50 mg tablet representing 100%
Tim e (hr)
0 4 8 12 16 20 24
BVM
Con
cent
ratio
n (u
g/m
L)
0
10
20
30
40
10% H P B C D Form ula tionA lcohol Form ula tionTween-80 Form ula tionW ater Form ula tion
Bioequivalence of liquid formulations vs. cyclodextrin reference in humansBioequivalence of liquid formulations vs. cyclodextrin reference in humans
10% HPBCDFormulation #1Formulation #2 Powder for Dispersion
Bevirimat PK/PD and formulation highlightsBevirimat PK/PD and formulation highlights
Predictable pharmacokinetics
Limited potential for drug-drug interactions
Top of the dose-response curve achieved
Target plasma concentration identified
Tablet and liquid formulations in development– 100 mg tablet available in 3Q08
– Proof-of-concept demonstrated for both liquid and powder for dispersion formulations. Currently optimizing both approaches
124
125
David E. Martin, Pharm.D., MBASenior Vice President
Drug Development
PK/PD Profile andPK/PD Profile andFormulation ProgressFormulation Progress
Graham P. Allaway, PhDChief Operating Officer
22ndnd and 3and 3rdrd Generation Generation Maturation InhibitorsMaturation Inhibitors
Presentation highlightsPresentation highlights
Panacos discovered maturation inhibition – Broad franchise of 2nd- and 3rd-generation maturation
inhibitors
2nd-generation: analogs of bevirimat with distinct properties– Several promising compounds identified
3rd-generation: proprietary assay to identify maturation inhibitors based on novel chemical scaffolds– Recent success: hits obtained and confirmed in follow-
up assays127
128
Panacos’ maturation inhibitor franchisePanacos’ maturation inhibitor franchise
Bevirimat
Second-generation HIV Maturation Inhibitor
Discovery Preclinical Phase 1 Phase 2 Phase 3
Third-generation HIV Maturation Inhibitor
Novel target discovered by Panacos and collaboratorsBroad IP position around compounds and targetStrong competitive position
Goals for 2nd-generation maturation inhibitor programGoals for 2nd-generation maturation inhibitor program
Develop bevirimat analogs to expand maturation inhibitor market – Distinct activity against polymorphic viruses, compared to bevirimat
– Reduced serum protein binding: potential for greater potency (bevirimat ~ 99.5% HSA bound)
• Potential for QD tablet co-formulations
• Maintain bevirimat metabolic profile (long half-life, lack of drug interactions)
PA-040 first to be tested in Phase 1 – 8 X lower protein binding compared to bevirimat, yet retained long
half-life suitable for QD dosing
– Did not reach target oral bioavailability
129
Additional 2nd-generation compounds identified with improved oral bioavailabilityAdditional 2nd-generation compounds identified with improved oral bioavailability
Select additional 2nd-generation compounds for clinical testing during 2008 based on:– Activity against polymorphic viruses
and/or
– Potential for lower dose, ideally single QD tablet
2nd-generation Lead CompoundIn vitro anti-HIV potency Similar to bevirimat and PA-040
Plasma-free fraction 13-fold greater than bevirimat
Oral bioavailability in rats 6-fold greater than PA-040
130
Goals for 3rd-generation maturation inhibitor programGoals for 3rd-generation maturation inhibitor program
Identify compounds, chemically unrelated to bevirimat, that inhibit CA-SP1 cleavage
Proprietary HTS assay developed
– Currently screening diverse drug-like small molecule libraries
Active compounds identified
– 2 active compounds confirmed in Gag processing assay
131
3rd-generation hits show specific, dose-dependent inhibition of CA-SP1 processing3rd-generation hits show specific, dose-dependent inhibition of CA-SP1 processing
bevirimat (µM)DM
SO 20 10 5 2.5
CA-SP1CA
Hit # 1 (µM)
80 40 20 10 5 2.5 80 40 20 10 5 2.5
Hit # 2 (µM)
Steady-state Gag Processing in Virions
132
Compounds are structurally distinct; tractable chemistry
Additional hits currently being followed up
3rd-gen. compounds will be selected for optimization based on:– Activity against polymorphic viruses– Potential for improved formulation or other characteristics
Panacos has a broad franchise of 2nd- and 3rd-generation maturation inhibitorsPanacos has a broad franchise of 2nd- and 3rd-generation maturation inhibitors
2nd-generation: poised to select next preclinical lead candidate based on:
– Activity against polymorphic viruses (screening ongoing)
and/or
– Potential for lower dose, ideally single QD tablet (compound identified)
3rd-generation: Panacos recently identified the first maturation inhibitors with novel scaffolds, compared to bevirimat
– Current goal: analyze multiple hits and select compounds for optimization and potential future clinical development
133
Graham P. Allaway, PhDChief Operating Officer
22ndnd and 3and 3rdrd Generation Generation Maturation InhibitorsMaturation Inhibitors
Karl Salzwedel, Ph.D.Senior Director
Virology and Drug Discovery
135
Oral HIV Fusion InhibitorsOral HIV Fusion Inhibitors
136
Presentation highlightsPresentation highlights
Identified small-molecule oral HIV fusion inhibitors– Panacos has succeeded where others have been
unsuccessful
Novel approach used in developing a proprietary high-throughput screening assayIdentified several families of oral HIV fusion inhibitorsFirst preclinical candidate selected: PA-161Continuing to optimize additional lead compounds
Panacos targets both ends of HIV-1 lifecyclePanacos targets both ends of HIV-1 lifecycle
OralFusion
Inhibitors
Maturation Inhibitors
137
138
3 distinct classes of HIV entry inhibitors3 distinct classes of HIV entry inhibitors
Attachment inhibitors– BMS-806 (development terminated)
– TNX-355 CD4 antibody (Genentech)
Coreceptor antagonists (CCR5)– maraviroc (Pfizer, approved)
– vicriviroc (Schering-Plough, in development)
Fusion inhibitors– enfuvirtide (Trimeris/Roche)
139
HIV fusion inhibitor pipelineHIV fusion inhibitor pipeline
Enfuvirtide (FUZEON, T-20): only approved fusion inhibitor– 36-aa peptide
– 106-step synthesis
– BID subcutaneous injection (90 mg)
– Most expensive HIV drug (>$20,000/yr, >$55/day)
– $266.8 million worldwide sales in 2007
No other fusion inhibitors currently in the clinic
HIV fusion: complex conformational changes = multiple drug targetsHIV fusion: complex conformational changes = multiple drug targets
140
gp41
gp120
gp120 comes
off
CD4binds
Coreceptorbinds
6-HelixBundle(6HB)
141
Enfuvirtide target is not amenable to small molecule inhibitionEnfuvirtide target is not amenable to small molecule inhibition
142
Panacos takes a unique approach to identify oral fusion inhibitorsPanacos takes a unique approach to identify oral fusion inhibitors
Unsuccessful efforts by other groups– Peptide-based biochemical screening for compounds
that work at the same molecular target as enfuvirtide– Computer-aided drug design focused exclusively on
enfuvirtide target
Panacos develops proprietary cell-based assay– Captures multiple targets in the cascade of molecular
changes that drive fusion and culminate in 6-helix bundle formation
143
Panacos’ proprietary fusion inhibitor screening assayPanacos’ proprietary fusion inhibitor screening assay
Panacos discovered novel class of orally bioavailable HIV-1 fusion inhibitorsPanacos discovered novel class of orally bioavailable HIV-1 fusion inhibitors
144
Potency (IC50; µM) PK
SeriesScreening
AssayInfection
AssayOral
Bioavailability
A 0.0005 0.004 19% (mouse)
B 0.3 1 30% (rat)
C 0.05 0.04 ND
>0.5 million compounds screened8 distinct, chemically tractable series identified for optimizationFocused on 3 series with greatest potencyExtensive laboratory studies confirm mechanism of action– Molecular target upstream of enfuvirtide target
145
PA-161 selected as preclinical leadPA-161 selected as preclinical lead
Nanomolar activity against diverse primary HIV-1 isolates in the presence of human serum
Good oral bioavailability, potential for BID or QD dosing
No significant off-target receptor binding, including functional hERG testing
Optimization ongoing of additional lead compounds
146
Panacos’ inhibitors retain activity against most enfuvirtide-resistant mutantsPanacos’ inhibitors retain activity against most enfuvirtide-resistant mutants
Series A Peptide-based Inhibitor
Fold Resistance
L33SV38EI37KN42T/N43KV38A/N42TV38E/N42SV38A
11.70.54.81.20.90.52.0
3.060.56.39.37.323.39.5
(Red = >2-Fold Resistance)
Mutant
147
Oral fusion inhibitor program highlightsOral fusion inhibitor program highlights
Developed & validated proprietary screening approach for oral fusion inhibitor discovery
Potent fusion inhibitors identified – Orally bioavailable, unlike enfuvirtide
– Active against both X4 & R5 strains, unlike maraviroc
– Novel target site and mechanism of action
– Distinct determinants of resistance
Preclinical lead candidate selected: PA-161
Continuing to optimize additional lead compounds
Karl Salzwedel, Ph.D.Senior Director
Virology and Drug Discovery
148
Oral HIV Fusion InhibitorsOral HIV Fusion Inhibitors
Bevirimat Market Potential Bevirimat Market Potential andand
HIV Marketplace DynamicsHIV Marketplace Dynamics
149
Frederick Schmid, DVM, MBASenior Vice President
Commercial Operations and Business Development
Questions we ask ourselvesQuestions we ask ourselves
How robust is the antiretroviral market going forward?
Isn't the market largely satisfied already?
Where will bevirimat business come from?
How will bevirimat fit into the treatment scheme?
Will polymorphism testing be a limiting burden?
150
What a difference 5 years can make…… In 2002, Combivir and Sustiva had locked up the marketWhat a difference 5 years can make…… In 2002, Combivir and Sustiva had locked up the market
151
TRx
mar
ket s
hare
How robust is the ARV market?How robust is the ARV market?
DataMonitor projects a $6B market growing to $11B by 2015
What factors will sustain that growth?– Only ~75% of people with HIV know their status
• Aggressive testing policies being implemented to expand that number
– Only 55% - 65% of people with HIV are on ARVs• Having more agents available will tips the scales toward starting earlier vs.
conserving
– Growing bolus of experienced patients still need new options• People living longer with HIV• Existing classes are compromised and of little use to long-time patients
Novel MOA is lynch pin for competitive advantageBevirimat is the only novel, oral ARV in late-stage development
152
There is significant room for growthThere is significant room for growth
2007 US HIV Market (Patients 000’s)
1,000 – 1,2001
1. CDC 20052. Synovate Healthcare US HIV Monitor 1Q07
HIV Infected Diagnosed On Anti-retroviralTreatment
750 – 9001
5002
153
Fusion Inhibitors
• Enfuvirtide
Entry Inhibitors
• Maraviroc
IntegraseInhibitors
• Raltegravir
Protease Inhibitors• Atazanavir
• Darunavir
• Fos-Amprenavir
• Indinavir
• Lopinavir
• Nelfinavir
• Ritonavir
• Saquinavir
• Tipranavir
NRTIs• Abacavir
• Didanosine
• Emtricitabine
• Lamivudine
• Stavudine
• Tenofovir
• Zidovudine
NNRTIs• Delavirdine
• Efavirenz
• Nevirapine
• Etravirine
Long list of drugs but in older classes, and Long list of drugs but in older classes, and intraintra--class crossclass cross--resistance reduces options resistance reduces options dramaticallydramatically
Of all the HIV drugs in development, there is just one novel, oral ARV drug
in late‐stage development
2007 201020092008 201320122011 2014 2015
BevirimatRaltegravir
Etravirine HIV Vaccine
Vicriviroc
PRO 140
TNX 355 Elvitegravir
Elvucitabine
Racivir Amdoxivir
Apricitabine
Incyte CCR5
HGS CCR5 MAb
Tai Med anti‐CD4 MAbTobira CCR5
Idenix NNRTI
Ardea NNRTI
Pfizer NNRTI
Koronis NRTI
Gilead NRTI
Entry Inhibitors
NNRTIs
NRTIs
Integrase Inhibitors
Maraviroc
PPL‐100
PIs
Maturation Inhibitor
As many switches onto 3rd+ lines as in first two lines even though patient prevalence is much higher in first two linesAs many switches onto 3rd+ lines as in first two lines even though patient prevalence is much higher in first two lines
Sources: CDC, Plan A HIV Alert- Lines of Therapy, 2006-2016156
Bevirimat captures substantial value at launch by penetrating later lines of therapy…Bevirimat captures substantial value at launch by penetrating later lines of therapy…
Volume: 115K patients will start new regimen in 3rd+ linesExisting major drug classes will be compromised– 75% of patients likely will have only 1-2 fully active and tolerable drugs
leftConservatively, 60% will not have Gag PMs– In such a highly tailored situation, bevirimat should reach 75% of these
patients
Price: “3rd-agent” pricing reference (boosted PIs) estimated to have average daily price of ~$45 by bevirimat launch
$13,500/patient-year (assuming 80% adherence)
115k pts x .75 x .60 x .75 = ~ 39k patients39k x $13.5k x 80% adherence ~ $420M
(at 2% penetration in first and second lines, >$500M)*U.S. only projections
157
…and builds into earlier lines, based on patient-friendly profile and formulation choice…and builds into earlier lines, based on patient-friendly profile and formulation choice
Current domination by Atripla is not fait acompli– One pill QD hailed as "Holy Grail"– But there are soft spots in the armor
• Component toxicitieso Efavirenzo Tenofovir
• Large pillso Sizeable niche of patients prefer “non-solid” formulations
Gaps in Atripla value proposition leaves room for Panacos to take share in early lines
158
No surprise, physicians focus on efficacy and toxicity, not pills vs. liquidsNo surprise, physicians focus on efficacy and toxicity, not pills vs. liquids
159 Panacos 3rd-party market research
But many patients have issues with pills, especially women and people of colorBut many patients have issues with pills, especially women and people of color
160
%
•26% of all patients report problems swallowing pills•2007 research by Harris Interactive supports this (40%)
Panacos 3rd-party market research
41
60
69
80
89
RAL (GSS = 0)
RAL
RAL + DAR
RAL + ENF
RAL + DAR + ENF
% C
opie
s <5
0
161Pooled data from BENCHMRK1 & 2 trials
Novel MOA and tailored fit offers advantages for including bevirimat in
compromised regimens
The more active agents the better: Where will bevirimat fit?The more active agents the better: Where will bevirimat fit?
Testing for polymorphisms will be nearly invisible to key constituents: doctors and payorsTesting for polymorphisms will be nearly invisible to key constituents: doctors and payors
Gag test will be based upon simple genotype test already in use
Patients receive genotyping before starting first treatment and whenever changing treatment– Most common resistance test used by clinicians
– Simple to perform, widely available, and fully reimbursed
– Cost $200-400…Results in 7-14 days…simple report to doctors
Simple bolt-on modifications routinely added to current assay by commercial testing companies– Not an entirely new phenotypic assay like TROPHILE™
– Each testing company adds new genotypes to stay relevant
– Engaged in advanced discussions with major players in HIV testing
162
Answers to our marketing questionsAnswers to our marketing questionsHIV market continues to be robust
More patients takings ARVsMore moving into later lines
The market is not satisfiedBurgeoning experienced patient population needs novel MOAsNext novel MOA to market will shore up regimen durability
Bevirimat will penetrate later lines, based upon its novel MOA, potency and tolerability
Penetrate earlier lines with patient-friendly formulations vs. "pill fatigue"
Bevirimat fits into future HIV treatment schemes Tailored fit and novel MOA adds certainty vs. archived mutationsLike Fuzeon, bevirimat is potent and novel, but in an oral form
Polymorphism testing will not be a burden
163
Bevirimat Market Potential Bevirimat Market Potential andand
HIV Marketplace DynamicsHIV Marketplace Dynamics
164
Frederick Schmid, DVM, MBASenior Vice President
Commercial Operations and Business Development
Partnership Strategy and Financial Review
Jane Pritchett HendersonChief Financial and Business Officer
166
Partnership strategies to build shareholder valuePartnership strategies to build shareholder value
Partnership opportunities for all programs– Retained worldwide rights to date– Interest from pharma/large biotech– Value-enhancing events increases interest
Panacos seeks to maintain co-marketing rights in N. America– Small sales force sufficient for HIV – Expertise to implement this strategy– Partner will be responsible for ROW– Retain significant economic upside
Potential for future pipeline expansion – In-house programs – Strategic alliances
Bevirimat is a commercially attractive drug candidateBevirimat is a commercially attractive drug candidate
Patients’ need for new options grows every year
Competitive profile– Potent, first-in-class, novel-mechanism drug– Side effects comparable to placebo– Simple, convenient dosing, forgiving– No clinically relevant drug interactions
• Use in any HAART regimen
– Tablet and liquid formulations under development• Maximizes potential market
Solid intellectual property position in maturation inhibition– Patent family gives protection through 2026 and beyond
Worldwide market potential: $500 - $750M167
Lead small molecule compound identified: PA-161Blocks conformational changes in gp41– Target distinct from FUZEON’s– Activity against FUZEON-resistant HIV
Leading position for oral product– Patented, innovative drug discovery platform
Market potential $500M - $1BAdditional partnership opportunity
Significant potential upside for an oral HIV fusion inhibitor Significant potential upside for an oral HIV fusion inhibitor
{gp41
HIV
Human cell
Panacos is in a sound financial position to negotiate optimal deal Panacos is in a sound financial position to negotiate optimal deal
Selected Financial Data (millions) 3/31/08
Cash, cash equivalents & marketable securities $43.6
Total debt $18.9
Shares outstanding 53.5
169
170
Significant accomplishments over the past 6 monthsSignificant accomplishments over the past 6 monthsBevirimat
Completed bevirimat Phase 2b functional monotherapy studies –no further dose escalation required
Identified predictors of response
Approximately 60-70% of HIV patients have responder Gag profile
Confirmed responder population prospectively
Identified commercializable tablet and liquid formulation
Initiated multinational studies with tablet dose
Oral FusionSelected an oral HIV fusion inhibitor lead
CorporateAppointed CFO
Partnership Strategy and Financial Review
Jane Pritchett HendersonChief Financial and Business Officer
Partnership Strategy and Financial Review
Jane Pritchett HendersonChief Financial and Business Officer
Panacos is in a very strong position to deliver shareholder valuePanacos is in a very strong position to deliver shareholder value
Bevirimat– Commercially attractive drug candidate – Addresses continued market need for novel, potent, safe and
oral HIV therapeutics● Steady flow of clinical milestones expected in near-term
Second- and third-generation maturation inhibition programs are progressingSignificant upside from oral fusion inhibitor – Expect to be first to enter the clinic – Strong interest from potential partners
New management team in place – Proven track record of drug development, approval, launch and
commercialization
173
Milestones that build shareholder value over next 12 monthsMilestones that build shareholder value over next 12 months
Bevirimat:Confirm 100mg tablet bioavailability in the clinic Complete multinational Phase 2b studiesInitiate registration studies for marketing approvalConduct discussions with FDA and EMEACollaborate with partner for registration and commercialization
Oral Fusion Inhibitor:Complete preclinical safety studiesFile INDEstablish development partnership
2nd/3rd-generation Maturation Inhibitor:Select lead compound for further development
174
Panacos in 2013, our 5-year goals Panacos in 2013, our 5-year goals
A fully integrated biotech company with U.S. sales force– Bevirimat is 1st commercial product
– Generating revenue
– Building brand awareness with physicians
– Strong support for Company from HIV community
Oral fusion inhibitor product candidate in Phase 3
Strong antiviral pipeline with multiple candidates in development to fuel commercial growth
At or nearing financial independence
Pharmaceutical collaborations to expand access to Panacos’drug candidates
Name recognition globally for positive impact on HIV therapy
175