Thomas Kakuda, PharmD

Scientific Director, Clinical Pharmacology

Challenges in Drug Development for Other Viruses Than HIV

or Hepatitis: Influenza

Rich Infectious Disease Therapeutics and Vaccines Portfolio

APPROVED PRODUCTS

PRODUCTS IN REGISTRATION

OR PLANNED FILINGS 2017-2021

SELECTED EARLY- TO

MID-STAGE PIPELINE1

PLANNED FILINGS

FILED

Darunavir STR (D/C/F/TAF) HIV (US)*

Rilpivirine rilpivirine/dolutegravir STR rilpivirine/cabotegravir long-acting maintenance therapy**

PREZCOBIX/REZOLSTA

HIV pediatric exclusivity

SIRTURO

Pediatric TB**

JNJ-4178 (3DAA) Hepatitis C

Pimodivir (JNJ-3872) Influenza A

Lumicitabine (JNJ-1575) Pediatric RSV infection Adult RSV infection Adult hMPV

JNJ-1860 (ExPEC vaccine) Bacterial infection

VAC18193 (RSV vaccine) RSV elderly

Darunavir STR (D/C/F/TAF) HIV (EU)

(US)

Monovalent Ebola Vaccine submitted to WHO for

Emergency Use Assessment and Listing (EUAL)

(EU)

Hepatitis B JNJ-5948/NVR3-778 (HBV capsid assembly modulator) JNJ-6379 (HBV capsid assembly modulator) JNJ-0440 (HBV capsid assembly modulator) JNJ-0535 (HBV therapeutic vaccine) JNJ-4964 (TLR Agonist)

Respiratory Syncytial Virus JNJ-8678 (RSV fusion inhibitor) JNJ-7184 (RSV non-nuc polymerase inhibitor) JNJ-8194/VAC18194 (RSV pediatric vaccine)

Influenza JNJ-5806/AL-794 (Influenza PA inhibitor) JNJ-7445 (Influenza antibody)

Dengue JNJ-8359 (NS4B inhibitor)**

HIV JNJ-9220/VAC89220 (HIV vaccine prophylactic) JNJ-9220/VAC89220 (HIV vaccine w/ MVA boost therapeutic)

Filovirus VAC69120 (Filovirus multivalent vaccine)

Poliomyelitis JNJ-2348 (Sabin IPV vaccine)

Cervical Cancer JNJ-1623/VAC81623 (HPV vaccine)

1. Potential filings up to 2027, non-risk adjusted. Products marketed worldwide, but not all products in all markets/regions.

* Indicates In Registration

**Indicates assets for Global Public Health

Note: Filings/approvals are in the US or EU, unless otherwise noted. This information is accurate as of the date hereof to the best of Johnson & Johnsons knowledge.

The Company assumes no obligation to update this information.

Line ExtensionsNew Molecular Entities

Flu (not the same as a cold or stomach flu)

Symptoms High fever

Sore throat

Headache

Myalgia

Cough

Fatigue

At-risk populations Very young

Elderly

Immunocompromised

Heart or lung disease, diabetics,

Complications Bacterial/viral pneumonia

Cardiac failure

Respiratory failure

Myositis

Encephalopathy (rare)

Influenza Causes Significant Morbidity and Mortality

1B* cases annually worldwide, with 250,000-500,000 deaths; 10-20% of the population in developed countries infected each season

IndicationAssociated Deaths

Per Year

Influenza Up to 56,000

Colon Cancer 49,190

Pancreatic Cancer 41,780

Breast Cancer 40,890

Prostate Cancer 26,120

Leukemia 24,400

Lymphoma 21,270

Skin Cancer 13,650

In the U.S. each season:

25M* total cases

12M attend medical specialist

390,000 hospitalizations

Spanish influenza pandemic of 1918 1919 caused ~50M deaths worldwide

* M = Millions, B = Billions

World Health Organization, 2016; Kostova et al., PLOS ONE, 2013; Zhou et al., Clinical Infectious Diseases, 2012; CDC MMWR Aug. 27, 2010; Sleeman, K. et al., AAC, 2010; American Cancer Association, Cancer Facts & Figures, 2016; Taubenberger, Jeffery K., and Morens, David M.,"1918 Influenza: The Mother of All Pandemics." Emerging Infectious Diseases 12.1, 2006: 15-22. Web.

Orthomyxovirus

Influenza types A, B, C and D Only replicates in epithelial cells

Type A involved in pandemics

Type B and C cause milder disease

Negative-strand RNA virus 8 segments of ssRNA

Codes for >10 proteins

Influenza A subtypes

Hemaglutinin (H) Binds sialic acid-containing receptors

Neuraminidase (N) Cleaves sialic acid (neuraminic acid)

Subtype Human Swine Horse Bird

H1 + + +

H2 + +

H3 + + + +

H4 +

H5 + + +

H6 +

H7 + + +

H8-H17 +

Subtype Human Swine Horse Bird

N1 + + + +

N2 + + +

N3 +

N4 +

N5 +

N6 +

N7 + +

N8 + +

N9 + +

Transmission

Nomenclature e.g. A(H1N1)pdm09 = influenza type A

with H1 and N1 antigens that caused the

pandemic swine flu in 2009

Low Pathogenicity Avian Influenza (LPAI)

High Pathogenicity Avian Influenza (HPAI)

B/Yamagata and B/Victoria lineages (no

subtypes)

Antigenic drift vs antigenic shift Drift: point mutations seasonal flu

Shift: major reassortment pandemic

H7N9 considered most likely to start the

next pandemic

Animal resevoir

Seasonal disease (in temperate climates)

Usually occur during winter (October to March)

Close proximity (e.g. schools, nursing

homes, office,)

Coughing and sneezing aerosolizes the

virus

100,000 to 1,000,000 virions per droplet

Virus can survive in colder temperature

https://www.cdc.gov/mmwr/volumes/66/wr/mm6606a2.htm

Prophylaxis and treatments are available but have limitations

1. Vaccines are strain specific have to be administered each

year and susceptible to strain mismatch which renders them

ineffective

2. Imperfect protection seasonal vaccines are 70-90% effective

in preventing influenza infection in healthy adults; 30-40%

effective in elderly patients who live in nursing homes and in

immunocompromised patients, and

Influenza: Critical Pathways and Targets

Prioritized Biological Pathways:

Inhibition of Viral Replication (polymerase)

Pimodivir* (JNJ-3872) PB2 inhibitor

JNJ-5806 (AL-794) PA inhibitor

Inhibition of Virus Attachment/Fusion JNJ-7445 Multi-domain influenza

antibody

REPLICATION

ENDOCYTOSIS

FUSION

CLEAVAGE

Neuraminidase

inhibitors (NAIs)1

ENTRY

1. Multiple NAIs approved: Oseltamivir (PO), Zanamivir (IN), Peramivir (IV), Laninamivir (IN)

* Licensed from Vertex Pharmaceuticals, Inc. Federal funds from the Office of the Assistant Secretary for

Preparedness and Response, BARDA, under Contract Number HHSO100201500014C.

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.nature.com/nature/journal/v459/n7249/fig_tab/nature08157_F2.html&ei=8nMHVbTrJoXSoASdoIGYAw&bvm=bv.88528373,d.cGU&psig=AFQjCNHvTpJRxLg26btbCHOdVXRHosRxVw&ust=1426638162945609http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.nature.com/nature/journal/v459/n7249/fig_tab/nature08157_F2.html&ei=8nMHVbTrJoXSoASdoIGYAw&bvm=bv.88528373,d.cGU&psig=AFQjCNHvTpJRxLg26btbCHOdVXRHosRxVw&ust=1426638162945609

Influenza challenge study

Healthy volunteer study (Phase 1b) Not considered an efficacy trial but helps determine antiviral activity or prophylaxis

Limited clinical sites with experience GMP influenza

Reproducible?

Limitations (to extrapolating to real-world infections) Attenuated strain

Infection rate ~50% (exclude vaccinated subjects)

Less symptoms

Very controlled environment

Drug administered within symptom-onset

AL-794-801 influenza viral challenge study in healthy volunteers:

ITT-I Viral Kinetics

Time from first dose (Days)

Me

an

(+

SE

) V

ira

l L

oa

d (

Lo

g1

0

TC

ID5

0/m

L)

LLOD

Placebo BID (N=14)

AL-794 50 mg BID (N=10)

AL-794 150 mg BID (N=18)

Observations less than two are not representedBID = Twice Daily

Phase 2-3 trials

Prophylaxis vs treatment Different indications

Uncomplicated vs complicated Trials in complicated patients are more difficult

High-risk (e.g. elderly)

Underlying disease (e.g. cardiac or respiratory)

Immunocompromised

No study has demonstrated efficacy in hospitalized patients

Unclear regulatory path

Active-controlled non-inferiority trial not possible

Add-on superiority trial (investigational drug + SoC vs SoC; SoC is off-label use)

Blinded, randomized, dose- or duration-response trial

Janssen Research & Development

TOPAZ

Phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-response, multicenter study

Participants were randomized 1:1:1:1 to one of four treatments:

Participants were followed for 14 days totalBID, twice-daily; OST, oseltamivir

Pimodivir 300 mg Pimodivir 600 mg Combination Pimodivir

+ OST

Placebo

pimodivir 300 mg + OST

placebo

pimodivir 600 mg + OST

placebo

pimodivir 600 mg + OST

75 mg

pimodivir placebo + OST

placebo

Dosing for 5 days,

twice-daily

Janssen Research & Development

Primary Endpoint: Viral load over time by qRT-PCR (log10copies/mL) [FAS]

Viral load assay LOQ = 4.0 log10 copies/mL, LOD = 3.48 log10 copies/mL. Results LOD (target detected) are

imputed with 3.75 log10 copies/mL; results

Janssen Research & Development

Primary Endpoint: Viral load (qRT-PCR)[FAS]

Treatment with pimodivir resulted in a significant and dose-dependent decrease in AUC of viral load (by qRT-PCR) over 7 days from start of dosing, showing a dose-response relationship

The viral culture data confirmed the qRT-PCR results and showed a shorter time to negativity compared to the qRT-PCR data

Pimodivir in combination with oseltamivir resulted in a significant lower AUC of viral load as compared to pimodivir 600 mg alone

a[day*log10 copies/mL]; AUC, area under the concentration time curve; qRT-PCR, quantitative real time-polymerase chain reaction

OST, oseltamivir

Comparison Pimodivir

300 mg vs placebo

Pimodivir

600 mg vs placebo

Pimodivir

600 mg+

OST 75 mg vs

placebo

Pimodivir

600 mg+

OST 75 mg vs

pimodivir 600 mg

Change in AUC viral

loada

(95% CI)

-3.6

(-7.1; -0.1)

-4.5

(-8.0; -1.0)

-8.6

(-12.0; -5.1)

-4.1

(-7.4;-0.7)

Janssen Research & Development

Results

Secondary Endpoint: Safety analyses [Safety set]

The most frequently reported TEAEs were diarrhea (reported mostly as loose stool without increased frequency) and nausea

The majority of these events were mild in severity

One case of severe diarrhea was reported in pimodivir 600 mg BID group

One case of severe nausea was reported in the pimodivir 600 mg +OST 75 mg group

Two serious TEAEs reported:

1 (1.4%) in placebo group with thrombocytopenia; started on Day 63 and resolved 5 weeks later

1 (1.4%) in pimodivir 600 mg BID with ALT increased; started on day 14 and resolved 21 weeks later

Pimodivir

300 mg

Pimodivir

600 mg

Pimodivir

600 mg+

OST 75 mg

Placebo

N 74 74 73 71

Any TEAE,

n (%)

32 (43.2) 39 (52.7) 30 (41.1) 31 (43.7)

Any serious TEAE, n

(%)

0 1 (1.4) 0 1 (1.4)

Any TEAE leading to

drug discontinuation,

n (%)

7 (9.5) 3 (4.1) 6 (8.2) 5 (7.0)

AEs occurring in 10% in any treatment group

Diarrhea 5 (6.8) 20 (27.0) 13 (17.8) 4 (5.6)

Nausea 3 (4.1) 3 (4.1) 8 (11.0) 0

AE, adverse event; BID, twice-daily; OST, oseltamivir; TEAE, treatment-emergent AE

Janssen Research & Development

Secondary Endpoint: Time-to-resolution of symptoms

[FAS]

A faster time-to-resolution of influenza symptoms versus placebo of 13% for pimodivir 600 mg BID and 17% for pimodivir 600 mg BID + OST 75 mg BID treatment groups

Pimodivir 600 mg + OST 75 mg combination therapy led to a comparable estimated time to resolution of influenza symptoms as pimodivir 600 mg alone

Comparison Pimodivir

300 mg vs

placebo

Pimodivir

600 mg vs

placebo

Pimodivir 600

mg+ OST

75 mg vs

placebo

Pimodivir 600

mg+

OST 75 mg

vs pimodivir

600 mg

Acceleration

factor (95%CI)

1.07

(0.76; 1.52)

0.87

(0.62; 1.23)

0.83

(0.60;

1.16)

0.96

(0.69;

1.34)

BID, twice-daily; OST, oseltamivir

Summary

Prophylaxis and treatment is available but limited Encourage flu vaccination (> 6 months)

Treatment of complicated influenza is an unmet medical need

Combination therapy with new mechanisms of action needed

Seasonal and acute self-limiting disease Enrollment challenges

Rapid diagnosis treatment

Clinical endpoints Symptom and outcome driven, viral load is secondary

No surrogate markers