The Business Case for Building the Janssen Brand
Challenges in Drug Development for Other Viruses Than HIV or Hepatitis: Influenza
Thomas Kakuda, PharmD Scientific Director, Clinical Pharmacology Rich Infectious Disease Therapeutics and Vaccines Portfolio
PRODUCTS IN REGISTRATION SELECTED EARLY- TO APPROVED PRODUCTS OR PLANNED FILINGS 2017-2021 MID-STAGE PIPELINE1 FILED Hepatitis B Darunavir STR (D/C/F/TAF) • JNJ-5948/NVR3-778 (HBV capsid assembly modulator) • HIV (EU) • JNJ-6379 (HBV capsid assembly modulator) • JNJ-0440 (HBV capsid assembly modulator) • JNJ-0535 (HBV therapeutic vaccine) PLANNED FILINGS • JNJ-4964 (TLR Agonist)
(US) Darunavir STR (D/C/F/TAF) Respiratory Syncytial Virus • HIV (US)* • JNJ-8678 (RSV fusion inhibitor) Rilpivirine • JNJ-7184 (RSV non-nuc polymerase inhibitor) • rilpivirine/dolutegravir STR • JNJ-8194/VAC18194 (RSV pediatric vaccine) • rilpivirine/cabotegravir long-acting maintenance therapy** Influenza PREZCOBIX®/REZOLSTA® • JNJ-5806/AL-794 (Influenza PA inhibitor) (EU) • HIV pediatric exclusivity • JNJ-7445 (Influenza antibody) SIRTURO® • Pediatric TB** Dengue JNJ-4178 (3DAA) • JNJ-8359 (NS4B inhibitor)** • Hepatitis C HIV Pimodivir (JNJ-3872) • JNJ-9220/VAC89220 (HIV vaccine prophylactic) • Influenza A • JNJ-9220/VAC89220 (HIV vaccine w/ MVA boost therapeutic) Lumicitabine (JNJ-1575) • Pediatric RSV infection Filovirus • Adult RSV infection • VAC69120 (Filovirus multivalent vaccine) • Adult hMPV Poliomyelitis JNJ-1860 (ExPEC vaccine) • Bacterial infection • JNJ-2348 (Sabin IPV vaccine) Monovalent Ebola Vaccine submitted to WHO for Emergency Use Assessment and Listing (EUAL) VAC18193 (RSV vaccine) Cervical Cancer • RSV elderly • JNJ-1623/VAC81623 (HPV vaccine) New Molecular Entities Line Extensions
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 & Johnson’s knowledge. The Company assumes no obligation to update this information. Flu (not the same as a cold or “stomach flu”)
• Symptoms • Complications • High fever • Bacterial/viral pneumonia • Sore throat • Cardiac failure • Headache • Respiratory failure • Myalgia • Myositis • Cough • Encephalopathy (rare) • Fatigue
• At-risk populations • Very young • Elderly • Immunocompromised • Heart or lung disease, diabetics, … 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
Associated Deaths Indication Per Year In the U.S. each season: Influenza Up to 56,000 Colon Cancer 49,190 25M* total cases Pancreatic Cancer 41,780 12M attend medical specialist 390,000 hospitalizations Breast Cancer 40,890 Prostate Cancer 26,120 Leukemia 24,400 Lymphoma 21,270 Skin Cancer 13,650 “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 • Negative-strand RNA virus • Only replicates in epithelial cells • 8 segments of ssRNA • Type A involved in pandemics • Codes for >10 proteins • Type B and C cause milder disease Influenza A subtypes
• Hemaglutinin (H) • Neuraminidase (N) • Binds sialic acid-containing receptors • Cleaves sialic acid (neuraminic acid) Subtype Human Swine Horse Bird Subtype Human Swine Horse Bird
H1 + + – + N1 + + + + H2 + – – + N2 + + – + H3 + + + + N3 – – – + H4 – – – + N4 – – – + H5 + – + + N5 – – – + H6 – – – + N6 – – – + H7 + – + + N7 – – + +
H8-H17 – – – + N8 – – + + N9 + – – + Transmission
• Nomenclature • Animal resevoir • 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 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 Vaccines Antivirals
1. Vaccines are strain specific – have to be administered each 1. Short window of administration – antivirals have to be year and susceptible to strain mismatch which renders them administered within 48 hours of becoming symptomatic to ineffective be effective. 2. Imperfect protection – seasonal vaccines are 70-90% effective in preventing influenza infection in healthy adults; 30-40% 2. Drug resistance over time – spontaneous mutations in effective in elderly patients who live in nursing homes and in the virus render treatment completely ineffective against immunocompromised patients, and <50% effective among those some flu strains sometimes in only one season. An older with one or more high-risk conditions, poor vaccine response in class of M2 ion channel inhibitors have been rendered young children necessitates two doses almost completely ineffective across the G7 regions due to 3. Require lag time to full protection – body develops antibodies drug resistance. against the viral strain about two weeks after vaccination2 3. Effectiveness is not well defined, especially in high- 4. Manufactured through a long and complicated production risk population – studies have shown Tamiflu and other cycle – manufactured in eggs, not easily scalable in case of a neuraminidase inhibitors to have a modest effect in pandemic, limited production capacity (limited antigen yield) reducing flu symptoms and infectivity but there is 5. Are administered intramuscularly – at least 15% of insufficient published data to know if they reduce unvaccinated patients mention needle-phobia as a reason for complications. not being vaccinated1 Influenza: Critical Pathways and Targets
ENDOCYTOSIS ENTRY
FUSION Prioritized Biological Pathways: • Inhibition of Viral Replication (polymerase) • Pimodivir* (JNJ-3872) – PB2 inhibitor • JNJ-5806 (AL-794) – PA inhibitor • Inhibition of Virus Attachment/Fusion REPLICATION • JNJ-7445 – Multi-domain influenza
CLEAVAGE antibody
Neuraminidase inhibitors (NAIs)1
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. 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
Placebo BID (N=14) AL-794 50 mg BID (N=10)
AL-794 150 mg BID (N=18)
10
TCID50/mL) Mean (+SE) Viral Load (LogLoad (+SE) Viral Mean
LLOD
Observations less than two are not represented Time from first dose (Days) BID = 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 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: Dosing for 5 days, twice-daily
Pimodivir 300 mg Pimodivir 600 mg Combination Pimodivir Placebo + OST pimodivir 300 mg + OST pimodivir 600 mg + OST pimodivir 600 mg + OST pimodivir placebo + OST placebo placebo 75 mg placebo . Participants were followed for 14 days total BID, twice-daily; OST, oseltamivir
Janssen Research & Development Primary Endpoint: Viral load over time by qRT-PCR (log10 copies/mL) [FAS]
Viral load assay LOQ = 4.0 log10 copies/mL, LOD = 3.48 log10 copies/mL. Results Janssen Research & Development Primary Endpoint: Viral load (qRT-PCR)[FAS] Comparison Pimodivir Pimodivir Pimodivir Pimodivir 300 mg vs placebo 600 mg vs placebo 600 mg+ 600 mg+ OST 75 mg vs OST 75 mg vs placebo pimodivir 600 mg Change in AUC viral -3.6 -4.5 -8.6 -4.1 loada (-7.1; -0.1) (-8.0; -1.0) (-12.0; -5.1) (-7.4;-0.7) (95% CI) . 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 Janssen Research & Development Results Secondary Endpoint: Safety analyses [Safety set] Pimodivir Pimodivir Pimodivir Placebo . The most frequently reported TEAEs were 300 mg 600 mg 600 mg+ diarrhea (reported mostly as loose stool OST 75 mg without increased frequency) and nausea N 74 74 73 71 . The majority of these events were mild Any TEAE, 32 (43.2) 39 (52.7) 30 (41.1) 31 (43.7) in severity n (%) . One case of severe diarrhea was Any serious TEAE, n 0 1 (1.4) 0 1 (1.4) reported in pimodivir 600 mg BID group (%) Any TEAE leading to 7 (9.5) 3 (4.1) 6 (8.2) 5 (7.0) . One case of severe nausea was drug discontinuation, reported in the pimodivir 600 mg +OST n (%) 75 mg group AEs occurring in ≥10% in any treatment group . Two serious TEAEs reported: Diarrhea 5 (6.8) 20 (27.0) 13 (17.8) 4 (5.6) . 1 (1.4%) in placebo group with Nausea 3 (4.1) 3 (4.1) 8 (11.0) 0 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 AE, adverse event; BID, twice-daily; OST, oseltamivir; TEAE, treatment-emergent AE Janssen Research & Development Secondary Endpoint: Time-to-resolution of symptoms [FAS] Comparison Pimodivir Pimodivir Pimodivir 600 Pimodivir 600 300 mg vs 600 mg vs mg+ OST mg+ placebo placebo 75 mg vs OST 75 mg placebo vs pimodivir 600 mg Acceleration 1.07 0.87 0.83 0.96 factor (95%CI) (0.76; 1.52) (0.62; 1.23) (0.60; (0.69; 1.16) 1.34) . 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 BID, twice-daily; OST, oseltamivir Janssen Research & Development 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