Theravance Biopharma, Inc. · NASDAQ:TBPH
Theravance Biopharma — Q1 2021 Earnings Presentation
54 slides from Theravance Biopharma's earnings presentation, May 4, 2021
Slide 1: Appendix
Appendix May 4, 2021 THERAVANCE BIOPHARMA®, THERAVANCE®, the Cross/Star logo and MEDICINES THAT MAKE A DIFFERENCE® are registered trademarks of the Theravance Biopharma group of companies (in the U.S. and certain other countries). All third party trademarks used herein are the property of their resp
Slide 2: Research and development portfolio of designed molecules: brain, lung, GI and eye
Research and development portfolio of designed molecules: brain, lung, GI and eye Symptomatic nOH (Neurogenic orthostatic hypotension) COPD (chronic obstructive pulmonary disorder) — APPROVED CD (Crohn’s disease) UC DME (diabetic macular edema) Biology DMPK Asthma COVID-19 (ulcerative colitis) Celia
Slide 3: Nezulcitinib (TD-0903) Program
Nezulcitinib (TD-0903) Program Nebulized lung-selective pan-JAK inhibitor to treat: ►Acute hyperinflammation of the lung in COVID-19 ►Chronic inflammation for the treatment and prevention of lung transplant rejection
Slide 4: Leveraging respiratory expertise for potential acute treatment in response to a global pandemic
Leveraging respiratory expertise for potential acute treatment in response to a global pandemic PATIENT POPULATION >149M patients worldwide1 >32M US patients1 ~2.4% patients become hospitalized2 CURRENT US TREATMENT LANDSCAPE 3 vaccines available via Emergency Use Authorization3,4 1 approved treatme
Slide 5: Nezulcitinib Phase 2 Part 2 Study 0188 design
*Loading dose (double the standard dose) administered on Day 1. NCT04402866 IMV, invasive mechanical ventilation; PK, pharmacokinetics; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2; SOC, standard of care, includes remdesivir, dexamethasone, anticoagulation. 5 Part 2 Study 0188 Key inc
Slide 6: Potential for nezulcitinib to improve lung immune system balance across disease progression
Potential for nezulcitinib to improve lung immune system balance across disease progression Asymptomatic or pre-symptomaticMild illnessModerate illnessSevere illnessCritical illnessCOVID recovery Features Positive SARS-CoV-2 test; no symptoms Mild symptoms (e.g., fever, cough, or change in taste or
Slide 7: Nezulcitinib Phase 2 study in hospitalized COVID-19 patients: dose finding data
Nezulcitinib: Phase 2 study in hospitalized patients with COVID-19 requiring oxygen support Dose Finding Data Study 0188 Key inclusion criteria: Hospitalized patients aged 18–80 y requiring supplemental oxygen to maintain >90% saturation (not requiring IMV) with positive SARS-CoV-2 test <72 h prior
Slide 8: Overall conclusions from Nezulcitinib Phase 2 dose finding data
https://www.medrxiv.org/content/10.1101/2021.03.09.21252944v1 CRP, C-reactive protein; IL, interleukin; PK, pharmacokinetics; RAGE, receptor for advanced glycation end-products; S/F ratio, ratio of oxygen saturation in the blood vs the flow of oxygen administered to the patient. 8 Overall conclusion
Slide 9: Nezulcitinib appears to stabilize clinical status within days, compared to placebo
Nezulcitinib appears to stabilize clinical status within 7 days, compared to placebo Nezulcitinib showed a positive trend toward more clinical improvement 50% of placebo patients required mechanical ventilation by Day 6 100 Placebo Nezulcitinib 10 mg Nezulcitinib 1 mg Nezulcitinib 3 mg 7 6 5Hosp, re
Slide 10: Nezulcitinib shows numerical improvement in clinical status compared to placebo through 28 days
Nezulcitinib shows numerical improvement in clinical status compared to placebo through 28 days 2 deaths on placebo and 1 death on 1 mg, but none on 3 and 10 mg groups More patients out of hospital and with no limitations by Day 28 with nezulcitinib than placebo 100 Placebo Nezulcitinib 10 mg Nezulc
Slide 11: Nezulcitinib lung-selective profile demonstrates low plasma exposure
Nezulcitinib lung-selective profile demonstrates low plasma exposure Day 7 steady-state exposures of nezulcitinib approximately dose proportional Initial loading dose on Day 1 for 1 mg and 3 mg doses in order to achieve near-steady-state exposures as quickly as possible Plasma exposures were low rel
Slide 12: Nezulcitinib showed positive trend in improving blood oxygenation versus placebo
Nezulcitinib 3 mg showed positive trend in improving blood oxygenation versus placebo as measured by S/F Ratio 150 S/F Ratio Mean SaO2/FiO2 Ratio Change From Baseline (SEM) Nezulcitinib 3 mg 50 0 -50 Placebo -100 1 234567 Day Nezulcitinib 3 mg progressed to Phase 2 Part 2 with data expected Q2 2021
Slide 13: Nezulcitinib reduces relevant systemic biomarkers
Nezulcitinib 3 mg reduces relevant systemic biomarkers 400 CRPIL-6 400 400 IL-10 400 Soluble RAGE % Difference in GM From BL (95% CI) 300 300 300 200 200 200 200 100 0 -100 41.0 -74.9 100 0 -100 -35.5 -80.2 100 0 -100 -24.0 -70.1 100 0 -100 -36.9 -83.0 -200 -200 -200 -200 Placebo Nezulcitinib 3 mg h
Slide 14: Ampreloxetine (TD-9855)
Ampreloxetine (TD-9855) Once-daily norepinephrine reuptake inhibitor to treat symptomatic neurogenic orthostatic hypotension
Slide 15: Reduced quality of life, significant caregiver burden and limited therapeutic options for symptomatic nOH
Reduced quality of life, significant caregiver burden and limited therapeutic options for symptomatic nOH patients PATIENT ~350K ~700K ~700K nOH is a symptom of MSA, PAF and PD 70–80% of MSA patients1, and POPULATIONUS patients APAC patients EU patients 30–50% of PD patients2 have nOH3 CURRENT TREAT
Slide 16: Ampreloxetine mechanism of action in nOH
Palma JA, Kaufmann H. Mov Disord Clin Pract 2017;4:298-308. NE, norepinephrine; NET, norepinephrine transporters; nOH, neurogenic orthostatic hypotension. 16 AXON TERMINAL NE DENDRITE Normal NE Release at Neurovascular Junction Systolic Blood Pressure Untreated nOH Vasodilation Normal Reduction in s
Slide 17: Ampreloxetine: potential to provide meaningful and durable symptom improvement
Baseline OHSA #1 (Orthostatic Hypotension Symptom Assessment Question 1) >4 points. Negative change indicates improvement in symptoms; improvement of 1 point is defined as the MCID (minimal clinically important difference). nOH, neurogenic orthostatic hypotension; SD, standard deviation. 17 Amprelox
Slide 18: Ampreloxetine: Phase 3 registrational program, Study 0169
Ampreloxetine: Phase 3 registrational program Randomized, double-blind, placebo-controlled study Study 0169 Key inclusion criteria: Age >30 y with symptomatic nOH with OHSA #1 score ≥4 Countries: Australia, Canada, Europe, New Zealand, Russia, UK, US Ampreloxetine Placebo N=188 Randomization Q3’21 E
Slide 19: Ampreloxetine: Phase 3 registrational program, Study 0170
Ampreloxetine: Phase 3 registrational program Placebo-controlled, randomized withdrawal study Study 0170 Key inclusion criteria: Age >30 y with symptomatic nOH with OHSA #1 score ≥4 Countries: Argentina, Australia, Canada, Europe, New Zealand, Russia, UK, US Ampreloxetine Ampreloxetine Placebo N=258
Slide 20: Ampreloxetine: Phase 3 registrational program, Study 0171
Ampreloxetine: Phase 3 registrational program 6-month safety study + 3-year optional extension Key inclusion criteria: patients who completed Study 0170 and, in investigator’s opinion, would benefit from long-term treatment with ampreloxetine Countries: Argentina, Australia, Canada, Europe, New Zeal
Slide 21: Global clinical trials are being decentralized along a continuum
Source: Theravance Biopharma Clinical Operations. 21 Global clinical trials are being decentralized along a continuum Traditional Trial Operations Decentralized Trial Site-centric operating model Burden on site resources Patient burden Patient-centric model Leverage technology for remote visits, mon
Slide 22: Ampreloxetine: potential to transform Theravance Biopharma into an independent commercial biopharma
Ampreloxetine: has the potential to transform Theravance Biopharma into an independent commercial biopharma Established disease, targeted market A strong value proposition MSA, multiple system atrophy; PD, Parkinson’s disease; QoL, quality of life; snOH, symptomatic neurogenic orthostatic hypotensio
Slide 23: Izencitinib (TD-1473/JNJ-8398)
Izencitinib (TD-1473/JNJ-8398) Oral gut-selective pan-JAK inhibitor to treat inflammatory bowel diseases
Slide 24: Need for new medicines to treat inflammatory bowel disease
Need for new medicines to treat inflammatory bowel disease PATIENT POPULATION 6.8M $16B global cases, 20171 global IBD treatment market, 20185 1.6M $31B current US patients2 US disease burden2 Current US 780K CD cases3 patients 907K UC cases4 CURRENT TREATMENT LANDSCAPE Standard of care: Biologics h
Slide 25: JAK-STAT pathway: orchestrating signaling of multiple pro-inflammatory cytokines
JAK-STAT pathway: orchestrating signaling of multiple pro-inflammatory cytokines αβγ JAK JAKJAK inhibitor STAT STAT STAT STAT STAT PInflammation NUCLEUS γc cytokines (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21) Type 1 IFNs, IL-10 family IL-6, IL-11, IL-13, IL-27, IL-31, IL-35IFNγIL-12, IL-23 EPO, TPO GM-C
Slide 26: Izencitinib: Phase 2b study in Crohn's disease
Izencitinib: Phase 2 study in Crohn’s disease Izencitinib* N=160Izencitinib Late Q4’21 Key inclusion criteria: Age ≥18 y with moderately-to-severely active CD (CDAI 220–450) with corticosteroid dependence or failure of conventional or biologic therapy Countries: Africa, Asia, Australia, EU, Middle E
Slide 27: Izencitinib: Phase 2b/3 study in ulcerative colitis
Key inclusion criteria: Age ≥18 y with moderately-to-severely active UC with corticosteroid dependence or failure of conventional or biologic therapy Countries: Africa, Asia, Australia, EU, Middle East, North America, Japan Izencitinib* Izencitinib Placebo Placebo Study 0157 N=240 Q3’21 Ph 2b Induct
Slide 28: Izencitinib: Phase 3 studies in ulcerative colitis
Izencitinib: Phase 3 studies in ulcerative colitis Key inclusion criteria: Age ≥18 y with moderately-to-severely active UC with corticosteroid dependence or failure of conventional or biologic therapy Countries: Africa, Asia, Australia, EU, Middle East, North America, Japan Izencitinib Izencitinib P
Slide 29: Izencitinib: Phase 3 long-term extension study 0164
NCT03758443 UC, ulcerative colitis. 29 Study 0164 Key inclusion criteria: Eligible patients from Ph 3 Maintenance Study of Protocol 0157 Countries: Africa, Asia, Australia, EU, Middle East, North America, Japan Izencitinib Long-term treatment 156 weeks (3 years) Endpoints Primary: –Assess the safety
Slide 30: Pan-JAK inhibitors can prevent transplant rejections
Pan-JAK inhibitors can prevent transplant rejections Noninferiority trial of tofacitinib vs cyclosporine (CsA) in kidney transplant recipients1 Tofacitinib is superior to CsA in efficacy measures Increased infection risk with tofacitinib over CsA Tofacitinib Acute Rejection First BPAR Rate (%) IF/TA
Slide 31: TD-8236: Potential first inhaled JAKi for asthma
TD-8236 Potential first inhaled JAKi for asthma
Slide 32: High medical and economic burden in uncontrolled asthma
High medical and economic burden in uncontrolled asthma PATIENT POPULATION 339M cases worldwide1 25M US cases 8% of adults 8% of children2 Moderate 1625 14 Severe* 61 Healthcare utilization3 ~$58B ~$15B US medical costs4 US asthma market (October 2020)5 CURRENT TREATMENT LANDSCAPE ICS + LABA (often
Slide 33: TD-8236: Phase 1 clinical trial design
TD-8236: Phase 1 clinical trial design Parts A & B completed September 2019; Part C enrollment completed — data reported in Q4 2020 Part C: MoA Biomarkers (Moderate-to-severe asthmatics + ICS) 4500 µg All cohorts: N=6 active/2 Placebo N=16 active/8 placebo 1500 µg 1500 µg 50 µg 150 µg T2-dominant, n
Slide 34: Biomarkers of JAK target engagement reduced in lungs of asthmatics
FeNO, fractional exhaled nitric oxide; ICS, inhaled corticosteroids; JAK, Janus kinase; PK, pharmacokinetic; PD, pharmacodynamic; pSTAT, phosphorylated signal transducer and activator of transcription; T2, type 2. 34 Biomarkers of JAK target engagement (pSTAT1 and pSTAT6) significantly reduced in lu
Slide 35: No impact of TD-8236 on the Late Asthmatic Response
No impact of TD-8236 on the Late Asthmatic Response (LAR) Significant reductions in inflammation marker (FeNO) and favorable safety and tolerability Late Asthmatic Response 150 µg 1500 µg Favors TD-8236 Favors Placebo Difference from Placebo, Liters (LS Means ± 95% CI) 0.2 Day 14Day 7 Favors Placebo
Slide 36: TD-8236 FeNO reductions consistent across Phase 1 and 2
TD-8236 FeNO reductions consistent across Phase 1 and 2 150 µg 1500 µg Phase 1 (Part B) Mild Asthmatics Difference from Placebo (%) (LS Means ± 95% CI) Phase 2 (LAC) Mild Asthmatics Phase 1 (Part C) Moderate–Severe Asthmatics + ICS Day 7Day 7Day 14Day 7 30 20 10 4.28 0 -10 -20 -30 -40 -50 -7.65 n=6
Slide 37: TD-5202: Organ-gut selective irreversible JAK3 inhibitor
TD-5202 Organ-gut selective irreversible JAK3 inhibitor to treat inflammatory intestinal diseases
Slide 38: Celiac disease has no current treatments and serious health consequences
Celiac disease has no current treatments and serious health consequences PATIENT1% 3.3M 2,3 4–4.5x >2x POPULATION Global prevalence1 US patients increase in US over past 50 y4 higher healthcare costs than controls5 CURRENT TREATMENT LANDSCAPE No approved treatment Normal Celiac STRATEGIC OPPORTUNITY
Slide 39: Celiac disease pathogenesis and localized JAK3 inhibition
Figure adapted from Jabri B and Sollid L. J Immunol 2017;198:3005-14. CD, Crohn’s disease; IE-CTL, intraepithelial cytotoxic lymphocyte; IEL, intraepithelial lymphocyte; IFN, interferon; IL, interleukin; JAK, Janus kinase; STAT, signal transducer and activator of transcription; Th1, T helper 1 cells
Slide 40: TD-5202 generally well-tolerated in healthy subjects
AE, adverse event; BID, twice daily; Cmax,ss, maximal steady-state concentration; ECG, electrocardiogram; IC50, inhibitory concentration at which 50% of JAK signaling is blocked; JAK, Janus kinase; IC50, NK, natural killer. 40 TD-5202: generally well-tolerated (single dose ≤2000 mg, multiple doses ≤
Slide 41: Inhaled ALK5i
Inhaled ALK5i Potential best-in-disease therapy for the treatment of idiopathic pulmonary fibrosis (IPF)
Slide 42: Idiopathic pulmonary fibrosis remains a fatal chronic lung disease with limited treatment options
Idiopathic pulmonary fibrosis (IPF) remains a fatal chronic lung disease with limited treatment options PATIENT POPULATION 140,000 US prevalence; currently orphan disease1,2 Profound dyspnea, unrelenting cough, impairment of activities of daily living Mortality with IPF remains high Lungs with IPF3
Slide 43: Significant opportunity remains for effective IPF treatments
Significant opportunity remains for effective IPF treatments Male Female Probability of Survival 0.6 0.4 0.2 0.0 051015 Goal To arrest disease progression with improved tolerability Mortality with IPF remains high –<50% alive 3 years after diagnosis1 1. King TE, et al. Am J Respir Crit Care Med 2001
Slide 44: Targeting the TGFβ pathway
Targeting the TGFβ pathway A core signaling pathway that drives fibrosis Normal TYPE 2 TYPE 1 ALVEOLAR EPITHELIAL CELLS (AEC) AEC damage Stimuli Genetic susceptibility Repetitive injury Fibrogenesis, proliferation TGFβ Collagen deposition MYOFIBROBLASTS SCARRING TISSUES TGFβ, transforming growth fac
Slide 45: Selectively targeting the TGFβ pathway through ALK5 inhibition
Adapted from: Neuzillet C, et al. Oncotarget 2013;5:78–94. αSMA, α-smooth muscle actin; ERK, extracellular signal-regulated kinase; IPF, idiopathic pulmonary fibrosis; JNK, c-Jun N-terminal kinase; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; Smad2/3, mothers against decapentaplegic homolog
Slide 46: ALK5i inhibition of fibroblast to myofibroblast transition
ALK5i, transforming growth factor β receptor I kinase inhibitor; αSMA, α-smooth muscle actin; FMT, fibroblast to myofibroblast transition. 46 % inhibition of αSMA FMT Negative control SMA expressed ALK5i treated SMA reduced Reference Standard ALK5i 150 100 50 0 -9 -8 -7 Log [M] -6 -5
Slide 47: ALK5i compared with nintedanib and pirfenidone
https://www.tga.gov.au/sites/default/files/auspar-nintedanib-esilate-160208.pdf. Ogura T, et al. Eur Respir J. 2015;45:1382-92. Cmax, maximal concentration; FMT, fibroblast to myofibroblast transition; IC50, half maximal inhibitory concentration. 47 Clinical Cmax Unbound1,2 Nintedanib IC50 Pirfenido
Slide 48: Minimizing systemic inhibition of a cytokine essential for homeostasis
Modified from: Akhurst RJ, Hata A. Nat Rev Drug Discov 2012;11:790-811. ALK5i, TGFβ receptor I kinase inhibitor; TGFβ, transforming growth factor β. 48 Minimizing systemic inhibition of a cytokine essential for homeostasis Inhaled ALK5i Maintaining key systemic regulatory roles of TGFβ Wound repair
Slide 49: Ocular JAKi
Ocular JAKi Potential best-in-disease, pan-JAK inhibitor with long-acting ocular anti-inflammatory activity
Slide 50: Diabetic macular edema patient population and treatment landscape
140% PATIENT million#1 cause of higher direct and indirect healthcare costs blindness in US prevalence1 diabetes2 in patients with DME vs diabetics without ocular disease3 Normal vision Vision with DME CURRENT TREATMENT 1st Anti-VEGF treatments Most patients have suboptimal response LANDSCAPE 2nd In
Slide 51: DME disease pathway and anti-VEGF limitations
1. Gonzalez VH, et al. Am J Ophthalmol 2016;172:72-79. DME, diabetic macular edema; VEGF, vascular endothelial growth factor. 51 Hyperglycemia Disruption of blood-retinal barrier Retinal capillary damage VEGF Inflammatory cytokines Intraocular anti-VEGF agents One third do not respond to anti-VEGF w
Slide 52: Unmet need for an anti-inflammatory drug: opportunity for eye-selective JAK inhibition
Unmet need for an anti-inflammatory drug: opportunity for eye-selective JAK inhibition 1.25 Effect of anti-VEGFEffect of Steroids VEGF IL-6 IP-10 MCP-1 Normalized Protein Level 1.00 0.75 0.75 0.50 0.50 0.25 0.25 0.00 0.00 VEGFIL-6IP-10MCP-1 Adapted from Sohn HJ, et. al. Am J Ophthalmol 2011; 152:686
Slide 53: TD-Eye JAKi inhibits IL-6 and interferon signaling
DME, diabetic macular edema; IL-6, interleukin-6; IP-10, interferon γ-induced protein 10; JAK, Janus kinase; MCP-1, monocyte chemoattractant protein-1; pSTAT, phosphorylated signal transducer and activator of transcription; Tyk, tyrosine kinase; VEGF, vascular endothelial growth factor. 53 IL-6 Inte
Slide 54: Single intravitreal injection of TD-Eye JAKi in rabbits
JAK, Janus kinase. 54 STAT STAT STAT STAT STAT Compound concentration (g/mL or g/g ) α βγ JAK JAK JAKi P P P P NUCLEUS Single intravitreal injection of TD-Eye JAKi in Rabbits 1000 100 10 Vitreous humor (depot) 1 Retina 0.1 0.01 0.001 0.0001 Plasma 0.00001 0.000001 0123 Time (months)