Egetis Therapeutics Ab · OMXSTO:EGTX
Egetis Therapeutics Ab — PledPharma — Investor Day (March 2019)
138 slides from Egetis Therapeutics Ab's investor day presentation, Mar 26, 2019
Slide 1: PledPharma Capital Markets Day
PledPharma Capital Markets Day 26th March, 2019 1|
Slide 2: Disclaimer
Disclaimer IMPORTANT: You must read the following before continuing. The following applies to this document, the oral presentation of the information in this document by PledPharma AB (the “Company”) or any person on behalf of the Company, and any question-and-answer session that follows the oral pr
Slide 3: Agenda
Agenda 1. Introduction, Company overview and drug candidates in development 2. PledOx® in Chemotherapy Induced Peripheral Neuropathy (CIPN) a. Unmet medical need b. Development of PledOx® in CIPN with oxaliplatin c. Commercial opportunity in CIPN with oxaliplatin d. Indication expansion – CIPN with
Slide 4: Todays speakers and moderator
Todays speakers and moderator Nicklas Westerholm Prof Per Pfeiffer, PhD CEO Prof. Pfeiffer, MD, PhD, currently Professor at the University of Southern Denmark, Head of Clinical Research Unit and the Digestive Oncology Unit at Took office in June 2017. Previously worked in the AstraZeneca Group since
Slide 5: PledPharma is an innovative, unique and integrated pharmaceutical drug development company
PledPharma is an innovative, unique and integrated pharmaceutical drug development company, focusing on improving treatments for diseases with substantial unmet medical need. The company’s most advanced project PledOx® is being developed to reduce nerve damage associated with chemotherapy. A global
Slide 6: Transformation into an integrated drug development company 2017/18
Transformation into an integrated drug development company 2017/18 with proven track-record of bringing new products to market… Scientific Advisory Board Science Medical Clinical Finance Operations Business Capital Market Regulatory Development Investor Relations CMC New or strengthened capabilities
Slide 7: Executive summary - PledOx
Executive summary - PledOx® Prevents nerve damage caused by chemotherapy treatment Phase III unmet medical need with No approved drug for ✓✓ Huge prevention or treatment of Chemotherapy Induced Peripheral Neuropathy ✓✓ Global phase III studies approved in US, EU and JPN with recruitment ongoing - fi
Slide 8: Executive summary - Aladote
Executive summary - Aladote® Prevents acute liver injury caused by paracetamol (acetaminophen) poisoning Phase II Phase II ✓ Paracetamol (acetaminophen) poisoning is one of ✓ the most common overdose ✓ ✓ No adequate treatment for high risk patients ✓ Successful results from a Phase Ib/IIa study in ✓
Slide 9: Supported by a robust IP portfolio
Supported by a robust IP portfolio with composition of matter protection until end-2032 • New chemical entity with composition of matter, manufacturing process and broad therapeutic use of calmangafodipir, with US, EU, China, Russia and Japan Patent family/ approved, end-2032 Patent applications / •
Slide 10: PledOx in Chemotherapy Induced Peripheral Neuropathy (CIPN)
2. PledOx® in Chemotherapy Induced Peripheral Neuropathy (CIPN) a. Unmet medical need b. Development of PledOx ® in CIPN with oxaliplatin c. Commercial opportunity in CIPN with oxaliplatin d. Indication expansion – CIPN with taxanes Phase III 10 |
Slide 11: Colorectal cancer
Colorectal cancer When we use oxaliplatin there is a medical need to prevent CIPN Per Pfeiffer, MD, PhD Professor in Clinical Oncology Dept of Oncology, OUH, Odense, Denmark Institute of Clinical Research, USD, Odense, Denmark 11
Slide 12: Colorectal cancer - Global cancer data
Colorectal cancer - GLOBAL CANCER DATA 12
Slide 13: Colorectal cancer - Global cancer data
Colorectal cancer GLOBAL CANCER DATA 13
Slide 14: Cancer today
owe ees CANCER TODAY The five most commonly diagnosed cancer types Percentages of new cancer cases and cancer deaths worldwide in 2018 tung C1) u oe hO14 14 oe tote tt eteterete aE ees taaoe eee! (2.094 million Breast ar deaths o FORGE 2] Colorectal $Oet44 He THS RE TE 9.2% of all new cases of all c
Slide 15: Colorectal cancer: cases vs pathological stage
Colorectal cancer Number of cases vs pathological stage - Denmark Total % Stage 1 +2 2,750 55 Stage 3, lymph node positive 1,500 30 Stage 4, metastatic disease 750 15 Total ~ 5,000 15
Slide 16: Colorectal cancer: cases in Denmark
Colorectal cancer Number of cases in Denmark Total Denmark, 2012-16 5,000 Denmark, 2032-36 8,200 Increase by 64% Similar increase globally 16
Slide 17: Basic oncological concept
Basic oncological concept Therapy with Therapy with curative intent palliative intent Non-curable Terminal Death Months/years Weeks/days Diagnosis Adjuvant oncological therapy Metastatic oncological therapy 17
Slide 18: Adjuvant therapy - definition
Adjuvant therapy - definition • Adjuvant therapy = supplementary treatment for (apparently) radically treated patients (often after surgery) • No signs of residual disease but high risk of recurrence (microscopic residual disease, locally or distant) • Aim is cure (prolong survival) 18
Slide 19: Colorectal cancer: stage vs cure
Colorectal cancer Stage vs cure Total % 5 year OS (%) Stage 1 1,250 25 75 Stage 2 1,500 30 65 Stage 3, lymph node positive 1,500 30 50 Stage 4, metastatic disease 750 15 < 10 19
Slide 20: Adjuvant treatment in colon cancer stage III
Adjuvant treatment in colon cancer stage III Lessons learned from randomized trials One giant leap for mankind • 12 months 5-FU (iv) increase 5 year OS Other minor steps • 6 months = 12 months Second large step forward - oxaliplatin • 5-FU + oxaliplatin (FOLFOX) better than 5-FU Moertel, NEJM 1990;
Slide 21: Efficacy of adjuvant therapy
Efficacy of adjuvant therapy Colorectal cancer stage 3 (lymph node metastasis) OS % Combination (FOLFOX) 100 5-FU Surgery 80 60 65% 60% 50% 40 20 0 1 2 3 4 5 years 21
Slide 22: Adjuvant therapy in CRC
Adjuvant therapy in CRC • Since 2004, FOLFOX has been standard adjuvant chemotherapy in patients with stage 3 colon cancer (lymph node +). • 3 randomized trials showed an improvement in overall survival • Accordingly, 6 months of FOLFOX or CapOx became the standard After IDEA (6 large phase III, 12,
Slide 23: IDEA - neurotoxicity after 3 and 6 months
IDEA – neurotoxicity (CIPN) after 3 and 6 months FOLFOX CapOx G1 G2 G3-4 G1-4 p G1 G2 G3-4 G1-4 p 3 mo 83 14 17% 3 100 0.001 86 12 15% 3 100 0.001 6 mo 52 32 48% 16 100 55 36 45% 9 100 Grothey et al, NEJM 2018 Chemo-induced peripheral neuropathy (CIPN)
Slide 24: Palliative therapy
Palliative therapy Survival Palliative therapy No therapy Palliative therapy Tid 24
Slide 25: Incremental steps in therapy improved overall survival
Small incremental steps and sequential use of many lines of therapy have led to major overall survival improvements in the last 15 years PS 0 PS 1 PS 2 Age 2000 FLv 41 45 13 61 Saltz 2000 IFL 39 46 15 62 Goldberg 2004 FOLFOX 50 43 5 61 Hurwitz 2004 IFL + Bev 58 41 0 60 Falcone 2007 FOLFOXIRI 61 37 2
Slide 26: Systemic Therapy in mCRC
Systemic Therapy in mCRC • 2 drugs better than 1 • At least 50% of CRC patients will receive oxaliplatin-based • FOLFOX standard regimens in mCRC • All available drugs should be used at some time Van Cutsem et al, Ann Oncol 2016 (ESMO guidelines)
Slide 27: Neuropathy
Neuropathy • In general the symptoms of CIPN are sensory typically located in the hands and feet • Tingling • Numbness • Pain • Motor symptoms may occur • Weakness, muscle cramps • Patients with neuropathy report worse quality of life • Future studies should focus on prevention of CIPN Mols et al. J
Slide 28: Oxaliplatin-Induced CIPN - Acute
Oxaliplatin-Induced CIPN - Acute • Acute form of CIPN (not seen with other platinums) characterized by peripheral nerve hyper-excitability triggered by exposure to cold • distal limb paraesthesias • sensory symptoms in the fingertips and toes • stocking and glove distribution • paraesthesias in the
Slide 29: Oxaliplatin-Induced CIPN - Chronic
Oxaliplatin-Induced CIPN - Chronic • Chronic form of CIPN characterized by • sensory paresthesias or dysesthesias • most often located in the extremities • persists between cycles • The risk of severe neuropathy is dose dependent • 10 - 20% at cumulative doses of 750 – 850 mg/m2 • 50% of patients re
Slide 30: Development of neurotoxicity over time
Development of neurotoxicity over time - Persist for years HANDS FEET Numbness or tingling Discomfort Data from SCOT study - FACT/GOG-Ntx
Slide 31: Use of oxaliplatin in CRC
Use of oxaliplatin in CRC • How many patients will receive oxaliplatin? • At least 20% will receive adjuvant oxaliplatin • At least 30% of patients with mCRC will receive oxaliplatin for 1st line therapy • 20% of patients with mCRC will receive oxaliplatin as 2nd line therapy • 80% of all patients w
Slide 32: Conclusions
Conclusions • CIPN is a major problem in colorectal cancer • The use of oxaliplatin will continue for many years, presently no alternative • CIPN percist for years and reduce quality of life • Medical need to prevent CIPN, so far no effective treatment
Slide 33: Video
VIDEO https://vimeo.com/323561992 33 |
Slide 34: PledOx in Chemotherapy Induced Peripheral Neuropathy (CIPN)
2. PledOx® in Chemotherapy Induced Peripheral Neuropathy (CIPN) a. Unmet medical need b. Development of PledOx® in CIPN with oxaliplatin c. Commercial opportunity in CIPN with oxaliplatin d. Indication expansion – CIPN with taxanes Phase III 34 |
Slide 35: PledOx drives value by...
PledOx drives value by… Development in Expansion to Commercialization CIPN/oxaliplatin CIPN/taxanes by strategic partnerships 35 |
Slide 36: Standard treatment of Colorectal Cancer cause CIPN
Standard treatment of Colorectal Cancer cause CIPN Numbness and Tingling Oxaliplatin is associated Burning pain with dose limiting and Cold sensitivity during oxaliplatin treatment debilitating toxicities Problems with sensation Impacts balance with risk of falling 40-60 % of patients get Challenge
Slide 37: PledOx Target Product Profile in CIPN/oxaliplatin
PledOx® Target Product Profile in CIPN/oxaliplatin - Prevention of CIPN without negative impact on the efficacy of chemotherapy Indication: Prevention of oxaliplatin-induced chronic peripheral neuropathy Patients treated with PledOx® report… Efficacy Safety & Tolerability … less numbness, tingling a
Slide 38: Mechanisms underlying CIPN are diverse and complex
Mechanisms underlying CIPN are diverse and complex Platinum compounds Taxanes Vinca alkaloids Dorsal root ganglion Thalidomide Taxanes Vinca alkaloids Microtubules Bortezomib Platinum compounds Mitochondria Taxanes Bortezomib Ion channels Oxaliplatin Bortezomib Myelin Thalidomide Blood vessels Vinca
Slide 39: Mitochondrial homeostasis maintained by MnSOD
In healthy cells, mitochondrial homeostasis is maintained by MnSOD • Superoxide is generated as a by-product of • MnSOD is an enzyme catalysing the energy production in the mitochondria degradation of superoxide 39 |
Slide 40: Chemotherapy leads to mitochondrial dysfunction and CIPN
Chemotherapy leads to mitochondrial dysfunction and CIPN • Oxaliplatin binds to mtDNA, leading to inefficient • More superoxide radicals drive harmful nitration energy generation and more superoxide and lipid peroxidation pathways 40 |
Slide 41: PledOx prevents mitochondrial dysfunction
PledOx® prevents mitochondrial dysfunction • Being a MnSOD mimetic, PledOx® supports • PledOx® binds free iron, inhibiting the Fenton superoxide regulation reaction and thus lipid peroxidation 41 |
Slide 42: Key neuropathy efficacy endpoints in Phase IIb PLIANT study
Summary of key neuropathy efficacy endpoints in Phase IIb PLIANT study PLIANT study: 173 patients with metastatic CRC treated with PledOx® or placebo together with chemotherapy FOLFOX (oxaliplatin) Type of CIPN Dose vs Placebo 2 µmol/kg 5 µmol/kg 2+5+10 µmol/kg assessment (Study Part†) (2a+2b) (2b)
Slide 43: PFS and OS in Phase IIb PLIANT study
Progression free survival (PFS) and Overall survival (OS) in Phase IIb PLIANT study No apparent negative effect on the efficacy of the chemotherapy treatment 43 |
Slide 44: PledOx Global Phase III program - the POLAR studies
PledOx® Global Phase III program – the POLAR studies Scientific Advisory Board POLAR-M (US, EU & Asia) Top line N=140 PledOx 5 umol/kg results + FOLFOX N=140 PledOx 2 umol/kg R + FOLFOX Primary PFS PFS Endpoint OS (CIPN) OS OS N=140 Placebo + FOLFOX t=0 EoT1 9 months 1 years 2 years 3 years POLAR-A
Slide 45: Design of POLAR program presented at ASCO GI
Design of POLAR program presented at Gastrointestinal Cancer Symposium (ASCO GI), San Fransisco, Jan, 2019 45 |
Slide 46: POLAR program - a global program across three regions
POLAR program – a global program across three regions US 1 country Europe 25 sites 7 countries Asia 60 sites 4 countries 21 sites 46 |
Slide 47: Basis for evaluation of CIPN in the POLAR program
The basis for evaluation of CIPN in the POLAR program Primary Endpoint Description FACT/GOG-NTx-4 4-question PRO instrument addressing key CIPN symptoms of numbness, tingling and discomfort in hands and feet Secondary & Exploratory Description Endpoints FACT/GOG-NTx-13 13-question PRO instrument add
Slide 48: Primary endpoint based on FACT/GOG-Ntx-4
Primary endpoint based on FACT/GOG-Ntx-4 is clinically relevant and interpretable Primary endpoint targeting a percentage of patients with 3 or 4 in any of the NTx-4 questions is clinically interpretable. Broad consensus on clinical relevance of the two response options 3 and 4. 48 | Throughout the
Slide 49: FACT/GOG-NTx-4 captures chronic CIPN symptoms
FACT/GOG-NTx-4 captures the majority of relevant chronic CIPN symptoms Note: “A” in Figure refers to the questions in Ntx-4 (1) Kopec et.al (2006) Validation of a self-reported neurotoxicity scale in patients with operable colon cancer receiving oxaliplatin 49 | (2) Huang et al. (2007) Validation an
Slide 50: SCOT study confirms sensitivity of FACT/GOG-Ntx-4
Results in SCOT study confirm the sensitivity of FACT/GOG- Ntx-4 in CRC patients treated with oxaliplatin HANDS FEET Numbness or tingling Discomfort 50 |
Slide 51: Other endpoints build a robust characterization of efficacy
Other endpoints build a robust characterization of efficacy Graduated tuning fork Grooved PEG board Cold sensitivity questionnaire (objective measure of chronic CIPN) (functional measure of chronic CIPN) (measure of acute CIPN symptoms during chemotherapy) EQ-5D-5L Numeric rating scale of Pain Quali
Slide 52: PledOx - development timeline
PledOx® – development timeline • ✓ Results Ph.1 Study JPN • ✓ Asian expansion of POLAR studies • POLAR CTAs approved in Top line results of ✓ US,JPN, UK, Spain, Italy, primary endpoint 2018 France & Belgium 2020 2018 (CIPN) and key 2022 First launch • First Patient In (POLAR safety endpoints (1 ✓ st
Slide 53: PledOx in Chemotherapy Induced Peripheral Neuropathy (CIPN)
2. PledOx® in Chemotherapy Induced Peripheral Neuropathy (CIPN) a. Unmet medical need b. Development of PledOx® in CIPN with oxaliplatin c. Commercial opportunity in CIPN with oxaliplatin d. Indication expansion – CIPN with taxanes Phase III 53 |
Slide 54: Epidemiology - Colorectal cancer
Epidemiology - Colorectal cancer (CRC) is the third most commonly diagnosed cancer “…and its burden is expected to increase by 60% by 2030” 54 | BMJ: Arnold M, et al. Gut 2016
Slide 55: Colorectal Cancer - Common treatment approaches
Colorectal Cancer – Common treatment approaches Stage I & II Stage III (adjuvant) Stage IV (metastatic) • Surgery +/- RT • Surgery + systemic therapy • Systemic therapy +/- RT +/- RT • Surgery + systemic therapy • Surgery + systemic therapy +/- RT (high-risk patients) +/- RT (resectable disease) In
Slide 56: CRC Stage IV (and III) clinical development landscape
CRC Stage IV (and III) Phase 3 Clinical development landscape 1L mCRC KEYTRUDA [pembrolizumab] TECENTRIQ [atezolizumab] (PD-1; Merck) (PD-L1; Roche) • Active, Not Recruiting: 1L dMMR or MSI-H mCRC; n=308 (May 2018) • Recruiting: 1L dMMR or MSI-H mCRC • Primary completion: August 2019 • Primary compl
Slide 57: CIPN - Competitive landscape
Chemotherapy Induced Peripheral Neuropathy - Competitive landscape COMMON TREATMENT CIPN EMERGING TREATMENTS APPROACHES FOR CIPN Prevention MN-166 E-52862 (Inflammation target) (Sigma-1 Receptor) No approved drug for prevention or Medicinova PledOx® treatment of Chemotherapy Induced Mundipharma Ph I
Slide 58: Market Research, Pricing & Reimbursement
PledOx® – Market Research, Pricing & Reimbursement CIPN market research with US and EU Oncologists and Payers to gain insight into Unmet needs in the management of CIPN, validate Target Product Profile and Pricing & Reimbursement CIPN Background TPP & IDI Guide Testing Team Expertise Development Eff
Slide 59: Physician Insight - confirms unmet need and verifies TPP
Physician Insight – confirms the unmet medical need and verifies TPP • All Oncologists interviewed stated CIPN has a major impact on the appropriate treatment of patients with various forms of cancer • Of the various chemotherapeutic regimens available, oxaliplatin was identified as one of the major
Slide 60: Payer Insight & combined EMA Scientific & Payer Advice
Payer Insight & combined EMA Scientific & Payer Advice - clarifies data collection in Phase 3 to build robust pricing arguments • With PledOx being first-in-class • Important to provide information of disease burden, unmet need, and costs of not treating or inadequately treating CIPN ‘You’re pushing
Slide 61: CIPN associated with high health care costs in the US
CIPN associated with high health care costs in the US Increased health care costs for CIPN patient: • Privately insured administrative claims database study (Ingenix Employer db, 4.7 million people) 17,344 USD • Patients with qualifying tumors, and claims for during first year after chemotherapy che
Slide 62: PledOx - Commercial potential in CRC patients
PledOx® – Commercial potential in CRC patients ~700k ~225k ~1.5m Drug Number of oxaliplatin Number of oxaliplatin treated CRC patients treated patients in cycles in US, EU5 & in US, EU5 & US, EU5 & JPN/ /year JPN /year JPN/year COGS Pricing assumption assumption +60% 1,000 Low single digit in CRC in
Slide 63: PledOx Summary and Opportunities in CIPN with oxaliplatin
PledOx® Summary and Opportunities in CIPN with oxaliplatin PREVENTS NERVE DAMAGE CAUSED BY OXALIPLATIN TREATMENT DEVELOPMENT STATUS BUSINESS OPPORTUNITY • Phase II data provide reason to believe in Phase III • CRC 3rd most diagnosed cancer • Global Phase III POLAR studies approved in US, EU • ~1.5M
Slide 64: PledOx in Chemotherapy Induced Peripheral Neuropathy (CIPN)
2. PledOx® in Chemotherapy Induced Peripheral Neuropathy (CIPN) a. Unmet medical need b. Development of PledOx® in CIPN with oxaliplatin c. Commercial opportunity in CIPN with oxaliplatin d. Indication expansion – CIPN with taxanes 64 |
Slide 65: PledOx drives value by...
PledOx drives value by… Development in Expansion to Commercialization CIPN/oxaliplatin CIPN/taxanes by strategic partnerships 65 |
Slide 66: CIPN/taxanes a strategic opportunity for PledOx
CIPN/taxanes a strategic opportunity for PledOx® NEW PRODUCTS EXISTING PRODUCTS diversification market expansion • Good strategic fit in PledPharma portfolio NEW MARKETS Aladote PledOx • Most attractive commercial opportunity POD CIPN taxanes with huge unmet medical need • Safety database generated
Slide 67: Unmet need for CIPN with taxanes similar to oxaliplatin
Unmet medical need for CIPN with taxanes is similar to that for oxaliplatin Oxaliplatin Paclitaxel • Similar percentage of patients • Similar type of chronic CIPN symptoms are experience CIPN with oxaliplatin experienced, i.e numbness, tingling in and paclitaxel(1) hands and feet(2) • Coasting prono
Slide 68: Mitochondrial dysfunction contributes to CIPN by taxanes
Mitochondrial dysfunction a contributing factor to CIPN by taxanes give reasons to believe in PledOx® Platinum compounds Taxanes Vinca alkaloids Dorsal root ganglion Thalidomide Taxanes Vinca alkaloids Microtubules Bortezomib Platinum compounds Mitochondria Taxanes Bortezomib Ion channels Oxaliplati
Slide 69: Attractive commercial opportunity in CIPN/taxanes
Attractive commercial opportunity in CIPN/taxanes Market size Use of platinum-based chemotherapy by tumor type Use of taxane-based chemotherapy by tumor type Competitive landscape No competitor clinical trials registred on clinicaltrials.gov IMS Health (2015); US data 69 |
Slide 70: Next steps in development path for CIPN/taxanes
Next steps in development path for CIPN/taxanes Regulatory Pre-clinical studies interactions (2019) (2019-2020) Clarify development path, including In collaboration with Prof Cavaletti, Univ Milano-Biocca a) Requirements for clinical efficacy & safety data for sNDA/MAA – how to 1) Preliminary dose-r
Slide 71: PledOx drives value by...
PledOx drives value by… Development in Expansion to Commercialization CIPN/oxaliplatin CIPN/taxanes by strategic partnerships 71 |
Slide 72: PledPharma Capital Markets Day
PledPharma Capital Markets Day 26th March, 2019 72 |
Slide 73: Agenda
Agenda 1. Introduction, Company overview and drug candidates in development 2. PledOx® in Chemotherapy Induced Peripheral Neuropathy (CIPN) a. Unmet medical need b. Development of PledOx® in CIPN with oxaliplatin c. Commercial opportunity in CIPN with oxaliplatin d. Indication expansion – CIPN with
Slide 74: Video
VIDEO https://vimeo.com/325159064 Phase II 74 |
Slide 75: Aladote in Paracetamol Overdose (POD)
3. Aladote in Paracetamol Overdose (POD) a. Unmet medical need b. Aladote® proof of principle study results c. Development of Aladote to prevent acute liver injury caused by POD d. Commercial opportunity in POD Phase II 75 |
Slide 76: Paracetamol overdose: epidemiology and management
Paracetamol overdose: - epidemiology and management - results from Aladote POP study Dr James Dear University of Edinburgh
Slide 77: Paracetamol is the world's most used drug
Paracetamol is the world’s most used drug
Slide 78: Hospital Episode Statistics 2017/18
Hospital Episode Statistics 2017/18 Emergency admissions Reason for admission (England) Paracetamol overdose 41,898 Fracture of neck of femur 47,334 Pulmonary embolism 29,541 Appendicitis 44,149 Acute pancreatitis 42,672
Slide 79: Epidemiology in UK every year
Epidemiology in UK every year: • 100,000 hospital attendances per year • 50,000 emergency admission for treatment • At least 12,500 lack an effective treatment (25%) • 112,000 hospital bed days occupied • 350 people registered for liver transplant • 225 deaths
Slide 80: POD Healthcare costs in US
POD Healthcare costs in US: • Healthcare costs were $1bn in 2010 • Average inpatient length of stay was 3.1 Days • Liver Transplant Costs between $125k - $473k
Slide 81: Problem is liver damage
Problem is liver damage
Slide 82: Mechanism of paracetamol hepatotoxicity
Mechanism of paracetamol hepatotoxicity Oxidation by cytochrome P450 enzymes — a minor route in therapeutic doses \ Paracetamol Conjugation — the major route of metabolism in therapeutic dose Paracetamol conjugates NAPQI Reacts with SH- od group in CL glutathione NAPQI conjugate
Slide 83: Mechanism of paracetamol hepatotoxicity
Mechanism of paracetamol hepatotoxicity In overdose, oxidation by Excess NAPQI binds to SH- groups in structural protein cytochrome P450s becomes important Paracetamol Conjugation — saturated in | overdose Paracetamol conjugates NAPQI conjugate | =| Glutathione supply exhausted Acetylcysteine
Slide 84: Who gets treatment after overdose?
PARACETAMOL QUESTION 1: Who gets treatment after overdose? Hugo Dear
Slide 85: Risk assessment
Risk assessment BJCP 2009 68 260 - 268 • Majority of patients present soon after OD before liver injury can be diagnosed using current tests such as ALT • Therefore, use surrogate marker • Blood paracetamol concentration
Slide 86: Risk assessment - paracetamol concentration
Risk assessment – paracetamol concentration UK . . .
Slide 87: Early, diagnostic markers
Early, diagnostic markers … Paracetamol OD ... Now … Presenting Risk stratify Detect cell death complaint time History of Timed paracetamol Liver enzymes overdose concentration ALT etc
Slide 88: Early, diagnostic markers: new marker
Early, diagnostic markers … Paracetamol OD ... New marker Presenting Risk stratify Detect cell death complaint time History of Timed paracetamol Liver enzymes overdose concentration ALT etc
Slide 89: Biomarker
Biomarker microRNA-122 (miR-122) Hepatology 2011: no of citations 364
Slide 90: Mechanism of Cell Death - Biomarkers
Mechanism of Cell Death - Biomarkers J Hepatol 2012: no of citations 223
Slide 91: Biomarkers on presentation in MAPP and BIOPAR
NORMAL ALT MAPP N=875 ON PRESENTATION BIOPAR N=176 NS NS NS NS Presentation APAP (mg/L) 1000 1000 Presentation ALT (U/l) 100 ALT 100 miR-122 and K18 are higher in patients who Paracetamol 10 10 develop ALI 1 1 0.1 0.1 <ULN >2xULN <ULN >2xULN Study <ULN >2xULNROC-AUC <ULN >2xULN P value Sens at 95% S
Slide 92: New markers correctly identified life threatening hepatotoxicity
CASE REPORT: 25 year old male Single overdose of 35g paracetamol at 02:30 (timing supported by Facebook message) Assessed 4.5h after OD No risk factors for hepatotoxicity. Paracetamol level 107 mg/L (below nomogram) Normal biochemical evidence of liver injury Assessed by senior doctor and not treate
Slide 93: New markers correctly identified life threatening hepatotoxicity
CASE REPORT: 25 year old male Single overdose of 35g paracetamol at 02:30 (timing supported by Facebook message) Assessed 4.5h after OD No risk factors for hepatotoxicity. Paracetamol level 107 mg/L (below nomogram) Normal biochemical evidence of liver injury Assessed by senior doctor and not treate
Slide 94: Case report: 25 year old male
CASE REPORT: 25 year old male Single overdose of 35g paracetamol at 02:30 (timing supported by Facebook message) Assessed 4.5h after OD No risk factors for hepatotoxicity. Paracetamol level 107 mg/L (below nomogram) Normal biochemical evidence of liver injury Assessed by senior doctor and not treate
Slide 95: Regulatory endorsement for miR-122 and K18 as a DILI biomarker
Qualification as tool in drug development Regulatory endorsement for miR-122 and K18 as a DILI biomarker
Slide 96: How should patients be treated?
PARACETAMOL QUESTION 2: How should patients be treated?
Slide 97: Acetylcysteine literature
Pediatrics. 1978 Nov,62(5 Pt 2 Suppl):898-903. Acetaminophen Overdose: Incidence, Diagnosis, and Management in 416 Patients Barry H. Rumack, M.D., and Robert G. Peterson, M.D., Ph.D. From the Departments of Pediatrics, Medicine, and Pharmacology. and the Division of Clinical Pharmacol- ogy. Universi
Slide 98: Acetylcysteine literature and adverse reactions
Pediatrics. 1978 Nov,62(5 Pt 2 Suppl):898-903. Acetaminophen Overdose: Incidence, Diagnosis, and Management in 416 Patients Barry H. Rumack, M.D., and Robert G. Peterson, M.D., Ph.D. From the Departments of Pediatrics, Medicine, and Pharmacology. and the Division of Clinical Pharmacol- ogy. Universi
Slide 99: Standard Regimen vs SNAP Regimen
Standard Regimen Blood sampling 300 mg/kg over 21h 20h Discontinue acetylcysteine if: Bag 1 Bag 2 Bag 3 150mg/kg 50mg/kg 100mg/kg INR 1.3 or less over 1h over 4h over 16h and ALT <100 U/L and ALT not doubled SNAP Regimen Blood sampling 10h Blood sampling 20h 300 mg/kg over 12h INR1.3 or less Bag 1 B
Slide 100: Standard Regimen vs SNAP Regimen
Standard Regimen Blood sampling 300 mg/kg over 21h 20h Discontinue acetylcysteine if: Bag 1 Bag 2 Bag 3 150mg/kg 50mg/kg 100mg/kg INR 1.3 or less over 1h over 4h over 16h and ALT <100 U/L and ALT not doubled SNAP Regimen Blood sampling 10h Blood sampling 20h 300 mg/kg over 12h INR > 1.3 Bag 1 Bag 2
Slide 101: Real clinical case
Real clinical case Mr AB 25 year old man Suffers from depression Took 70 paracetamol tablets (35g – 500mg/kg body weight) around 20 hours ago Wants to die but happy to stay in hospital and receive treatment Agrees to take part in a clinical study (MAPP2 Study) Blood results: ALT 3340 U/L (ULN 50 U/L
Slide 102: Results from first clinical study with Aladote
Results from first clinical study with Aladote
Slide 103: Design of Aladote clinical study
Design of Aladote clinical study Cohort 3 Design Aladote 10 µmol/kg add-on to NAC (N=6) • Single ascending dose study in 3 dosing cohorts of 8 NAC alone patients (N=24) as add-on to (N=2) NAC regime Cohort 2 Aladote 5 µmol/kg Treatment period 90 days Patients add-on to NAC (N=6) (up to 22h) follow-u
Slide 104: Aladote for Overdose of Paracetamol (POP) study
Aladote (Calmangafodipir) for Overdose of Paracetamol (POP) (NCT03177395) Bag 1 NAC Bag 2 NAC 100mg/kg over 2h 200mg/kg over 10h T(h) 0 2 10 20 Blood sampling Blood sampling
Slide 105: Aladote for Overdose of Paracetamol (POP) study
Aladote (Calmangafodipir) for Overdose of Paracetamol (POP) (NCT03177395) Aladote / nothing Bag 1 NAC Bag 2 NAC 100mg/kg over 2h 200mg/kg over 10h T(h) 0 2 2.5 10 20 Blood sampling Blood sampling Blood sampling Adverse events Adverse events Adverse events Vital signs Vital signs Vital signs ECG ECG
Slide 106: Primary outcome
Primary outcome Event NAC alone NAC + NAC + NAC + 2 μmol/kg 5 μmol/kg 10 μmol/kg Aladote Aladote Aladote Any adverse 6 (100%) 6 (100%) 6 (100%) 6 (100%) event Any serious 2 (33%) 4 (67%) 2 (33%) 3 (50%) adverse event Serious 1 (17%) 1 (17%) 1 (17%) 2 (33%) adverse event starting within 7 days No AE
Slide 107: Aladote represents a new treatment for patients like Mr AB
Real clinical case Mr AB 25 year old man Suffers from depression Took 70 paracetamol tablets Aladote represents a new (35g – 500mg/kg body weight) around 20 hours ago Wants to die but happy to stay in hospital and receive treatment treatment Agrees forstudy to take part in a clinical patients (MAPP2
Slide 108: Key points
KEY POINTS • Paracetamol overdose is very common • Current treatment is not effective in at least a quarter of patients (12,500/year in UK) • We can deliver clinical trials in this clinical space galvanised by new biomarkers • Aladote is safe and may reduce liver injury when added to standard of car
Slide 109: Aladote in Paracetamol Overdose (POD)
3. Aladote® in Paracetamol Overdose (POD) a. Unmet medical need b. Aladote® proof of principle study results c. Development of Aladote to prevent acute liver injury caused by POD d. Commercial opportunity in POD Phase II 109 |
Slide 110: Paracetamol poisoning: no adequate treatment for high risk patients
Paracetamol (acetaminophen) poisoning … no adequate treatment for high risk patients 19bn units of paracetamol packages sold every year in the US. Minimum toxic dose of paracetamol in adults – only 89,000 cases of paracetamol 7.5g overdose in US per year 105,000 cases of paracetamol ~50 % of overdos
Slide 111: Aladote Target Product Profile
Aladote Target Product Profile in high-risk paracetamol overdose patients Indication: To reduce hepatic injury in high-risk patients Patients treated with Aladote (in combination with NAC) has … Efficacy Safety & Tolerability … lower risk of requiring additional … similar adverse event profile as ba
Slide 112: Early and late presenters are both at high risk of liver damage
Early presenters with high paracetamol levels and late presenters are both at high risk of liver damage Paracetamol level Number of % of pts with % of pts with (by nomogram line) patients ALT>150 ALT>1000 0-100 70 7% 4% 101-150 195 7% 4% 151-200 149 9% 5% 201-300 186 12% 6% 301-500 82 18% 10% >500 4
Slide 113: Aladote potential for reducing APAP-induced acute liver injury
Aladote® has potential for reducing APAP-induced acute liver injury in high risk patients • APAP overdose leads to formation of the toxic metabolite NAPQI • In the metabolic phase, this leads to depletion of reduced glutathione (GSH) and binding of NAPQI to liver proteins ▪ NAC is effective in this
Slide 114: Design and results of Aladote POP study
Design and results of Aladote® POP study Randomised Open Label Exploratory, Safety and Tolerability Study with Calmangafodipir in Patients Treated with the 12-hour Regimen of N-Acetylcysteine (NAC) for Paracetamol Overdose Cohort 3 Phase Ib/IIa Study – Positive results Aladote 10 µmol/kg • In total
Slide 115: POP study results presented at Society of Toxicology
Results of the PoP study presented at the 58th Annual Meeting of the Society of Toxicology Baltimore, March 2019 115 |
Slide 116: Aladote granted Orphan Drug Designation by the FDA
Aladote® granted Orphan Drug Designation by the FDA (March 18, 2019) ODD benefits • Lowered development cost – driven by patient safety and efficacy requirements (typically < 300 patients in Phase II / III studies) • Shortened development time • Commitment of the regulators to support development •
Slide 117: Tentative study design for next clinical study
Tentative study design for next clinical study - pending finalization after regulatory interactions Design item Patient population High risk POD patients (Early >300 nomogram OR Late (>8h) with >20mg/L paracetamol) requiring treatment with NAC NAC regims 12 hr or 21 hr regims Initiation of randomize
Slide 118: Aladote - timeline
Aladote® – timeline ✓• Orphan Drug Designation • Calmangafodipir granted composition of matter patent ✓• Presentation of study expires results at Society of Toxicology • Presentation of study results EASL ILC 2019 • Regulatory interactions – 2032 development program • Initiate next study - subject t
Slide 119: Aladote in Paracetamol Overdose (POD)
3. Aladote® in Paracetamol Overdose (POD) a. Unmet medical need b. Aladote® proof of principle study results c. Development of Aladote to prevent acute liver injury caused by POD d. Commercial opportunity in POD Phase II 119 |
Slide 120: POD incidence in EU5 and US - Hospital visits 2018
POD incidence in EU5 and US – Hospital visits 2018 105,000 26,000 26,000 9,000 89,000 16,000 120 | Note: Paracetamol (acetaminophen) Overdose 2018 estimate Epidemiology.
Slide 121: Burden on society - POD US Healthcare Costs
Burden on society - POD US Healthcare Costs were $1bn in 2010 In the US the annual cost in 2010 The POD Emergency was estimated at $1,059 million Department and inpatient cost is to treat Patients with POD around $13K-40K The average POD inpatient length of stay was 3.1 Days, with US liver transplan
Slide 122: No competitor in development
No competitor in development TREATMENT APPROACHES FOR POD EMERGING TREATMENTS POD Active Charcoal N-Acetylcysteine (NAC) Liver transplant Aladote® PledPharma Phase I Phase II Phase III 122 |
Slide 123: Aladote - Initial Market Research, Pricing & Reimbursement
Aladote® – Initial Market Research, Pricing & Reimbursement Market research with US and EU Physicians and Payers to gain insight into unmet needs, validate Target Product Profile and Pricing & Reimbursement POD CIPN Background Background TPP & IDI Guide Testing Team Expertise Development Efficacy vs
Slide 124: Physician & Payer Insight confirms unmet need and verifies TPP
Physician & Payer Insight – confirms the unmet medical need and verifies TPP • Patients as defined in study design (ie early high level /late presenters) confirmed as being high risk • Unmet Need Ultimately Prevention Of Liver Failure Requiring Transplant And Death • Unmet Need Is Unanimously A Redu
Slide 125: Physician & Payer Insight - time in hospital
Physician & Payer Insight – time in hospital a major driver of value in a cost-benefit analysis ‘Really working in, for us, a primary ‘As just outlined {21 hours, 3 infusions} endpoint of 'time for readiness for it’s a bit difficult the administration of the discharge'. That would speak volumes drug
Slide 126: Aladote - Commercial potential in POD patients
Aladote® – Commercial potential in POD patients Pricing ~135k assumption Hospital admissions ~5,000 POD patients in US USD/dose in the and EU5 /year US¹ COGS assumption Low single digit percent 126 | Note: (1) Up to $5000 based on initial and limited research
Slide 127: Aladote - Summary and Opportunities
Aladote® - Summary and Opportunities PREVENTS ACUTE LIVER FAILURE CAUSED BY PARACETAMOL (ACETAMINOPHEN) POISONING DEVELOPMENT STATUS BUSINESS OPPORTUNITY • Positive study results Ph Ib/IIa announced in September • Paracetamol (acetaminophen) poisoning is one of the most 2018 – presented at the 58th
Slide 128: Corporate Strategy
4. Corporate Strategy a. Finance and up listing b. Business development c. Direction and opportunities to enhance value 128 |
Slide 129: Finance
Finance Finance Income statement SEKk 2018 2017 Jan-Dec Jan-Dec • 2018 operating results were SEK -92.5M Revenue Sales 28,211 13,585 Other operating income 2 302 • Q4-2018 Cash position was reported at SEK 28,212 13,886 230M Operating expenses Project costs -83,855 -76,974 Other external costs -11,3
Slide 130: Nasdaq main market up-listing
Nasdaq main market Up-listing • Up-listing process ongoing • Listing of shares on Nasdaq main market estimated to Q4 2019 • Aligned with the maturity level of the company • PledPharma shares will be accessible and visible to a global investor base 130 |
Slide 131: Corporate Strategy
4. Corporate Strategy a. Finance and up listing b. Business development c. Direction and opportunities to enhance value 131 |
Slide 132: Proactively pursue Business development
Proactively purse Business development Business development • Commercialize PledOx through strategic partnership o PledPharma is open for license agreement/s for major regions before read- out, if the terms are attractive • Opportunistic approach to partnering during development for Aladote • Ambiti
Slide 133: License agreement to develop and commercialize PledOx in Asia
License agreement develop and commercialize PledOx®in Asia 133 |
Slide 134: Key value drivers of Asia licensing agreement
Key value drivers of Asia licensing agreement Partnership with Solasia 3-4 years of accelerated and its capabilities development in Asia Expansion of Phase 3 Milestones & Royalties program will further enhance robustness 134 |
Slide 135: PledOx Asia deal structure & Expansion of Phase III to Asia
PledOx® Asia deal structure & Expansion of Phase III to Asia • PledOx® for Chemotherapy Induced Peripheral Neuropathy (CIPN) – Colorectal cancer. 1 • License to develop and commercialize PledOx® in Japan, China, Hong Kong, Macau, South Korea, and Taiwan. • Solasia will pay upfront, development, regu
Slide 136: Corporate Strategy
4. Corporate Strategy a. Finance and up listing b. Business development c. Direction and opportunities to enhance value 136 |
Slide 137: Summary - Direction, opportunities and enablers to enhance value
Summary - Direction, opportunities and enablers to enhance value PledOx® Aladote® Business development • Huge unmet medical • Substantial unmet medical • Strategic partnerships 1 need with no treatment 2 for patient where NAC not 3 • Maximise PledOx value approved today adequate • Ongoing global pha
Slide 138: Closing remarks
Closing remarks Chairman of the Board – Håkan Åström 138 |