Marine-Derived Novel Moa Oncology Drugs

Marine-Derived Novel Moa Oncology Drugs

Loading
Loading Social Plug-ins...
Language: English
Save to myLibrary Download PDF
Go to Page # Page of 27

Description: This document includes only summary information and is not intended to be comprehensive. This document includes "forward-looking statements" that are based on Managementís current expectations. Factors that could cause future results to differ materially from such expectations include, but are not limited to: the success of the Companyís research strategy; the applicability of discoveries made therein; the difficulties inherent in the development of pharmaceuticals, including uncertainties as to the timing and results of preclinical studies; delayed achievements of milestones; reliance on collaborators; uncertainty as to whether the Companyís potential products will succeed in entering human clinical trials and uncertainty as to the results of such trials; uncertainty as to whether adequate reimbursement for these products will exist from the government.

 
Author: PharmaMar  | Visits: 180 | Page Views: 324
Domain:  Medicine Category: Biotech/Pharma 
Upload Date:
Link Back:
Short URL: https://www.wesrch.com/medical/pdfME1XXF000OAAY
Loading
Loading...



px *        px *

* Default width and height in pixels. Change it to your required dimensions.

 
Contents:
CORPORATE PRESENTATION
November 2016

CORPORATE PRESENTATION
March 2017

Disclaimer

This document includes only summary information and is not intended to be comprehensive. This
document includes "forward-looking statements" that are based on Management’s current expectations.
Factors that could cause future results to differ materially from such expectations include, but are not
limited to: the success of the Company’s research strategy; the applicability of discoveries made therein;
the difficulties inherent in the development of pharmaceuticals, including uncertainties as to the timing and
results of preclinical studies; delayed achievements of milestones; reliance on collaborators; uncertainty as
to whether the Company’s potential products will succeed in entering human clinical trials and uncertainty
as to the results of such trials; uncertainty as to whether adequate reimbursement for these products will
exist from the government, private healthcare insurers and third-party payers; and the uncertainties as to
the extent of future government regulation of the pharmaceutical business. Therefore those statements
involve risks and uncertainties beyond the Company's control and actual results may differ materially from
those stated by such forward-looking statements. The Company expressly disclaims any obligation to
review or update any forward-looking statements, contained in this document to reflect any change in the
assumptions, events or circumstances on which such forward-looking statements are based unless so
required by applicable law.

2

Investment Highlights
A leader in the development & commercialization of marine-derived oncology drugs
 Multinational biotechnology company developing marine-derived and novel MoA
oncology drugs
 Fully integrated biotechnology company – from discovery to commercialization
 Highly productive R&D organization (1 approved drug and 2 in late stage development)

 Established oncology sales force in Europe:
 Strong partners in the US (Janssen), Europe (Chugai), and Japan (Taiho, Chugai)

 Late stage development pipeline driving future value
 Lurbinectedin (PM1183): Next generation Yondelis®
 Aplidin®: Positive pivotal data in Multiple Myeloma with an EMA NDA filed in Sept 2016

 Track record of operational excellence with a strong financial position
 Company with growing revenues and robust cash flow
 Headquartered and traded in Madrid
 Yondelis sales & royalties €94mm (2016)
 C. €615m market cap (as of 02/24/17)
 €63.5m in cash and cash equivalents (2016)*
 €8.4m operating cash burn + debt service (2016)
* Proforma for Chugai Lurbinectedin partnership, €30mn upfront, announced Dec 22nd 2016

3

Yondelis® - Commercial expansion worldwide

PHM territories




Western EU.
Scandinavia and Eastern Europe: Swedish Orphan Biovitrum
Greece, Cyprus and Balkans:Genesis Pharma

Partner territories
EEUU and rest of the word (exclud. EU) :Janssen
Japan : Taiho

PharmaMar subsidiaries

4

Unique fully integrated platform

Fully integrated capabilities
Marine expeditions




Marine derived
products
Global expeditions

Screening
& Synthesis

Sample library





New drug
candidates
Molecule
optimization
c.200,000
samples





Patent protection
Synthesis
FDA approved
production facility

Clinical Trials





Pre-clinical trials
Clinical trials
Phase IV
supportive trials

Commercialization




Oncology-focused sales
force in Europe (~ 65
people)
Geographic licensing &
partnering with
experienced companies.

Marine-derived compounds with novel mechanisms of action
Regulatory inspections passed from FDA, AEMPS,PMDA (US, Spain/EU, Japan)
5

The Plan for Growth
Potential to commercialize new oncology products in more indications

PharmaMar in
the near future
PharmaMar
tomorrow
PharmaMar
today
• 1 marketed
product
• 2 indications

 Yondelis®



Soft Tissue
Sarcoma
R/R Ovarian
Cancer

• 2 marketed
products
• 3 indications

 Aplidin®


R/R multiple
myeloma

• 3 marketed
products
• ≥ 5 indications

 Lurbinectedin
(PM1183)




Small Cell Lung
Cancer
Platinum resistant
ovarian cancer
BRCA 2 Breast cancer

6

A Balanced portfolio of product candidates
Overview
Clinical Program / Indication

Phase I

Phase II

Phase III

Market

Partner

Data timing

Yondelis®
Soft Tissue Sarcoma 2nd/3rd line

Ovarian Cancer

2nd/3rd line

Single agent

Yondelis®+Doxil

EU, US, Japan

J&J (US)
Taiho (Japan)

EU/Others

Aplidin®
Chugai/
Regionals

R/R multiple myeloma 4th line;

Aplidin® + Dexameth.

EU/Others

R/R Angioimmunoblastic T-cell lymphoma

Single agent (Pivotal)

EU/Others

Ongoing

R/R multiple myeloma

Aplidin® + Bortezom+
Dexameth.

EU/Others

Ongoing

Lurbinectedin (PM1183)
Plat. Resistant ovarian cancer

2H´17

Chugai (Japan)
Single agent

Global

2H´17

SCLC 2nd line

Lurbinec + Doxo

Global

2019

BRCA 1/2 Breast cancer

Single agent

Global

Finalizing
protocol

Single agent

Global

Ongoing

Combinations

Global

Ongoing

Single agent

Global

Ongoing

Single agent and
combinations

Global

Ongoing

Basket trial

Solid tumors

PM184
Advanced Breast Cancer

Solid tumors

3rd/4th line

7

Pipeline – Lurbinectedin (PM1183)
Targeted transcription Inhibitor as a cancer therapeutic

 Cancer cells aberrantly deregulate specific gene expression programs with critical
functions in cell differentiation, proliferation and survival (Hoadley et al 2014)
 These altered gene programs in cancer cells have a striking dependence on continuous
active transcription (transcription addiction)

 Lurbinectedin only affects activated transcription. Does not affect basal transcription*.
 Examples of tumors with transcription addiction:
− Small Cell Lung Cancer (SCLC) cells are addicted to lineage-specific and protooncogenic transcription factors that support their growth (Christensen et al 2015)
− Soft Tissue Sarcomas (STS) bearing translocations.
− Effect on tumor microenvironment: Lurbinectedin inhibits the activated
transcription of certain cytokines as IL-6, IL-8, CCL2 and PTX3

* Source: Molecular Cancer Therapeutics 2016 Oct;15(10):2399-2412. Lurbinectedin Specifically Triggers the Degradation of
Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells.

8

Lurbinectedin (PM1183):
Key oncology compound – accelerating growth

Lurbinectedin, a second generation Yondelis®, with improved PK and other attributes

YONDELIS®

Lurbinectedin
MO
e

H
O
OH
C3

N
H

MO
e

IMPROVED PK PROFILE

H
O

O
AO
c
O

O

N

N

O





S
H
N

N

O

H
O

O
AO
c

S
H

OH
C3

N
H

N
H

O

O
H

Lurbinectedin is administered as a 1h
peripheral infusion versus 24h
continuous central catheter infusion with
Yondelis®.
Lurbinectedin linear PK profile

O







O
H

4x tolerated dose.
15x exposure at RD.
Less toxicity
More oncology “office
practice” friendly.

9

Pipeline – Lurbinectedin (PM1183)
Key oncology compound – accelerating growth




Inhibition of trans-activated transcription but not of basal transcription.
Induction of the degradation of RNA Pol II but not of RNA Pol I or III.

RNA POL II INHIBITION

RNA POL II DEGRADATION
P

CDK7

P

CDK9

RNAPII
P

P
P

PM1183

P

PROTEASOME

PM1183
DNA

RNAPII

Initiation

RNAPII

X

Elongation

DNA

Blockade of repair
Generation of double strand-breaks

Source: Molecular Cancer Therapeutics 2016 Oct;15(10):2399-2412. Lurbinectedin Specifically Triggers the Degradation of
Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells.

10

Pipeline – Lurbinectedin (PM1183)
Development strategy

CLINICAL PROGRAM/
INDICATION

PHASE I

SCLC
2nd line

PHASE III

MARKET

PARTNERS

Chugai (Japan)

Lurbinectedin PM1183®
Plat. Resistant ovarian cancer
2nd/3rd line

PHASE II

Single agent

Combo Doxorubicin

BRCA2 Breast cancer*
2nd/3rd line

Single agent

Basket Trial

Single agent

Combination Studies

Solid Tumors

* Subsequent to FDA meeting December 2016; subject to finalization in 2017

11

Lurbinectedin – Platinum Resistant Ovarian Cancer
Market overview: Orphan Indication US/EU





~ 250,000 WW new cases of ovarian cancer
~ 150,000 WW deaths from ovarian cancer
Platinum resistant patients account for ~15% of all ovarian cancer patients
80% relapse after first line treatment with platinum

Primary
treatment

Time to recurrence (months)

0 months

6 months

30%
Refractory

12 months

70%
Resistant

Sensitive

End of frontline
therapy

Source: Estimated ovarian cancer incidence and mortality, all ages. GLOBOCAN 2012 and PharmaMar market research studies

12

Standard of care for Ovarian Cancer (per labels)
Lurbinectedin: Competitive Landscape


PARP inhibitors work by blocking the action of poly (ADP-ribose) polymerase, a DNA repair
enzyme; they are used after DNA damaging drugs which are highlighted below
Front Line

Maintenance

Second line

3rd line and beyond

Sensitive
 Same as 1L
 Yondelis/PLD (EU)
 Avastin

 Platinum/ Taxane

 Olaparib (EU)
 Niraparib filed
(US/EU)*

Resistant
 PLD
 Topotecan



Olaparib, (US) germline
BRCAm, after 3 or more
lines of chemo
Rucaparib (US) BRCAm
after 2 or more lines of
chemo

 Lurbinectedin*
Refractory
 Same as resistant

* Investigational drug; not approved

13

Lurbinectedin:Phase II Platinum Resistant Ovarian Cancer

Cumulative probability

Trial results
PM01183 (N=17 C=4)

1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0

Topotecan (N=16 C=2)

PFS

Censored

HR: 0.30 (95%CI 0.12-0.72)

5.7 mo.

p=0.005*

0

1

2

3

4

5

6

7

8

9

probability
Cumulative

Superior PFS

10 11 12 13 14 15 16

1.0
Cumulative probability



1.7 mo.

PM01183
PM01183
Topotecan
Topotecan
Censored

0.9
0.8

(N=17 C=9)
(N=16 C=4)

HR: 0.40 (95%CI 0.16 --0.99)
HR: 0.40 (95%CI 0.16 0.99)

0.7

Not reached

p=0.039*



p=0.039*

0.6

Superior OS

0.5
8.3 mo.

0.4
0.3
0.2
0.1
0.0
0

2

4

6

8

10

12

14

16

18

Time ( months )

20

22

24

26

28

* log -rank test

Source: ASCO 2014 Poveda et al.

14
14

Lurbinectedin:Phase III Platinum Resistant Ovarian Cancer
CORAIL Trial Design

Phase III
443 Patients

Randomization 1:1
Stratified by:




Arm A:
Lurbinectedin
(D1 q3wk i.v.)
3.2mg/m²

ECOG PS (0 vs. ≥1
PFI (1-3 vs. > 3mths)
Prior CT (1-2 vs. 3 lines)

No Crossover

Arm B:
PLD
(D1 q4wk i.v.)
or
Topotecan
(D1-D5 q3wk i.v.)

Primary Endpoint: PFS, 90% power for HR=0.7; p=0.025 (one-sided)
Interim safety analysis: passed @ 80 events
Interim analysis : @ 210 patients, July 2016
Patient recruitment completed: October 2016; Data expected 2H17
15

Lurbinectedin: Small Cell Lung Cancer (SCLC)
Market overview. Orphan Indication US/EU

In the US per annum:

In EU-28 per annum:







~ 33,200 new cases of small cell lung cancer
~ 24,040 deaths from small cell lung cancer
(~ 27% of all cancer deaths)

~ 46,645 new cases of small cell lung cancer
~ 40,700 deaths from small cell lung cancer

 SCLC represents a significant unmet medical
need with limited late stage options.
 SOC: Topotecan, CAV (off label)
 Last FDA approval, Topotecan, October 2007
 Last EMA approval, Topotecan, August 2009

Source: American Cancer Society, Decision Resources, Inc.

16

Standard of care for Small Cell Lung Cancer
Lurbinectedin: Competitive Landscape


First line treatment. Platinum/Etoposide

2nd line

3rd line

N

ORR (%)

PFS

Notes

Lurbinectedin/Doxo

21

67

4.6

ASCO 2015

Paclitaxel

Literature

29

Topo

Literature

24

3.0

Glisson, 2011

CAV

Literature

19

2.8

Glisson, 2011

Nature Reviews
Glisson, 2011

Nivo

Nivo

98

11

1.4

2nd/3rd line

Nivo/Ipi

Nivo/Ipi

61

25

2.6

2nd/3rd line

Pembro

Pembro

24

33

1.9

‘heavily pre-treated’

Rova-T

Rova-T

61

18

2.8

2nd and 3rd line

Rova-T

Rova-T

48

38

4.3

DLL3 ‘high’

Source: Nature Reviews 2011;8:611-19. William N, Glisson, Lancet Oncology 6/4/16; Merck PR 12/6/16; Lancet Oncology 12/5/16
For information purposes, not head to head data

17

Lurbinectedin: Phase I/II Small Cell Lung Cancer
Trial results – Active treatment as second-line therapy with Doxorubicin

Best RECIST v.1.1 overall response
during treatment (n=21)

Kaplan-Meier global PFS and according to CTFI (n=21)
ORR: 67 %

CR
10%

SD
14%

PR
57%
PD
19%

Cumulative probability

(95%CI: 43-85)

1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0

0

PFS: 4.6 months (95%CI:
3.3-8.0 months)

1

2

3

4

5

6

7

8

9

10 11 12

Months
Global (N=21 C=3)

M. Forster et al. ASCO 2015

Censored

Other examples ORR in SCLC:






CAV 19%
Topotecan 24%
Paclitaxel 29%
Gemcitabine 12%
Vinorelbine 12%

Source: Nature Reviews 2011;8:611-19. William N, Glisson

PFS reported in registration Topotecan trial study :
• CAV
: 2.8 months
• Topotecan : 3 months

Source: J Clin Oncol, 1999, Von Pawel et al

18

Lurbinectedin: Phase III 2nd line Small Cell Lung Cancer
ATLANTIS Trial Design SCLC (Trial initiated August 2016)
• Primary endpoint: median PFS
─ HR≤ 0.7 in PFS with 90% power;
─ Futility analysis planned at n=150 patients approximately
• Key secondary endpoints:


OS

• Registration Strategy



Trial supported by ongoing n=50 monotherapy trial
Factorial synergy supported by CAV control arm (includes Anthracycline ~ Doxo)

Arm A:
Lurbi & Doxo (40mg/m2)
(up to 10 cycles)

Eligible SCLC pts
1 prior platinum
n~600
Stratification by prior PD1/PDl-1

R
(1:1)

Lurbi mono (following doxo
maximum cumulative dose)
at 3.2 mg/m2 q3w until PD

No Crossover
Arm B:
Topotecan or
CAV

19

Lurbinectedin: Phase llb in BRCA 1/2- Breast Cancer
Clinical efficacy: Progression Free Survival (PFS) and Overall Survival OS

Median PFS BRCA 1/2:
4.1 months 95% CI (2.8-5.9)
BRCA 1: 2.7 95% CI (2.1-4.6)
BRCA 2: 5.9 95% CI (4.1-7.9)

Median OS BRCA 1/2:
20.0 months 95% CI (10.9-31.8)
BRCA 1: 11.8 95% CI (6.5-20.0)
BRCA 2: 31.8 95% CI (20.7-38.9)

Source: ESMO 2016

20

Lurbinectedin – Phase llb in BRCA 1/2- Breast Cancer
Best ORR in specific subpopulations

Prior Platinum
No
(n: 27)

Yes
(n: 27)

Hormone
Status

BRCA
1
(n: 31)

2
(n: 23)

1/2
(n: 54)

Triple
Negative
(n: 33)

HR+
(n: 21*)

Prior
advanced
CT lines
0-1
(n: 31)

2-3
(n: 23)

ORR

56%

26%

26%

61%

40.7%

36%

48%

52%

26%

(95% CI)

(35.3-55.6)

(11.1-25.9)

(11.9-25.8)

(38.5-60.9)

(27,6-55,0)

(13.3-27.3)

(38.4-81.9)

(33.1-69.9)

(10.2-48.4)

Duration of
Response
(95% CI)
Disease
control
rate
Clinical
benefit
(CR+PR+SD
≥ 3 mo)

10.2 m

5.9 m

6.6 m

6.7 m

6.7 m

7.7 m

6.7 m

8.5 m

3.4 m

(3.0-13.5)

(2.8-12.8)

(2.8-12.8)

(3.4-13.5)

(3,0-13)

(2.8-12.8)

(2.8-13.4)

(3.0-12.8)

(2.8-20.5)

25 (93%)

19 (70%)

23 (74%)

22 (96%)

45 (83%)

26 (79%)

19 (90%)

27 (87%)

18 (78%)

19 (70%)

14 (52%)

14 (45%)

19 (83%)

33 (61%)

29 (88%)

14 (67%)

21 (68%)

12 (52%)

* Includes
2 pts also
HER-2 +
Source: ESMO 2016

21

Lurbinectedin: Planned Registrational trial BRCA 2- Breast ca.
Subject to finalization and changes

In the US per annum:

In the EU-28 per annum:





~ 7,500 new cases of HR+, HER2-, BRCA2
mutated Breast cancer,

HR+, HER2-, BRCA2 mutated mBC pts
n~116

~ 11,000 new cases of HR+, HER2-, BRCA2
mutated Breast cancer

Lurbinectedin single arm
(3,5mg/m2 iv d1 q3wk)

 Primary endpoint :

ORR

 Secondary endpoints: DOR
PFS

2 prior hormone Tx
1 CDK4/6 if available
1 or 2 prior chemo
no prior PARP

Source: US: seercancer.gov , EU28: Globocan2012, Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and
advanced breast cancer: a proof-of-concept trial. Andrew Tutt et al. Lancet 2010; 376: 235–44

22

Pipeline - Aplidin®
First in class drug with a novel mechanism of action
Aplidium albicans

MECHANISM OF ACTION

PLITIDEPSIN



Targets eEF1A2
Proto-oncogene over-expressed
in different tumor types e.g.
multiple myeloma

eEF1A2


Non-canonical functions of eEF1A2:




Regulation of oxidative stress (e.g. peroxiredoxin-1, etc.)
Regulation of apoptosis (e.g. esfingosina-1 quinasa)

Source: Scientific Reports. 2016 Oct 7;6:35100. Translation Elongation Factor eEF1A2 is a Novel
Anticancer Target for the Marine Natural Product Plitidepsin.

Aplidin®
23

Pipeline – Aplidin®
First in class drug with a novel mechanism of action

CLINICAL PROGRAM/
INDICATION

PHASE I

PHASE II

PHASE III

REGISTRATION
APPLICATION

MARKET

PARTNERS

Aplidin®
R/R multiple myeloma 4th line;
EU/others
R/R Angioimmunoblastic T-cell
lymphoma
R/R multiple myeloma

Aplidin® + Dexameth

Single agent

(Pivotal)

Aplidin® +
Bortezomib+
Dexameth

Partnered with Roche’s Chugai in 8 European countries
Other partners for Aplidin®
Commercial opportunity for Europe in M.M. estimated at c.€300mm
24

Aplidin® - ADMYRE Trial
Phase III in Relapsed / Refractory Multiple Myeloma

Phase III MM
250 Patients
After 3, but no more than 6
lines of chemotherapy

Randomization 2:1

Aplidin®

Arm A:
+ Dexamethasone
(n=167)

Arm B:
Dexamethasone only
(n=83)

Primary Endpoint Achieved: PFS, HR=0.65 (p=0.0054)

Dossier Submitted September 2016, decision expected 2H17

OS data expected 2H17
25

Key Events
Transformative times for Pharma Mar; catalyst rich 2017
 Lurbinectedin Phase III pivotal trial initiated for SCLC (Aug. 2016)
 Lurbinectedin interim activity analysis Phase III in platinum-resistant ovarian cancer (Aug`16)
 Aplidin® positive data for Phase III for multiple myeloma and dossier submitted (Sept. 2016)
 Lurbinectedin data for Phase II metastatic breast cancer (Sept. 2016)

 Lurbinectedin Phase III in platinum-resistant ovarian cancer: recruitment completed (Oct`16)
 Lurbinectedin license agreement in Japan (Chugai, Dec´16)
 Update Breast cancer trial, following FDA meeting
 Yondelis INNOVATYON (IST) interim analysis relapsed OC (2q´17)
 SCLC Phase II combo and monotherapy update (2H 2017)
 Aplidin® CHMP recommendation in multiple myeloma (2H 2017)
 Lurbinectedin Phase III data in platinum-resistant ovarian cancer (2H 2017)
 Aplidin® OS data Phase III for multiple myeloma (2H 2017)
26

For more information: www.pharmamar.com