Strong progress and two partnership deals despite covid -19
Transcript of Strong progress and two partnership deals despite covid -19
© ISOFOL MEDICAL AB (publ)
Disclaimer
This company presentation of Isofol Medical AB (publ) (“Isofol”) has been prepared for advertisement purposes. It is not a prospectus and has not been prepared in accordance with the prospectus requirements in the Swedish Financial Instruments Trading Act (lagen (1991:980) om handel med finansiella instrument) or the European prospectus regulation (809/2004/EC) (the “Prospectus Regulations”). This company presentation is not subject to any registration or approval requirements under the Prospectus Regulations and has not been, and will not be, examined, approved or registered by the Swedish Financial Supervisory Authority or any financial supervisory authority or other supervisory body within the EU.
The company presentation may not be forwarded, reproduced or made available in or into any jurisdiction in which such publication or distribution would require any additional documentation to be prepared or registration effected or that any measures are taken in addition to those required under Swedish law or where it would be in conflict with any law or regulation in such jurisdiction. Persons who come into possession of this document are required to inform themselves about, and to observe, such restrictions.
The courts of Sweden shall have exclusive jurisdiction over any dispute arising out of or in connection with this document company presentation and the City Court of Gothenburg, Sweden, shall be the court of first instance.
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© ISOFOL MEDICAL AB (publ)
Isofol at a glance
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Developing arfolitixorin for the treatment of colorectal cancer
Board and management with broad and long experience
Strategic CMC partnerships with Merck & Cie and Recipharm
Licensing agreement with Solasia in Japan andwith Endo/Paladin in Canada
Source: Holdings.se, September 30 2020
Listed on NASDAQ First North Premier, Stockholm (ticker: ISOFOL)
Headquarters in Gothenburg
Shareholders Number ofshares
Capital/Votes(%)
Futur Pension (f d Danica) 5 324 312 6,39%
Avanza Pension 4 487 840 5,38%
Bengt Gustafsson 3 515 434 4,22%
Handelsbanken Fonder 3 393 412 4,07%
Hans Enocson 2 602 992 3,12%
Alfred Berg Fonder 2 429 898 2,91%
Swedbank Robur Fonder 2 413 791 2,90%
Fjärde AP-fonden 2 400 000 2,88%
Swedbank Försäkring 2 057 629 2,47%
Peak Partners 1 926 560 2,31%
10 largest shareholders 27 486 876 32,97%
Other owners 55 879 090 67,03%
TOTAL 83 365 966 100%
Number of shareholders approx. 4500
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The arfolitixorin opportunity
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mCRC is a significant urgent unmet medical need with no new treatment options for allcomers in over 16 years
MTHF added to the cornerstone cytotoxic 5-FU more than doubles its efficacy - arfolitixorin is MTHF
Limited competition and few new drugs in development for 1st line mCRC, no branded products
Unprecedented low regulatory hurdle for approval in 1st line mCRC
Late-stage asset with established mechanism of action aiming for launch within 3 years
Fully validated CMC package in place
A $1B opportunity in 1st line mCRC only
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Arfolitixorin - Significant Commercial Opportunity
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Large Patient Population
AGENT study infirst-line mCRC
Limited competition
Straightforwardadoption intoStandard of Care
Premium pricing$mCRC Peak sales potential>$1B
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Arfolitixorin - Aim to Increase Efficacy of current standard of care-the first pure form of [6R]-MTHF – the biological active substance
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The Problem: 5-FU + [6R]-MTHF treatment with the pro-drug leucovorin 400 mg/m2
The Solution: 5-FU + Arfolitixorin 120 mg/m2 (120 mg/m2 [6R]-MTHF)
IV bolus push1-3 min
[6R]-MTHF essential for 5-FU anticancer effect
• With only up to 40% - 45% responding to current SOC in All-Commers
Strength of the arfolitixorin program:
• Hemisulfate guarantees stability
• Significantly higher intracellular tumor concentrations of [6R]-MTHF
• Significant higher inhibition of TS inhibition
• Use of 5-FU and arfolitixorin iv bolus push significantly inhibits TS
© ISOFOL MEDICAL AB (publ)
Arfolitixorin is a De-risked Opportunity- Phase III AGENT Study has a high probability of success with low regulatory hurdles for approval
● Significant Commercial Opportunity● Physicians understand and support the value proposition
● Established mechanism of action:● [6R]-MTHF role in potentiating 5-FU is well described in the literature1
● Arfolitixorin is the first pure form of [6R]-MTHF, require no activation and has the potential to help all patients treated with5-FU● FDA and EMA have granted approval to evaluate arfolitixorin in a first line 1st line pivotal registrational trial in mCRC setting, as an
improvement of established care based on:• Favorable safety profile with established MoA• Pre-clinical and clinical documentation
● Positive Clinical Data:● PK/PD data has demonstrated significantly increased [6R]-MTHF levels in Tumors from CRC patients vs SOC2
● Study 005 resulted in promising efficacy of 59% ORR in the ARFOX patient population after at least 16 weeks of treatment3
● Full CMC process in place:● ISOFOL and MERCK has spent over 15 years developing a manufacturing process and know-how together ● CMC and commercial scale manufacturing process has been completed and there will be no delays for clinical
trials or commercial launch
9Source: 1. PV Danenberg et. al. Critical Reviews in
Oncology/Haematology 106 2016 118-131. 2. Y Wettergren et. al. Cancer Chemother Pharmacol. 2015 Jan;75(1):37-47. 3 Isofol data on file
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Colorectal cancer is the third most common cancer 111% of cancers discovered annually are colorectal cancer
COLORECTAL CANCER FACTSHEET
The 5-year survival rate for patients with stage 4 colorectal cancer (mCRC) falls to around 10%2
10%
GROWING INCIDENCE
The global burden of CRC is expected to increase by over 70% from 1.8 million 2018 cases to 3.1 million in 20401
>70%
Source: (1) GLOBOCAN 2018, Cancer Incidence and Mortality Worldwide(2) GlobalData 2017
1.8m people are diagnosed with CRC each year globally11.8m
GLOBAL CRC MARKETTotal market size will grow in $bn from 2018 to 20252
Colorectal cancer (CRC)- 3rd most common and 2nd deadliest cancer with a urgent unmet need
0,00,20,40,60,81,01,21,41,61,82,02,2
Lung Breast Colorectal Prostate Stomach Liver
An
nu
alg
lob
al i
nci
den
ce(m
illio
ns)
12% 12%
11%
8%
6%5%
20182025
CAGR: ~3%
11
8.5
11
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5-FU based chemotherapy will remain a cornerstone treatment in CRC
Metastatic CRC, spread
to distant organs
1st line 2nd line 3rd line
Localtumour
Tumour spread
to nearbylymph nodes
Source: (1) GlobalData 2017 12
© ISOFOL MEDICAL AB (publ)
[6R]-MTHF plays a vital role in improving the efficacy of 5-FU
13TS-Tymidylate Synthase; 5-FU – 5 Fluorouracil
5-FU displaced due to [6R]-MTHF shortage
5-FU is an anti metabolite i.e. a false building block that out competes the natural TS substrate
Arfolitixorin is [6R]-MTHF
i.e. [6R]/MTHF
© ISOFOL MEDICAL AB (publ)
PK/PD data from Phase I/II study ISO-CC-002 demonstrate significantly increased MTHF levels in tumors from Colorectal Cancer patients treated with arfolitixorinvs Levoleucovorin
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Significantly higher Methylene THF ([6R]-MTHF) concentrations in colorectal tumor after two equimolar dose
levels of arfolitixorin or L-LV, all dosages (analysis of variance; P < 0.01)
Methylene THF ([6R]-MTHF) levels in colorectal tumor
Con
c (p
mol
/g)
0
2000
4000
6000
8000
10000
Arfolitixorin 60mg/m2
Levoleucovorin 60mg/m2
Arfolitixorin 200mg/m2
Levoleucovorin200 mg/m2
n=32
© ISOFOL MEDICAL AB (publ)
Gene expression studies indicate that arfolitixorin has the potential to increase Progression Free Survival (PFS) in metastatic Colorectal Cancer (mCRC) patients
Background Low expression of the ABCC3 gene has been linked to poor
conversion of leucovorin into [6R]-MTHF and associated with potentially worse clinical outcome
Source: ASCO 2018, Isofol Data on file
PFS is dependent on ABCC3 expression High ABCC3 expression: 11,4 months Low ABCC3 expression: 6.7 months
Hypothesis 75% of patients with low expression of ABCC3 do not
optimally benefit from LV optimization of 5-FU efficacy and correlates with worse PFS vis-à-vis high gene expression
GENE EXPRESSION DATA based on validated method
D = 4.7
Fig. 1 & 2. Kaplan-Meier Curves showing PFS when patients with synchronous mCRC were categorised based on ABCC3 expression
High ABCC3 in 25% of pts
Low ABCC3 in 75% of pts
N=144; p:0.0002Quartiles
ABCC3 expression levels and PFSin patients treated with 5-FU/LV regimens
Results from the phase III AGENT study will confirm the Hypothesis that arfolitixorin substitution of leucovorin results in significant better efficacy, with those with low gene expression having the most benefit
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© ISOFOL MEDICAL AB (publ)
2. Arfolitixorin generates significantly higher MTHF levels in patients tumors, can’t be
compensated by increasing the LV dose
1. MTHF is critical for 5-FU’s mode of action by blocking DNA replication and triggering cell death
MTHF in cancer treatment ABCC3 expression and PFS
3. Arfolitixorin could rescue up to ~ 75% of all mCRC patients treated with 5-FU unable to convert LV to MTHF
(improved Progression Free Survival PFS 11.4 vs 6.7 months)
Arfolitixorin – a novel drug for improving response and survival in mCRC patients- Arfolitixorin aim to improve ORR and PFS by potentiating 5-FU’s cytotoxicity
MTHF levels in colorectal tumor tissue
High ABCC3 in 25% of pts
Low ABCC3 in 75% of pts
N=144; p:0.0002Quartiles
Source: ASCO 2018, Isofol Data on file
antimetabolite
5-FU TS-substrateout-competed
arfolitixorin([6R]-MTHF)
Thymidine synthetaseinhibition
persistent thymidine shortage
persistent DNAsynthesis arrest
tumor cell death through apoptosis
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Based upon a well understood MoA, solid preclinical data, indicative gene expression and clinical data, plus a favorable safety profile –
Arfolitixorin may be the first novel drug to improve Standard Of Care for allcomers in 1st line mCRC in over 16 years
© ISOFOL MEDICAL AB (publ)
Clinical Development Program and Accelerated Developmentresulted in a shortened route to market- Due to strong support from regulatory authorities
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© ISOFOL MEDICAL AB (publ)
Target Product Profilearfolitixorin Minimal acceptable results Ideal Results
Primary Product IndicationFor the treatment of
1st line mCRC in combination with 5-FU
For the treatment of advanced colorectal cancer in combination with 5-FU
Patient Population 1st line mCRC 1st line mCRC
ORR (%) >55% - >10% improvement compared to current SOC
>60% - >15% improvement compared to current SOC
PFS (months)*>11,8 months –
>1,8 months improvement compared to current SOC
>12,5 months –>2,5 months improvement compared to current SOC
Incidence of Grade III/IV AEs (%)
Similar frequency to current SOC Similar frequency to current SOC
To improve efficacy
● with no additional toxicity
● by a proven concept
● no change in clinical practice required for use
● Low hurdles for incorporation into current treatment practice
Arfolitixorin promises
Arfolitixorin has the potential to optimize 5-FU based treatment efficacy
* FDA requires a positive trend in PFS as the lowest hurdle
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ISO-CC-005 – Phase I/IIa dose defining studySafety and dose finding with extension cohorts
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Dose finding part; MTD & RP2D
Patients (n=62)
mCRC 1st to 5th lineMTD and RP2D
Primary Endpoint
Secondary Endpoints
2020ARF/ARFOX/ARFIRI +/- BevacizumabmCRC
ORR @ 8wObjective response rate
Patients (n=43)
mCRC 1st line
ARFOX or ARFIRI (120mg/m2)mCRC
Safety2020
ORR @ 8w
Primary Endpoint
Secondary Endpoints
Objective response rate
Final results
(Expected)
Safety extension cohorts 1 & 2 Treatment/Efficacy(followed 16 weeks and beyond with CT)
1st line Cohorts 1 & 2 (31 patients)
SafetyTo date, no safety issues related to the use of arfolitixorin have been raised at the dose of 120 mg/m2
Overall Response Rate (ORR)
ARFOX 59%ARFIRI 50%
Final results
(Expected)
Results 1st-5th line (62 patients)
Dose FindingMaximal Tolerated DoseRecommended Phase 2 Dose
120 mg/m2 arfolitixorinWas the selected dose
SafetyTo date, no safety issues related to the use of arfolitixorin have been
raised at any tested dose
Recommended Phase 2 Dose
Source: Isofol data on file
© ISOFOL MEDICAL AB (publ)
The 005 study results in promising efficacydespite an unanticipated high frequency of poor prognostic factors
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43 ITT patients5 patients in the ITT population did not have an efficacy evaluation (CT scan) after base line according to protocol or RECIST at end of main study and were thus excluded for efficacy assessment according to RECIST
1.1
31 patients evaluated at 16 wks+
Best ORR: 55%
38 RECIST Evaluable pts
Best ORR: 53%
(39% right-sided and 24% BRAF mutations) (42% right-sided and 26% BRAF mutations)
17 ARFOX patients
Best ORR: 59%
(53% rightsid + 24% BRAFm)14 ARFIRI patients
Best ORR: 50%
(29% rightsid + 29% BRAFm)
4 patients with Stable Disease and3 patients with Partial Response not followed beyond 8 weeks with a CT-
evaluation
Patients followed at least 16 weeks (CT - evaluation)
© ISOFOL MEDICAL AB (publ)
55% Overall Response Rate (≥-30%) in 31 first line patients in ISO-CC-005 (Cohort I & II)- Results 16 weeks and beyond of treatment with 120 mg/m2 Arfolitixorin + 5-FU + irinotecan or oxaliplatin (ARFIRI/ARFOX)
Source: Isofol Data on file
17 out of 31 patients had partial response, PR (≥-30%)
ORR according to RECIST 1.1
PD (≥20%)
PR (≥-30%)
ARFOX 59%ARFIRI 50%
0,00% 0,00% 0,00% 0,00%
-5,63%
-11,54%-14,71% -16,00%
-29,69%-34,02%
-36,67% -37,18%
-44,00%-46,22%
-50,00%
-57,00% -57,45% -57,69%
-63,64% -64,15%-67,35% -68,00%
-73,77% -75,53%-79,59%
-84,71%-90,00%
-80,00%
-70,00%
-60,00%
-50,00%
-40,00%
-30,00%
-20,00%
-10,00%
0,00%
10,00%
20,00%
30,00%
40,00%
#1 1
20 m
g AR
FOX
#2 1
20 m
g AR
FOX
#20
120
mg
ARFO
X
#21
120
mg
ARFO
X
#22
120
mg
ARFI
RI
#4 1
20 m
g AR
FIR
I
#5 1
20 m
g AR
FIR
I
#6 1
20 m
g AR
FIR
I
#30
120
mg
ARFI
RI
#7 1
20 m
g AR
FOX
#28
120
mg
ARFO
X
#33
120
mg
ARFI
RI
#3 1
20 m
g AR
FOX
#9 1
20 m
g AR
FIR
I
#11
120
mg
ARFI
RI
#8 1
20 m
g AR
FOX
#10
120
mg
ARFO
X
#32
120
mg
ARFI
RI
#15
120
mg
ARFO
X
#13
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120
mg
ARFO
X
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120
mg
ARFI
RI
#19
120
mg
ARFO
X
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120
mg
ARFI
RI
#36
120
mg
ARFO
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#12
120
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#39
120
mg
ARFI
RI
#25
120
mg
ARFO
X
#26
120
mg
ARFO
X
#16
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mg
ARFI
RI
% CHANGE OF TUMOUR SIZE FROM BASELINE
*
*
*
*
SD19 mts*
PR21 mts
pCR15 mts*
1 Patient (#9) with SD followed for 19 months and censored at study end.
1 Patient (#18) with PR resected and reached pCR after surgery at 15 months.
1 (#16) Patient with PR + resection was followed for 21 months until PD.
* Received bevacizumab after 8 weeks** Received panitumumab after 8 weeks+ 13 Confirmed responses
++ + +++ ++ +++ +
**
*
*
*
*
Extension cohort I & II (ORR beyond 8 weeks – 31 patients) of ISO-CC-005 - ARFOX/ARFIRI
+
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© ISOFOL MEDICAL AB (publ)
ORR The ORR for Arfolitixorin in the phase I/IIa “ISO-CC-005” (ARFOX/ARFIRI) trial is higher compared to the commonly used chemotherapy combinations in all-comer patient populations and is in line with the target readout from the ongoing Phase 3 AGENT study.
Abbreviations: 5-FU: 5-fluorouracil; anti-EGFR: anti-epidermal growth factor receptor; ARFOX: : infusional 5-FU,Arfolitixorin, oxaliplatin; ARFIRI: : infusional 5-FU,Arfolitixorin, irinetocan; FOLFIRI: infusional 5-FU, l-leucovorin, irinetocan; FOLFOX: infusional 5-FU, l-leucovorin, oxaliplatin; BV: bevacizumab; CTX: cetuximab; ORR: overall/objective response rate; PFS: progression free survival; PMAB: panitumumab; SOC: standard of care; LV: leucovorin; mCRC: metastatic colorectal cancer
Source: [1] Giuliani and Bonetti (2018) First-line therapies in metastatic colorectal cancer: integrating clinical benefit with the costs of drugs. International Journal of Colorectal Disease
Syneos Health analysis of average ORR based on pivotal Phase III trials considered in a recent meta-analysis/review by Giuliani & Bonetti [1] compared to ISO-CC-005 patients with poor prognostic factors
20,0%
27,0%
45,0%
59,0%
40,0%
50,0%
0,0%
10,0%
20,0%
30,0%
40,0%
50,0%
60,0%
70,0%
5FU/LV capacitabine FOLFOX ARFOX FOLFIRI ARFIRI
005 Data
Historical controls
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The phase I/IIa – ISO-CC-005-study – Key Conclusions- Promising efficacy – despite an unanticipated high frequency of poor prognostic factors
© ISOFOL MEDICAL AB (publ)
AGENT study – Ongoing global Phase 3 study design
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Study summary:
Study sites
44USA, Canada
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IndicationFirst line
treatment
Randomized controlled study
mCRC
mFOLFOX-6 + Bevacizumab**
ORRObjective response rate
Primary Endpoint
PFS, DORProgression-free survivalDuration of Response
Key Secondary Endpoints
H12022
Final results
EuropeJapan
*ARFOX (Arfolitixorin + 5-FU + Oxaliplatin) + bevacizumab**mFOLFOX-6 (Leucovorin + 5-FU + Oxaliplatin) + bevacizumab
Australia
10
2
ARFOX + Bevacizumab*
440 patients
mFOLFOX-6 + Bevacizumab**
Interim analysis around year-end 2020 – Adaptive design330 patients observed for 16 weeks - event driven
iDSMBrecommendation
Possible sample size increase with 220
Coordinating Principal Investigator:
Prof Joseph Tabernero, MD, PhD
Prof Heinz-Josef Lenz, MD, PhD
H22021
Final results
* As of November 2020
660 patients
Solidify validation of gene expression
© ISOFOL MEDICAL AB (publ)
Regulatory requirement for marketing approval of arfolitixorin:
FDA & EMA, TGA (Aus) and PMDA (Jpn)
● Primary Objective: Objective Response Rate, at least 10% increase above SOC
● Secondary Objective: Positive trend in PFS and DOR
● Safety: No deterioration in OS, at least maintained risk/benefit ratio
● Required sample size: 440 patients
Interim Analysis ● Basis for adaptive design, allows study to be expanded to achieve statistical significance on secondary endpoints● With 330 patients that has been observed for at least 16 weeks and two tumor assessments, the iDSMB will review safety
and efficacy (ORR and trend in PFS) and recommend based on outcomes;
AGENT study – with Adaptive Design, a De-Risked Program
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1.Complete study with 440 patients
Carry on observing patients to readout H2 2021
2.Sample size increase to 660 patientsInclude additional 220 patients to secure
statistical significance on PFS
© ISOFOL MEDICAL AB (publ)
Strong support from leading CRC KOL’s
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Prof. Heinz Josef Lenz – Keck School of Medicine, University of Southern California, USA
Professor Lenz has supported the AGENT study forthe initiation of the project. He is also chairman forour international advisory board. During our lastadboard, he gave his strong support for our projectand helped in facilitating the connections with theleading KOL network internationally.
Professor Tabernero, is the coordinating PI for theAGENT trial and as previous chairman for ESMO heis also one of the leading KOL’s worldwide. Prof.Tabernero recently published a very positivereview on the arfolitixorin opportunity (attached)and has been a strong supporter of our programfor several years back. He is also part of ourinternational advisory board.
Prof Joseph Tabernero - Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
Prof. Sebastian Stintzing - CharitéUniversitätsmedizin Berlin, Berlin, Germany
Professor Yoshino is the leading colorectal KOL inJapan. When presented to the AGENT trial andarfolitixorin a bit more than a year ago, heimmediately realized the importance of the moleculeand agreed to be PI in Japan, he is also part of ourinternational adboard. Prof Yoshino was pivotal forthe success in discussions with PMDA and a verystrong supporter of the study design and endpoints.
Prof. Takayuki Yoshino - National Cancer Center Hospital East, Chiba, Japan
Professor Stintzing participated in our recentoncology seminar in Stockholm and is also both aninvestigator and adboard member. His messageduring the seminar is that Arfolitixorin is a uniqueopportunity in 1st line mCRC where there havebeen no improvements for a decade. He alsostrongly supports our endpoints in the AGENT trial.He also clearly stated the importance of theAGENT trial as a physician.
Link to presentation
© ISOFOL MEDICAL AB (publ)
Blockbuster potential in Colorectal Cancer alone
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~ $1Bin annual market potential
only in the 1st line treatment setting in the 7MM
1.8mGlobal colorectal cancer
(CRC) incidence
>370kAnnual mCRC drug treated patient
pool in 1st-3rd treatment line
Source: GLOBOCAN 2018, Cancer Incidence and Mortality Worldwide.;GlobalData 2017; GlobalData Colorectal Cancer: Competitive landscapeto 2026; Deallus Market research and forecast model 2018.
© ISOFOL MEDICAL AB (publ)
Primary market research in 7 major markets (7MM) + South Korea- Healthcare professionals (HCPs) view on arfolitixorin TPP
0% 20% 40% 60% 80% 100%
Asia
EU
US
Global
Minor Importance Significant Improvement Very significant Improvement
HCP opinion on arfolitixorin significance
HCPs were excited about arfol i t ixorin, 74% of HCPs indicated i t offered a signif icant or very signif icant
improvement vs. current treatment options
Region 1 2 3 4 5 6 7 8 9 10
Global
US
EU
Asia
Very excitingNot exciting
Source: Deallus Market research and forecast model 2018
A total of 34 physicians were interviewed (N=34 (US: 12, EU: 16, Asia: 6). Study performed by Deallus Consulting for Isofol Medical.
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© ISOFOL MEDICAL AB (publ)
Arfolitixorin could see market share of 50%, 42% and 31% in the US, Asia and EU respectively within the 1L mCRC setting
Source: Deallus Market research and forecast model 2018
A total of 34 physicians were interviewed (N=34 (US: 12, EU: 16, Asia: 6). Study performed by Deallus Consulting for Isofol Medical.
31%40%
31%24%25%
50%
33%
20%29% 31%
26%20%
47%42% 40% 40%
0%
10%
20%
30%
40%
50%
60%
Adjuvant 1L mCRC 2L mCRC 3L mCRC
Arfolitixorin MS (%) by Region & Line of Therapy
Global US EU Asia
• Arfolitixorin market share data is based on HCP willing to prescribe among all drug treated patients in each line of therapy
• Willingness to prescribe Arfolitixorin is greatest in the US (50% in 1LmCRC), followed by Asia (42% in 1L mCRC) and lowest in the EU (31% in 1L mCRC)
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© ISOFOL MEDICAL AB (publ)Source: GLOBOCAN 2018, Cancer Incidence and Mortality Worldwide.;GlobalData 2017; GlobalData Colorectal Cancer: Competitive landscapeto 2026; Deallus Market research and forecast model 2018.
Arfolitixorin target patient populations and estimated market share- A large number of drug treated mCRC patients in 1st to 3rd line is expected to be treated with arfolitixorin
mCRC treated patient pool 7MM
372 000
US: 50%
22 500
Arfolitixorin market share 1st line
26 700
15 600
About 65 000mCRC patients eligible for arfolitixorin treatment
in 1st line in the 7MM
EU531%
Japan42%
~ 9 months Average treatment length
Arfolitixorin market potential 1st line
16 000
Additional market share for arfolitixorin in 2nd-3rd line
24 000
19 000
Annual mCRC drug treated patient pool independent of 1st-3rd
treatment line
Arfolitixorin peak market share in 1st
line mCRC
About 60 000additional mCRC patients eligible for arfolitixorin
treatment in 2nd to 3rd line in the 7MM
>$1Bin annual market potential only in the 1st line treatment setting in the 7MM
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© ISOFOL MEDICAL AB (publ)Source: GlobalData 2017
Colorectal cancer market 2015 – 2025 (7MM)- Arfolitixorin expected to be used in 1st – 3rd line with peak market sales >$1B
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VEGF inhibitorsAvastin, Zaltrap, Cyramza
1st and 2nd line Target population: 100%
CRC market 2025 - ~$3B
EGFR inhibitors Erbitux & Vectibix
1st and 2nd lineTarget population: ~40%
CRC market 2023 - ~$2B
PD1/PD-L1 inhibitorsKeytruda & Optivo
1st and 2nd lineTarget population: 4%
CRC market 2025 - ~$1B
Novel 3rd line drugsLonsurf & Stirvaga
3rd and 4th lineTarget population: 100%
CRC market 2025 - ~$500M
Arfolitixorin – Novel TS inhibition1st line trial (possible extension to 2nd and 3rd)
Target population: 100%
CRC market 2026 > $1B in first line alone
Approved drugs
Clinical development
© ISOFOL MEDICAL AB (publ)
GlobalData CRC report 2018 – 2028 for 8MM- Arfolitixorin is presented as one of the most promising pipeline drugs in the new CRC report by GlobalData
● Global sales in 2028 estimated to be 8,1BUSD in 8MM with an CAGRof 2,4% from 2018. China has the highest growth rate, CAGR 4,8%.
● Avastin will maintain leadership despite introduction of biosimilarswith decreased sales from 2,4BUSD in 2018 to 1,5BUSD in 2028
● Arfolitixorin is perceived as one of the most promising pipeline drugsin CRC together with encorafenib (Braftovi).
● In US, EU and Japan, Global Data rate the launch of arfolitixorin asone of few events with major impact on the market.
● In the rating of the most important events the expected launch ofarfolitixorin in 2023 is expected to have a significant impact of themarket and perceived as a future leading brand.
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Avastin
Clinical attributes
Low High
Com
mer
cial
att
ribu
tes
Hig
hLo
w
Pipeline candidates
Marketed drugs
Zaltrap
Cyramza
ArfolitixorinOpdivo + Yervoy
Keytruda
Erbitux
VectibixGRANITE-001
TS-1
LonsurfNapabucasin
Stivarga
Tucatinib
Vitrakvi
Note: Adapted from ”Figure 3: Competitive Assessment of the Late-Stage CRC Pipeline Agents” from GlobalData April 2020 CRC report.Bubble size represents approximate peak-year sales extimates for recently approved and late-stage pipeline drugs for the treatment of CRC.
Mektovi + Braftovi
Tafinlar + Mekinist
Isofol’s drug candidateArfolitixorin
© ISOFOL MEDICAL AB (publ)
Arfolitixorin is the only drug in late stage to improve SoC for all-comers
3rd-line or greater1st-line 2nd-line 3rd-line
Novel Immuno CRC Agent~4% of patients
Stat inh + SoCNo threat to Arfolitixorin
B-Raf/MEK inh10% of patients
Line extension projectsSmall fraction of fragile
patients
ARFOX vs mFOLFOX6+ bev
AGENT
Very few late stage development projects in 1st or 2nd Line mCRC• IO projects targets 4% of patient population• Line extension project in a very small patient population• 2nd line projects in niche patient populations or on top of SoC
Arfolitixorin only drug in late stage to improve SoC and target all-comers
Current Phase III development landscape for mCRC Competitive analysis performed by Deallus Consulting
Source: Adapted from Oncology Resources Group , ONCrg Pipelines Strategies 2019. Deallus Primary Market research 2018 34
© ISOFOL MEDICAL AB (publ)
Breakthrough license agreement entered with Solasia Pharma K.K. – To develop and commercialize arfolitixorin in Japan
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Securing the Japanese market – the 2nd largest market for arfolitixorin
Strong validation from a specialized innovative oncology partner
Significant deal value – ~ USD 100 million as upfront and milestone payments
Tiered royalties on net sales in solid double-digit figures
Additional indications will be evaluated jointly by Solasia Pharma K.K. and Isofol
Solasia’s proven capabilities to developand commercialize oncology treatments in Japan and other Asian markets as well as their commitment to cancer patients make
them the ideal partner to supportour development and commercialization
efforts in Japan
© ISOFOL MEDICAL AB (publ)
The partnership for the Canadian market– A compelling strategic rationale
5 In par with commercialization strategy to ensure global access of arfolitixorin
1 Strong validation from a specialty pharmaceutical company
2 Significant deal value in relation to market size
3 Up to USD 23 million as upfront and milestone payments
4 Tiered royalties on net sales in solid double-digit figures
Endo and its operating company Paladin has a very successful track record of
commercializing innovative pharmaceutical products in Canada
and our partnership with them will be an invaluable component
of our strategy to ensure global access to arfolitixorin
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© ISOFOL MEDICAL AB (publ)
Pre-commercial preparations well in progress for launch readiness
37
● Ensure the success of the AGENT study in colorectal cancer
● Execute pre-commercialization activities in order to achieve Submission and launch readiness for approval Negotiation readiness for a global deal
Solid commercial forecast model established
● Favorable competitive environment
● Pricing and market access analysis established
● Commercial uptake analysis
Partnering
● Japanese and Canadian partner agreement secured
● Pre-Commercialization and negotiation readiness are
progressing well
Global commercial plan in development
● Partnership with Syneos Health to support in commercialization
● Medical affairs activities initiated in major markets
● Medical communication platform is being built
● Establishment of a Global commercial plan including life cycle
management plans well underway
Our focus
© ISOFOL MEDICAL AB (publ)Source: (1) GLOBOCAN 2018, Cancer Incidence and MortalityWorldwide. (2) GlobalData 2019, (3) Deallus Consulting December2014, (4) Datamonitor gastric camcer treatment tree Sruvery 2016, (5)Monocl Strategy Servoces Analysis 2016
Life cycle management - additional indications- Arfolitixorin can be used anywhere 5-FU is used and as rescue therapy after High Dose Methotrexate Treatment (HDMTX)
Pancreatic Cancer
Head & Neck Cancer
Gastric Cancer
Tripple Negative Breast CancerAdjuvant treatment setting• Almost 120 000 annual
Stage II/III patient treatments with 5-FU/LV in 7MM
Colorectal Cancer
Large cancer populations in which the current 5-FU/LV or capecitabine treatments can be optimized. Only for gastric and pancreatic cancer, the annual number of 5-FU/LV treated patients are about 63 000 in the 7MM
Suggested additional label expansions in combination with 5-FU Additional label expansions in HDMTX indications
Osteosarcoma
Burkitt’s Lymphoma PCNSLPrimary central nervous system lymphoma
About 33 000 patients in the 7MM are estimated to be treated with HDMTX followed
by rescue therapy with reduced folates (LV/LLV)
ALLAcute Lymphoblastic Leukemia
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© ISOFOL MEDICAL AB (publ)
Commercial grade manufacturing process in place
ACTIVE PHARMACEUTICAL INGREDIENT
arfolitixorin
Production technology patented by Merck
Use patents by Isofol
First large scale GMP batch completed and released summer 2017
First validation batch manufactured in February 2020
IP & SUPPLY AGREEMENTS WITH MERCK & CIE VALID AT LEAST UNTIL 2038
FINAL DRUG PRODUCT
LARGE SCALE DRUG MANUFACTURING SECURED
40
© ISOFOL MEDICAL AB (publ)
Patent Type Region Expiry Status Patent holder
[6R]-MTHF Substance / Formulation USA 2037 Granted
Europe, Japan, China, etc. 2034 Granted in several regions including
Europe, Japan & China
MTHF Formulation USA 2029 Granted
Europe, Japan, Canada, etc. 2024 Granted
New clinical discovery Clinical treatment, dosage regimen
US, Europe, Japan, Canada, etc. 2038 Granted in US and Japan pending in
other regions
New clinical discovery Clinical treatment,dosage regimen
US, Europe, Japan, Canada, etc. 2038 Patent pending
New clinical discovery Gene Expression US, Europe, Canada and Australia 2035 Granted in US, pending in other regions
New clinical discovery Biomarker in blood US, Europe, Japan,Canada, etc. 2038 Granted in US, pending in other regions
New clinical discovery Clinical treatment, dosage regimen
US, Europe, Japan,Canada, etc. 2039 Patent pending
Intellectual property overview of main patents
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© ISOFOL MEDICAL AB (publ)
ManagementJarl Ulf Jungnelius, MD
CEO
Tony Gustavsson, BScChief Commercial Officer
Gustaf Albèrt, MSCChief Financial Officer, Vice CEO
Roger Tell, MD, PhDChief Medical OfficerChief Scientific Officer
Pär-Ola Mannefred, MBAChairman of the Board
Experience as aBoard memberand investments
Magnus Björsne, PhD, MBABoard Member
Paula BoultbeeBoard Member
Alain Herrera, MD, PhDBoard Member
Anna Belfrage, MBABoard Member
Bob Marchesani, MBABoard Member
Board of directors
Aram Mangasarian, PhD, MBABoard Member
Experienced Leadership
Over 20 years experiencein the biotechnology industry
Over 20 years of oncologycommercialization
Over 20 years of oncologysales & marketing
Over 20 years of oncology drug development experience
Over 20 years of businessdevelopment
Over 20 years of oncology drug development experience
Board certified Oncologist
Exclusive experience asa Board member with financial background
BSc in Business, Administrationand Economics
Master of Science in Economics andInternational Accounting and Auditing
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© ISOFOL MEDICAL AB (publ)
The arfolitixorin opportunity
● Arfolitixorin: late-stage de-risked CRC opportunity
● Strong validation from two licensing agreements entered during 2020
● Unprecedented low regulatory hurdle for approval in 1st line mCRC
● Study readout H2 2021 (440 patients) or H1 2022 (660 patients)
● Submission and negotiation readiness prior to NDA
● Global launch starting in 2023
● Long IP protection US and Japan 2038, RoW 2034
● Blockbuster market potential – more than $1bn in annual sales in first line mCRC
● Excellent life cycle opportunity in other cancer indications
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© ISOFOL MEDICAL AB (publ)
Ongoing and completed clinical trials in osteosarcoma and CRCNCT ID Study ID Start End Phase Patients
enrolled Interventions Status Results
Osteosarcoma
01987102 ISO-MTX-003 12/2013 03/2017 I/II 18 Arm 1: HDMTX+[6R]-MTHF (2 dose levels) Completed Final report available
02383901 ISO-MTX-OB1* 10/2014 09/2015 NA 118 MAP treatment including LV(not including arfolitixorin) Completed Final report available
Colorectal/Rectal Cancer
03750786 ISO-CC-007 12/2018 ~06/2021 III 387***Arm 1: [6R]-MTHF+5-FU+oxaliplatin+bevacizumab
Arm 2: LV+5-FU+oxaliplatin+bevacizumab Recruiting N/A
02244632 ISO-CC-005 09/2014 01/2020 I/II 105Arm 1-6: [6R]-MTHF+5-FU, [6R]-MTHF+5-
FU+Irinotecan, [6R]-MTHF+5-FU+Oxaliplatin±bevacizumab, [6R]-MTHF+5-
FU+Irinotecan1
Completed Initial results
01681472 ISO-CC-002 09/2012 08/2013 I/II 32Arm 1: LLVArm 2: LLV
Arm 3: [6R]-MTHFArm 4: [6R]-MTHF
Completed**
Published
01397305 ISO-MC-091 04/2011 11/2014 I/II 24 Arm 1: Pemetrexed+[6R]-MTHF Completed Published
03203564 ISO-FF-001 06/2017 08/2017 I 33 Arm 1: [6R]-MTHF (3 dose levels)Arm 2: Placebo Completed Final report available
* Observational retrospective study** Has results on clinicaltrials.gov*** As of 09.30.20201) There are in total 6 study Arms, with between 30 mg/m2 and 240 mg/m2 [6R]-MTHF in combination with 5-FU only or with 5-FU plus irinotecan or oxaliplatin ± bevacizumab
Reference: clinicaltrials.gov
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© ISOFOL MEDICAL AB (publ)
Extensive research has been performed building a strong scientific case around the potential benefits of arfolitixorin
Area Title Article Link
PK-MOA Folate levels measured by LC -MS/MS in patients with colorectal cancer treated with different leucovorin dosages
Cancer Chemother Pharmacol. 2014 74. 1167-74.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236605/
PK-MOAA pharmacokinetic and pharmacodynamic investigation of *Modufolin® compared to Isovorin® after single dose intravenous administration to patients with colon cancer: a randomized study
Cancer Chemother Pharmacol. 2015 Jan;75(1):37-47
https://www.ncbi.nlm.nih.gov/pubmed/25342290
REVIEW A Review of the Evolution of Systemic Chemotherapy in the Management of Colorectal Cancer
Clinical Colorectal Cancer, Vol. 14, No. 1, 1-10 2015
https://www.ncbi.nlm.nih.gov/pubmed/25579803
MOA-GENETIC BIOMARKER
Expression of Folate Pathway Genes in Stage III Colorectal Cancer Correlates with Recurrence Status Following Adjuvant Bolus 5-FU-Based Chemotherapy
MOL MED 21:597-604, 2015 https://www.ncbi.nlm.nih.gov/pubmed/26193446
PK-SAFETYPhase 1 dose de-escalation trial of the endogenous folate [6R]-5,10-methylene tetrahydrofolate in combination with fixed-dose pemetrexed as neoadjuvant therapy in patients with resectable rectal cancer.
Invest New Drugs. 2015 Oct;33(5):1078-85.
https://www.ncbi.nlm.nih.gov/pubmed/26189513
REVIEW Folates as adjuvants to anticancer agents: Chemical rationale and mechanism of action Critical Reviews in Oncology/Haematology106 2016 118-131
https://www.croh-online.com/article/S1040-8428(16)30175-5/pdf
CLINICALISO-CC-005 An open label multiple-site dose cohort phase I/Ii study in patients with stage IV Colorectal cancer (Phase 1/Iia / 4 doses + 5FU +/-irinotecan or oxaliplatin+/-bevacizumab. Tolerability in stage 4 CR in 1st/2nd line over 8 weeks).
POSTER ABSTRACT / ECCO 2017 / February 2017 Volume 72, Supplement 1, Page S71
https://www.ejcancer.com/article/S0959-8049(17)30310-6/abstract
GENETIC-BIOMARKER
Expression of folate pathway genes with putative impact on leucovorin metabolism and outcome of patients with advanced colorectal cancer
POSTER / Annals of Oncology, Volume 28, Issue suppl_3, 1 June 2017
https://academic.oup.com/annonc/article/28/suppl_3/mdx261.279/3893944
GENETIC-BIOMARKER
Folate gene prediction of treatment response to 5-FU and leucovorin in advanced colorectal cancer
ABSTRACT - GI ASCO 2018 / JCO http://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.3550
GENETIC-BIOMARKER
Folate gene prediction of treatment response to 5-FU and leucovorin in metastasizing colorectal cancer
POSTER / ASCO 2018 poster https://meetinglibrary.asco.org/record/158945/abstract
MOA-SAFETY-CLINICAL
ISO-CC-005; a phase I/II study of arfolitixorin ([6R]-5,10-MTHF) in combination with 5-fluorouracil (5-FU), irinotecan and oxaliplatin ± bevacizumab in patients with metastasizing colorectal cancer
POSTER / ESMO 2018 poster https://academic.oup.com/annonc/article/29/suppl_8/mdy281.115/5142250
* Modufolin® = arfolitixorin 49
© ISOFOL MEDICAL AB (publ)
Extensive research has been performed building a strong scientific case around the potential benefits of arfolitixorin
Area Title Article Link
PK-MOA Increasing Effectiveness of Chemo for Metastatic Colorectal Cancer Oncology Times. 2019 April; 41(8)https://journals.lww.com/oncology-times/Fulltext/2019/04200/Increasing_Effectiveness_of_Chemo_for_Metastatic.1.aspx
CLINICAL Open-label Phase III Study of Arfolitixorin vs Leucovorin in Modified FOLFOX-6for First-line Treatment of Metastatic Colorectal Cancer: AGENT
POSTER/ABSTRACT / ESMO 2019 poster https://www.annalsofoncology.org/article/S0923-7534(19)58884-6/fulltext
CLINICAL Novel Therapy May Boost Efficacy of Chemotherapy Backbone in mCRC OncolyLive. 2019 November; 20(22)https://www.onclive.com/view/novel-therapy-may-boost-efficacy-of-chemotherapy-backbone-in-mcrc
PK-MOAPlasma deoxyuridine levels in metastatic colorectal cancer patients correlate with clinical responseafter 5-FU-based therapy in combination with arfolitixorin
ASCO-GI Congress 2020 POSTER. Abstract 185
https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.4_suppl.185
CLINICAL An open-label Phase III study of arfolitixorin vs leucovorin in modified FOLFOX-6 for first-line treatment of metastatic colorectal cancer
ASCO-GI Congress 2020 POSTER. Poster no. TPS268
https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.4_suppl.TPS268
PK-MOAPlasma deoxyuridine as a surrogate marker for toxicity and early clinical response in patients with metastatic colorectal cancer after 5-FU-based therapy in combination with arfolitixorin
Cancer Chemother Pharmacol. 2020 Oct 24. doi: 10.1007/s00280-020-04173-2.
https://link.springer.com/article/10.1007/s00280-020-04173-2
* Modufolin® = arfolitixorin 50
Isofol Medical AB (publ)
Biotech CenterArvid Wallgrens Backe 20SE-413 46 Göteborg, Sweden
© ISOFOL MEDICAL AB (publ)
Company presentation, November 2020. ISO-44, rev6 draft