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TGF-b ANTISENSE THERAPY(OT-101/TRABEDERSEN)

In Situ Cancer Vaccine

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Cancer- Current Landscape

In 2015- cancer death increased to 8.8 million of the 55.8 million deaths- or 1 of every 6 deaths.

In 2035- cancer death and new cases are projected to be 14.6 million and 24 million. AACR Cancer Progress

Report 2018

Despite robust gain in survival between 1977 and 2013, pancreatic cancer (PC) and glioblastoma (GBM) remain low. JNCI J Natl Cancer Inst (2017) 109(9)

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Cancer Vaccine

Genetic mutations are characteristics of cancer and are associated w/ treatment failures.

Harnessing innate immunity against these neoepitopes has potential lasting disease control

Mutation-based vaccines are agnostic to the cancer type and universally applicable to any patient.

However, current platform will require overcoming the challenges of optimized vaccine design, manufacturing and affordability, and identification of the most suitable clinical setting. Nature Biomedical Engineering 2:566–569 (2018)

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In Situ Cancer Vaccine (ISCV)- Oncotelic Invention

PC and GBM are poor candidates for Immunotherapy/Vaccine due to low somatic mutations.

ISCV eliminates the complexity of tumor vaccine and fully operational in low somatic mutation states such as Pancreatic Cancer and Glioblastoma. N Engl J Med 2017; 377:2500.

ISCV: TGF-β inhibitor (ie. OT-101) lifts the immunosuppression and primes the innate immune system against the tumor. Subsequent chemotherapy boost further expands the neoepitopes via chemotherapy-induced immunogenic cell death (ICD)

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TGF-β- Centrally Important Target in Immunotherapy

Interest in TGF-β and immunotherapy started since 2000 and has remained high to date.

Immunotherapy publications on galunisertib (TGF-β receptor inhibitor) started to build in 2014 and growing.

TGF-β is important in suppression of Treg and other immune mediators

Combinations of galunisertib and checkpoint inhibitors are promising in preclinical testings.

August 2018- $625M licensing deal for preclinical stage TGF-beta inhibitor between biotech Argenxand AbbVie.

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Publication record of galunisertibwith years as obtained from Pubmed literature survey

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OT-101/ Trabedersen. Oncotelic Clinical Stage TGF-β Asset

mRNA Therapeutics against human TGF-β2 messenger RNA

Targeting centrally important TGF-β. June 2018 Scholar Rock went IPO at $400M valuation based on preclinical stage TGF-β assets.

Utilize cutting edge antisense platform. Antisense platform is one of the mRNA therapeutics identified as among the top 10 disruptive technologies. Dec 2018- Moderna went IPO at $8B valuation on early stage mRNA therapeutics; and May 2018- A Billion dollar deal for an antisense drug candidate between Ionis and Biogen/ Ionis – an antisense company- with a valuation of $7B.

Potential for breakthrough designation for early approval

Strong Patent protection until 2037

Orphan designation granted for three tumor indications in US & EU

Manufacturing process optimized and scaled up sufficient drug to treat over 10,000 glioma pts

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G004- Phase 2b Clinical Trial

Title: A multi-national, multi-center, open-label, active-controlled, randomized parallel-group dose-finding study to evaluate the efficacy and safety of two doses of OT-101 in adult patients with recurrent high-grade glioma, administered intratumorally as continuous high-flow microperfusion over a 7-day period every other week.

Pts#: N = 145. OT-101 10 μM, N = 40; OT-101 80 μM, N = 49; Control, N = 45

Primary Objective: To evaluate the efficacy of two doses (10 μM and 80 μM) of AP 12009/ OT-101 on the tumor control rate (CR+PR+SD) at six months based on central MRI assessment in comparison to standard treatment (Temozolomide [TMZ] or combination of Procarbazine, CCNU [Lomustine], and Vincristine [PCV]).

Secondary Objectives:

Overall survival/ 6-month and 12-month overall survival

Tumor control rates at 3, 8, 10, 12 and 14 months/Best of all response rates

6-month progression-free survival/Time to progression/Time to response

Quality of Life (QoL) at 3, 6, 8, 10, and 12 months /Independent Living Score (ILS)-like score. Change of Karnofsky Performance Status (KPS) at 3, 6, 8, 10, and 12 months

Safety and tolerability

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G004: Tumor Reduction as Proof Of Concept for In Situ Cancer Vaccine

CR and PR were associated with tumor reduction; SD and PD were associated with tumor growth.

T1/2 to achieve 50% tumor reduction was 199 days - the same as OT-101 treatment time of 180 days.

Early tumor reduction (0-180 days) from OT-101 single agent activity; and, late tumor reduction (>180 days) from OT-101/Chemotherapy combination activity

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G004: Target Population – Chemo naïve Recurrent GBM

Overall OT-101 is noninferior to TMZ in efficacy but superior to TMZ in being non-myelosuppressive

OT-101 is superior to TMZ in chemo naïve patients with recurrent glioblastoma with 33.3% survival when the TMZ group has only 5.6% survival at 2 yr (p=0.0258, Fisher exact test, two-sided). This was further improved by combination with chemotherapy to 50%.

As typical for immunotherapy OT-101 major impact was not on the slope of the survival curve (mOS) but the tail of the survival curve (2-year survival). Harris SJ et al. (2016) Immuno-oncology combinations: raising the tail of the survival

curve. Cancer Biol. Med. 13:171-193

Efficacy- Long Overall Survival

Events

OT-101Chemo

naïve pts + Chemo

OT-101 Chemo

naïve pts

TMZ Chemo naïve

pts

# alive 7 9 0

# deaths 23 36 18

mOS (mos) 26.2 13.3 11.1

2 yr Survival

Alive 15 15 1

Dead 15 30 17

% 50.0% 33.3% 5.6%

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TMZ(N = 45)

Patients with at least one AE n(%)n§ n(%)n§

Leukopenia 0 8 (17.8) 9

Neutropenia 2 (2.2) 2 10 (22.2) 25Thrombocytopenia 0 8 (17.8) 28

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P001- Phase 1/2 Clinical Trial

Title: An Open-Label, Multicenter Dose-escalation Study to Evaluate the Safety and Tolerability of OT-101 (TGF-β2-specific Phosphorothioate Antisense Oligodeoxynucleotide), Administered Intravenously in Adult Patients with Advanced Tumors Known to Overproduce TGF-β2, Who are Not or No Longer Amenable to Established Therapies.

Pts#: 61 (37 with pancreatic cancer; 19 with malignant melanoma; 5 with colorectal cancer)

Primary Objective: To determine the maximum tolerated dose (MTD) and the dose limiting toxicities (DLTs) of two cycles of trabedersen administered intravenously (i.v.) for 7 days or for 4 days every other week.

Secondary Objectives:

To determine the safety and tolerability of OT-101

To assess the plasma and urine pharmacokinetic profile of OT-101

To determine the effect of OT-101 on TGF-β2 plasma concentration levels.

To assess the potential antitumor activity of OT-101, as assessed by the effect on tumor size and tumor markers.

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P001 Phase 1/2 Trial: Proven Efficacy/Safety in PC

Patient 1006: CR as far out as 77 mos

Surgery: Whipple’s procedure

1st line: 5-FU/LV, Dose 425 mg/m2

2nd line: 5-FU/LV, Dose 2600 mg/m2/24hr

3rd line: Gemcitabine, Dose 1000 mg/m2/week

OT-101- Liver mets/ Complete Response (Black Line)

Patient 1022: OS of 40 months

Surgery: Whipple’s procedure

1st line: Radiation therapy (50 Gy)

2nd line: 5FU

OT-101- Liver Mets/ Stable Disease (Blue Line)

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OT-101 Immunotherapy Combinations

Immunotherapy Combinations

OT-101 Facilitation of Immune cells Entry to the tumor

External Collaborations

IL-2 / NK- Immune reservoir expansion

Internal Program

Antibody Directed CART

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Enhanced Adoptive Immunotherapy with OT-101

In vitro- OT-101 (AP 12009) reduced TGF-β2 secretion and increased LAK cell-activity against all tumor lines by 400% and 364% in comparison to the untreated control and compared to the Lipofectin control, respectively.

Addition of active rh-TGF-β2 protein added suppressed the cytotoxic activity of the immune cells in a dose dependent manner.

PBMC – LAK in vitro

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Enhanced Adoptive Immunotherapy with OT-101

Preclinical- LS174T xenograft was treated with PBMC or PBMC + OT-101. OT-101 significantly enhanced the activity of PBMC against the xenograft.

Clinical- OT-101 treatment resulted in delayed tumor response typical of immunotherapy

PBMC- Xenograft In Vivo

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/ 15Confidential

Expertise: Drug Development & Commercialization

Vuong Trieu PhD Founder/CEO/Chairman of IgDrasol

CSO/Director of Sorrento Therapeutics (SRNE:Nasdaq)

Founder/CEO/Executive Chairman of Marina Biotech (MRNA:OTCQB)

Founder/CEO/Chairman of Autotelic Inc – an incubator of late stage assets

Founder/CEO/Chairman of Oncotelic Inc- a developer of TGF-beta antisense with potential to cure cancer

Proven Entrepreneur• Start ups

• Public Cos

• Financing

• Reverse Merger

• FDA Regulatory

• Sales & Marketing

Broad Industry Experience

Select Commercial Successes for Vuong Trieu

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• Total Care Platform