Imugene — In-licensing deal for CF33 oncolytic virus

Imugene — In-licensing deal for CF33 oncolytic virus

Imugene has agreed to acquire a worldwide exclusive licence for a highly potent, chimeric oncolytic poxvirus known as CF33. The company proposes to progress CF33 into a Phase I safety study in 2020, including a cohort treated with CF33 in combination with a checkpoint inhibitor. This strategy is similar to that pursued by Viralytics, which was acquired by Merck for A$502m in 2018 after conducting studies of its Cavatak oncolytic virus in combination with Merck’s checkpoint inhibitor, Keytruda. The CF33 acquisition strengthens Imugene’s immunooncology pipeline, which is currently focused on B-cell vaccines. As the CF33 deal is a related party transaction and therefore contingent on shareholder approval, we maintain our published valuation of A$159m or 4.4 cents per share.

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Imugene

In-licensing deal for CF33 oncolytic virus

In-licensing deal for CF33

Pharma & biotech

15 July 2019

Price

A$0.016

Market cap

A$58m

US$0.76/A$

Net cash (A$m) at 31 March 2019

21.0

Shares in issue

3,609.8m

Free float

69%

Code

IMU

Primary exchange

ASX

Secondary exchange

N/A

Share price performance

%

1m

3m

12m

Abs

(0.0)

(5.9)

(38.4)

Rel (local)

(2.4)

(12.0)

(42.4)

52-week high/low

A$0.03

A$0.01

Business description

Imugene is developing B-cell vaccines that aim to induce polyclonal antibody responses against important cancer targets, as an alternative to monoclonal antibodies. HER-Vaxx is in Phase II in HER2 +ve gastric cancer. Imugene has agreed to in-license CF33, a potent oncolytic virus that attacks and kills cancer cells.

Next events

Shareholder vote on CF33 transaction

TBD

Submit CF33 IND

H120

Initiate CF33 Phase I

2020

Analysts

Dennis Hulme PhD

+61 (0)2 8249 8345

John Savin PhD

+44 (0)20 3077 5735

Imugene is a research client of Edison Investment Research Limited

Imugene has agreed to acquire a worldwide exclusive licence for a highly potent, chimeric oncolytic poxvirus known as CF33. The company proposes to progress CF33 into a Phase I safety study in 2020, including a cohort treated with CF33 in combination with a checkpoint inhibitor. This strategy is similar to that pursued by Viralytics, which was acquired by Merck for A$502m in 2018 after conducting studies of its Cavatak oncolytic virus in combination with Merck’s checkpoint inhibitor, Keytruda. The CF33 acquisition strengthens Imugene’s immunooncology pipeline, which is currently focused on B-cell vaccines. As the CF33 deal is a related party transaction and therefore contingent on shareholder approval, we maintain our published valuation of A$159m or 4.4 cents per share.

Year end

Revenue (A$m)

PBT*
(A$m)

EPS*
(c)

DPS
(c)

P/E
(x)

Yield
(%)

06/17

1.2

(2.5)

(0.1)

0.0

N/A

N/A

06/18

1.8

(3.9)

(0.1)

0.0

N/A

N/A

06/19e

2.4

(6.1)

(0.2)

0.0

N/A

N/A

06/20e

3.3

(8.2)

(0.2)

0.0

N/A

N/A

Note: *PBT and EPS are normalised, excluding exceptional items.

CF33: Potent oncolytic virus that targets cancer cells

CF33 is a novel, chimeric oncolytic poxvirus developed at the City of Hope Cancer Center in California, which was deliberately designed to maximise its potency at killing cancer cells. Like other oncolytic viruses in development, CF33 replicates in tumour cells, causing those cells to rupture, as well as triggering the body’s immune system to recognise and attack the cancer cells. Imugene proposes to develop CF33 in combination with checkpoint inhibitors (a strategy sometimes described as pushing on the accelerator while releasing the brakes on the immune response).

Shareholder approval required

CF33 is being in-licensed from a company associated with Imugene’s chairman, Paul Hopper. Approval will be sought at a shareholder meeting (date TBD).

HER-Vaxx Phase II started, PD1-Vaxx Phase I planned

Imugene initiated a randomised Phase II study of its HER-Vaxx B cell vaccine in HER2-positive gastric cancer in March. It also aims to initiate a Phase I study of its PD1-Vaxx PD1 B-cell vaccine in 2020.

Valuation: Maintained at A$159m or 4.4 cents/share

As the proposed transaction is contingent on shareholder approval, we have not attempted to place a value on the CF33 programme, so for now we maintain our published forecasts and last published valuation of A$159m or 4.4 cents per share. With cash of A$21m at 31 March 2019, Imugene’s existing clinical programme is funded beyond our FY20 forecast horizon (not including licensing deal costs or trial expenditure for CF33).

CF33 oncolytic virus licensing deal

Imugene has agreed to acquire a worldwide exclusive licence to the novel, highly potent, oncolytic poxvirus known as CF33, which is poised to enter Phase I clinical trials in 2020.

The CF33 technology was developed at the City of Hope Cancer Center in Los Angeles, California (City of Hope). Imugene has agreed to pay City of Hope licence fees comprising an upfront payment, annual maintenance fees, development and commercial milestone payments, a royalty on net sales and sublicensing fees.

As part of the overall transaction, Imugene has entered an agreement to acquire 100% of the unlisted company, Vaxinia. As Vaxinia’s major shareholder is Paul Hopper, Imugene’s executive chairman, the deal is a related party transaction that requires shareholder approval at an extraordinary general meeting (date to be set). The Vaxinia acquisition includes an upfront cash payment of A$462,500 and the issue of Imugene shares valued at A$1.6m. The Vaxinia shareholders will also be eligible for equity payments on the achievement of development milestones including granting of the Investigational New Drug (IND) by the US FDA, dosing the first patient in a Phase I clinical trial and the Phase I trial demonstrating safety.

The proposed clinical development strategy for CF33 (combination therapy with immune checkpoint inhibitors) is similar to that pursued by Viralytics, which led to its acquisition by Merck for A$502m, announced in February 2018. While the transaction gives Imugene a foothold in a space that has attracted a lot of pharma interest, it is also an area where there are a large number of competing products in development. Therefore, we suspect that Imugene will need to demonstrate superior efficacy in the clinic in order to attract a pharma partner.

Overview of CF33

Oncolytic viruses aim to infect and kill cancer cells. A large number of oncolytic virus candidates have been developed and tested over the past 30 years; while they have been shown to be safe, their efficacy to date has been modest.

In an attempt to improve on this modest efficacy, CF33 was developed through a process that aimed to maximise its potency against cancer cells while at the same time maintaining adequate safety. CF33 has been shown in preclinical studies to selectively target and destroy tumour cells without affecting healthy cells.

CF33 was created by researchers at the City of Hope by infecting a cell line with six different strains of the vaccinia virus (widely used in smallpox vaccines) plus raccoonpox, rabbitpox and cowpox viruses. The presence of the nine different virus strains in the cells at the same time allowed the genes from the different strains to be rearranged by homologous recombination to form novel chimeric daughter viruses that contained different combinations of genes from the parental virus strains. One hundred different chimeric viruses were purified and tested for potency against a panel of cancer cell lines. CF33 was the most potent of the 100 chimeric viruses tested.

Exhibit 1 shows that CF33 was more potent than each of the parental virus strains when compared across a panel of 54 solid tumour cell lines. Exhibit 2 shows the individual results from a subset of the panel, comprising four triple-negative breast cancer (TNBC) cell lines. Exhibit 2 shows that whereas none of the viruses was effective against the first two cell lines at the dose tested, CF33 (bright green bar) was more effective than any of the parental viruses against the BT549 and HS578T cell lines.

Exhibit 1: CF33 showed superior cancer cell killing compared to parental viruses in a panel of 54 solid cancer cell lines

Exhibit 2: CF33 killed more TNBC cells than the parental viruses in high-throughput screen

Source: O’Leary et al. J Transl Med (2018) 16:110. Note: CF17 is a second chimeric pox virus that was created at the same time as CF33; the other columns represent the nine parental viruses/virus strains.

Source: Choi et al Surgery 163 (2018) 336–342. Notes: bright green bar=CF33; none of the viruses were effective against the first two cell lines at the dose tested (MD-MBA-231 and MD-MB-468). CF33 was more effective than any of the parental viruses against BT549 and HS578T cell lines. VACV= parental vaccinia virus strains.

Exhibit 1: CF33 showed superior cancer cell killing compared to parental viruses in a panel of 54 solid cancer cell lines

Source: O’Leary et al. J Transl Med (2018) 16:110. Note: CF17 is a second chimeric pox virus that was created at the same time as CF33; the other columns represent the nine parental viruses/virus strains.

Exhibit 2: CF33 killed more TNBC cells than the parental viruses in high-throughput screen

Source: Choi et al Surgery 163 (2018) 336–342. Notes: bright green bar=CF33; none of the viruses were effective against the first two cell lines at the dose tested (MD-MBA-231 and MD-MB-468). CF33 was more effective than any of the parental viruses against BT549 and HS578T cell lines. VACV= parental vaccinia virus strains.

While the rationale behind the design of CF33 is the belief that the higher potency will give it an efficacy advantage in the clinic, the strategy has a number of other advantages. These include the fact that the new chimeric virus has generated fresh intellectual property (patent application filed) and that the lower number of virus particles needed to infect tumour cells will reduce the cost of manufacturing each dose of virus used to treat patients.

Like other vaccinia-based oncolytic viruses in development, CF33 has had its cancer selectivity enhanced through the inactivation of the thymidine kinase (TK) gene. The inactivation of TK increases tumour selectivity and improves safety, as it means that the virus can only replicate in rapidly dividing cells (such as tumour cells) which have a large pool of available nucleotides, including thymidine. Preclinical studies have shown that inactivating the TK gene does not affect the growth and cytotoxic potential of CF33 in cancer cells.

In addition, CF33 has been engineered to express the human sodium iodide symporter (hNIS) gene. hNIS is a cell surface protein that transports iodine into the thyroid gland for thyroid hormone synthesis. When expressed in tumour cells, hNIS transports radioactive iodine (131I) or rhenium (188Re) into the cell for tumour imaging or therapy.

CF33 is effective in a range of animal models of cancer

CF33 has shown promising efficacy in a range of mouse models of cancer. Exhibits 3 to 5 show that CF33 was able to either shrink tumours or arrest the growth of both injected and non-injected tumours, when administered by either intratumoural or intravenous injection. The studies shown in Exhibits 3 to 5 were carried out in standard xenograft models of breast, pancreatic and colorectal cancers, in which human cancer cell lines were injected into immunocompromised ‘nude’ mice, which do not reject the transplanted human cells.

Exhibit 8, on page 7, shows that CF33 is also effective at low doses in an animal model of lung cancer.

Some of the preclinical studies were conducted using CF33 virus that has been modified to express the firefly luciferase gene. Firefly luciferase is an enzyme that produces a bioluminescent light signal in the presence of an appropriate substrate. The light signal allows real-time imaging of CF33-infected tissue in live animals. The modified virus is known as CF33-Fluc.

Exhibit 3: Injection of as few as 1,000 CF33 virus particles caused tumour shrinkage in TNBC model

Source: Imugene, based on data presented in Choi et al Surgery 163 (2018) 336–342

Exhibit 4: CF33 arrested colorectal cancer tumour growth after intratumoural or intravenous injection in mouse model

Source: O’Leary et al. Molecular Therapy: Oncolytics Vol. 9 June 2018

Exhibit 5: Intratumoural injection of CF33 caused injected pancreatic cancer tumours to shrink and inhibited growth of non-injected tumours in mouse model

Source: O’Leary et al. J Transl Med (2018) 16:110

Exhibit 5: Intratumoural injection of CF33 caused injected pancreatic cancer tumours to shrink and inhibited growth of non-injected tumours in mouse model

Source: O’Leary et al. J Transl Med (2018) 16:110

Abscopal effect: CF33 causes shrinkage in uninjected tumours

The abscopal effect refers to a phenomenon in the treatment of metastatic cancer whereby shrinkage of untreated tumours occurs following the localised treatment of distant tumours by methods such as radiation therapy or intratumoural injection. Instances of abscopal effects have been reported for other oncolytic viruses, including for Viralytics’ Cavatak.1

  Fountzilas et al. Oncotarget, 2017, Vol. 8, (No. 60), pp: 102617–102639

Published reports of preclinical studies conducted with CF33 data show a number of examples of the virus spreading to non-injected tumours and causing tumour shrinkage, in human cancer cells implanted in immunocompromised ‘nude’ mouse models. Exhibit 6 shows an example of this in a pancreatic cancer model.2

  O’Leary et al. J Transl Med (2018) 16:110.

Athymic nude mice are used in these studies because they have impaired immune systems and do not reject the transplanted human cell lines. The impaired immune system also means that it is easier for virus to spread in nude mice than it is in animals with intact immune systems. Therefore, it is important to note that Imugene’s slide presentation on the CF33 deal states that it has preclinical data showing regression of tumours that did not have viral spread (ie presumably due to an adaptive immune response), and increased infiltration of both injected and uninjected tumours by CD8+ T cells and other immune cells.

Furthermore, cells infected by poxviruses such as vaccinia secrete two forms of virus, an extracellular enveloped virus (EEV) form, which is surrounded by a host-derived membrane and is largely invisible to the host’s immune system, which makes it easier to spread within the body.

These two factors may enable CF33 to generate abscopal responses in clinical studies in cancer patients.

Exhibit 6: CF33 carrying luciferase reporter gene illustrates viral spread to non-injected pancreatic cancer tumour in immunocompromised mouse model

Source: O’Leary et al. J Transl Med (2018) 16:110. Note: (c) CF33-Fluc is the CF33 chimeric virus engineered to express firefly luciferase to enable real time imaging of CF33-infected tissue. The injected pancreatic cancer tumour is shown on the left hand side of each image – over the course of 27 days the injected tumour regresses and the non-injected tumour (shown on the RHS of the mouse) becomes infected with CF33-Fluc and expresses high levels of luciferase activity. (d) CF33-Fluc virus counts were at least 10,000-fold higher in tumour tissue than other organs. This study was conducted in immunocompromised ‘nude’ mice.

CF33 safety examined in an immunocompetent mouse model

The safety of vaccinia virus, which contributes the majority of the CF33 genome, has been confirmed over a long period of time via its use as a smallpox vaccine. However, given that CF33 also contains components of the cowpox, rabbitpox and raccoonpox viruses, less is known about the safety characteristics of the chimeric virus.

To date, more than 500 mice have been treated with derivatives of CF33. More than 50 mice have been treated with doses of up to 10 million infectious virus particles (pfu), both intravenously and intratumourally, without any sign of toxicity. Exhibit 7 shows that when immunocompetent mice were injected intratumourally with 10m pfu of two different CF33 derivatives, no virus was detected in any other organ seven days after the injection, whereas virus was detected in the tumour.

Furthermore, as the chart labelled (d) in Exhibit 6, above, shows, in the immunocompromised nude mice tumour model, CF33 virus counts were at least 10,000 fold higher in tumour tissue than other organs. This shows that CF33 is highly selective for replicating in tumour cells rather than in normal tissue.

Exhibit 7: In immunocompetent mice, CF33 virus derivatives were undetectable in any other organ seven days after intratumoural injection

Source: Imugene. Note: Immunocompetent BALB/c mice were injected with 10m pfu intratumourally into a single tumour in the mammary fat pad.

CF33 beats Amgen and Genelux viruses in lung cancer model

The potency of CF33 was compared to that of Amgen’s marketed oncolytic virus, Imlygic (T-vec) and a vaccinia-based virus that is in clinical development, GLV-1h68 (GL-ONC1, Genelux) that could be potential competitors to CF33. The study in cancer cell lines showed that CF33 was two to three orders of magnitude more potent than the other two viruses. That is, a 100-fold to 1,000-fold lower dose of CF33 virus particles was required to kill tumour cells in culture, compared to the two other oncolytic viruses (Exhibit 8, left hand panel).

CF33 was also tested against T-vec and GL-ONC1 in a mouse mode of lung cancer. The two panels on the right in Exhibit 8 show that an intratumoural injection of CF33 results in greater tumour shrinkage than an injection of either T-vec or GL-ONC1, both in the injected tumour and in a non-injected tumour in the same mouse.

Exhibit 8: CF33 causes more cancer cell killing and tumour shrinkage than the Amgen or Genelux viruses

Source: Imugene. Notes: Left hand panel compares the three oncolytic viruses in a pancreatic cancer cell line; the two panels on the right hand side compare the effect of the three viruses on injected and non-injected tumours in A549 lung cancer xenografts in immunocompromised nude mice that were injected at a dose of 1,000pfu/mouse; OncoVex= T-vec; 1pfu = 1 infectious virus particle (plaque forming unit).

CF33 clinical development plan

Imugene proposes to commence clinical studies of CF33-hNIS in 2020. The plan includes a pre IND (investigational new drug) meeting with the FDA planned for H219, and submission of an IND application in H120 to gain permission from the FDA to conduct the study in the US.

The proposed clinical development plan is to start a US-based Phase I study in lung, TNBC, melanoma, bladder and gastrointestinal cancers in 2020. The proposal is that 15 patients would be treated with intratumoural (IT) CF33 as a single agent at up to three dose levels. A further 15 patients would be treated with IT CF33 in combination with an immune checkpoint inhibitor (ICI, to be selected) at two dose levels, as shown in Exhibit 9. The estimated trial cost is ~A$5m.

While oncolytic viruses have consistently killed tumour cells in preclinical studies, few have been able to stimulate the immune system to the degree required to generate meaningful clinical benefit. Imugene aims to overcome this challenge by using CF33 in combination with an immune checkpoint inhibitor.

This strategy of combining oncolytic virotherapy with a checkpoint inhibitor is sometimes described as putting your foot on the accelerator (stimulating greater recognition of the tumour by the immune system) at the same time as releasing the brakes (overcoming the immunosuppressive tumour microenvironment by blockade of inhibitory checkpoints).

The intention is for the Phase I study to be followed by a Phase I/II study of CF33 plus an ICI in four tumour types selected from the Phase I cohorts. The plan would be to enrol four cohorts of ~30 patients each, for a total of 100–120 subjects. It is envisaged that the Phase I/II trial could potentially start in H221 (estimated cost A$15-18m).

The manufacture of GMP virus material for the Phase I clinical studies has commenced. An experienced team with prior oncolytic virus development experience at Viralytics will be joining Imugene to guide the development of CF33.

Exhibit 9: Proposed Phase I/II clinical development plan for CF33

Source: Imugene

Patent filed

A patent covering the composition of matter and use of chimeric pox viruses was filed under the international Patent Cooperation Treaty in 2017. If granted, its estimated expiry date would be in late 2037.

Oncolytic vaccinia viruses in context

Researchers have been exploring the utility of modified vaccinia viruses and other poxviruses as oncolytic virus therapies over the past 20 years.3 Exhibit 10 lists some examples of oncolytic viruses that have been investigated in preclinical studies. Each of these viruses has been modified using recombinant DNA technology to inactivate the thymidine kinase gene and express inserted transgenes to modify the virus properties, in order to improve safety and/or efficacy (in the case of CF33-hNIS, the inserted transgene is hNIS).

  Guo et al. Journal for ImmunoTherapy of Cancer (2019) 7:6. https://doi.org/10.1186/s40425-018-0495-7

Exhibit 10: Selected examples of oncolytic vaccinia viruses used in preclinical studies

Virus name

Inserted transgene

Antitumor activities, especially immunity

Pre-clinical tumour models

Pexa-Vec (JX-594)

GM-CSF

Tumour cell infection and lysis; antitumor immune response; tumour vascular disruption

Liver and other cancers

vvDDGFP

EGFP; (later CD; GM-CSF)

CD11b + cells and CD11b + Ly6G+ cells (dendritic cells and neutrophils)

Breast, colon, and ovarian cancer

GLV-1 h68

Renilla luciferase- GFP fusion protein, β-galactosidase, β-glucuronidase

Immune defence activation via IFN-stimulated genes (STAT-1 and IRF-7), cytokines, chemokines, and innate immune effector function

Breast cancer and other cancer types

VG9- GMCSF

GM-CSF

Antitumor activity and induced tumour-specific immune response

Melanoma

ΔF4LΔJ2R

Luciferase

Durable tumour-antigen specific cytotoxic T-cell response

Bladder cancer

CVV

GFP

Complete regression of liver tumourigenicity and metastasis to the colon

Liver cancer

TG6002 (deVV5-fcu1)

chimeric virus + FCU1

Higher tumour selectivity and more viral replication in cancer cells

Glioblastoma, colorectal, liver, gastric, bladder, oesophageal cancers

CF33-hNIS

chimeric virus + hNIS

Effective at low viral dose; abscopal antitumor effect

Triple negative breast, colorectal, pancreatic, lung cancers

Source: Edison Investment Research, Guo et al 20193

Three vaccinia-based oncolytic viruses are currently undergoing clinical studies (Pexa-Vec, GL-Onc1 and TG6002) and at least one other has previously been tested in Phase I (vvDD-CDSR), as shown in Exhibit 11.

The most advanced of these is Pexa-Vec, which is currently being studied in the Phase III PHOCUS trial in first-line liver cancer. Pexa-Vec is an oncolytic vaccinia virus engineered to express the granulocyte-macrophage colony stimulating factor (GM-CSF) gene to stimulate a systemic anti-tumour immune response.

PHOCUS is a 600-patient randomised, open-label study comparing overall survival (OS) in patients treated by Pexa-Vec followed by sorafenib (tyrosine kinase inhibitor) versus those treated with sorafenib alone. PHOCUS was initiated in January 2016 and was expected to undergo an interim analysis in H119. According to the record on clinicaltrials.gov (NCT02562755), the trial is expected to complete in December 2020.

In a previous Phase II dose-finding study of Pexa-Vec in liver cancer (n=30; 80% first-line), those receiving high-dose Pexa-Vec (intratumoural delivery) had a median overall survival of 14.1 months compared to 6.7 months for those on a low dose. However, the subsequent Phase IIb TRAVERSE study in second-line liver cancer was terminated early in 2013 as data from the first 80 events showed no evidence of overall survival benefit associated with Pexa-Vec.

Early stage clinical studies are underway of Pexa-Vec combined with the checkpoint inhibitors Nivolumab, Ipilimumab and REGN2810 in liver cancer, kidney cancer and solid tumours, respectively.

Exhibit 3: Oncolytic vaccinia viruses used in clinical studies

Virus name/ sponsor

Inserted transgene

Status

Notes

Pexa-Vec (JX-594)/SillaJen and Transgene

GM-CSF

Pexa-Vec + Nexavar in ongoing global Phase III PHOCUS study in 1L liver cancer. Ongoing Phase I/II Pexa-Vec + nivolumab in liver cancer. Ongoing Phase Ib Pexa-Vec + REGN2810 (anti-PD1) in kidney cancer. Ongoing Phase I Pexa-Vec + ipilimumab in solid tumours

Phase III Futility analysis expected Q219; interim data 2020. N=600. Randomised Phase IIb in 2L liver cancer failed (NCT01387555). In prior Phase IIa in 2L liver cancer OS 6.7mth for low dose, 14.1mth for high dose (n=30)

GL-ONC1/Genelux Corporation

luciferase/GFP fusion, beta-galactosidase, beta-glucuronidase

Phase II study in ovarian cancer ongoing (NCT02759588). GL-ONC1 via intraperitoneal infusion alone or in combination with chemotherapy/Avastin

Primary completion expected December 2019. In Ovarian cancer Phase Ib 1/11 partial response, 5/11 stable disease for at least 15 weeks

vvDD-CDSR/SillaJen, University of Pittsburgh

cytosine deaminase (CD), somatostatin receptor (SR)

no ongoing studies

Two Phase I studies in solid tumours conducted (NCT00574977)

TG6002/Transgene

FCU1

Phase I/IIa in glioblastoma; Phase I in colorectal cancer; Phase I ICI combo studies underway with Nivolumab, Ipilimumab and REGN2810

TG6002 combined with oral flucytosine (5-FC). The enzymes encoded by FCU1 convert the prodrug 5-FC to the approved anti-cancer drug 5-FU in infected cells

Source: Edison Investment Research

High deal values in oncolytic virus transactions

Pharma companies have shown considerable interest in oncolytic virus technologies, with a number of significant deals in recent years (Exhibit 12). This has included the acquisition of three oncolytic virus developers by pharma companies in 2018 alone, totalling US$770m (~A$1bn) in upfront payments and a further US$900m (~A$1.2bn) in potential milestone payments. The transactions included Merck’s acquisition of ASX-listed Viralytics for US$394m (A$502m) announced in February 2018, primarily for the purpose of studying Cavatak in combination with its checkpoint inhibitor, Keytruda. This was followed by the acquisition of two companies with preclinical oncolytic viruses, first Janssen (J&J) buying BeneVir for US$140m upfront and up to US$900m in potential milestones, and then Boehringer Ingelheim buying out its partner Viratherapeutics for ~US$236m.

The most notable licensing transaction is the December 2016 deal between Bristol-Myers Squibb and the unlisted British biotech PsiOxus for its preclinical armed oncolytic virus NG-348 (US$50m upfront and up to $886m in development, regulatory and sales-based milestones).

While the deals listed in Exhibit 12 demonstrate the high level of interest from pharma companies in oncolytic virus technologies, they also illustrate that it is a highly competitive space. While in the previous section we have discussed in some detail other vaccinia/poxviruses in development, we note that only two of the 15 oncolytic virus deals shown in Exhibit 12 involve vaccinia-based viruses (Transgene and Jennerex). This reflects the fact that several other virus species are also being developed as oncolytic virus therapies and are potential competitors for Imugene. To attract a Pharma partner, we suspect that Imugene will need to demonstrate that the high potency of CF33 at infecting tumour cells translates into improved efficacy in the clinic.

Exhibit 4: Selected oncolytic virus deals

Date

Source

Buyer

Deal type

Up-front (US$m)

Total deal value (US$m)

Notes

May-19

Transgene

AstraZeneca

Licensing

10

Undisclosed

Five research candidates

Sep-18

Viratherapeutics

Boehringer Ingelheim

Acquisition

236

236

VSV-GP project, preclinical

May-18

BeneVir

Janssen (J&J)

Acquisition

140

1,040

Proprietary T-Stealth Oncolytic Virus Platform

Feb-18

Viralytics

Merck & Co

Acquisition

394

394

Cavatak, Phase II asset

Nov-17

Oncolytics

Adlai Norte

Licensing

5

65

Far East development of Reolysin

Oct-17

Turnstone Biologics

Abbvie

Licensing

Undisclosed

Undisclosed

Ad-MG1-MAGEA3, Phase I/II asset

Dec-16

Ignite Immunotherapy

Pfizer

Acquisition

Undisclosed

Undisclosed

50% stake

Dec-16

Psioxus

Bristol-Myers Squib

Licensing

50

936

NG-348, preclinical asset

Dec-16

Takara Bio

Otsuka

Licensing

Undisclosed

28

Japan rights to HF10

Nov-16

Virttu Biologics

Sorrento

Acquisition

25 (equity)

35

Seprehvir, Phase II asset

Jun-16

Psioxus

Bristol-Myers Squib

Licensing

10

Undisclosed

Enadenotucirev, Phase I collaboration

Jun-15

Oncos

Targovax

Acquisition

Undisclosed

Undisclosed

Structured as a 50/50 merger

Jan-15

Omnis

Astrazeneca

Licensing

Undisclosed

Undisclosed

VSV project, Phase II

Nov-13

Jennerex

Sillajen

Acquisition

100

150

Pexa-Vec, Phase II asset; currently in Phase III

Jan-11

Biovex

Amgen

Acquisition

424

1,000

Imlygic, approved for melanoma in 2015

Source: Edison Investment Research, Imugene, Evaluate Vantage, company announcements

CF33 adds to Imugene’s immunooncology portfolio

The CF33 licensing deal expands Imugene’s portfolio of immunooncology products, which is currently focused on B cell vaccines. It is the company’s second significant in-licensing deal in less than 12 months and follows on from the in-licensing of anti-HER2 and anti PD1 B cell vaccines from Ohio State University in June 2018.

If the CF33 licensing deal is approved by shareholders, Imugene’s pipeline will comprise the CF33 oncolytic virus plus two anti-HER2 B-cell vaccines that are in Phase II clinical development, plus a preclinical anti-PD1 B cell vaccine, as shown in Exhibit 13.

Exhibit 13: CF33 expands Imugene’s anti-cancer immunotherapy pipeline

Source: Imugene

Sensitivities

Imugene is exposed to the same clinical, regulatory and commercialisation risks as all biotech companies. The CF33 licensing deal is subject to shareholder approval and therefore it is not certain that the transaction will proceed, so we leave our forecasts and valuation unchanged for now. If the deal is approved, it remains to be seen whether the increased potency of CF33 in cancer cell lines and animal models will translate into improved efficacy in the clinic. The incorporation of genetic material from other poxviruses into CF33 increases the potential of unexpected safety concerns, compared to the long-established safety record of vaccinia viruses.

Given that there are a lot of other oncolytic viruses at various stages of development, we think it most likely that CF33 will need to demonstrate superior efficacy in clinical studies order to attract a pharma partner. On the other hand, it is possible that the anticipated long patent life for CF33 (if granted) could attract interest from Pharma even if efficacy only matches rather than exceeds that of competing oncolytic virus therapies, in our view. Imugene had A$21.0m cash at the end of March 2019, which should be sufficient to fund operations beyond our FY20 forecast horizon (excluding expenditure related to the CF33 transaction).

Exhibit 12: Financial summary

 

A$'000s

2016

2017

2018

2019e

2020e

Year end 30 June

AASB

AASB

AASB

AASB

AASB

PROFIT & LOSS

Sales, royalties, milestones

0

0

0

0

0

Other (includes R&D tax rebate)

1,525

1,164

1,841

2,400

3,280

Revenue

 

 

1,525

1,164

1,841

2,400

3,280

R&D expenses

(2,698)

(2,472)

(4,148)

(6,000)

(9,000)

SG&A expenses

(1,596)

(1,232)

(1,718)

(2,326)

(2,396)

Other

0

0

0

0

0

EBITDA

 

 

(2,769)

(2,540)

(4,025)

(5,926)

(8,116)

Operating Profit (before GW and except.)

 

(2,770)

(2,542)

(4,028)

(5,927)

(8,136)

Intangible Amortisation

0

0

0

(282)

(271)

Exceptionals

0

0

0

0

0

Operating Profit

(2,770)

(2,542)

(4,028)

(6,209)

(8,407)

Net Interest

39

35

94

78

201

Profit Before Tax (norm)

 

 

(2,731)

(2,507)

(3,934)

(6,131)

(8,206)

Profit Before Tax (reported)

 

 

(2,731)

(2,507)

(3,934)

(6,131)

(8,206)

Tax benefit

0

0

0

0

0

Profit After Tax (norm)

(2,731)

(2,507)

(3,934)

(6,131)

(8,206)

Profit After Tax (reported)

(2,731)

(2,507)

(3,934)

(6,131)

(8,206)

Average Number of Shares Outstanding (m)

1,449.0

2,069.0

2,637.9

3,232.4

3,609.8

EPS - normalised (c)

 

 

(0.19)

(0.12)

(0.15)

(0.19)

(0.23)

EPS – diluted (c)

 

 

(0.19)

(0.12)

(0.15)

(0.19)

(0.23)

Dividend per share (c)

0.0

0.0

0.0

0.0

0.0

BALANCE SHEET

Fixed Assets

 

 

6,623

6,623

7,081

6,898

6,707

Intangible Assets

6,600

6,600

7,057

6,775

6,504

Tangible Assets

3

3

4

103

182

Investments

20

20

20

20

20

Current Assets

 

 

2,913

6,054

9,833

22,696

14,682

Stocks

0

0

0

0

0

Debtors

1,313

1,220

1,915

2,474

3,354

Cash

1,583

4,814

7,822

20,126

11,232

Other

18

20

96

96

96

Current Liabilities

 

 

(694)

(297)

(438)

(438)

(438)

Creditors

(657)

(232)

(343)

(343)

(343)

Short term borrowings

0

0

0

0

0

Other

(36)

(65)

(96)

(96)

(96)

Long Term Liabilities

 

 

(985)

(985)

(1,001)

(1,001)

(1,001)

Long term borrowings

0

0

0

0

0

Other long term liabilities

(985)

(985)

(1,001)

(1,001)

(1,001)

Net Assets

 

 

7,857

11,395

15,475

28,156

19,950

CASH FLOW

Operating Cash Flow

 

 

(3,089)

(2,708)

(4,508)

(6,475)

(8,996)

Net Interest

39

35

46

78

201

Tax

0

0

0

0

0

Capex

(71)

(2)

(461)

(100)

(100)

Acquisitions/disposals

0

0

0

0

0

Equity Financing

2,735

5,928

7,930

19,095

0

Dividends

0

0

0

0

0

Other

(20)

(0)

0

(294)

0

Net Cash Flow

(385)

3,253

3,008

12,598

(8,894)

Opening net debt/(cash)

 

 

(1,957)

(1,583)

(4,814)

(7,822)

(20,126)

HP finance leases initiated

0

0

0

0

0

Other

11

(21)

0

0

0

Closing net debt/(cash)

 

 

(1,583)

(4,814)

(7,822)

(20,126)

(11,232)

Source: Edison Investment Research, Imugene accounts

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This report has been commissioned by Imugene and prepared and issued by Edison, in consideration of a fee payable by Imugene. Edison Investment Research standard fees are £49,500 pa for the production and broad dissemination of a detailed note (Outlook) following by regular (typically quarterly) update notes. Fees are paid upfront in cash without recourse. Edison may seek additional fees for the provision of roadshows and related IR services for the client but does not get remunerated for any investment banking services. We never take payment in stock, options or warrants for any of our services.

Accuracy of content: All information used in the publication of this report has been compiled from publicly available sources that are believed to be reliable, however we do not guarantee the accuracy or completeness of this report and have not sought for this information to be independently verified. Opinions contained in this report represent those of the Edison analyst at the time of publication. Forward-looking information or statements in this report contain information that is based on assumptions, forecasts of future results, estimates of amounts not yet determinable, and therefore involve known and unknown risks, uncertainties and other factors which may cause the actual results, performance or achievements of their subject matter to be materially different from current expectations.

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The Investment Research is a publication distributed in the United States by Edison Investment Research, Inc. Edison Investment Research, Inc. is registered as an investment adviser with the Securities and Exchange Commission. Edison relies upon the "publishers' exclusion" from the definition of investment adviser under Section 202(a) (11) of the Investment Advisers Act of 1940 and corresponding state securities laws. This report is a bona fide publication of general and regular circulation offering impersonal investment-related advice, not tailored to a specific investment portfolio or the needs of current and/or prospective subscribers. As such, Edison does not offer or provide personal advice and the research provided is for informational purposes only. No mention of a particular security in this report constitutes a recommendation to buy, sell or hold that or any security, or that any particular security, portfolio of securities, transaction or investment strategy is suitable for any specific person.

Frankfurt +49 (0)69 78 8076 960

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Frankfurt +49 (0)69 78 8076 960

Schumannstrasse 34b

60325 Frankfurt

Germany

London +44 (0)20 3077 5700

280 High Holborn

London, WC1V 7EE

United Kingdom

New York +1 646 653 7026

1,185 Avenue of the Americas

3rd Floor, New York, NY 10036

United States of America

Sydney +61 (0)2 8249 8342

Level 4, Office 1205

95 Pitt Street, Sydney

NSW 2000, Australia

General disclaimer and copyright

This report has been commissioned by Imugene and prepared and issued by Edison, in consideration of a fee payable by Imugene. Edison Investment Research standard fees are £49,500 pa for the production and broad dissemination of a detailed note (Outlook) following by regular (typically quarterly) update notes. Fees are paid upfront in cash without recourse. Edison may seek additional fees for the provision of roadshows and related IR services for the client but does not get remunerated for any investment banking services. We never take payment in stock, options or warrants for any of our services.

Accuracy of content: All information used in the publication of this report has been compiled from publicly available sources that are believed to be reliable, however we do not guarantee the accuracy or completeness of this report and have not sought for this information to be independently verified. Opinions contained in this report represent those of the Edison analyst at the time of publication. Forward-looking information or statements in this report contain information that is based on assumptions, forecasts of future results, estimates of amounts not yet determinable, and therefore involve known and unknown risks, uncertainties and other factors which may cause the actual results, performance or achievements of their subject matter to be materially different from current expectations.

Exclusion of Liability: To the fullest extent allowed by law, Edison shall not be liable for any direct, indirect or consequential losses, loss of profits, damages, costs or expenses incurred or suffered by you arising out or in connection with the access to, use of or reliance on any information contained on this note.

No personalised advice: The information that we provide should not be construed in any manner whatsoever as, personalised advice. Also, the information provided by us should not be construed by any subscriber or prospective subscriber as Edison’s solicitation to effect, or attempt to effect, any transaction in a security. The securities described in the report may not be eligible for sale in all jurisdictions or to certain categories of investors.

Investment in securities mentioned: Edison has a restrictive policy relating to personal dealing and conflicts of interest. Edison Group does not conduct any investment business and, accordingly, does not itself hold any positions in the securities mentioned in this report. However, the respective directors, officers, employees and contractors of Edison may have a position in any or related securities mentioned in this report, subject to Edison's policies on personal dealing and conflicts of interest.

Copyright: Copyright 2019 Edison Investment Research Limited (Edison). All rights reserved FTSE International Limited (“FTSE”) © FTSE 2019. “FTSE®” is a trade mark of the London Stock Exchange Group companies and is used by FTSE International Limited under license. All rights in the FTSE indices and/or FTSE ratings vest in FTSE and/or its licensors. Neither FTSE nor its licensors accept any liability for any errors or omissions in the FTSE indices and/or FTSE ratings or underlying data. No further distribution of FTSE Data is permitted without FTSE’s express written consent.

Australia

Edison Investment Research Pty Ltd (Edison AU) is the Australian subsidiary of Edison. Edison AU is a Corporate Authorised Representative (1252501) of Crown Wealth Group Pty Ltd who holds an Australian Financial Services Licence (Number: 494274). This research is issued in Australia by Edison AU and any access to it, is intended only for "wholesale clients" within the meaning of the Corporations Act 2001 of Australia. Any advice given by Edison AU is general advice only and does not take into account your personal circumstances, needs or objectives. You should, before acting on this advice, consider the appropriateness of the advice, having regard to your objectives, financial situation and needs. If our advice relates to the acquisition, or possible acquisition, of a particular financial product you should read any relevant Product Disclosure Statement or like instrument.

New Zealand

The research in this document is intended for New Zealand resident professional financial advisers or brokers (for use in their roles as financial advisers or brokers) and habitual investors who are “wholesale clients” for the purpose of the Financial Advisers Act 2008 (FAA) (as described in sections 5(c) (1)(a), (b) and (c) of the FAA). This is not a solicitation or inducement to buy, sell, subscribe, or underwrite any securities mentioned or in the topic of this document. For the purpose of the FAA, the content of this report is of a general nature, is intended as a source of general information only and is not intended to constitute a recommendation or opinion in relation to acquiring or disposing (including refraining from acquiring or disposing) of securities. The distribution of this document is not a “personalised service” and, to the extent that it contains any financial advice, is intended only as a “class service” provided by Edison within the meaning of the FAA (i.e. without taking into account the particular financial situation or goals of any person). As such, it should not be relied upon in making an investment decision.

United Kingdom

Neither this document and associated email (together, the "Communication") constitutes or form part of any offer for sale or subscription of, or solicitation of any offer to buy or subscribe for, any securities, nor shall it or any part of it form the basis of, or be relied on in connection with, any contract or commitment whatsoever. Any decision to purchase shares in the Company in the proposed placing should be made solely on the basis of the information to be contained in the admission document to be published in connection therewith.

This Communication is being distributed in the United Kingdom and is directed only at (i) persons having professional experience in matters relating to investments, i.e. investment professionals within the meaning of Article 19(5) of the Financial Services and Markets Act 2000 (Financial Promotion) Order 2005, as amended (the "FPO") (ii) high net-worth companies, unincorporated associations or other bodies within the meaning of Article 49 of the FPO and (iii) persons to whom it is otherwise lawful to distribute it. The investment or investment activity to which this document relates is available only to such persons. It is not intended that this document be distributed or passed on, directly or indirectly, to any other class of persons and in any event and under no circumstances should persons of any other description rely on or act upon the contents of this document (nor will such persons be able to purchase shares in the placing).

This Communication is being supplied to you solely for your information and may not be reproduced by, further distributed to or published in whole or in part by, any other person.

United States

The Investment Research is a publication distributed in the United States by Edison Investment Research, Inc. Edison Investment Research, Inc. is registered as an investment adviser with the Securities and Exchange Commission. Edison relies upon the "publishers' exclusion" from the definition of investment adviser under Section 202(a) (11) of the Investment Advisers Act of 1940 and corresponding state securities laws. This report is a bona fide publication of general and regular circulation offering impersonal investment-related advice, not tailored to a specific investment portfolio or the needs of current and/or prospective subscribers. As such, Edison does not offer or provide personal advice and the research provided is for informational purposes only. No mention of a particular security in this report constitutes a recommendation to buy, sell or hold that or any security, or that any particular security, portfolio of securities, transaction or investment strategy is suitable for any specific person.

Frankfurt +49 (0)69 78 8076 960

Schumannstrasse 34b

60325 Frankfurt

Germany

London +44 (0)20 3077 5700

280 High Holborn

London, WC1V 7EE

United Kingdom

New York +1 646 653 7026

1,185 Avenue of the Americas

3rd Floor, New York, NY 10036

United States of America

Sydney +61 (0)2 8249 8342

Level 4, Office 1205

95 Pitt Street, Sydney

NSW 2000, Australia

Frankfurt +49 (0)69 78 8076 960

Schumannstrasse 34b

60325 Frankfurt

Germany

London +44 (0)20 3077 5700

280 High Holborn

London, WC1V 7EE

United Kingdom

New York +1 646 653 7026

1,185 Avenue of the Americas

3rd Floor, New York, NY 10036

United States of America

Sydney +61 (0)2 8249 8342

Level 4, Office 1205

95 Pitt Street, Sydney

NSW 2000, Australia

Research: Investment Companies

Hansa Investment Company — Finding opportunities away from the mainstream

Hansa Trust (HAN/HANA) is arguably unique in its sector, with a portfolio made up of global equities, regional and thematic funds, diversifying (mainly hedge) funds and a large strategic position in Ocean Wilsons Holdings (OWHL), which in turn has a majority stake in Brazilian maritime services company Wilson Sons (WSON). Lead Manager Alec Letchfield’s focus on capital preservation as well as growth has enabled the portfolio to outperform UK and global equity indices in the recent stock market volatility, with new holdings such as Selwood Asset Management Liquid Credit Strategy already having a positive impact. The trust has recently published proposals to redomicile to Bermuda (see Recent developments).

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