4SC — Domatinostat programme to deliver Phase II data

4SC — Domatinostat programme to deliver Phase II data

4SC has reported progress with both its clinical-stage assets – resminostat, a broad spectrum HDAC inhibitor, and domatinostat, a specific Class 1 HDAC inhibitor. In January 2019, the investigator-led Phase II EMERGE study was initiated, which is testing domatinostat in gastrointestinal cancer. 4SC has developed a broad development programme for this drug, which will include several strategic options to commercialize the asset including out-licensing based on data from multiple Phase II studies and internal pivotal development for Merkel cell carcinoma. In January 2019, the resminostat RESMAIN study received a second positive DSMB safety review and the top-line results are expected in H120. 4SC remains well funded with cash of €30.8m at end-Q318, which should fund operations into 2020. Our valuation is virtually unchanged at €328m or €10.7/share.

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Written by

4SC

Domatinostat programme to deliver Phase II data

R&D update

Pharma & biotech

31 January 2019

Price

€3.11

Market cap

€95m

Net cash (€m) at end-Q318

30.8

Shares in issue

30.6m

Free float

35%

Code

VSC

Primary exchange

Frankfurt (Xetra)

Secondary exchange

N/A

Share price performance

%

1m

3m

12m

Abs

13.8

(2.8)

(53.6)

Rel (local)

7.5

(1.9)

(45.2)

52-week high/low

€8.5

€2.6

Business description

4SC is a Munich-based cancer biopharmaceutical company. Resminostat (HDAC inhibitor) is the lead candidate for cutaneous T-cell lymphoma (CTCL, pivotal study started in Q416). It has a second compound, domatinostat (Phase Ib/II started in Q317) and a preclinical asset, 4SC-208. 4SC also has several partners including Yakult Honsha for resminostat in Japan in various indications.

Next events

2018 full year results

20 March 2019

SENSITIZE top-line data published

H119

EMERGE early efficacy data published

H219

Top-line data from RESMAIN study

H120

Analysts

Jonas Peciulis

+44 (0)20 3077 5728

Alice Nettleton

+44 (0)20 3077 5700

4SC is a research client of Edison Investment Research Limited

4SC has reported progress with both its clinical-stage assets – resminostat, a broad spectrum HDAC inhibitor, and domatinostat, a specific Class 1 HDAC inhibitor. In January 2019, the investigator-led Phase II EMERGE study was initiated, which is testing domatinostat in gastrointestinal cancer. 4SC has developed a broad development programme for this drug, which will include several strategic options to commercialize the asset including out-licensing based on data from multiple Phase II studies and internal pivotal development for Merkel cell carcinoma. In January 2019, the resminostat RESMAIN study received a second positive DSMB safety review and the top-line results are expected in H120. 4SC remains well funded with cash of €30.8m at end-Q318, which should fund operations into 2020. Our valuation is virtually unchanged at €328m or €10.7/share.

Year end

Revenue (€m)

PBT*
(€m)

EPS*
(€)

DPS
(€)

P/E
(x)

Yield
(%)

12/16

2.1

(10.9)

(0.54)

0.0

N/A

N/A

12/17

4.2

(10.0)

(0.41)

0.0

N/A

N/A

12/18e

5.7

(16.6)

(0.54)

0.0

N/A

N/A

12/19e

3.1

(19.2)

(0.63)

0.0

N/A

N/A

Note: *PBT and EPS are normalised, excluding amortisation of acquired intangibles, exceptional items and share-based payments.

Resminostat: Changing treatment paradigm in CTCL

In November 2018, the 100th patient was recruited into the pivotal RESMAIN study and top-line results are expected in H120. The RESMAIN study is evaluating resminostat in a novel indication – maintenance treatment of patients with advanced-stage cutaneous T-cell lymphoma (CTCL) who have achieved disease control with prior therapy. If the study results are positive, the company plans to submit applications for approval in Europe and potentially the US, while Yakult is expected to submit an application in Japan. If subsequently approved, resminostat would be the first HDAC inhibitor approved for CTCL in Europe, and the first and only therapy approved for maintenance in either Europe, Japan or the US.

Preclinical data add to domatinostat combo options

As part of the broad domatinostat development programme, a collaborator presented new preclinical data demonstrating the synergistic effect of domatinostat in combination with chemotherapy in pancreatic cancer cell lines. While pancreatic cancer is not a focus indication for 4SC, it nevertheless adds insight about the mode of action. In addition, we expect further preclinical combination studies with checkpoint inhibitors in H119 in other indications. The domatinostat Phase II EMERGE study in gastrointestinal cancer (investigator-led) has now been initiated, with the first study sites open for recruitment.

Valuation: €328m or €10.7/share

Our rNPV-based valuation is virtually unchanged at €328m or €10.7/share, due to rolling our model forward, which was offset by a lower net cash position. We keep all assumptions in our risk-adjusted NPV model unchanged. A key near-term catalyst is interim data from the SENSITIZE study (H119).

Positioning resminostat for novel indication

Resminostat is an orally administered, broad spectrum histone deacetylase (HDAC) inhibitor, which could act as a monotherapy or in combination with other anti-cancer drugs. Resminostat inhibits HDAC classes I, IIb and IV. 4SC is currently running a pivotal trial (the RESMAIN study) with resminostat to evaluate it for a novel indication – maintenance treatment of patients with advanced-stage CTCL, who have achieved disease control with prior systemic therapy.

Typical symptoms of CTCL include painful and itchy skin lesions resulting in disfigurement and a severely impaired quality of life. Resminostat downregulates the expression of IL-31, which is upregulated in CTCL cells and strongly associated with pathological, chronic itching. In addition, studies have shown that resminostat upregulates STAT4 and downregulates STAT6 expression, which leads to T-cell differentiation to Th1-type helper T-cells and stabilization of the disease.

4SC’s pivotal trial RESMAIN (Exhibit 1) is evaluating resminostat in a novel indication – maintenance treatment of patients with advanced-stage CTCL who have achieved disease control with prior therapy. The primary endpoint is progression-free survival (PFS). Late-stage CTCL is an incurable disease and patients typically receive many different lines of therapy over their lifetime, as none of the current therapeutic options achieves stable disease for long periods, with virtually all patients progressing after three to four months on average. Should resminostat show efficacy as a maintenance therapy – prolonging the period in which patients are stable and not progressing – it means that the target population for resminostat is virtually all late-stage patients who have received at least one line of therapy.

Overall 10-year survival rates vary from 98% if diagnosed at stage IA to 20% if diagnosed at clinical stage IVB. Theoretically, this means that patients could receive multiple cycles of therapy-resminostat-therapy-resminostat and so on. Because of resminostat’s unique positioning as a maintenance therapy, the company believes this would clearly differentiate it from two other HDAC inhibitors approved in the US: vorinostat (Zolinza, Merck & Co) and romidepsin (Istodax, Celgene), which are indicated for patients with progressive disease in second or later lines and typically used only once as a single line of therapy. If approved, resminostat would be the first HDAC inhibitor approved for CTCL in Europe, and the first and only therapy approved for maintenance in either Europe, Japan or the US. The pivotal RESMAIN study and top-line results are expected in H120.

External validation of strategy from partner Yakult Honsha

In March 2018, 4SC’s Japanese partner Yakult, which has in-licensed the rights to resminostat in Japan, announced that it had joined 4SC’s pivotal RESMAIN study. By enrolling additional patients in Japan, Yakult will be able to submit resminostat for approval, assuming the data are positive. In our view, this indicates an external validation of 4SC’s R&D strategy. Previously, Yakult conducted a Phase I study with resminostat in biliary tract cancer patients in Japan. Based on positive results, Yakult initiated its own Phase II study in biliary tract cancer (n=100) in combination with S-1 chemotherapy. S-1 is widely used in Japan and other Asian countries to treat patients following relapse after a first-line chemotherapy regimen. The final data readout is expected in mid-2020.

Exhibit 1: Design of the pivotal RESMAIN study

Source: 4SC

Domatinostat – broad R&D programme

Domatinostat is 4SC’s second epigenetic drug, an orally administered small molecule Class I selective HDAC inhibitor. The drug was tested in a Phase I study with 24 heavily pre-treated patients with several types of advanced haematologic cancers and was shown to be well tolerated with signs of initial antitumor efficacy.

Checkpoint inhibitors have quickly become the mainstay treatment option in many solid tumours. However, there remain a majority of patients who neither respond to therapy nor experience durable responses. Preclinical data gathered by 4SC indicate that there is significant potential for domatinostat to be combined with anti-PD-L1 antibodies to expand the treatable patient population. With this in mind, 4SC has developed a broad programme for the drug (Exhibit 2).

Exhibit 2: Domatinostat development programme

Source: 4SC. Note: CI – checkpoint inhibitors

In late 2017, 4SC initiated the Phase Ib/II SENSITIZE study with domatinostat in combination with the anti-PD-1 checkpoint inhibitor pembrolizumab in advanced melanoma. In August 2018, the FDA approved 4SC’s IND application, so the company now can expand the study into the US. Results are expected in H119. More recently, another investigator-led Phase II study, EMERGE, was initiated. It is testing domatinostat in combination with another checkpoint inhibitor, avelumab (anti-PD-L1 antibody), for treating microsatellite-stable gastrointestinal tumours, which tend to be resistant to checkpoint inhibition. Early efficacy data are expected in H219.

4SC believes that the broader mid-stage development program is a sensible strategy because the accumulated data will allow it to assess the safety profile and initial efficacy of domatinostat in combination with two main classes of checkpoint inhibitors (anti-PD-1 and anti-PD-L1). This would form the basis for potential partnering discussions in respective areas, while for pivotal development 4SC will aim for Merkel cell carcinoma (MCC), an orphan dermatological cancer. If the data are sufficiently positive, domatinostat could be the first drug to market in a checkpoint inhibition refractory MCC population, which could prove a significant commercial opportunity.

Financials and valuation

In October 2018, 4SC announced that it had received a single-digit million euro milestone payment from its partner Link Health, which in-licensed the cancer therapeutic candidate 4SC-205 in 2016. We therefore add €1m as income to our 2018 estimate. 4SC’s last reported cash was €30.8m (end-Q318). Average monthly cash burn for the first nine months of 2018 was €1.17m, which should bring the average monthly cash burn for FY18 to €1.3–1.5m, below previous guidance of €1.8–2.0m, and provide some flexibility for FY19. Current funds are sufficient to finance the company’s activities into 2020, past several R&D catalysts (Exhibit 3).

Our rNPV-based valuation is unchanged at €328m or €10.7/share, due to rolling our model forward, which was offset by a lower net cash position. We keep all assumptions for the assets unchanged, as discussed in our previous reports. Main near-term catalysts are data readouts from the SENSITIZE and EMERGE studies expected over the course of this year.

Exhibit 3: Upcoming newsflow relating to clinical trials and other activities

H119

H219

H120

H220

Resminostat clinical studies

RESMAIN (Pivotal study, CTCL)

Top-line data expected

Marketing authorisation filing in Europe

Yakult study (Phase II, biliary tract cancer)

Final study results expected by partner Yakult

Domatinostat clinical studies

SENSITIZE (Phase Ib/II, melanoma)

Cohorts 1, 2 top-line data available

Cohort 3 enrolment expected to complete

Cohort 3 data set published

EMERGE (Phase II, GI cancers)

Safety data published

Early efficacy data published

Domatinostat in Merkel cell carcinoma

MCC preclinical data to be published

Initiation of MCC Phase II study (TBD)

Additional domatinostat combination studies

Update on R&D strategy

New preclinical triple combination data to be published

Initiate the first triple combination therapy study in combination with a new partner

Other activities

Fund-raising

Potential new fund-raise (current cash reach into early 2020)

Source: 4SC, Edison Investment Research. Note: Bold indicates key catalysts (efficacy data, marketing authorisation).


Exhibit 4: Financial summary

€'000s

2016

2017

2018e

2019e

Year end 31 December

IFRS

IFRS

IFRS

IFRS

PROFIT & LOSS

Revenue

 

 

2,060

4,197

5,724

3,133

Cost of sales

(76)

(574)

(574)

(574)

Gross profit

1,984

3,623

5,150

2,559

R&D expenditure

(10,601)

(11,475)

(19,555)

(19,461)

Administrative, distribution and other

(3,175)

(3,084)

(3,195)

(3,289)

Operating profit

(11,792)

(10,936)

(17,600)

(20,191)

Intangible amortisation

(892)

(892)

(892)

(892)

Exceptionals (impairment / restructuring costs)

0

0

0

0

Share-based payments

0

0

(20)

(20)

EBITDA

 

 

(10,900)

(9,819)

(16,463)

(19,054)

Operating Profit (before amort and except.)

 

(10,900)

(10,044)

(16,688)

(19,279)

Net interest

(14)

9

100

100

Other (profit/loss from associates)

711

0

0

0

Profit before tax (norm)

 

 

(10,914)

(10,035)

(16,588)

(19,179)

Profit before tax (FRS 3)

 

 

(11,095)

(10,927)

(17,500)

(20,091)

Tax

(71)

(33)

0

0

Profit after tax (norm)

(10,274)

(10,068)

(16,588)

(19,179)

Profit after tax (FRS 3)

(11,166)

(10,960)

(17,500)

(20,091)

Average Number of Shares Outstanding (m)

19.0

24.8

30.6

30.6

EPS - normalised (€)

 

 

(0.54)

(0.41)

(0.54)

(0.63)

EPS - FRS 3 (€)

 

 

(0.59)

(0.44)

(0.57)

(0.66)

Dividend per share (€)

0.0

0.0

0.0

0.0

BALANCE SHEET

Fixed assets

 

 

7,096

6,365

5,452

4,539

Intangible assets

6,499

5,694

4,806

3,918

Tangible assets

497

570

545

520

Investments and other

100

101

101

101

Current assets

 

 

11,959

41,548

23,457

5,522

Stocks

0

0

0

0

Debtors

95

30

30

30

Cash

10,048

41,327

23,236

5,301

Other current assets

1,816

191

191

191

Current liabilities

 

 

(3,257)

(2,759)

(4,136)

(2,840)

Creditors

(834)

(1,175)

(1,175)

(1,175)

Short-term borrowings

0

0

0

0

Deferred revenue (short term)

(1,431)

(1,485)

(2,862)

(1,566)

Other current liabilities

(992)

(99)

(99)

(99)

Long-term liabilities

 

 

(525)

(461)

(511)

(486)

Long-term borrowings

0

0

0

0

Deferred revenue (long term)

(493)

(394)

(444)

(419)

Other long-term liabilities

(32)

(67)

(67)

(67)

Net assets

 

 

15,273

44,693

24,263

6,735

CASH FLOW

Operating cash flow

 

 

(12,320)

(8,508)

(17,890)

(17,734)

Net interest

(531)

0

3

3

Tax

(71)

(33)

0

0

Capex

(404)

(168)

(200)

(200)

Expenditure on intangibles

(60)

(4)

(4)

(4)

Acquisitions/disposals

2,808

39

0

0

Financing

0

39,953

0

0

Other

650

0

0

0

Net cash flow

(9,928)

31,279

(18,091)

(17,935)

Opening net debt/(cash)

 

 

(19,514)

(10,048)

(41,327)

(23,236)

HP finance leases initiated

0

0

0

0

Other

462

0

0

0

Closing net debt/(cash)

 

 

(10,048)

(41,327)

(23,236)

(5,301)

Source: 4SC accounts, Edison Investment Research

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This report has been commissioned by 4SC and prepared and issued by Edison, in consideration of a fee payable by 4SC. 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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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.

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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).

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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

Avon Rubber — Protection of growth

The trading update released with the AGM indicates that growth in Avon Protection is continuing to offset challenging conditions for milkrite | Interpuls in dairy markets. As a result, management’s expectations for the full year are maintained and our group estimates are unchanged. The shares trade on a modest FY20 P/E premium to defence peers, which we feel is warranted by higher margins and growth in cash flow and EPS.

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