Unexpected CAR clinical benefit

Celyad 28 November 2016 ADR Update

Celyad

Unexpected CAR clinical benefit

Q3 update

Pharma & biotech

28 November 2016

ADR research

Price

$20.52

Market cap

$191m

ADR/Ord conversion ratio 1:1

Cash ($m) as at 30 Sept 2016

97

ADRs in issue

9.31m

ADR Code

CYAD

ADR exchange

NASDAQ

Underlying exchange

Euronext Brussels

Depository

CITI

ADR share price performance

52-week high/low

$58.7

$16.7

Business description

Celyad is developing an innovative CAR T-cell (NKR-2) immuno-oncology technology. Phase I/II studies have reached the highest 30m cell dose.
C-Cure, an autologous stem cell therapy for chronic heart disease, missed its primary endpoint. A part-US trial may run if partnered.

Next events

Final FY16 results

Q217

NKR-2 safety data

December 2016

Analysts

John Savin PhD

+44 (0)20 3077 5735

Lala Gregorek

+44 (0)20 3681 2527

Celyad is a research client of Edison Investment Research Limited

Celyad has noted that the Phase I safety study on its NKR-2 CAR T-cell autologous therapy produced some “reports of clinical benefit”. The THINK Phase Ib trial has been approved in Belgium and awaits FDA clearance. This is a major expansion of CAR therapy with five solid tumors plus AML and MM being explored. As a result, we have raised the probability of success to 20% from 18.5%. There is a challenge to the granted 2009 US patent on allogeneic CAR T-cells. While the claim is being re-examined, the patent remains in force; other patents and patent applications provide protection. Edison’s interim indicative value has been rebased and increased to $50 per share, formerly $46 per share.

Year end

Revenue ($m)

PTP*
($m)

EPADR
($)

DPADR
($)

P/E
(x)

Gross yield
(%)

12/14

0.2

(20.5)

(3.03)

0.0

N/A

N/A

12/15

0.0

(31.5)

(3.62)

0.0

N/A

N/A

12/16e

12.5

(27.9)

(3.00)

0.0

N/A

N/A

12/17e

0.0

(34.7)

(3.73)

0.0

N/A

N/A

Note: Converted at €0.89/US$1. Dividend yield excludes withholding tax. Investors should consult their tax advisor regarding the application of any domestic and foreign tax laws.

NKR-2 takes a lead positon in solid tumors

In the completed Phase I, Celyad’s CEO noted “reports of unexpected clinical benefit”: unexpected because the single, low doses were not expected to show efficacy; data will be presented at ASH in early December. Celyad now has Belgium approval to start immuno-oncology autologous NKR-2 trials (THINK) in two hematological and five solid tumors at high doses. The exploration of NKR-2 in solid tumors puts Celyad in a leading position in this area. Other CAR companies will have to compete for a limited number of patients in the congested CD19 area.

Patents need patience

In November 2015, the US patent office granted US9,181,527; this was filed by Prof Sentman in 2009. Claim 1 covers the basis of Celyad’s TIM technology and was challenged in February 2016. Claim 1 only is being re-examined by the US patent office; this will take many months. The patent remains in force during the process. Celyad holds another granted US patent, US9,273,283, that specifies the way in which the allogeneic cell is made TCR deficient. In Europe (EP2844742) and elsewhere, this is an application. The Asian deal with Ono is not affected.

Valuation: Rebased and adjusted to $50 per share

Our valuation model for Celyad has been rebased to focus on NKR-2 indications. As Celyad is initiating an NKR-2 trial in solid tumors, these have also been added to the valuation but with caution as this could be a challenging set of indications and there is very little current clinical data on the NKR-2 product. The C-Cure value is unchanged at 35% probability and is now regarded as an indicative deal value on partnering. Celyad has also cut its cash burn to no more than $34m per year to conserve cash to mid-2019. These adjustments give an interim indicative value of $50 per share, formerly $46 per share.

CAR Phase I status: Unexpected clinical benefit

NKR-2 CAR T-cell therapy involves adding a new set of genes into the patient’s CD8 T-cells so they have an artificial natural killer (NK) cell receptor as well as their natural T-cell receptors (TCR). The NK receptor recognizes a wide variety of cell surface proteins (ligands) which are expressed at high levels on cancer cells; these ligands are also produced by stressed normal cells. In theory, this targets the NKR-2 construct to a wide variety of cancer types. Most other CAR T-cell therapies in the clinical target CD19, a ligand only found on immune cells associated with antibody production.

The completed Phase I safety study involved four cohorts (of three patients each) treated sequentially with a rising single dose of NKR-2 cells. The dose was increased to 30m cells for the last cohort. Given that Celyad ended the Phase I at a relatively low single dose it would be unexpected on current CD19 CAR criteria to detect significant signs of efficacy. What efficacy signs were reported have not yet been disclosed. However, they were noted at a dose between 50 and 1,000 times lower than Celyad had observed in animal experiments.

Solid moves

A major drawback with the current CAR CD19 focus of other companies is that while it is excellent for B-cell tumors (like leukemia and lymphomas) CD19 will not target other cancers. Each solid tumor type has a different profile of antigens and often these are also found on normal tissues, albeit at much lower levels.

Of the leading CAR companies Novartis, Juno, Kite and Bellicum, only Bellicum has a single solid tumor trial running: a Phase I in advanced pancreatic cancer with an anti-PSCA CAR construct. This is a 30-patient dose ranging and safety study due to complete in 2020. A National Cancer Institute melanoma study by the Rosenberg group reported in 2016. It used CD4 CAR T-cells targeted to the MAGE antigen. Melanoma responds well to immunotherapies. The Rosenberg group has taken the view that CD4 T-cells will be better for solid tumors than CD8 T-cells used in CD19 CAR therapies.

The main effort in solid tumors in immune oncology is based around checkpoint inhibitors like the marketed products Yervoy (ipilimumab), which targets cytotoxic T-lymphocyte-associated protein 4 in melanoma, and Opdivo, an anti-PD-1 monoclonal antibody used in melanoma, gastric cancer and renal cell carcinoma. It is possible that checkpoint inhibitors will be combined with CAR therapy at some point in future but this is currently some way off clinical development.

With the advantage of the different mechanism of cell targeting used by NKR-2, Celyad plans to use NKR-2 in multiple cancer types. NKR-2 attacks multiple targets found on severely stressed cells, a profile shown by most cancer types. A risk is that NKR-2 may attack normal but stressed cells so some side effects are to be expected. Celyad does not report any significant side effects to date but the safety study was small.

Celyad THINKs of a solid plan

The next Phase Ib study, THINK (THerapeutic Immunotherapy with NKR-2), has been designed by Celyad as an open-label, multiple-dose US and European study. It will assess higher dose levels, safety and clinical activity of autologous NKR-2 cells in seven refractory cancers:

haematological:

acute myeloid leukemia (AML), and

multiple myeloma (MM).

solid tumors:

colorectal,

ovarian,

bladder,

triple-negative (hormone therapy unresponsive) breast cancer, and

pancreatic cancer.

In the THINK Phase Ib, Celyad intends to increase the dose starting at 3x108 (adjusted for body weight) then 1x109 then 3x109. At each dose, the patients will receive three successive administrations, two weeks apart, of NKR-2 T-cells. There will be 24 patients and eight per dose group. They can be from any of the above cancer types.

In the expansion phase to test efficacy, Celyad intends to enrol up to 86 more patients to evaluate each tumor type independently. Combined with patients in the dose escalation phase with the same tumor type, this should give at least 14 patients per cancer.

Celyad plans to use three doses because it has been shown in CD19 CAR T-cell dosing that giving two high cell doses rather than one very big cell dose gives fewer side effects like cytokine release syndrome (CRS) and neurotoxicity. It is also apparently more effective. There are some crucial differences between NKR-2 and CD19 CAR T-cell therapy however:

Celyad does not precondition patients with chemotherapy. Preconditioning allows the transplanted, genetically engineered cell population to grow, perhaps ending with 10-100 fold more cells than were injected. Preconditioning also helps to prevent a regulatory T-cell response. Preconditioning is chemotherapy often involving fludarabine and cyclophosphamide or similar agents. One patient died in summer 2016 in a Juno trial due to side effects from the use of a preconditioning regimen.

The NKR-2 cell population does not appear to grow after grafting and may only persist for a number of days. This means that giving repeat doses could be particularly important as without graft expansion, the dose of NKR-2 cells is still relatively low compared to the CD19 experience so far when over 1010 cells may be need after cell expansion in the patient. The NKR-2 approach has the advantage that the procedure should be more predictable in the short term as the dosing is more precise. It may also be safer over the longer term.

NKR-2 CAR T-cell therapy targets cells showing a wide range of “stress” ligands so can potentially apply to multiple cancer types. Classic CAR T-cell approaches need a new specific ligand for each new tumor type so are still effectively restricted to CD19.

NKR-2 in preclinical work is able to target the endogenous immune system for a memory response against the tumor. If this is seen in the clinic, and multiple dosing will help, it should give long-lasting protection. This might in future be potentiated by combination with checkpoint inhibitors. This is another reason why Celyad does not precondition patients as this memory effect is harder to achieve if the endogenous immune response is damaged by chemotherapy.

Timelines

Currently, the THINK study is only approved in Belgium; approval in other European countries and the US will be required. The overall timelines have not been disclosed by Celyad and there is no record as yet posted to ClinicalTrials.gov. Edison estimates that if the FDA approves the trial design by the end of 2016, the dose escalation phase may have completed by approximately springtime. In that event, the expansion phase should run for the rest of 2017 implying data possibly by late 2017 or more realistically from early 2018.

Timelines beyond this point are inevitably unclear at this time but Edison is currently assuming that potentially pivotal studies start in 2019 or earlier and complete by 2021 or earlier. This implies that NKR-2 products could receive approvals from 2022 onwards, particularly if breakthrough and fast-track designations are received. There is insufficient data to form an opinion about this at this time.

Solid tumor challenges

A recent review in Molecular Therapy – Oncolytics by Newick et al (2016), based at the University of Pennsylvania, a leading centre for CAR therapy development, clarifies the multifactorial difficulties involved in solid tumor therapy.

The grafted CAR T-cells have to move from the injection site into the solid tumor. To do this, the CAR T-cells have to have the right adhesion molecules to even bind to the cancer cells. Once inside the tumor, the CAR T-cells will be in a difficult and hostile environment due to low oxygen and nutrient levels and high levels of acid. It is also full of other immune cells, some of which will down regulate a killer T-cell response. The tumor environment is also believed to contain multiple inhibitors of T-cells. Finally, the tumor itself is often heterogeneous so not all tumor cells may be recognised by the CAR construct. Generally, haematological cancers like leukaemia are relatively homogeneous. The review indicates that about 30 solid tumor antigens are being evaluated for use in CAR therapy. Finally, because of the lack of highly specific solid tumor antigens, there is a risk of the CAR T-cells attacking healthy tissues that express the antigen at a low level. This is not theoretical; a case study from 2010 reported that a HER2 CAR patient died due to off-target toxicity.

NKR-2 tumor markets

It is too early to develop detailed predictive models for solid tumor NKR-2 sales. Exhibit 1 looks at the number of US deaths (SEER database) in each for the two haematological cancers and the five solid cancer types. The cancer incidence is also given. The Edison value assumes $150,000 per treatment. This may be perceived as very low in the putative acute lymphoblastic leukaemia (ALL) market, where $500,000 is talked about currently as affordable. However, if and when a therapy treats many cancer types, the overall cost to the healthcare system becomes crucial. Exhibit 1 values are also based on deaths as a proxy for refractory late-stage cancers. Earlier-stage cancers could be treated as well, which would magnify the market potential in some cases.

Exhibit 1: NKR-2 potential indications in Phase Ib THINK study

Indication

US incidence

US deaths

Peak share

Potential US sales ($m)

Probability

Global sales
($m)

AML

20,386

10,460

50%

638

20%

127

MM

26,850

11,240

50%

686

20%

136

 Total haematological

1,324

263

Colorectal

136,830

50,310

36%

2,721

10%

222

Ovarian

21,290

14,180

69%

1,464

20%

244

Bladder

76,960

16,390

69%

1,692

10%

141

Breast

232,670

40,000

36%

2,163

10%

177

Pancreatic

46,420

39,590

69%

4,086

5%

170

 Total solid tumors

12,125

955

Source: SEER database, Edison Investment Research

In context, the CD19 favourite, ALL, has about 1,500 deaths per year, all tragic, mostly children, so a worthwhile indication but a small market.

The probabilities used reflect a best estimate at this point but have no substantive evidence base. Ovarian scores highest as there is published preclinical work. Pancreatic cancer is notoriously hard to treat, so a high market share could be expected if NKR-2 had an impact on survival, but a very low probability is assigned.

The global market opportunity is based on 75% of the potential US sales as the US is the main market for high-value biological therapies.

Patents on CAR T-cells: Claims and prior arts

TCR-Inhibitory Molecules (TIMs) are an approach used by Celyad, currently in preclinical development, to manufacture allogeneic (from another person) CAR T-cells that will not attack the host tissue triggering graft-versus-host (GvH) disease. GvH occurs when allogeneic T-cells are injected (grafted) into a cancer patient and start to attack healthy tissue as the patient (host) is detected as non-self to the graft. As T-cells recognise foreign tissue through the TCR, eliminating functional TCRs in an allogeneic graft will avoid GvH disease. Autologous therapy, the current paradigm, avoids this as it uses “self” cells, but it is expensive as every dose is custom made. Allogenic T-cells would be cheaper to produce and could be “out of the freezer”, enabling rapid treatment. However, it might also be necessary to have a wide bank of different tissue types to ensure some level of tissue matching as otherwise the host immune system would attack and eliminate the grafted cells.

TIMS are either short hairpin RNA (ShRNA) or dominant negative proteins. These genes are linked to the CAR gene construct used to transfect the cells. ShRNA stop the production of TCR proteins; dominant negative proteins are synthesised by the T-cell and assembled into non-functional TCR. These T-cells now only attack patient tumor cells as they cannot “see” any healthy tissue.

Patent issues

A successful patent requires that the idea is novel, that there is an inventive step, and that the invention has a practical function. Most of any patent is taken up with a description of what was already known and a detailed description and examples of the invention and its application. What is protected is stated in the claims. It is usual to start with a very broad Claim 1 and then move to more specific claims that are more easily defended if challenged.

In November 2015, the US patent office granted US9,181,527; this was filed by Prof Sentman in 2009. Claim 1 covers any TCR deficient CAR T-cells to prevent graft-versus-host disease. No international filings were made so Claim 1 only applies in the US. There is no direct prior art cited in the literature so the US examiner in October 2015 granted the patent including Claim 1.

Claim 1 was challenged in February 2016 and is being re-examined by the US patent office; this will take many months and follows a set procedure. Claim 1 remains in force during the process.

The position notified by the examiner in August 2016 was that there was a case that the invention was obvious so an initial opinion has been issued that would, if implemented, strike out Claim 1 only. The basis of the opinion is that diverse elements of the concept of TCR-disabled CAR modified T-cells have now been identified in literature. These are from three diverse literature references separated widely in time and from different journals. The examiner mostly disregarded the prior art cited by the challenger. However, no one prior to Professor Sentman in 2009 had made a specific invention with the function of avoiding graft-versus-host disease. There is always a danger of hindsight in that what now appears obvious can be selectively picked out retrospectively and claimed to be obvious to the idealised “person skilled in the art”.

Again, as is normal Celyad did not respond to the initial examination but waited for the initial findings. Celyad will now respond to the examiner’s initial report. This may cause a reconsideration or maybe a reaffirmation of the original finding. Whatever the outcome, it is likely that one of the parties will appeal. Eventually, the US patent office or courts will either uphold Claim 1 or amend the patent and remove it. Other claims are not affected but may depend upon Claim 1.

While this process proceeds, the patent with Claim 1 remains in force. This could, in theory, block a number of other companies from developing allogeneic therapies. However, allogeneic CAR therapy is many years from any possible regulatory approval and launch in the United States. Patents do not prevent research work from occurring and using the invention but they can block commercial exploitation. Celyad has indicated that it may initiate an allogeneic NKR-2 trial in H217.

Celyad holds other IP covering the TIM technology in detail. In the US, granted patent US9,273,283 specifies the way in which the allogeneic cell is made TCR deficient. In Europe (EP2844742) and elsewhere, the related patent is still an application. These patents do not have the broad scope of Claim 1 in the 2009 patent, but are more specific and potentially therefore stronger patents. Edison assumes that Celyad is filing further intellectual property. Any patent applications will normally be published about 18 months after their filing date.

At the current time, the patent challenge is of minimal relevance to investors because of the early nature of the allogeneic CAR technology space. It does not for example affect the Ono deal on allogeneic CAR therapy in Asia as the patent does not apply there. The key aspect for Celyad investors is the scope and speed of development of the current autologous NKR-2 product.

C-Cure status

C-Cure remains as a large part of the Celyad value. It is currently at a 35% US and European probability as the CHART-1 study did not meet its overall primary endpoint. This includes the probability that a partner will be found to fund the CHART-2 study. A presentation on the data in Rome on 28 August focused on a responsive subgroup based on end-diastolic volume (EDV); the full data set has not yet been published. Edison notes that this probability may be too low given the EDV-defined subgroup response. It is anticipated that the CHART-2 trial will focus on this group. Celyad management has commented that in this EDV-defined subgroup, “a statistically significant positive difference was seen in all individual elements of the composite primary endpoint”.

Financials

In H216, Celyad will receive an $12.5m upfront fee from Ono in respect of the allogeneic CAR deal signed in July. Celyad’s H116 results showed increased R&D spend leading to a cash outflow from operations of $23.1m. This includes a working capital outflow of $4.0m in H1 largely due to a $5.6m payment in respect of the Oncyte acquisition in January 2015. Edison now estimates that the cash outflow over 2016 as a whole will be $32.8m, indicating year end cash of about $87m, previously $95m.

In 2016, Edison forecasts R&D expenditure of $36m and cash admin costs of around $6m. This fits with the $10m per quarter cash use rate in 2016 and $97m 30 September 2016 cash level after the Ono payment. Celyad management has stated (Q316 report) that it believes that Celyad has cash to mid-2019. Given that any other deal payments are not clear, Edison has adjusted its forecast of the cash burn to about $38m per year in 2017, 2018 and 2019. This gives a 2017 year end cash estimate of about $51m (formerly $31m). This implies R&D spend will have to average no more than $32m per year or that additional cash will be obtained from deals and milestones, for example, from partnering of C-Cure.

Celyad has made some adjustments in its H116 accounts. It acquired BMS SA for $1.7m (biological manufacturing services); BMS is a separate but closely linked Belgian company that owns the clean rooms used for NKR-2 manufacturing. It has also adjusted the fair value of Belgian government loans provided for C-Cure development. These loans are repayable in the main part if C-Cure is commercialised. As the earliest C-Cure launch date is now in the 2020s and depends upon partnering, management has reduced the fair value of the loans by $2.2m, giving an exceptional gain in the P&L. In addition, the fall in the share price has led to an accounting adjustment to share-based payments recorded in the P&L as a loss of $2.4m.

Valuation adjustments

The valuation structure has now been revised to put NKR-2 CAR T-cell therapy into the lead position in Exhibit 2. This gives rise to the following changes:

The cash flows ascribed to AML and multiple myeloma before probability adjustment are unchanged; probability has been increased from 18.5% to 20% as the Phase I study has completed successfully.

Cash flows attributed to solid tumors have been added in as these indications have now entered clinical study. However, the individual probabilities ascribed to different variations do vary; see Exhibit 1. As it is inherently unlikely that all five indications will reach the market, a weighted average value has been taken and divided by five so the model currently assumes only one indication is successful. This will be adjusted as clinical data is obtained.

A nominal value for allogeneic NKR-2 therapy, expected to enter the clinic in H217, is retained at $11m as in the previous note.

At this point in development, rather than trying to assign specific sales costs to NKR-2 indications, Edison makes a simplifying assumption that sales are direct and that 35% of revenues translate into cash flows. A more detailed forecast will be made as efficacy and the competitive situation become clearer.

C-Cure is no longer formally forecast as the time to market is now uncertain and partnering is required. The value of $180m has been retained as in the previous model but is now regarded as being equivalent to the net present value of a future C-Cure partnering deal. This will be adjusted to the actual value when a partnering deal is announced or depreciated if a deal is delayed significantly.

Costs are now assigned purely to the development of CAR T-cell therapies. Costs of $38m per year are assumed until 2019 (as detailed above under financials, see Exhibit 3) with substantial rises from 2020 to over $61m per year to enable pivotal trials to be run. Cash flows from products are used from 2024.

Exhibit 2: Revised Celyad valuation

Item

Indication

Probability 

Value ($m)

CAR values

AML

20.0%

126.5

 

MM

20.0%

136.0

 

Solid tumors (weighted average of one success)

Variable

188.0

 

Allogeneic

 

11.1

CAR value

 

 

461.6

C-Cure partnered value (milestones plus royalties) 

35.0%

180.3

Costs

(Risk adjusted 2017-23)

 

(164.6)

Total indicative value

 

 

477.3

Shares

 

 

9.31

Warrants and options

 

 

0.30

Value per share (€)

 

 

49.7

Source: Edison Investment Research

In July, we increased on an interim basis the NKR-2 probability from 17.5% to 18.5%. A nominal $11m value for allogeneic technology was added after the ONO deal. This gave an indicative value of $46/share. The new indicative value on the revised interim basis is $50 per share. No further dilution is expected until 2019 and possibly later depending on any deals in the interim.

Exhibit 3: Financial summary

US$'000s

2013

2014

2015

2016e

2017e

Year end 31 December

IFRS

IFRS

IFRS

IFRS

IFRS

PROFIT & LOSS

Revenue

 

 

0

162

3

12,488

0

Cost of Sales

0

(128)

(1)

0

0

Gross Profit

0

34

2

12,488

0

EBITDA

 

 

(12,006)

(20,254)

(31,789)

(28,193)

(34,692)

Operating Profit (before amort and except)

 

 

(12,239)

(20,468)

(32,092)

(28,496)

(34,995)

Intangible Amortisation

(744)

(751)

(844)

(844)

(844)

Other income and charges

0

4,194

0

0

0

Share-based payments

(1,396)

(1,219)

(882)

199

199

Operating Profit

(14,379)

(18,245)

(33,818)

(29,141)

(35,640)

Net Interest

(1,704)

(18)

619

555

278

PTP (norm)

 

 

(13,943)

(20,486)

(31,473)

(27,941)

(34,718)

PTP (FRS 3)

 

 

(16,083)

(18,263)

(33,199)

(28,586)

(35,363)

Tax

0

0

0

0

0

PAT (norm)

(13,943)

(20,486)

(31,473)

(27,941)

(34,718)

PAT (FRS 3)

(16,083)

(18,263)

(33,199)

(28,586)

(35,363)

Average number of ADRs outstanding (m)

4.1

6.8

8.7

9.3

9.3

EPADR - normalised ($)

 

 

(3.40)

(3.03)

(3.62)

(3.00)

(3.73)

EPADR - (IFRS) ($)

 

 

(3.92)

(2.71)

(3.82)

(3.07)

(3.80)

Dividend per ADR ($)

0.0

0.0

0.0

0.0

0.0

Gross Margin (%)

N/A

N/A

N/A

N/A

N/A

EBITDA Margin (%)

N/A

N/A

N/A

N/A

N/A

Operating Margin (before GW and except) (%)

N/A

N/A

N/A

N/A

N/A

BALANCE SHEET

Fixed Assets

 

 

10,860

12,256

55,617

55,825

54,845

Intangible Assets

10,434

11,395

54,156

53,314

52,471

Tangible Assets

270

664

1,261

2,311

2,174

Investments

156

196

200

200

200

Current Assets

 

 

25,088

33,594

121,456

89,199

53,844

Stocks

0

0

0

0

0

Debtors

468

921

609

1,517

1,517

Cash

24,484

30,673

119,339

86,654

51,299

Other

136

2,000

1,507

1,028

1,028

Current Liabilities

 

 

(3,763)

(6,719)

(12,754)

(10,222)

(9,467)

Creditors

(3,287)

(5,856)

(11,757)

(8,776)

(8,776)

Deferred revenue

0

0

0

0

0

Walloon loans for cash payment

(476)

(862)

(997)

(1,446)

(691)

Long Term Liabilities

 

 

(13,430)

(12,475)

(40,583)

(37,756)

(37,756)

Walloon loans (non-current)

(13,400)

(11,964)

(11,637)

(8,346)

(8,346)

Other long term liabilities

(30)

(512)

(28,945)

(29,409)

(29,409)

Net Assets

 

 

18,756

26,656

123,736

97,047

61,467

CASH FLOW

Operating Cash Flow

 

 

(11,808)

(19,312)

(30,927)

(30,129)

(34,398)

Net Interest

(1,704)

(18)

619

716

138

Tax

0

0

0

0

0

Capex

(590)

(710)

(930)

(1,665)

(167)

Acquisitions/disposals

0

(1,721)

(5,756)

0

0

Financing

34,269

29,323

121,162

0

0

Dividends

0

0

0

0

0

Other

2,492

1,818

(3,649)

(1,607)

0

Net Cash Flow

22,659

9,381

80,519

(32,685)

(34,427)

Opening net debt/(cash)

 

 

12,050

(10,609)

(17,847)

(106,705)

(76,862)

HP finance leases initiated

0

0

0

0

0

Walloon loan recognition (non-cash)

0

(2,142)

8,339

2,842

(220)

Closing net debt/(cash)

 

 

(10,609)

(17,847)

(106,705)

(76,862)

(42,215)

Source: Edison Investment Research, Celyad accounts. Note: Solely for the convenience of US readers the financial summary table has been converted at a rate of US$1 to €0.89. Celyad reports statutory accounts in euros. These translations should not be considered representations that any such amounts have been or could be converted into US dollars at the assumed conversion rate.

Edison, the investment intelligence firm, is the future of investor interaction with corporates. Our team of over 100 analysts and investment professionals work with leading companies, fund managers and investment banks worldwide to support their capital markets activity. We provide services to more than 400 retained corporate and investor clients from our offices in London, New York, Frankfurt, Sydney and Wellington. Edison is authorised and regulated by the Financial Conduct Authority. Edison Investment Research (NZ) Limited (Edison NZ) is the New Zealand subsidiary of Edison. Edison NZ is registered on the New Zealand Financial Service Providers Register (FSP number 247505) and is registered to provide wholesale and/or generic financial adviser services only. Edison Investment Research Inc (Edison US) is the US subsidiary of Edison and is regulated by the Securities and Exchange Commission. Edison Investment Research Limited (Edison Aus) [46085869] is the Australian subsidiary of Edison and is not regulated by the Australian Securities and Investment Commission. Edison Germany is a branch entity of Edison Investment Research Limited [4794244]. www.edisongroup.com

DISCLAIMER
Copyright 2016 Edison Investment Research Limited. All rights reserved. This report has been commissioned by Celyad and prepared and issued by Edison for publication globally. 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. Opinions contained in this report represent those of the research department of Edison at the time of publication. The securities described in the Investment Research may not be eligible for sale in all jurisdictions or to certain categories of investors. This research is issued in Australia by Edison Aus and any access to it, is intended only for "wholesale clients" within the meaning of the Australian Corporations Act. The Investment Research is distributed in the United States by Edison US to major US institutional investors only. Edison US is registered as an investment adviser with the Securities and Exchange Commission. Edison US 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. As such, Edison does not offer or provide personalised advice. We publish information about companies in which we believe our readers may be interested and this information reflects our sincere opinions. The information that we provide or that is derived from our website is not intended to be, and should not be construed in any manner whatsoever as, personalised advice. Also, our website and 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 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. This document is provided for information purposes only and should not be construed as an offer or solicitation for investment in any securities mentioned or in the topic of this document.
A marketing communication under FCA Rules, this document has not been prepared in accordance with the legal requirements designed to promote the independence of investment research and is not subject to any prohibition on dealing ahead of the dissemination of investment research. Edison has a restrictive policy relating to personal dealing. 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. Edison or its affiliates may perform services or solicit business from any of the companies mentioned in this report. The value of securities mentioned in this report can fall as well as rise and are subject to large and sudden swings. In addition it may be difficult or not possible to buy, sell or obtain accurate information about the value of securities mentioned in this report. Past performance is not necessarily a guide to future performance. 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. 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 (ie 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. To the maximum extent permitted by law, Edison, its affiliates and contractors, and their respective directors, officers and employees will not be liable for any loss or damage arising as a result of reliance being placed on any of the information contained in this report and do not guarantee the returns on investments in the products discussed in this publication. FTSE International Limited (“FTSE”) © FTSE 2016. “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.

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

245 Park Avenue, 39th Floor

10167, New York

US

Sydney +61 (0)2 9258 1161

Level 25, Aurora Place

88 Phillip St, Sydney

NSW 2000, Australia

Wellington +64 (0)48 948 555

Level 15, 171 Featherston St

Wellington 6011

New Zealand

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

245 Park Avenue, 39th Floor

10167, New York

US

Sydney +61 (0)2 9258 1161

Level 25, Aurora Place

88 Phillip St, Sydney

NSW 2000, Australia

Wellington +64 (0)48 948 555

Level 15, 171 Featherston St

Wellington 6011

New Zealand

Edison, the investment intelligence firm, is the future of investor interaction with corporates. Our team of over 100 analysts and investment professionals work with leading companies, fund managers and investment banks worldwide to support their capital markets activity. We provide services to more than 400 retained corporate and investor clients from our offices in London, New York, Frankfurt, Sydney and Wellington. Edison is authorised and regulated by the Financial Conduct Authority. Edison Investment Research (NZ) Limited (Edison NZ) is the New Zealand subsidiary of Edison. Edison NZ is registered on the New Zealand Financial Service Providers Register (FSP number 247505) and is registered to provide wholesale and/or generic financial adviser services only. Edison Investment Research Inc (Edison US) is the US subsidiary of Edison and is regulated by the Securities and Exchange Commission. Edison Investment Research Limited (Edison Aus) [46085869] is the Australian subsidiary of Edison and is not regulated by the Australian Securities and Investment Commission. Edison Germany is a branch entity of Edison Investment Research Limited [4794244]. www.edisongroup.com

DISCLAIMER
Copyright 2016 Edison Investment Research Limited. All rights reserved. This report has been commissioned by Celyad and prepared and issued by Edison for publication globally. 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. Opinions contained in this report represent those of the research department of Edison at the time of publication. The securities described in the Investment Research may not be eligible for sale in all jurisdictions or to certain categories of investors. This research is issued in Australia by Edison Aus and any access to it, is intended only for "wholesale clients" within the meaning of the Australian Corporations Act. The Investment Research is distributed in the United States by Edison US to major US institutional investors only. Edison US is registered as an investment adviser with the Securities and Exchange Commission. Edison US 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. As such, Edison does not offer or provide personalised advice. We publish information about companies in which we believe our readers may be interested and this information reflects our sincere opinions. The information that we provide or that is derived from our website is not intended to be, and should not be construed in any manner whatsoever as, personalised advice. Also, our website and 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 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. This document is provided for information purposes only and should not be construed as an offer or solicitation for investment in any securities mentioned or in the topic of this document.
A marketing communication under FCA Rules, this document has not been prepared in accordance with the legal requirements designed to promote the independence of investment research and is not subject to any prohibition on dealing ahead of the dissemination of investment research. Edison has a restrictive policy relating to personal dealing. 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. Edison or its affiliates may perform services or solicit business from any of the companies mentioned in this report. The value of securities mentioned in this report can fall as well as rise and are subject to large and sudden swings. In addition it may be difficult or not possible to buy, sell or obtain accurate information about the value of securities mentioned in this report. Past performance is not necessarily a guide to future performance. 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. 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 (ie 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. To the maximum extent permitted by law, Edison, its affiliates and contractors, and their respective directors, officers and employees will not be liable for any loss or damage arising as a result of reliance being placed on any of the information contained in this report and do not guarantee the returns on investments in the products discussed in this publication. FTSE International Limited (“FTSE”) © FTSE 2016. “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.

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

245 Park Avenue, 39th Floor

10167, New York

US

Sydney +61 (0)2 9258 1161

Level 25, Aurora Place

88 Phillip St, Sydney

NSW 2000, Australia

Wellington +64 (0)48 948 555

Level 15, 171 Featherston St

Wellington 6011

New Zealand

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

245 Park Avenue, 39th Floor

10167, New York

US

Sydney +61 (0)2 9258 1161

Level 25, Aurora Place

88 Phillip St, Sydney

NSW 2000, Australia

Wellington +64 (0)48 948 555

Level 15, 171 Featherston St

Wellington 6011

New Zealand

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