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Targeting IPF with its i-body platform

AdAlta 22 February 2021 Initiation
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AdAlta

Targeting IPF with its i-body platform

Initiation of coverage

Pharma & biotech

22 February 2021

Price

A$0.19

Market cap

A$45m

A$1.35/US$

Net cash (A$m) at 31 December 2020

8.1

Shares in issue

245.2m

Free float

95.1%

Code

1AD

Primary exchange

ASX

Secondary exchange

N/A

Share price performance

%

1m

3m

12m

Abs

32.1

54.2

125.0

Rel (local)

31.2

47.2

130.6

52-week high/low

A$0.20

A$0.04

Business description

AdAlta is an Australian healthcare company focused on using its proprietary i-body discovery platform to target diseases, with an initial focus on conditions involving fibrosis. Its lead programme is AD-214 for the treatment of idiopathic pulmonary fibrosis, currently in Phase I. AdAlta has also licensed its platform to GE Healthcare for the purpose of diagnostic imaging.

Next events

AD-214 Phase I Part A results

March 2021

AD-214 Phase I Part B initiation

Q2 CY21

Analysts

Maxim Jacobs

+1 646 653 7027

Nathaniel Calloway

+1 646 653 7036

AdAlta is a research client of Edison Investment Research Limited

AdAlta is a clinical-stage company that uses its proprietary i-body discovery platform to target diseases, with an initial focus on conditions involving fibrosis. Its lead programme is AD-214, a C-X-C chemokine receptor type 4 (CXCR4) inhibitor for the treatment of idiopathic pulmonary fibrosis (IPF), which is in the healthy volunteer portion of a 98-subject Phase I trial. IPF is an orphan progressive lung disease that remains a significant unmet medical need, despite two approved blockbuster therapies, with median survival post-diagnosis of three to five years.

Year end

Revenue (A$m)

PBT*
(A$m)

EPS*
(A$)

DPS
(A$)

P/E
(x)

Yield
(%)

06/19

3.5

(5.9)

(0.05)

0.0

N/A

N/A

06/20

3.8

(5.9)

(0.04)

0.0

N/A

N/A

06/21e

3.2

(6.1)

(0.02)

0.0

N/A

N/A

06/22e

3.3

(6.2)

(0.02)

0.0

N/A

N/A

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

IPF: A severe disease with poor options

IPF is an orphan indication that involves the formation of scar tissue in the lungs for unknown reasons, but with factors such as age, smoking and genetics increasing the likelihood. It is estimated that over 100,000 people in the US and a similar number in Europe have the condition. IPF is a progressive disease where median survival after diagnosis is three to five years and the two approved medications for IPF (US$2.9bn in sales in 2019) have limited efficacy and toxicity issues.

Significant pharma industry interest in IPF

As the two approved IPF medications are blockbusters, there is significant pharma industry interest in this area. In 2019, Promedior (lead programme is an IPF drug in Phase II) was purchased by Roche for US$390m upfront and up to US$1bn in potential milestones. Boehringer Ingelheim licensed a Phase I asset from Bridge Biotherapeutics in 2019 for €45m upfront and over €1.1bn in milestones (but the collaboration has since terminated).

GE Healthcare licensing deal

Beyond AD-214, AdAlta licensed the i-body platform to GE Healthcare for the purpose of diagnostic imaging. The objective is to discover and optimise i-bodies against granzyme B, a known marker of T-cell activation. This could help select and monitor patients who are receiving immunotherapy. Lead optimisation is underway and is expected to complete in H1 CY21.

Valuation: A$60m or A$0.25 per basic share

We value AdAlta at A$60m or A$0.25 per basic share using a risk-adjusted net present value (NPV) model. We only attribute value to AD-214 as it is the only programme in human clinical trials. The company had A$8.1m in cash at 31 December 2020 and we estimate will likely need to raise an additional A$11m through the end of FY23, barring additional licensing deals.

Investment summary

AdAlta is an Australia-headquartered healthcare company that went public on the ASX in 2016. AdAlta is focused on using its proprietary i-body discovery platform to target diseases, with an initial focus on conditions involving fibrosis. Its lead programme is AD-214, a CXCR4 inhibitor for the treatment of IPF, which is in the healthy volunteer portion of a Phase I trial. IPF is an orphan disease affecting over 100,000 people in the US and a similar number in Europe. It is progressive and serious with life expectancy after diagnosis estimated to be three to five years. The two approved medications for IPF totalled US$2.9bn in sales in 2019, despite relatively limited efficacy and some safety issues. AdAlta will seek to expand its AD-214 development programme to other fibrotic conditions, chronic kidney disease and cancer. Additionally, the company is seeking to have five internal programmes and three to five external pipeline partnerships by 2023. In 2019, AdAlta licensed the i-body platform to GE Healthcare for the purpose of diagnostic imaging. The goal is to identify molecular markers of activated T cells, which could help in the selection and monitoring of patients who are receiving immunotherapy.

Valuation: A$60m or A$0.25 per basic share

We are initiating coverage of AdAlta at A$60m or A$0.25 per basic share using a risk-adjusted NPV model focused strictly on the AD-214 programme in IPF, as it is the only programme in human clinical trials. We attribute a 12.5% chance of success to AD-214, a premium to our standard 10% probability of success for a Phase I programme, as 42 subjects have already been dosed with no adverse safety events of clinical concern, increasing our confidence in AD-214’s safety profile. We are also modelling peak sales of A$718m and launch in 2028. We will adjust our assumptions as AD-214 advances through clinical studies. Additionally, there is a potential for a valuation inflection point and a validating partnership after the end of Phase I.

Financials: A$8.1m in cash

AdAlta had A$8.1m in cash at 31 December 2020. The company raised A$8.1m in gross proceeds from a fully subscribed placement and entitlement offer in Q1 FY21. We estimate the company will likely need to raise an additional A$11m for AD-214 through the end of FY23 (at which point AD-214 should be in the midst of Phase II testing), which we model as illustrative long-term debt, barring additional licensing deals.

Sensitivities: IPF a difficult and competitive indication

As the underlying cause of IPF is unknown, current treatments are limited to targeting the symptoms, which historically has led to limited efficacy as the disease continues to progress even with treatment. This also makes the clinical trial programme more costly as large pivotal trials are needed to obtain a statistically significant results from small differences versus placebo. And while IPF has historically been an indication with no or limited choices, there are several potential candidates in clinical trials, all of which can reach the market before AD-214. Additionally, AD-214 will be disadvantaged potentially due to its intravenous (IV) administration (the two marketed products are oral though pirfenidone requires nine pills a day, which is not a convenient dosing schedule), although the two competitive programmes in Phase III are intravenous as well, suggesting this mode of administration is viable. Beyond the branded competition, both the approved products will be generic by the time AD-214 reaches the market, which may delay its usage to later lines of therapy. The company may also face significant dilution if funding needs are met through equity issuances. Share issuance over the next few years may be higher than current shares outstanding, depending on the prevailing stock price at the time of such raise(s).

Company description: Building on the i-body platform

AdAlta is an Australia-headquartered healthcare company focused on using uses its proprietary ibody discovery platform to target diseases, with an initial focus on conditions involving fibrosis. We believe it is the first fully human single domain antibody platform. I-bodies are proteins generated to mimic the shape of shark antibodies and engineered to create unique compounds. I-bodies are around 10% of the size of a human antibody and are highly stable at high temperatures and low pH environments. Also, the long binding loop in i-bodies enables them to target a diverse range of drug targets, some of which are difficult to access using conventional antibody therapies. Additionally, ibodies can be tailored into a wide variety of formats including mono-specific, bi-specific (two specific targets) and drug conjugate configurations. AdAlta has a library containing billions of i-bodies that may have a plethora of uses and it has proof of principle against over 25 targets, according to the company.

Exhibit 1: AdAlta’s proprietary i-body platform

Source: AdAlta

Its lead program is AD-214 for the treatment of IPF, which is in the healthy volunteer portion (Part A) of a three-part Phase I trial. As of late January, 42 participants had received AD-214 or placebo, with doses up to 20mg/kg showing no safety issues (note that preclinical studies indicate a target human therapeutic dose of 10mg/kg given intravenously either weekly or every other week). The results of Part A are expected in early March. Part B of the study, which will include interstitial lung disease (ILD) and IPF patients, is expected to begin in Q2 of CY21. With regards to external partnerships, AdAlta licensed the i-body platform to GE Healthcare for the purpose of diagnostic imaging. licensed the i-body platform to GE Healthcare for the purpose of diagnostic imaging. The objective is to discover and optimise i-bodies against granzyme B, a known marker of T-cell activation. This could help select and monitor patients who are receiving immunotherapy. Lead optimisation is underway and is expected to complete in H1 CY21. The company’s goal is to have five internal programmes and three to five external pipeline partnerships by 2023.

Exhibit 2: AdAlta pipeline

Programme

Class of targets

Indication

Status

Partners

Comments

AD-214

G protein-coupled receptor

IPF

Phase I

None

Currently in Part A of Phase I trial. Part A tested a single dose of AD-214 in 42 healthy volunteers. Results of Part A expected in early March 2021. Part B will test a single dose in 15-30 ILD/IPF patients and is expected to start in Q2 CY21 and finish by the end of that year. Part C will test multiple doses in 12-24 ILD/IPF patients and is expected to start in late CY21 and complete in mid-CY22.

Granzyme B

Serine protease

Oncology

Lead optimisation

GE Healthcare

Working on developing i-bodies for diagnostic imaging and to help identify molecular markers of activated T cells to assist in the selection and monitoring of patients receiving cancer immunotherapy. Lead optimisation stage is expected to complete in H1 CY21. A$1.15m in milestones and research fees earned to 30 September 2020.

Source: AdAlta

AD-214 for IPF

AdAlta’s lead programme is AD-214, which is being developed for the treatment of IPF. It is an i-body that is designed to be a CXCR4 antagonist. CXCR4 is a G-protein coupled receptor, which plays an important role in the maintenance of stem cells in bone marrow (CXCR4 inhibitor plerixafor has been FDA approved since 2008 for stem cell mobilisation), is upregulated in a number of cancers, is a co-receptor for HIV and, importantly, is a key player in fibrosis. Proof of concept has been demonstrated by the company in preclinical models where an anti-CXCR4 i-body was shown to reduce invasion of IPF fibroblasts and collagen secretion.1 AD-214 also demonstrated novel anti-CXCR4 pharmacology in that it does not mobilise stem cells, removing at least one of the key safety concerns that prevent chronic use of plerixafor. It is also highly specific for CXCR4. This combination of features position it for multiple fibrotic indications. Additional proof of concept came from testing AD-214 in the mouse bleomycin model, which is considered the gold standard model for IPF. Statistically significant reductions in the Ashcroft Score (a scale to evaluate lung fibrosis) were seen at dose ranges between 1mg/kg and 30mg/kg every second day and between 10mg/kg and 30mg/kg every fourth day (Exhibit 3).

  Griffiths et al., i-bodies, Human single domain antibodies that antagonize chemokine receptor CXCR4. Journal of Biological Chemistry. Vol. 291, No. 24, pp. 12641–12657. June 10, 2016

Exhibit 3: AD-214 reduced fibrosis in mouse bleomycin model

Source: AdAlta

Also, preclinical toxicology in three non-human primate studies found that AD-214 was well tolerated with no deaths or clinically noticeable side effects. There was no major organ toxicity observed on repeat dosing at high doses or any suggestion of off-target toxicities (which speaks to the specificity of i-bodies). Pharmacokinetics (PK) and pharmacodynamics (PD) seen in the non-human primate studies indicate a target human therapeutic dose of 10mg/kg given intravenously either weekly or every other week.

AD-214 is in a three-part Phase I study that can enrol up to 98 subjects. The primary objective of the Phase I is to assess the safety and tolerability of AD-214 both in healthy volunteers and ILD/IPF patients. Secondary objectives are to understand the PK/PD and immunogenicity of AD-214. The study will also explore whether there is an effect from AD-214 on respiratory function and the drug’s distribution and receptor occupancy as measured through positron emission tomography (PET) tracing.

So far 42 healthy subjects have received a single dose of either AD-214 or placebo at around a 3:1 ratio as part of Part A. Dosing for cohorts up to 20mg/kg have been completed with no concerning findings. Importantly, AD-214 exhibited higher receptor occupancy of 86% at the 10mg/kg dose seven days after dosing, suggesting the potential for prolonged dosing interval. Due to this finding, the company amended the protocol to investigate receptor occupancy at two and three weeks following infusion. Part A dosing has completed with results expected in early March. This will be followed by Part B, a single-dose study in ILD/IPF patients that will then be followed by Part C, which will study weekly dosing in ILD/IPF patients over four weeks. However, the results of Part A may enable Parts B and C to be conducted differently, so these are subject to change.

Exhibit 4: Phase I design

Subject types

Subjects

Dose ranges

Number of sites

Timing

Comments

Part A

Healthy volunteers

42

0.01–20mg/kg IV single dose

2

Completed. Data expected early March 2021.

42 participants received AD-214 or placebo at a ~3:1 ratio. Doses up to 20mg/kg complete with no clinically concerning safety findings. Receptor occupancy at 2 and 3 week time points is being investigated.

Part B

ILD/IPF patients

~15-30

0.01–20mg/kg IV single dose

2-3

H1 CY21 to late CY21

Includes AD-214 PET tracing to investigate distribution and receptor occupancy

Part C

ILD/IPF patients

~12-24

IV weekly for 4 weeks, dose TBD

2-3

Late CY21 to mid-CY22

Includes AD-214 PET tracing to investigate distribution and receptor occupancy

Source: AdAlta

Over time, AdAlta will seek to expand its AD-214 development programme to other fibrotic conditions, chronic kidney disease and cancer as well. ILDs are a diverse range of pulmonary fibrotic disorders that have been difficult to classify. Estimates suggest that IPF represents between 17% and 86% of ILDs2 though it is likely closer to about a third. As with IPF, patients with ILDs have a short life expectancy after diagnosis of about three years3. As the company is also enrolling ILD patients into the Phase I, any development in this area could leap directly into Phase II if the Phase I portion of the current trial is completed successfully.

  Wakwaya et al., Idiopathic Pulmonary Fibrosis: Epidemiology, Diagnosis and Outcomes. The American Journal of Medical Science. 2019;357(5):359-369.

  Raghue et al, The epidemiology of interstitial lung disease and its association with lung cancer. British Journal of Cancer (2004) 91, Supplement 2, S3 – S10.

In Q4 CY20, the company received encouraging results in a mouse model for fibrosis in chronic kidney disease and these results are being prepared for publication. Chronic kidney disease is a major unmet medical need. According to the US National Institute of Diabetes and Digestive and Kidney Diseases, 14% of the population has chronic kidney disease with an estimated 661,000 in kidney failure. The company also has preclinical data with predecessor molecules to AD-214 in eye fibrosis and other organs such as the liver and skin.

With regards to cancer, CXCR4 is highly expressed in a variety of tumour types and is correlated with poor outcomes (Exhibit 5) as it is associated with tumour immune evasion, angiogenesis and metastasis.4 Importantly, inhibiting CXCR4 has been shown in preclinical experiments to impair tumour migration,5 growth and angiogenesis.6 Although CXCR4 inhibition does not appear to have much of a cytotoxic effect by itself, there does appear to be evidence of an enhanced cytotoxic/chemosensitisation effect per both clinical and preclinical data when combined with chemotherapy. The company has commenced studies in two mouse models of breast cancer to explore the potential for treating/preventing metastatic disease as well as improving the efficacy of checkpoint inhibitors.

  Xu et al., CXCR4 in breast cancer: oncogenic role and therapeutic targeting. Drug Design, Development and Therapy. 2015;9: 4953–4964.

  Muller et al., Involvement of chemokine receptors in breast cancer metastasis. Nature. Volume 410. 1 March 2001

  Xu et al., CXCR4 in breast cancer: oncogenic role and therapeutic targeting. Drug Design, Development and Therapy. 2015;9: 4953–4964.

Exhibit 5: CXCR4 expression is associated with shorter survival in cancer patients

Source: Zhao et al., CXCR4 over-expression and survival in cancer: A system review and meta-analysis.

Oncotarget. 2015 Mar 10;6(7):5022-40.

The IPF market

IPF is a serious progressive disease that involves the formation of scar tissue in the lung for unknown reasons (hence it is referred to as idiopathic) and is one of the most common ILDs (a group of pulmonary diseases often characterised by inflammation and/or fibrosis). It often starts as shortness of breath and a nonproductive cough, progressing through acute exacerbations with significant respiratory deterioration that leads to acute lung injury and fibrosis. Mean survival is only of three to five years after diagnosis.7 It is estimated that over 100,000 people in the US and a similar number in Europe have the condition, although the exact number is unknown due to a challenging diagnostic process. Additionally, the epidemiologic studies often will have different criteria for IPF. For example, using narrow case definitions, annual incidence for IPF in the US are estimated at 6.8–8.8 per 100,000 population while using broader criteria garners estimates of 16.3–17.4 cases per 100,000 cases (as a reminder, prevalence is a multiple of incidence as people survive multiple years). There are multiple factors that may increase the likelihood of developing IPF, such as age (older), sex (male), smoking and genetics. Also, studies indicate IPF sufferers have disproportionately high levels of pulmonary arterial hypertension, emphysema and gastroesophageal reflux disease.8

  Wakwaya et al., Idiopathic Pulmonary Fibrosis: Epidemiology, Diagnosis and Outcomes. The American Journal of Medical Science. 2019;357(5):359-369.

  Kim et al., Natural History of Idiopathic Pulmonary Fibrosis. Respiratory Medicine (2015) 109(6), 661-670

There are two approved medications for IPF with a combined US$2.9bn in sales in 2019 but they both have limited efficacy and toxicity issues (Exhibit 6).

Exhibit 6: Marketed IPF products

Drug

Company

Target

Administration

Sales

Cost

Generic competition date

Efficacy

Toxicities

Ofev (nintedanib)

Boehringer Ingelheim

Multiple growth factor receptors, including FGFR, PDGFR and VEGFR

Oral, 150mg twice daily

US$1,669m

US$97,331 per patient (US), US$30,000 per patient (EU)

2021 (US), 2030 (EU)

45–52% reduction in annual rate of forced vital capacity (FVC) decline versus placebo in two Phase III trials. Not statistically significant difference in all-cause mortality.

Major side effects include diarrhoea, nausea, abdominal pain, vomiting, liver enzyme elevation and weight loss.

Esbriet (pirfenidone)

Roche

Unknown

Oral, 801mg (3 capsules), 3 times daily

US$1,136m

US$94,904 per patient (US), US$30,000 per patient (EU)

2026

28–52% reduction in FVC decline after 48 weeks across three Phase III trials. However, one Phase III was not statistically significant as FVC decline benefit almost completely evaporated by week 72. No statistically significant benefit in all-cause mortality.

Major side effects include nausea, rash, abdominal pain, fatigue, dyspepsia, photosensitivity and weight loss.

Source: FDA, GlobalData

Both Ofev and Esbriet have been shown through multiple studies to reduce the rate of decline by up to around half but have not been shown to either stop the progression or improve all-cause mortality (although they both had trends to improving mortality, clinical trials would probably have to be multi-year to show a statistically significant difference). Additionally, they are not without side effects. Patients on either drug may have to deal with diarrhoea, nausea, vomiting, abdominal pain, fatigue and other issues. Liver enzyme elevation is a particular problem for Ofev whereas Esbriet can make patients photosensitive, limiting its use in those that spend a lot of time outside.

Exhibit 7: Adverse events in clinical trials for currently marketed IPF products

Ofev clinical trials

Esbriet clinical trials

Ofev

Placebo

Esbriet

Placebo

Nausea

24%

7%

36%

16%

Rash

30%

10%

Diarrhoea

62%

18%

26%

20%

Fatigue

11%

7%

26%

19%

Abdominal Pain

15%

6%

24%

15%

Headache

8%

5%

22%

19%

Dyspepsia

19%

7%

Dizziness

6%

4%

18%

11%

Vomiting

12%

3%

13%

6%

Anorexia

13%

5%

GERD

11%

7%

Weight loss

10%

4%

10%

5%

Insomnia

10%

7%

Arthralgia

10%

7%

Photosensitivity

9%

1%

Decreased appetite

11%

5%

8%

5%

Liver enzyme elevation

14%

3%

4%

1%

Source: FDA product labels

It certainly speaks to the seriousness of the disease that medicines with somewhat limited efficacy and with this sort of profile are blockbusters. Hence, this an area of interest for the biopharmaceutical industry with several products being in development.

Pamrevlumab from Fibrogen is viewed as the most promising based on the data from its 103-patient Phase II trial in which there was a 60% reduction in the decline of FVC versus placebo at the 48-week mark.9 It is in two Phase III trials with 340 participants each, with data expected in 2023 (the Zephyrus I and Zephyrus II trials). Unlike Ofev and Esbriet, pamrevlumab is given through intravenous infusion every three weeks.

  Richeldi et al., Pamrevlumab, an anti-connective tissue growth factor therapy, for idiopathic pulmonary fibrosis (PRAISE): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Respiratory Medicine 2020 Jan;8(1):25-33

PRM-151 is being developed by Roche following its acquisition of Promedior in November 2019 for US$390m upfront and an additional $1bn in potential milestones. In a 117-patient Phase II trial, PRM-151 demonstrated a 48% reduction in FVC decline versus placebo at the 24-week point. Roche recently initiated a 658-patient Phase III trial for the programme, with completion expected in 2023. Participants are given IV infusions over 50–70 minutes on days one, three and five followed by infusions every four weeks for 48 weeks.

Galapagos is developing GLPG-1205, which demonstrated a 55% reduction in the rate of FVC decline versus control at the 26-week mark in the Phase II PINTA trial. Patients were allowed to be on Ofev, Esbriet or nothing, on top of GLPG-1205. Galapagos is progressing the programme into a dose-finding Phase IIb, which we expect to be initiated sometime in CY21. In total, Galapagos is developing several molecules for IPF, GLPG-1205, the recently acquired GLPG-4716 (finished Phase I) and the preclinical candidates GLPG-4124 and GLPG-4586. Recently, however, GLPG-1690 from Galapagos failed in Phase III (although the precise reasons were undisclosed) and all clinical trials for this molecule were discontinued. In a Phase IIa trial in 23 patients over a 12-week period, patients receiving GLPG-1690 showed an FVC increase of 8mL while those on placebo had an FVC decrease of 87mL. While the data was from a small trial and of limited duration, the absence of FVC deterioration in the GLPG-1690 arm was considered encouraging.

Other programmes of note are fezagepras/PBI-4050 from Liminal Biosciences. It ran a 41-patient trial with three arms, one with its drug alone and the other two in combination with the marketed products. The results are a little hard to interpret without a placebo arm and there does seem to be a drug interaction with Esbriet; however, the arm in combination with Ofev was promising with a small increase in FVC after 12 weeks.10 Initiation of a Phase IIb is expected in H221. TD-139/GB-0139 by Galecto/PharmAkea is the only inhaled therapy in the pipeline and this may be a troublesome mode of action as it might be difficult to have the patients inhale enough of the drug into their lungs if they are short of breath. Data for this drug are limited to a Phase I/IIa in 36 healthy subjects and 24 IPF patients, with IPF patient data mostly related to biomarkers.11 It is recruiting a 450-patient Phase IIb trial with completion expected by the end of 2021. Bristol Myers is working on CC-90001. Data so far are limited to biomarker data from Phase Ia and Ib in 100 healthy adults and 16 patients with pulmonary fibrosis. A Phase II in 210 participants is recruiting, with the study expected to complete the 24-week treatment phase in mid-2021.

  Khalil et al., Phase 2 clinical trial of PBI-4050 in patients with idiopathic pulmonary fibrosis. European Respiratory Journal 2019; 53: 1800663

  Hirani et al., Target-inhibition of Galectin-3 by Inhaled TD139 in Patients with Idiopathic Pulmonary Fibrosis. European Respiratory Journal. 2020 Nov 19:2002559

Exhibit 8: Later stage competitive landscape in IPF

Drug

Company

Target

Administration

Status

Efficacy

Comments

Pamrevlumab

Fibrogen

Connective tissue growth factor

IV every three weeks

Phase III, monotherapy

60% reduction in FVC decline at 48 weeks in 103 patient Phase II trial

Strongest data of pipeline programmes. Also appears to have milder safety profile compared to approved products. Key adverse events in Phase II were infections, dyspnoea, fatigue and diarrhoea.

PRM-151

Roche (through Promedior acquisition)

Pentraxin-2

IV infusion, three times in first week and then every four weeks

Phase III, including those with or without standard of care

48% reduction in FVC decline at 24 weeks in 117 patient Phase II trial

Promedior was bought by Roche for US$390m upfront and additional contingent payments of up to US$1bn after the PRM-151 Phase II data. Most frequent adverse event was cough.

GLPG-1205

Galapagos

G-protein-coupled receptor 84 (GPR84)

Oral, 100mg once daily

Phase IIb

55% reduction in FVC decline at week 26 in 68 patient Phase II trial

Patients had the option of staying on standard of care or be on nothing. Appeared to have no additive toxicities on top of Esbriet but a higher rate of early discontinuations and high-grade treatment related adverse events in combination with Ofev. The company has stated it will progress to a Phase IIb dose-finding trial.

Fezagepras
(PBI-4050)

Liminal Biosciences

G-protein-coupled receptor 40 (GPR40) and
G-protein-coupled receptor 80 (GPR80)

Oral, 800mg once a day

Phase IIb (design not publicly disclosed)

In 41 patient Phase II trial in three arms, drug in combination with Ofev showed increase in FVC after 12 weeks of treatment of 1.87ml. Alone FVC fell 12.2ml and in combination with Esbriet, FVC fell 102ml

May have drug interaction with Esbriet. Lack of placebo arm in Phase II makes current data difficult to interpret. Phase IIb initiation expected H221.

TD-139/GB-0139

Galecto/PharmAkea

Galectin 3

Inhaled, 10mg once a day

Phase IIb

Only biomarker data so far

Currently recruiting a 450 patient Phase IIb. Data is limited so far. Inhaled route may prove to be an issue due to shortness of breath in patients.

CC-90001

Bristol-Myers (through Celgene acquisition)

Mitogen activated protein kinase 8

200–400mg once a day

Phase II

Only biomarker data so far

Currently recruiting 210 patient Phase II trial. Nausea was most frequent adverse event in Phase I.

Source: EvaluatePharma, GlobalData, clinicaltrials.gov, company reports

Importantly, as the two approved IPF medications are blockbusters, there is significant pharma industry interest in this area. Besides the Promedior acquisition by Roche in 2019, in the same year Boehringer Ingelheim licensed a Phase I asset from Bridge Biotherapeutics for €45m upfront and over €1.1bn in milestones (but the collaboration has since terminated). More recently, in November 2020, Galapagos signed a deal with the Polish biotech company OncoArendi for OATD-01 (now GLPG-4716), a chitotriosidase/acidic mammalian chitinase (CHIT1/AMCase) inhibitor that has completed Phase I. Galapagos paid €25m upfront and OncoArendi will be eligible for €320m in total potential milestones and tiered royalties up to the low double digits.

AD-214 estimates in IPF

Our estimates for AD-214 for the treatment of IPF are based on the assumptions that approximately 65% of IPF patients are diagnosed and 35% of them are treated in the US and 50% of them are treated in the EU5 (recall that the price of current treatments in the EU is substantially less than in the US). We then estimate that at peak the market share for AD-214 will be 5% of those patients in both regions as we expect there will be competition from a number of branded and generic players by the time AD-214 reaches the market. AD-214 will also be an IV therapy in a market with existing oral medication alternatives, potentially limiting its uptake to those who either have failed or cannot tolerate current medications. Our market share estimates may prove conservative if the therapy has a superior efficacy and toxicity profile compared to the currently marketed competitive products. However, as we have no human clinical data, we estimate approval is not likely until 2028 (and hence we do not know what the competitive landscape may look like at that point) and the mode of administration is more inconvenient, we believe conservatism is prudent.

Using a US$125,000 price per patient per course of therapy in the US and US$40,000 in the EU (a premium to the marketed therapies) we arrive at peak sales of US$540m (A$718m) a year for the therapy. We apply a 12.5% chance of success to AD-214, a premium to our standard 10% probability of success for a Phase I programme. This is due to the fact that 42 subjects have already been dosed with no adverse safety events of clinical concern (including at the highest planned dose of 20mg/kg), increasing our confidence in AD-214’s safety profile. We also model revenues to 2040. Granted patents provide protection until 2036, but we do expect additional patents to be filed. Additionally, AD-214 will be eligible for 12-year exclusivity (given that it is a biologics drug) on approval in the US and 10 years in the EU (as it is an orphan drug) as well as up to five years of patent extensions in both jurisdictions.

Granzyme B partnership with GE Healthcare

In September 2019, AdAlta licensed the i-body platform to GE Healthcare for diagnostic purposes in combination with PET tracing. The objective is to identify molecular markers of activated T cells, which could help in the selection and monitoring of patients who are receiving immunotherapy. The initial focus of the collaboration is granzyme B, which has been shown to be a potentially helpful early biomarker for immunotherapy response in tumours.12 Lead optimisation is underway as the collaboration has yielded a panel of i-bodies with affinity, specificity and activity properties against granzyme B that warrant further development. Lead optimisation is expected to complete in H1 CY21 after which GE Healthcare may progress a lead i-body into preclinical development. A$1.15m in milestones and research fees have been earned to 30 September 2020. However, additional financial details of the collaboration have not been disclosed. AdAlta is seeking to license the i-body platform to at least one additional partner by the middle of CY21. We do not currently attribute value to this partnership due to both the lack of financial details related to it and the early stage of development. We expect to add it into our valuation once it reaches human clinical trials.

  Larimer et al., Granzyme B PET Imaging as a Predictive Biomarker of Immunotherapy Response. Cancer Research. May 1 2017 (77) (9) 2318-2327

Sensitivities

As the underlying cause of IPF is unknown, companies are limited to targeting the symptoms, which historically has led to limited efficacy as the disease continues to progress even with treatment. This would make the clinical trial programme more costly as large pivotal trials are needed to obtain a statistically significant result from a small treatment effect differences versus placebo or standard-of-care. And while IPF has historically been an indication with no or limited choices, there are several potential candidates in clinical trials, all of which can reach the market before AD-214. Additionally, AD-214 may be disadvantaged potentially due to its intravenous (IV) administration (the two marketed products are oral although pirfenidone requires nine pills a day, which is not a convenient dosing schedule), although the two competitive programmes in Phase III are intravenous as well, suggesting this mode of administration is viable. Considerations from the IV dosing route may be mitigated if the dosing schedule can be reduced to only once every two or three weeks. Beyond the branded competition, both the currently approved products will be generic by the time AD-214 reaches the market (Ofev starting in 2021 in the US and Esbriet in 2026), which may delay AD-214 usage to later lines of therapy unless combination therapy with AD-214 makes treatment more effective. However, some of these competitive issues may be countered if AdAlta is able to sign an effective partner for AD-214, possibly Roche or Boehringer Ingelheim, both of which have extensive experience with IPF and are active on the IPF business development front. The company also faces financing risks, which can lead to potentially significant dilution if funding needs are met through equity issuance. Share issuance over the next few years may be higher than current shares outstanding, depending on the prevailing stock price at the time of such raise(s).

Valuation

We are initiating coverage of AdAlta at A$60m or A$0.25 per basic share using a risk-adjusted NPV model focused strictly on the AD-214 programme in IPF, as it is the only programme in human clinical trials. We attribute a 12.5% chance of success to AD-214, a premium to our standard 10% probability of success for a Phase I programme. This is due to the fact that 42 subjects have already been dosed with no adverse safety events of clinical concern (including at the highest planned dose of 20mg/kg), increasing our confidence in AD-214’s safety profile. We are also modelling peak sales of A$718m and launch in 2028. We will adjust our assumptions as AD-214 advances through clinical studies. For the sake of illustration of how this might look, based on our current model, by 2023 AD-214 would be worth A$182m if it is at the start of Phase II and if a 30% probability of success is assumed at that time.

Additionally, as some of the recent business development deals in this indication have occurred in Phase I or Phase II, there is a potential for a valuation inflection point and/or a validating partnership after the end of Phase I. Also, we intend to add additional AD-214 indications, such as ILD, additional pipeline products and additional platform deals as necessary. All of which would likely have positive impacts on our valuation.

Exhibit 9: AdAlta valuation

Product

Main Indication

Status

Probability of successful commercialization

Approval year

Peak sales (A$m)

Economics

rNPV (A$m)

AD-214

IPF

Phase I

12.5%

2028

718

100.0%

52.0

Total

 

 

 

 

 

 

52.0

Net Cash (as of December 31, 2020)

8.1

Total firm value (A$)

60.1

Total basic shares (m)

245.2

Value per basic share (A$)

0.25

Options (m)

30.2

Total number of shares (m)

275.4

Diluted value per share (A$)

0.22

Source: Edison Investment Research

Financials

AdAlta reported A$8.1m in cash on its balance sheet at the end of December 2020. The company owed Radium Capital A$2.2m as part of facility, but repaid it through funds received as part of the Australian Research and Development Tax refund in October 2020. AdAlta raised A$8.1m during the quarter ended September 2020 through a placement and entitlement offer of 81.2m shares at A$0.10 each. Historically, the company has had a relatively low burn rate in terms of operating cash flow, of about A$5.9m in FY20 and A$5.8m in FY19. In H1 FY21, the burn rate was only A$0.8m, benefiting from the receipt of a A$3.1m R&D tax incentive refund for FY20. We estimate AdAlta will likely need to raise an additional A$11m through the end of FY23 (at which point AD-214 should be in the midst of Phase II testing), which we model as illustrative long-term debt, barring additional licensing deals. The financing needs of the company through profitability will greatly depend on its ability to find a partner for AD214 as Phase II and Phase III development will accelerate spending and the pace that it progresses its internal pipeline of products. The Ofev clinical trial programme included two Phase III studies totalling 1,061 patients. Assuming a cost of US$100,000 per patient and a similar size for the pivotal trials, the total cost of Phase III could be US$106m (A$138m). Hence, we anticipate a partner is likely needed for Phase III, although our modelling/valuation is based on the company retaining full economics and developing the product internally.

Exhibit 10: Financial summary

A$'000s

2019

2020

2021e

2022e

Year end 30 June

AIFRS

AIFRS

AIFRS

AIFRS

PROFIT & LOSS

Revenue (including R&D tax credit)

 

 

3,539

3,828

3,244

3,276

Cost of Sales (including R&D)

(7,354)

(7,012)

(7,082)

(7,153)

Gross Profit

(3,815)

(3,185)

(3,838)

(3,877)

Sales, General and Administrative Expenses

(1,315)

(1,265)

(1,316)

(1,368)

EBITDA

 

 

(5,957)

(5,798)

(5,920)

(6,011)

Operating Profit (before amort. and except.)

 

 

(5,989)

(5,840)

(5,961)

(6,052)

Intangible Amortisation

0

0

0

0

Other

(827)

(1,348)

(766)

(766)

Exceptionals

20

(70)

0

0

Operating Profit

(5,969)

(5,910)

(5,961)

(6,052)

Net Interest

51

(96)

(100)

(104)

Other

0

0

0

0

Profit Before Tax (norm)

 

 

(5,938)

(5,936)

(6,062)

(6,157)

Profit Before Tax (FRS 3)

 

 

(5,918)

(6,006)

(6,062)

(6,157)

Tax

0

0

0

0

Deferred tax

(0)

(0)

(0)

(0)

Profit After Tax (norm)

(5,938)

(5,936)

(6,062)

(6,157)

Profit After Tax (FRS 3)

(5,918)

(6,006)

(6,062)

(6,157)

Average Number of Shares Outstanding (m)

118.4

164.0

250.0

252.5

EPS - normalised (c)

 

 

(5.02)

(3.62)

(2.42)

(2.44)

EPS - Reported ($)

 

 

(0.05)

(0.04)

(0.02)

(0.02)

Dividend per share (c)

0.0

0.0

0.0

0.0

BALANCE SHEET

Fixed Assets

 

 

141

177

170

163

Intangible Assets

0

0

(8)

(17)

Tangible Assets

138

99

100

102

Other

3

78

78

78

Current Assets

 

 

9,169

6,731

6,681

6,202

Stocks

0

0

0

0

Debtors

3,613

3,364

3,364

3,364

Cash

5,556

3,367

3,317

2,838

Other

0

0

0

0

Current Liabilities

 

 

(1,819)

(3,205)

(860)

(860)

Creditors

(1,819)

(1,014)

(860)

(860)

Short term borrowings

0

(2,191)

0

0

Long Term Liabilities

 

 

0

0

0

(5,000)

Long term borrowings

0

0

0

(5,000)

Other long term liabilities

0

0

0

0

Net Assets

 

 

7,491

3,702

5,990

505

CASH FLOW

Operating Cash Flow

 

 

(5,816)

(5,889)

(5,559)

(5,476)

Net Interest

0

0

0

0

Tax

0

0

0

0

Capex

(171)

(2)

(2)

(3)

Acquisitions/disposals

0

0

0

0

Financing

9,237

1,626

7,796

0

Dividends

0

0

0

0

Other

0

0

0

0

Net Cash Flow

3,250

(4,265)

2,234

(5,479)

Opening net debt/(cash)

 

 

(2,306)

(5,556)

(1,175)

(3,317)

HP finance leases initiated

0

0

0

0

Exchange rate movements

0

0

0

0

Other

0

(116)

(93)

0

Closing net debt/(cash)

 

 

(5,556)

(1,175)

(3,316)

2,162

Source: Company reports, Edison Investment Research

Contact details

Revenue by geography

15/2 Park Drive
Bundoora 3083 Victoria
Australia
+61 3 9479 5159
https://adalta.com.au/

N/A

Contact details

15/2 Park Drive
Bundoora 3083 Victoria
Australia
+61 3 9479 5159
https://adalta.com.au/

Revenue by geography

N/A

Management team

CEO: Tim Oldham, PhD

CSO: Michael Foley, PhD

Dr. Oldham was appointed CEO and MD in October 2019. Immediately before this, he was executive leader of Tijan Ventures, an advisory business focused on growing life sciences companies through strategic advisory and interim CEO, executive and non-executive leadership services, with a particular focus on biologics, cell and gene therapies and immunotherapy. Previous roles include CEO and managing director of Cell Therapies, a leading contract manufacturer and distributor cellular therapies in Asia Pacific, president of Asia Pacific for Hospira and a variety of senior management roles with Mayne Pharma before its acquisition by Hospira. Prior to this, he was an engagement manager with McKinsey & Co. Industry leadership roles include currently serving as a director of BioMelbourne Network and terms as chairman of the European Generic Medicines Association Biosimilars and Biotechnology Committee, a director of the Alliance for Regenerative Medicine and a Director of the Generic Medicines Industry Association. He is a non-executive director at Acrux (ASX:ACR).

Dr. Foley is the founding scientist of AdAlta and a key inventor of AdAlta’s lead i-body candidate AD-214. Upon completion of his PhD he was awarded a Wellcome Training Fellowship and worked at the Walter and Elisa Hall Institute. In 1995 he was awarded an ARC QEII Fellowship where he established the phage display of antibodies and peptide technology as a means of answering fundamental questions of immunity to infectious diseases. Dr. Foley has significant experience in phage display, the technology used to screen the i-body library to identify new drug candidates. Having published over 70 scientific publications he has received funding from ARC, NHMRC and NIH (US).

COO: Dallas Hartman, PhD

VP, clinical product development: Claudia Gregorio-King

Dr. Hartman is the chief operating officer of AdAlta and has over 15 years’ experience in the biotechnology industry. Prior to joining AdAlta, he was vice president of product development at the NASDAQ listed biotechnology company Nexvet where he was responsible for scalable bioprocess development, formulation, stability, analytical characterisation and cell line development. Dr. Hartman worked at CSL for 14 years in a number of roles, most notably director of analytical biochemistry. Before moving to industry, he undertook postdoctoral research at the University of Texas Southwestern Medical Center and the University of Melbourne where his worked was supported by fellowships from the Howard Hughes Medical Institute and the Australian Research Council. Dallas holds an MBA with specialist streams in finance and marketing and was Australasian Bioscience Business Manager for Biolab.

Dr. Gregorio King has 14 years’ experience as a biotechnology senior manager with highly developed scientific, research and product development skills and a strong track record across small biotechnology and large pharmaceutical companies. Before joining AdAlta, she was vice president of operations at clinical-stage oncology company, Prescient Therapeutics overseeing the manufacturing, preclinical and clinical programs of Prescient’s two lead drug candidates for the treatment of AML, breast and ovarian cancer. She has held previous regulatory affairs, intellectual property, pre-clinical and clinical management roles within large and small biotechnology & pharmaceutical companies, and contract research organisations both global and Australian. Her experience includes the development of cellular therapies, biologicals, small molecules & gene therapies within Australia and the US.

Management team

CEO: Tim Oldham, PhD

Dr. Oldham was appointed CEO and MD in October 2019. Immediately before this, he was executive leader of Tijan Ventures, an advisory business focused on growing life sciences companies through strategic advisory and interim CEO, executive and non-executive leadership services, with a particular focus on biologics, cell and gene therapies and immunotherapy. Previous roles include CEO and managing director of Cell Therapies, a leading contract manufacturer and distributor cellular therapies in Asia Pacific, president of Asia Pacific for Hospira and a variety of senior management roles with Mayne Pharma before its acquisition by Hospira. Prior to this, he was an engagement manager with McKinsey & Co. Industry leadership roles include currently serving as a director of BioMelbourne Network and terms as chairman of the European Generic Medicines Association Biosimilars and Biotechnology Committee, a director of the Alliance for Regenerative Medicine and a Director of the Generic Medicines Industry Association. He is a non-executive director at Acrux (ASX:ACR).

CSO: Michael Foley, PhD

Dr. Foley is the founding scientist of AdAlta and a key inventor of AdAlta’s lead i-body candidate AD-214. Upon completion of his PhD he was awarded a Wellcome Training Fellowship and worked at the Walter and Elisa Hall Institute. In 1995 he was awarded an ARC QEII Fellowship where he established the phage display of antibodies and peptide technology as a means of answering fundamental questions of immunity to infectious diseases. Dr. Foley has significant experience in phage display, the technology used to screen the i-body library to identify new drug candidates. Having published over 70 scientific publications he has received funding from ARC, NHMRC and NIH (US).

COO: Dallas Hartman, PhD

Dr. Hartman is the chief operating officer of AdAlta and has over 15 years’ experience in the biotechnology industry. Prior to joining AdAlta, he was vice president of product development at the NASDAQ listed biotechnology company Nexvet where he was responsible for scalable bioprocess development, formulation, stability, analytical characterisation and cell line development. Dr. Hartman worked at CSL for 14 years in a number of roles, most notably director of analytical biochemistry. Before moving to industry, he undertook postdoctoral research at the University of Texas Southwestern Medical Center and the University of Melbourne where his worked was supported by fellowships from the Howard Hughes Medical Institute and the Australian Research Council. Dallas holds an MBA with specialist streams in finance and marketing and was Australasian Bioscience Business Manager for Biolab.

VP, clinical product development: Claudia Gregorio-King

Dr. Gregorio King has 14 years’ experience as a biotechnology senior manager with highly developed scientific, research and product development skills and a strong track record across small biotechnology and large pharmaceutical companies. Before joining AdAlta, she was vice president of operations at clinical-stage oncology company, Prescient Therapeutics overseeing the manufacturing, preclinical and clinical programs of Prescient’s two lead drug candidates for the treatment of AML, breast and ovarian cancer. She has held previous regulatory affairs, intellectual property, pre-clinical and clinical management roles within large and small biotechnology & pharmaceutical companies, and contract research organisations both global and Australian. Her experience includes the development of cellular therapies, biologicals, small molecules & gene therapies within Australia and the US.

Principal shareholders

(%)

Yuuwa Capital

26.5

HSBC

12.5

Meurs Holdings

5.1

Knight61 Investments

2.1


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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 research department of Edison 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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Copyright: Copyright 2021 Edison Investment Research Limited (Edison).

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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

1185 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

1185 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 AdAlta and prepared and issued by Edison, in consideration of a fee payable by AdAlta. 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 research department of Edison 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 2021 Edison Investment Research Limited (Edison).

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

This document is prepared and provided by Edison 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.

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.

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

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

1185 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

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NSW 2000, Australia

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