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Balixafortide Phase III data coming soon

Polyphor 5 October 2020 Initiation
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Polyphor

Balixafortide Phase III data coming soon

Initiation of coverage

Pharma & biotech

5 October 2020

Price

CHF7.4

Market cap

CHF82m

CHF0.91/US$

Net cash (CHFm) at 30 June 2020

42

Shares in issue

11.1m

Free float

80.5%

Code

POLN

Primary exchange

SWX

Secondary exchange

N/A

Share price performance

%

1m

3m

12m

Abs

0.4

9.0

29.2

Rel (local)

1.7

8.3

23.0

52-week high/low

CHF10.64

CHF5.05

Business description

Polyphor is a development stage company focused on oncology and antibiotics. Its lead programme is balixafortide, a CXCR4 inhibitor currently in Phase III for breast cancer. Data are expected in 2021. Additionally, the company plans to start its Phase I programme of inhaled murepavadin to treat P. aeruginosa infections in cystic fibrosis patients by the end of the year.

Next events

Balixafortide Phase III ORR data

Q221

Balixafortide Phase III PFS data

Q421

Analysts

Maxim Jacobs

+1 646 653 7027

Nathaniel Calloway

+1 646 653 7036

Polyphor is a research client of Edison Investment Research Limited

Polyphor is a development-stage company focused on oncology and antibiotics. Its lead programme is balixafortide, a C-X-C chemokine receptor type 4 (CXCR4) inhibitor currently in a randomised-controlled Phase III trial in 407 previously treated human epidermal growth factor receptor 2 (HER2) negative advanced breast cancer patients. Objective response rate (ORR) data from the trial are expected in Q221 and could allow for an accelerated approval filing in the US. Additionally, it plans to start its Phase I programme of inhaled murepavadin to treat P. aeruginosa infections in cystic fibrosis (CF) patients by the end of the year.

Year end

Revenue (CHFm)

PBT*
(CHFm)

EPS*
(CHF)

DPS
(CHF)

P/E
(x)

Yield
(%)

12/18

6.5

(45.6)

(4.87)

0.0

N/A

N/A

12/19

0.0

(64.2)

(5.81)

0.0

N/A

N/A

12/20e

13.7

(45.1)

(4.04)

0.0

N/A

N/A

12/21e

0.0

(48.8)

(4.28)

0.0

N/A

N/A

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

Balixafortide Phase III to read out in 2021

The FORTRESS study is a randomised controlled trial studying balixafortide ± eribulin in 407 previously treated (320 third line and 87 second line) HER2-negative advanced breast cancer patients. ORR data from third line patients with measurable disease are expected in Q2 and, if positive, an accelerated approval filing would become possible in the US. Otherwise, progression-free survival (PFS) data are expected by the end of 2021, which would enable a standard NDA filing with the FDA and a filing with the EMA.

HER2-negative market a large, mostly unmet need

According to the National Cancer Institute, 78% of the estimated 276,480 new cases of breast cancer every year are HER2 negative. For those who are HER2 negative and hormone-receptor positive (68% of breast cancers), chemotherapy remains the standard of care in over 90% of cases once past front-line therapy.

CF infections remain a big problem

Inhaled murepavadin is an antibiotic being developed to treat P. aeruginosa infections due to CF. Despite the approval of CF transmembrane conductance regulators (CFTRs) for the treatment of CF, infections remain a major problem for these patients. According to the Cystic Fibrosis Foundation patient registry, 60% of young patients have at least one microorganism, which increases to 80% in older patients. P. aeruginosa is the leading cause of infection, found in 43% of patients.

Valuation: CHF413m or CHF37 per basic share

We value Polyphor at CHF413m or CHF37 per basic share using a risk-adjusted net present value (NPV) model. We currently only attribute value to balixafortide as it is the only programme in human clinical trials. Once inhaled murepavadin enters the clinic we expect to include it in our valuation. The company had CHF42m in net cash (CHF44m gross cash) at 30 June 2020 and will likely need to raise cash in 2021, which we estimate at CHF40m.

Investment summary

Company description: A focus on oncology and antibiotics

Polyphor is a clinical-stage Swiss-headquartered biopharmaceutical company formed in 1996 that went public on the Swiss Exchange in 2018. It is focused on balixafortide, a potent and selective blocker of CXCR4, a G-protein coupled receptor (GPCR) that has been implicated in the invasiveness and metastasis of numerous cancers. It has a Phase III trial ongoing in HER2-negative advanced breast cancer patients as overexpression of CXCR4 is associated with both recurrence and unfavourable survival in those patients. Additionally, it is developing inhaled murepavadin to treat P. aeruginosa infections in CF patients. That programme is expected to enter the clinic by the end of the year. The company has additional early-stage programmes in oncology and antibiotics that are expected to enter the clinic over the next few years.

Valuation: CHF413m or CHF37 per basic share

We are initiating coverage of Polyphor at CHF413m or CHF37 per basic share using a risk-adjusted NPV model focusing strictly on the balixafortide programme. We attribute a 40% probability of success to the balixafortide programme, which takes into account the fact that it is in a large Phase III trial and prior clinical data. We forecast peak sales for the US and EU5 at CHF730m. We will include the other programmes in our valuation once they enter the clinic. Inhaled murepavadin is expected to enter the clinic in Q420.

Financials: Funding needed to advance programmes

Polyphor reported CHF42m in net cash (CHF44m gross) at 30 June 2020 and will likely need to raise cash in 2021, which we estimate at CHF40m. The company expects to partner balixafortide likely following Phase III data, which should greatly alleviate a significant portion of any future financing needs (especially if it is a standard deal with upfront, milestones and royalties). Polyphor in August 2020 licensed China rights to Fosun Pharma for US$15m upfront, development milestones of US$19m, commercial milestones of US$148m and double-digit royalties. However, if it does not partner the product in the US and EU we estimate it would need to raise CHF220m through 2024.

Sensitivities: Near-term development risk dominates

The bulk of our valuation for Polyphor comes from balixafortide, currently in a Phase III trial. There will be two key readouts in 2021, which will help decide the future of the product. First, in Q221, ORR data are expected in third line patients with measurable disease and, if positive, could allow for an accelerated approval of the product in the US. If Polyphor does not clear the hurdle on the ORR data cut, the next key piece will be PFS data, expected by the end of the year, which could lead to full approval of balixafortide if positive. Interim overall survival data are also likely to be needed for that approval especially for the EMA. The basis for the hypothesis of balixafortide’s efficacy in HER2-negative metastatic breast cancer was a single-arm Phase I dose-escalation trial that enrolled 56 patients (with a 38% response rate in patients on the Phase III dose of balixafortide plus eribulin compared to the 13% that was seen in the original eribulin registration trial), so it is unclear if those data will carry over into a 407-patient randomised-controlled trial. Inhaled murepavadin also has risk as the intravenous version had a Phase III halted due to kidney toxicity issues. However, the inhaled version has a much lower level of systemic exposure so could have a higher safety margin. Additional risk comes from dilution (with new issuances potentially greater than current shares outstanding) as the company will have to raise significant capital if it is unable to fund operations through partnerships.

Company description: Developing innovative therapies

Polyphor is a clinical-stage Swiss-headquartered biopharmaceutical company focused on balixafortide, a potent and selective blocker of CXCR4, a GPCR that has been implicated in the invasiveness and metastasis of numerous cancers. It has a Phase III trial ongoing in HER2-negative advanced breast cancer patients as overexpression of CXCR4 is associated with both recurrence and unfavourable survival in those patients. Additionally, the company is developing inhaled murepavadin to treat P. aeruginosa infections in CF patients. That programme is expected to enter the clinic by the end of the year. The company has additional early-stage programmes in oncology and antibiotics that are expected to enter the clinic over the next few years.

Exhibit 1: Polyphor pipeline

Programme

Indication

Status

Partners

Comments

Balixafortide

HER2 negative breast cancer

Phase III

Fosun Pharma (China)

In Phase III ± eribulin in 407 second and third line patients. ORR data expected Q221. PFS data YE21. Approval expected 2022/23. Phase II study in expanded indication expected to start 2021

Inhaled murepavadin

CF infections

Pre-IND

Focus on P. aeruginosa infections. Expected to enter the clinic by YE20. 50% of funding coming from Innovative Medicines Initiative

POL7306/BamA

All WHO Priority 1 pathogens

Preclinical

Expected to enter the clinic around 2022

Thanatin

Multidrug resistant Enterobactericaea

Research

Expected to enter the clinic after 2022

Novel oncology products

Various cancers

Research

Novel molecules expected to be in clinic around 2022.

Source: Polyphor

Balixafortide

Polyphor’s lead programme is balixafortide, a CXCR4 antagonist. CXCR4 tends to have low or no expression in most healthy tissues (among healthy tissue it is most highly expressed in bone marrow and lymphoid tissues according to the Human Protein Atlas) but is highly expressed in a variety of tumour types and is correlated with poor outcomes (Exhibit 2) as it is associated with tumour immune evasion, angiogenesis and metastasis.1 Importantly, inhibiting CXCR4 has been shown in preclinical experiments to impair tumour migration,2 growth and angiogenesis.3 While 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, hence the combination with eribulin in the Phase III programme.

  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 2: 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.

While there are other CXCR4 inhibitors in the pipeline, balixafortide appears to be the only candidate for breast cancer. That is likely because there are so many potential targets for a CXCR4 inhibitor. For example, Mozobil (plerixafor) was approved in 2008 in combination with granulocyte colony-stimulating factor (G-CSF) for hematopoietic stem cell mobilisation and is marketed by Sanofi. We should note that Polyphor previously had a programme to develop balixafortide for this indication but stopped development in 2015 when it was in Phase II. The company has stated that the compound demonstrated proof of mechanism and that it induced hematopoietic stem cell mobilisation but further development was not pursued for commercial reasons.

Exhibit 3: CXCR4 inhibitor pipeline

Molecule

Company

Lead indication

Status

Delivery

Comments

Plerixafor

Sanofi

Hematopoietic stem cell mobilisation

Approved since 2008

Subcutaneous

Mavorixafor

X4 Pharma

WHIM syndrome (a rare immunodeficiency disorder)

Phase III

Oral

Also in Phase II for clear cell renal cell carcinoma and Phase I for severe congenital neutropenia and Waldenstrom macroglobulinemia

Motixafortide

BiolineRx

Hematopoietic stem cell mobilisation for autologous transplantation

Phase III

Subcutaneous

Also in Phase II for pancreatic cancer and acute myeloid leukemia (AML)

Balixafortide

Polyphor

Metastatic breast cancer

Phase III

Intravenous

A Phase II in earlier lines of breast cancer and in combination with other regimens is planned for Q420

Source: Edison Investment Research, Polyphor

The reasoning for choosing breast cancer is clear. In 13 studies covering 2,318 breast cancer patients (of which 31% were CXCR4 expressors), the hazard ratio was 1.8, indicating a significantly negative survival impact from being CXCR4 positive.4 In one study of 101 breast cancer patients, which compared the impact of high CXCR4 expression to other prognostic factors in breast cancer, it appeared to be the most important prognostic factor by far, more important than tumour size, hormone receptor status or the grade of the cancer5 (Exhibit 4).

  Zhao et al., CXCR4 over-expression and survival in cancer: a system review and meta-analysis. Oncotarget. 2015 Mar 10;6(7):5022-40.

  Chu et al., Chemokine receptor CXCR4 overexpression predicts recurrence for hormone receptor-positive, node-negative breast cancer patients. Surgery. 2011 Feb;149(2):193-9.

Exhibit 4: Relative risk of high CXCR4 expression compared to other factors

Indicator

Relative risk of cancer returning

Relative risk of death

High CXCR4

7

18.7

Size of the tumour

2.9

2.93

Hormone receptor positivity

0.3–0.33

0.19–0.21

Grade of cancer

0.76

0.51

Source: Chu et al., Chemokine receptor CXCR4 overexpression predicts recurrence for hormone receptor-positive, node-negative breast cancer patients. Surgery. 2011 Feb;149(2):193-9. Note: A relative risk of 1 would equate to an average risk of recurrence or death for a breast cancer patient. Values over 1 are a higher risk of recurrence or death.

Breast cancer also remains a high unmet medical need, particularly in HER2-negative patients who tend to have lower rates of five-year survival than HER2-positive patients. In the United States alone there will be an estimated 276,480 new cases of breast cancer this year (with a total prevalence of 3.6 million) according to the National Cancer Institute, and there were 522,513 cases in Europe in 2018 according to the Global Cancer Observatory. A total of 68% of cases are ‘Luminal A’ (Exhibit 5), which means they are positive for hormone receptors on tumour cells (and that hormones such as oestrogen and progesterone may promote their growth) but have low levels of HER2.

Exhibit 5: Breast cancer subtypes and survival

Type

Percent of breast cancer cases

Five-year survival (localised)

Five-year survival (regional)

Five-year survival (distant)

Hormone receptor positive/HER2 negative (‘Luminal A’)

68%

100.0%

89.9%

30.4%

Hormone receptor negative/HER2 negative (‘Triple Negative’)

10%

91.2%

65.0%

11.5%

Hormone receptor positive/HER2 positive (‘Luminal B’)

10%

98.7%

89.5%

43.5%

Hormone receptor negative/HER2 positive (‘HER2-enriched’)

4%

96.1%

81.7%

36.8%

Unknown

8%

95.7%

77.1%

15.3%

Total

100%

98.9%

85.7%

28.1%

Source: National Cancer Institute

Localised tumours are treated surgically, with or without radiotherapy. This is typically followed by adjuvant treatment including one or more anti-hormone therapies (also known as endocrine therapies), for instance aromatase inhibitors such as anastrozole and selective oestrogen receptor modulators such as tamoxifen. Adjuvant chemotherapy is not typically recommended for this population, due to the generally positive prognosis with hormone-based adjuvant therapy.

Non-resectable tumours or metastatic tumours of this class are typically treated initially with drugs such as Faslodex (fulvestrant, AstraZeneca), anastrozole, tamoxifen, or other drugs that interfere with HR signalling. A new class of drug that can be combined with hormone therapy are CDK4/6 inhibitors such as Ibrance (palbociclib, Pfizer) Kisqali (ribociclib, Novartis) and Verzenio (abemaciclib, Eli Lilly). Ibrance was the first drug of this class to be approved in 2015 and had sales of over $5bn in 2019, which speaks to the size of this market (Exhibit 6). These drugs have significant antiproliferative and antimetastatic activity and their increasing integration into the treatment algorithm is expected to replace or delay the use of other therapies for refractory disease.

Exhibit 6: Top 10 breast cancer drugs by 2019 sales

Drug

Generic name

Company

Mechanism

Indication

2019 sales ($m)

Year of approval

Patent expiry

Herceptin

Trastuzumab

Roche

Epidermal growth factor receptor ErbB-2 (HER2) antibody

First and second line therapy in HER2+ metastatic breast cancer patients. Also approved as an adjuvant therapy for breast cancer. Has an additional approval in gastric cancer.

5,728

1998

2019

Ibrance

Palbociclib

Pfizer

Cyclin-dependent kinase 4 (CDK4) inhibitor; Cyclin-dependent kinase 6 (CDK6) inhibitor

HR+ HER2- metastatic breast cancer patients.

4,961

2015

2028

Perjeta

Pertuzumab

Roche

Epidermal growth factor receptor ErbB-2 (HER2) antibody

HER2+ metastatic breast cancer patients. Also approved in adjuvant and neo-adjuvant breast cancer setting.

3,544

2012

2025

Kadcyla

Ado-trastuzumab emtansine

Roche

Tubulin polymerisation inhibitor; Epidermal growth factor receptor ErbB-2 (HER2) antibody

HER2+ metastatic breast cancer patients after prior treatment with Herceptin and a Taxane. Also used in the adjuvant setting.

1,402

2013

2025

Faslodex

Fulvestrant

AstraZeneca

Oestrogen receptor antagonist

HR+ HER2- advanced metastatic breast cancer patients.

892

2002

2019

Afinitor

Everolimus

Novartis

Mammalian target of rapamycin (mTOR) inhibitor

Advanced HR+ HER2- breast cancer. Also approved in kidney, neuroendocrine tumours at various locations and tuberous sclerosis complex-related indications.

831

2008

2020

Verzenio

Abemaciclib

Eli Lilly

Cyclin-dependent kinase 4 (CDK4) inhibitor; Cyclin-dependent kinase 6 (CDK6) inhibitor

Newly diagnosed HR+ HER2- metastatic breast cancer.

580

2017

2029

Kisqali

Ribociclib

Novartis

Cyclin-dependent kinase 4 (CDK4) inhibitor; Cyclin-dependent kinase 6 (CDK6) inhibitor

HR+ HER2- advanced metastatic breast cancer patients.

480

2017

2028

Abraxane

Paclitaxel (albumin-bound)

Bristol Myers

Tubulin polymerisation inhibitor

Advanced metastatic breast and pancreatic cancers as well as advanced non-small cell lung cancer.

460

2005

2022

Halaven

Eribulin mesylate

Eisai

Tubulin polymerisation inhibitor

Metastatic breast cancer patients who have failed at least two chemotherapeutic regimens for metastatic disease. Also approved for liposarcoma.

370

2010

2027

Source: Evaluate Pharma, FDA labels

Polyphor will be especially focused on Luminal A patients (although there will be some focus on triple negative patients as well) as they make up the bulk up of breast cancer patients but also have a low level of usage of novel agents once the patients progress past hormone therapy, with monotherapy chemotherapy remaining the standard once Luminal A patients reach that stage. Monotherapy chemotherapy is also the standard for these patients who are in a visceral crisis even if they have not previously been treated with hormone therapy. According to Global Data, this is not likely to change in the near future. They project the novel agent share in second to fifth line in 2023 being in the 4–9% range, with the rest being monotherapy chemotherapy. There is also not much of a standard chemotherapeutic regimen once patients have failed front line agents. In the eribulin Phase III Embrace registration trial of the drug in 762 heavily pretreated (87% had three or more prior lines of chemotherapy, 85% had prior hormone therapy, 83% had prior radiotherapy and 86% had surgery) locally recurrent or metastatic breast cancer patients, the comparator was a physician’s choice of therapy. In the control arm 25% of patients received vinorelbine, 19% gemcitabine, 18% capecitabine, 15% taxanes, 10% anthracyclines, 10% other chemotherapies and 4% hormone therapy.6

  Cortes et al., Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 2011; 377:914-23

The balixafortide Phase I data

Data we have so far have been positive, although early, and come from a Phase I dose-escalation study in combination with eribulin in 56 HER2-negative metastatic breast cancer patients (23% of which were triple negative). These patients were heavily pretreated with 78% having three or more prior chemotherapy regimens.7 In this trial there was a clear dose response with the high dose (the dose chosen in the Phase III FORTRESS study) achieving ORR, median PFS and median overall survival (OS) greater than was previously seen with eribulin alone. It is always tough to compare across trials, especially small Phase I trials versus Phase III results, but eribulin has not typically seen 38% response rates as a monotherapy (ORR has typically been around 13% as seen in its Phase III trial, see Exhibit 7) so this is likely indicative of an effect of balixafortide therapy.

  Pernas et al., Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial. The Lancet Oncology, 25 Apr 2018, 19(6):812-824

Exhibit 7: Balixafortide Phase I comparison to eribulin Phase III

Group

Sample size

Balixafortide dose

Eribulin dose

ORR

Median PFS (months)

Median OS (months)

Lower dose group

15

0.5–2.0mg/kg

1.1–1.4mg/m2

13%

3.3

9.4

Mid dose group

15

2.5–4.5mg/kg

1.4mg/m2

33%

3

11.2

High dose/expanded cohort)

24

5.5mg/kg

1.4mg/m2

38%

6.2

18

Eribulin Phase III EMBRACE study

762 (508 on rribulin)

1.4mg/m2

13%

3.6

13.1

Source: Polyphor, Pernas et al., Balixafortide plus eribulin in HER2-negative metastatic breast cancer: A Phase 1, single-arm, dose-escalation trial. The Lancet Oncology, 25 Apr 2018, 19(6):812-824. Cortes et al., Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): A Phase 3 open-label randomised study. Lancet 2011; 377:914-23

Toxicity was very similar to the eribulin safety profile seen in the Phase III programme. In Phase I, only two patients discontinued due to treatment-related adverse events, one due to Grade 2 fatigue and another treatment-related to Grade 1 peripheral neuropathy. A total of 18% of patients required a reduction in eribulin dose but only 2% (one patient) required a reduction in balixafortide to manage infusion reactions at the first cycle (although the full dose was resumed in subsequent cycles). Two patients died during the trial due to adverse events although this is likely due to their advanced status as well as known eribulin toxicity. One patient enrolled in cohort one (the lowest dose for both balixafortide and eribulin), developed neutropenia (45% of patients in the eribulin Phase III developed Grade 3 or 4 neutropenia) and pneumonia and died of septic shock. They had multiple comorbidities on study entry and had received four lines of hormonal therapy, three lines of chemotherapy as well as radiation. The second patient was enrolled in the high dose/expanded cohort and had a history of asthma. They previously received three lines of hormonal therapy and three lines of chemotherapy as well as radiation. They died of pneumonia after having Grade 4 neutropenia.

Infusion reactions seem to be the biggest issue related specifically to balixafortide and the only one observed to have a dose response. In total, 46% of patients in the trial had a Grade 1–2 reaction and 2% (one patient) had a Grade 3 infusion reaction with reactions highest during the first cycle.

The FORTRESS study

Polyphor is enrolling its pivotal FORTRESS study, which is a randomised global controlled trial studying balixafortide with eribulin versus eribulin alone, in 407 previously treated (320 third line and 87 second line) HER2-negative advanced breast cancer patients. Enrolment started in June 2019 and by early September 2020, 366 patients had been recruited, including all 87 second line patients, so a further 41 third line patients are needed for the trial to complete enrolment (expected at the end of September). The primary endpoint of the trial is PFS 12 months after the last patient is randomised. Those data are expected for Q421 and, if positive, would enable a standard NDA filing with the FDA as well as a filing with the EMA (although the EMA may also require some interim overall survival data for approval).

However, depending on the data, the company may be able to file for accelerated approval with the FDA (but not the EMA) on ORR data assessed in patients with measurable disease who are third line or later (estimated by the company to be 66–75% of the study population) based on discussions with the agency. These results should be available in Q221, six months after the last patient is randomised. Additionally, if the p-value of the balixafortide + eribulin arm versus eribulin is p≤0.001, the company plans to first apply for breakthrough therapy designation (BTD) with the FDA (the agency typically responds within just 60 days) prior to filing for accelerated approval. A BTD allows for more intense FDA involvement in the drug development process, an organisational commitment of senior managers and eligibility for both rolling and priority review.

Based on the characteristics of the pre-approval studies for drugs previously being granted accelerated approval from 2009 and 2013 (Exhibit 8), Polyphor would have a strong case if it is able to achieve the necessary ORR hurdle. The FORTRESS study is much larger than the median for those receiving accelerated approval, has an active comparator (63% of those receiving approval had no comparator at all) and has an appropriate endpoint.8 Also as recently as June 2020, lurbinectedin (Zepzelca) from PharmaMar/Jazz was approved on an accelerated basis by the FDA based on ORR from 105 small cell lung cancer patients in a single arm trial. In April 2020 Immunomedics (an acquisition by Gilead Sciences for $21bn was announced in September) received an accelerated approval for sacituzumab govitecan (Trodelvy) in third line or later triple-negative breast cancer based on a single arm trial with data from 108 patients (with a 33.3% ORR).

  Naci et al., Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval by the US Food and Drug Administration. JAMA. 2017;318(7):626-636.

Exhibit 8: Characteristics of studies for drugs receiving accelerated approval

Characteristics

Number or percentage

Median enrolment

132

Active comparator

10%

Placebo comparator

20%

No comparator

63%

Add-on comparator

7%

Primary endpoint - disease response surrogate (such as ORR)

70%

Primary endpoint - Progression free survival

3%

Other surrogate

27%

Characteristics

Median enrolment

Active comparator

Placebo comparator

No comparator

Add-on comparator

Primary endpoint - disease response surrogate (such as ORR)

Primary endpoint - Progression free survival

Other surrogate

Number or percentage

132

10%

20%

63%

7%

70%

3%

27%

Source: Naci et al., Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval by the US Food and Drug Administration. JAMA. 2017;318(7):626-636.

With regards to timing of an accelerated approval, Polyphor believes an accelerated approval could occur in Q422 while the standard approval in the US/EU could happen in Q123.

Beyond Phase III

The company also has a plan beyond the FORTRESS study and approval. Polyphor is conducting preclinical studies in combination with other drugs and in other tumour types. Also, in Q420 the company expects to begin an improved dose scheduling study as well as a Phase I/II in combination with other chemotherapies in earlier-stage metastatic breast cancer. Additionally, in Q221 the company expects to begin work on a non-intravenous formulation that may be more convenient for patients. The company is also working on a CXCR4 companion diagnostic that may help select appropriate patients when on the market, although it is unclear what level of expression is necessary. All the Phase I patients were CXCR4 positive although 61% in that trial had low expression and responses were observed regardless of the level of expression.

Market estimates

Our estimates for balixafortide are based on the assumption that 60,000 patients in the US and another 90,000 patients in the EU5 will be eligible for therapy. This encompasses advanced/metastatic Luminal A patients who are third line or later in the US and second line or later in the EU5. We are not including triple-negative breast cancer patients in our estimates as it is both a smaller market (10% of breast cancer incidence versus 68% for Luminal A) and a more competitive one with a higher degree of novel therapies in use. These patients are included in the FORTRESS trial so we may decide to add them to our estimates but this will depend on the data as well as the commercial focus once balixafortide is on the market.

We estimate launch in 2023 and peak share to be 3% in the respective markets as the later line metastatic breast cancer market is relatively fragmented across different therapies, although this may change if the FORTRESS data are particularly strong. Our market share assumption also includes potential competition from Immunomedics, which is conducting a Phase III of sacituzumab govitecan in 400 third line or later Luminal A patients, with data likely in 2022/23. In 54 Luminal A patients in the sacituzumab govitecan Phase I/II study, the ORR was 31% with a PFS of 6.8 months, which is relatively similar to the data seen with balixafortide in the dose Polyphor is moving forward with in the FORTRESS study.

It is important to note this market share assumption does not include any future label expansions or use with other chemotherapies other than eribulin. We estimate a price of US$100,000 per treated patient in the United States, which we believe is reasonable for that market, especially as balixafortide will likely be considered a targeted therapy due to the CXCR4 mode of action. By way of reference, Kisqali, the CDK4/6 inhibitor for Luminal A patients, costs between $5,021 and $12,553 per month depending on the dose, according to Novartis, whereas sacituzumab govitecan for triple-negative breast cancer costs US$16,096 per 21-day cycle on average. In the EU, we assume a price of US$50,000 per patient. Taken together, we arrive at peak sales at CHF730m, which again focuses only on Luminal A patients and no label expansions.

Inhaled murepavadin for CF

Polyphor is also developing inhaled murepavadin for the treatment of P. aeruginosa infection in CF patients. It is a potentially first-in-class outer membrane protein targeting antibiotic (OMPTA). CF is an autosomal recessive condition caused by mutations in both copies of the CFTR gene. CFTR is involved with the production of sweat, digestive fluids and mucus. These fluids are normally thin and slippery but the defective gene in CF patients leads to the secretions becoming thick and sticky instead. In the lungs, CF patients have airway hyper-inflammation and the development of chronic bacterial infection, which leads to the accumulation of thick mucus, airway obstruction/destruction and fibrosis. Over time there is a decline in lung function leading to respiratory failure and then either lung transplantation or death. Infections of airways usually begin in the first months of life so this tends to be a lifelong problem. P. aeruginosa is the most common microbe involved in CF infection, involved in the infection of over 60% of CF patients once they reach the age of 30 (Exhibit 9).

Exhibit 9: Microbial infections in CF patients by age

Source: Cystic Fibrosis Foundation Patient Registry 2018 Annual Data Report

There are a number of antibiotics used to treat these infections, usually tobramycin, aztreonam and colistin. However, there are multi-drug resistant P. aeruginosa strains, which made up 16.9% of total CF-related P. aeruginosa infections in 2018 in the US according to the Cystic Fibrosis Foundation and at some age groups has infected around 20% of individuals with CF (see Exhibit 10).

Exhibit 10: P. aeruginosa infection and multi-drug resistance

Source: Cystic Fibrosis Foundation Patient Registry 2018 Annual Data Report

These multi-drug infections are the area of the market where Polyphor can have the most impact with inhaled murepavadin, which would be a new class of antibiotic. In vitro testing has indicated it has activity against P. aeruginosa including multi-drug resistant strains (Exhibit 11).

Exhibit 11: In-vitro activity in 414 P. aeruginosa isolates from CF patients

Drug

MIC50 (mg/L)

MIC90 (mg/L)

Murepavadin

0.12

2

Aztreonam

8

128

Tobramycin solution

1

16

Colistin

1

2

Source: Polyphor. Note: MIC50 is the minimal inhibitory concentration to inhibit 50% of isolates and MIC90 is the minimum concentration to inhibit 90% of the isolates with lower numbers indicating greater potency/inhibitory activity.

The company plans to submit a clinical trial application and start the Phase I programme in Q420, which will include single and multiple dosing in healthy volunteers for up to seven days. Data are expected in 2021. A Phase II would then be expected to start by the end of that year. Part of the funding for this programme comes from the Innovative Medicines Initiative, a partnership between the European Union and the European pharmaceutical industry. Polyphor is also seeking additional external sources of funding for this programme.

One issue with the market potential for this product is that CFTR modulator therapies (the first CFTR modulator, Kalydeco (ivacaftor) was approved in 2012) help restore some CFTR function, which appears to be reducing the frequency of P. aeruginosa infections in CF patients although approximately 43% of CF patients have the infection according to the 2019 Cystic Fibrosis Patient Registry (down from around 60% historically). We are not including inhaled murepavadin in our model at present as it is not in the clinic. But assuming around 30,000 patients in the US and another 20,000 in the EU and a falling rate of P. aeruginosa, 15% peak market share and a US$50,000 per year price in the US and US$30,000 per year price in the EU, we calculate peak potential sales of CHF157m. For the sake of reference, Tobramycin (which is one of the standards of care for CF infections) sales peaked at US$387m in 2013.

Other programmes

The company has additional early-stage programmes in antibiotics and oncology that are planned to enter the clinic over the next few years. The preclinical antibiotics programme consists of OMPTA BamA and Thanatin. OMPTA BamA is targeting gram-negative bacteria such as Enterobacteriaceae, P. aeruginosa and A. baumannii and so far has shown a very low propensity for resistance in in-vitro experiments, according to the company. Polyphor is working on the formulation and peptide design. The Thanatin programme is a narrow spectrum gram-negative antibiotic focusing on carbapenem-resistant Enterobacteriaceae as commonly used antibiotics are generally inactive against this infection.9 Polyphor believes it should be able to receive external funding for at least part of the development of these molecules given the high public health concern for such resistant infections. With regards to oncology, the company is creating a pipeline of novel molecules based on its macrocycle platform in both liquid and solid tumours.

  Lovleva et al., Carbapenem-Resistant Enterobacteriaceae. Clinics in Laboratory Medicine. 2017 June ; 37(2): 303–315.

Sensitivities

Most of the risk is development related as the bulk of our valuation for Polyphor comes from balixafortide, which is in a Phase III trial. There will be two key readouts in 2021 that will help decide the future of the product. First, in Q221, ORR data are expected in third line patients with measurable disease and, if positive, could allow for an accelerated approval of the product in the US. If Polyphor does not clear the hurdle on the ORR data cut, the next key piece will be PFS data expected by the end of the year, which, if positive, could lead to full approval of balixafortide. Interim overall survival data are also likely to be needed for that approval especially for the EMA. The basis for the hypothesis of balixafortide’s efficacy in HER2-negative metastatic breast cancer was a single-arm Phase I dose-escalation trial that enrolled 56 patients (with a 38% response rate in the 24 patients treated at the same balixafortide plus eribulin dosing level chosen for the ongoing Phase III trial, compared to the 13% rate that was seen in the original eribulin registration trial), so it is unclear if those data will carry over into a 407-patient randomised-controlled trial. Additionally, it is unclear what the correlation is between efficacy and patient CXCR4 expression levels or how the levels differ in the Phase III versus Phase I. Inhaled murepavadin also has risk as the intravenous formulation had Phase III halted due to kidney toxicity issues, although the inhaled version has a much lower level of systemic exposure so should have a higher safety margin. And while P. aeruginosa does continue to be an unmet need with resistant infections, the incidence of these infections is falling due to disease-modifying treatments affecting infection rates. Additional risk comes from dilution (with new issuances potentially greater than current shares outstanding) as the company will have to raise significant capital if it is unable to fund operations through partnerships. However, the recent Fosun Pharma partnership for China indicates there is demand on the business development front and provides some comfort that the company will find partners for the US and EU.

Valuation

We are initiating coverage of Polyphor at CHF413m or CHF37 per basic share using a risk-adjusted NPV model focusing strictly on the balixafortide programme. We attribute a 40% probability of success to the balixafortide programme, which takes into account the fact that it is in a large Phase III trial and prior clinical data (which, while limited, did demonstrate promising efficacy and a relatively clean toxicity profile for balixafortide itself). We forecast peak sales for the US and EU5 at CHF730m. The composition of matter patent in the US expires in 2028 with a 2027 expiry in the EU; however, both can be extended by up to five years. There is also a pending balixafortide/eribulin patent that expires in 2038, which is the date we model sales to. As the company has stated it is working on different formulations and different combinations, patent protection may be potentially further extended.

We will include the other programmes in our valuation once they enter the clinic. Inhaled murepavadin is expected to enter the clinic in Q420. Also the company has stated that it plans to expand the balixafortide programme into other cancers, which we will include once clinical development commences. Additionally, we currently model the company marketing Balixafortide itself in the US and EU5. We will adjust our model for partnerships in these regions once they are announced.

Exhibit 12: Polyphor valuation

Product

Main indication

Status

Probability of commercialisation

Launch year

Peak sales (CHFm)

Economics

rNPV (CHFm)

Balixafortide

Second to fifth line breast cancer

Phase III

40%

2023

730

Fully owned

371

Total

 

 

 

 

 

 

371

Net cash (30 June 2020)

41.5

Total firm value

413

Total basic shares (m)

11.1

Value per basic share (CHF)

37

Total options (m)

0.2

Total diluted shares (m)

11.2

Diluted value per share (CHF)

37

Source: Edison Investment Research

Financials

The company recently reported H120 results. The net loss was CHF27.8m, roughly in line with the net loss of CHF27.9m from H119. The vast majority of this was due to R&D expenses, which were CHF24.6m in H120, down slightly from the CHF25.3m the same period the prior year. Polyphor reported CHF41.5m in net cash (CHF43.7m gross cash) at 30 June 2020 and we estimate will need to raise CHF40m in FY21 to fund the company through key inflection points.

To potentially assist with near-term funding, in July 2020 the company announced an equity-linked financing arrangement with IRIS, a French financial firm, to raise up to CHF19.3m over the next two years. Under the terms of the agreement, IRIS may buy 24 tranches of CHF800,000 worth of zero-coupon mandatory convertible bonds on a monthly basis. These bonds would then convert into shares at a discount to the volume weighted average price every month. It is unclear whether Polyphor will use this arrangement as other forms of financing would be preferable, especially non-dilutive funding from partnerships (likely after Phase III data) or investments from long-term investors.

If the company partners balixafortide, it should greatly alleviate a significant portion of any future financing needs as commercialisation and any additional R&D would likely be the responsibility of the partner. Polyphor recently licensed China rights to Fosun Pharma for US$15m upfront (which we have included in FY20 revenues), development milestones of US$19m, commercial milestones of US$148m and double-digit royalties, indicating demand exists with regards to business development. However, if it does not partner the product in the US and EU we estimate it would need to raise CHF220m through 2024, which we record as illustrative debt per Edison policy.

Exhibit 13: Financial summary

CHF'000s

2018

2019

2020e

2021e

Year end 31 December

IFRS

IFRS

IFRS

IFRS

PROFIT & LOSS

Revenue

 

 

6,546

10

13,663

0

Cost of Sales

0

0

0

0

Gross Profit

6,546

10

13,663

0

Sales, General and Administrative Expenses

(3,620)

(6,102)

(6,054)

(6,296)

Research and Development Expense

(44,767)

(60,735)

(52,849)

(42,279)

EBITDA

 

 

(41,570)

(64,925)

(44,891)

(48,575)

Operating Profit (before amort. and except.)

 

 

(41,570)

(64,925)

(44,891)

(48,575)

Intangible Amortisation

0

0

0

0

Other

271

1,903

349

0

Exceptionals

0

0

0

0

Operating Profit

(41,570)

(64,925)

(44,891)

(48,575)

Net Interest

(4,008)

685

(249)

(259)

Other

(5,342)

(432)

(419)

0

Profit Before Tax (norm)

 

 

(45,578)

(64,239)

(45,140)

(48,834)

Profit Before Tax (FRS 3)

 

 

(50,920)

(64,671)

(45,559)

(48,834)

Tax

0

0

0

0

Deferred tax

(0)

(0)

(0)

(0)

Profit After Tax (norm)

(45,578)

(64,239)

(45,140)

(48,834)

Profit After Tax (FRS 3)

(50,920)

(64,671)

(45,559)

(48,834)

Average Number of Shares Outstanding (m)

9.4

11.1

11.2

11.4

EPS - normalised (CHF)

 

 

(4.87)

(5.81)

(4.04)

(4.28)

EPS - FRS 3 (CHF)

 

 

(5.44)

(5.85)

(4.08)

(4.28)

Dividend per share (CHF)

0.0

0.0

0.0

0.0

BALANCE SHEET

Fixed Assets

 

 

8,180

11,560

11,333

10,587

Intangible Assets

4,564

2,255

2,029

1,826

Tangible Assets

3,169

8,857

8,857

8,314

Other

447

447

447

447

Current Assets

 

 

135,912

81,208

31,227

25,533

Stocks

0

0

0

0

Debtors

725

703

363

363

Cash

134,552

77,411

27,816

22,123

Other

635

3,094

3,047

3,047

Current Liabilities

 

 

(12,967)

(20,137)

(13,392)

(13,135)

Creditors

(12,729)

(19,886)

(13,135)

(13,135)

Short term borrowings

(238)

(251)

(257)

0

Long Term Liabilities

 

 

(10,471)

(17,523)

(14,708)

(55,983)

Long term borrowings

(2,340)

(2,089)

(1,958)

(41,958)

Other long term liabilities

(8,132)

(15,434)

(12,750)

(14,025)

Net Assets

 

 

120,655

55,108

14,460

(32,997)

CASH FLOW

Operating Cash Flow

 

 

(44,042)

(56,204)

(47,818)

(45,174)

Net Interest

57

200

49

0

Tax

0

0

0

0

Capex

(299)

(503)

(500)

(520)

Acquisitions/disposals

0

0

0

0

Financing

161,890

97

1

0

Dividends

0

0

0

0

Other

(11,135)

(1,335)

(533)

0

Net Cash Flow

106,471

(57,746)

(48,800)

(45,694)

Opening net debt/(cash)

 

 

(19,727)

(131,975)

(75,072)

(25,600)

HP finance leases initiated

0

0

0

0

Exchange rate movements

(38)

296

671

0

Other

5815

547

-1342

257

Closing net debt/(cash)

 

 

(131,975)

(75,072)

(25,600)

19,836

Source: company reports, Edison Investment Research

Contact details

Revenue by geography

Polyphor Ltd

Hegenheimermattweg 125

CH-4123 Allschwil

Switzerland

+41 61 567 16 00

www.polyphor.com

N/A

Contact details

Polyphor Ltd

Hegenheimermattweg 125

CH-4123 Allschwil

Switzerland

+41 61 567 16 00

www.polyphor.com

Revenue by geography

N/A

Management team

Chief executive officer: Gökhan Batur

Chief scientific officer: Daniel Obrecht

Gökhan Batur joined from Merck, where he was executive director, as global brand leader, responsible for leading the global commercial strategy and execution for the entire Merck antibiotics portfolio managing multiple in line, launch and pipeline products and sales of c US$2bn. Prior to this role he was executive director, global brand leader, gram negative antibiotics. Previous roles at Merck included executive director, hospital acute care franchise for emerging markets and China and, before, he held positions both at regional and country level in marketing and sales including regional marketing leader for hospital products and oncology in the EEMEA region. He studied management information systems and holds a Bachelor of Science from Bosphorus University, Istanbul.

Daniel Obrecht, PhD, spent 11 years at the Central Research Laboratories of Roche Basel. In his previous position he was head of the Combinatorial Chemistry Group. He obtained his PhD in chemistry from the University of Zurich in 1985 under the supervision of Professor H Heimgartner, after which he was associated with Professor RE Ireland at Caltech as a postdoctoral fellow for two years. Dr Obrecht is the author of numerous publications and books and holds several patents in the field of pharmaceuticals. He was appointed Roche lecturer in 1993.

Chief medical and development officer: Frank Weber

Chief financial officer: Hernan Levett

Frank T Weber, MD is chief medical officer of Probiodrug and head of market access at Santhera (both part time). He has 25 years of industry experience, having served as senior vice president, EU Medical and global medical adviser of Intermune and prior to that as chief medical officer at Merck Serono. Dr. Weber held also various clinical development medical affairs positions at American Cyanamid/Lederle, Sythelabo and Merck and worked as a Medical Director in managed care with MedNet, a Munich Re/United Health Care joint venture. Dr Weber trained as a maxillo-facial surgeon and immunologist. He holds a medical degree from the University of Cologne.

Hernan Levett joined the Polyphor management team from NASDAQ listed company Auris Medical where he served as CFO. He started his pharma international career at Novartis where he held roles of increasing responsibility in various countries and regional functions and as CFO for one its affiliates. Following a 10-year tenure at Novartis, Mr Levett continued to build his experience in biotech joining InterMune where he served as VP of finance. Mr Levett brings over 25 years of finance and pharma / biotech experience at leading companies and holds a CPA degree from the University of Buenos Aires, faculty of economics.

Management team

Chief executive officer: Gökhan Batur

Gökhan Batur joined from Merck, where he was executive director, as global brand leader, responsible for leading the global commercial strategy and execution for the entire Merck antibiotics portfolio managing multiple in line, launch and pipeline products and sales of c US$2bn. Prior to this role he was executive director, global brand leader, gram negative antibiotics. Previous roles at Merck included executive director, hospital acute care franchise for emerging markets and China and, before, he held positions both at regional and country level in marketing and sales including regional marketing leader for hospital products and oncology in the EEMEA region. He studied management information systems and holds a Bachelor of Science from Bosphorus University, Istanbul.

Chief scientific officer: Daniel Obrecht

Daniel Obrecht, PhD, spent 11 years at the Central Research Laboratories of Roche Basel. In his previous position he was head of the Combinatorial Chemistry Group. He obtained his PhD in chemistry from the University of Zurich in 1985 under the supervision of Professor H Heimgartner, after which he was associated with Professor RE Ireland at Caltech as a postdoctoral fellow for two years. Dr Obrecht is the author of numerous publications and books and holds several patents in the field of pharmaceuticals. He was appointed Roche lecturer in 1993.

Chief medical and development officer: Frank Weber

Frank T Weber, MD is chief medical officer of Probiodrug and head of market access at Santhera (both part time). He has 25 years of industry experience, having served as senior vice president, EU Medical and global medical adviser of Intermune and prior to that as chief medical officer at Merck Serono. Dr. Weber held also various clinical development medical affairs positions at American Cyanamid/Lederle, Sythelabo and Merck and worked as a Medical Director in managed care with MedNet, a Munich Re/United Health Care joint venture. Dr Weber trained as a maxillo-facial surgeon and immunologist. He holds a medical degree from the University of Cologne.

Chief financial officer: Hernan Levett

Hernan Levett joined the Polyphor management team from NASDAQ listed company Auris Medical where he served as CFO. He started his pharma international career at Novartis where he held roles of increasing responsibility in various countries and regional functions and as CFO for one its affiliates. Following a 10-year tenure at Novartis, Mr Levett continued to build his experience in biotech joining InterMune where he served as VP of finance. Mr Levett brings over 25 years of finance and pharma / biotech experience at leading companies and holds a CPA degree from the University of Buenos Aires, faculty of economics.

Principal shareholders

(%)

Ingro Finance

11.2

Varuma

8.6

Credit Suisse Asset Management

6.0


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Frankfurt +49 (0)69 78 8076 960

Schumannstrasse 34b

60325 Frankfurt

Germany

London +44 (0)20 3077 5700

280 High Holborn

London, WC1V 7EE

United Kingdom

New York +1 646 653 7026

1185 Avenue of the Americas

third 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

third 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 Polyphor and prepared and issued by Edison, in consideration of a fee payable by Polyphor. 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.

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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 2020 Edison Investment Research Limited (Edison).

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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.

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United Kingdom

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Frankfurt +49 (0)69 78 8076 960

Schumannstrasse 34b

60325 Frankfurt

Germany

London +44 (0)20 3077 5700

280 High Holborn

London, WC1V 7EE

United Kingdom

New York +1 646 653 7026

1185 Avenue of the Americas

third 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

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