Hybrigenics — Inecalcitol shows promise in CML, R&D refocus

Hybrigenics — Inecalcitol shows promise in CML, R&D refocus

Hybrigenics’ main focus is the development of inecalcitol as a niche treatment for leukaemia. In February it presented encouraging initial results for inecalcitol in combination with oral imatinib in chronic myeloid leukaemia (CML), with 43% of patients responding in a Phase II study that will complete in H218. A Phase II trial in acute myeloid leukaemia (AML) is ongoing with data expected in H119. Inecalcitol is Phase III-ready for chronic lymphocytic leukaemia (CLL) where it slowed progression in half of patients. The company has sold the proteomic services division and refocused on biopharma R&D. Our valuation is €141m; net cash at end 2016 was €8.5m.

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Hybrigenics

Inecalcitol shows promise in CML, R&D refocus

Outlook

Pharma & biotech

12 May 2017

Price

€0.81

Market cap

€29m

Net cash (€m) at 31 December 2016

8.5

Shares in issue

35.8m

Free float

87%

Code

ALHYG

Primary exchange

Alternext

Secondary exchange

N/A

Share price performance

%

1m

3m

12m

Abs

2.5

(15.6)

(6.9)

Rel (local)

(2.8)

(24.3)

(25.1)

52-week high/low

€1.10

€0.71

Business description

Hybrigenics is a French biotech company. It is conducting Phase II studies on lead drug inecalcitol in orphan adult leukaemias: chronic myeloid leukaemia and acute myeloid leukaemia.

Next events

Orphan designation in CML in EU & US

2017

CML Phase II completion

H218

AML Phase II data

H119

Analysts

Juan Pedro Serrate

+44 (0)20 3681 2534

Lala Gregorek

+44 (0)20 3681 2297

Hybrigenics is a research client of Edison Investment Research Limited

Hybrigenics’ main focus is the development of inecalcitol as a niche treatment for leukaemia. In February it presented encouraging initial results for inecalcitol in combination with oral imatinib in chronic myeloid leukaemia (CML), with 43% of patients responding in a Phase II study that will complete in H218. A Phase II trial in acute myeloid leukaemia (AML) is ongoing with data expected in H119. Inecalcitol is Phase III-ready for chronic lymphocytic leukaemia (CLL) where it slowed progression in half of patients. The company has sold the proteomic services division and refocused on biopharma R&D. Our valuation is €141m; net cash at end 2016 was €8.5m.

Year end

Revenue (€m)

PBT*
(€m)

EPS*
(c)

DPS
(c)

P/E
(x)

Yield
(%)

12/15

2.2

(4.5)

(13.2)

0.0

N/A

N/A

12/16

3.6

(3.9)

(10.8)

0.0

N/A

N/A

12/17e

3.7

(4.9)

(13.8)

0.0

N/A

N/A

12/18e

5.6

(3.6)

(9.9)

0.0

N/A

N/A

Note: *PBT and EPS are normalised, excluding intangible amortisation, exceptional items and share-based payments. Accounts have been restated to reflect the sale of 75.8% of Hybrigenics Services.

Inecalcitol’s strategic positioning in oncology

Interim data for inecalcitol in combination with oral imatinib in CML showed that 43% of patients achieved a major molecular response (MMR). Moreover, after one year 33% of patients achieved a deep molecular response (DMR). A DMR could lead to functional cures and potential cessation of treatment, avoiding side effects and reducing the economic burden of tyrosine kinase inhibitors (TKIs). A Phase II study in AML is ongoing, after preclinical studies showed increased survival in animal models of AML. Lastly, inecalcitol also has potential in CLL where it slowed progression in 52% of patients. It is Phase III-ready, awaiting funding.

Refocus on biopharma R&D

Hybrigenics has sold its controlling stake in the proteomics services division to management for €796k in total. It continues the discovery and development of new inhibitors of deubiquitinating enzymes (DUBs), particularly the subset known as ubiquitin-specific proteases (USP). Hybrigenics has a solid patent portfolio and protection until 2032. The oncology deal with Servier continues, with up to €12m in potential milestone payments until registration.

Valuation: DCF of €141m or €3.9 per share

Our DCF valuation is €141m or €3.9 per share, from €146m or €4.1 per share. The key change to our numbers relates to inecalcitol in CML, where we have increased the probability of success to 40% from 30% due to positive interim data; and to CLL, where we have reduced the probability of success to 20% from 30% as we await guidance on the development path. We have also updated our model for the FY16 net cash position of €8.5m.

Investment summary

Company description: Focus on adult leukaemias

Hybrigenics is a French biotech company formed from a spinout from Institut Pasteur. Its main activity is developing vitamin D analogue inecalcitol as a treatment for adult leukaemias, in particular chronic lymphocytic leukaemia (CLL), chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML); and for other solid tumours. In addition, it has a drug discovery collaboration with Servier based on the ubiquitin-specific proteases class and focused on oncology in pre-clinical development. Hybrigenics’ services activity now only comprises the Helixio division providing specialised genomics services for life sciences researchers from academia or pharmaceutical, cosmetic and agrochemical industries. Hybrigenics is listed on Alternext and entered the CAC PME mid-cap index in April 2014.

Valuation: DCF valuation of €141m

Our risk-adjusted DCF valuation is €141m or €3.9 per share, a slight decrease from €146.1m or €4.1 per share due to changes in the probability of success of inecalcitol in CML and CLL. We have increased the probability of success in CML from 30% to 40% on the back of the positive interim data. Development of inecalcitol in CLL is currently paused, despite its potential, because Hybrigenics requires funding or a partner to move development forward in this indication. Therefore, until we have further updates on the development plans, we are reducing the probability of success from 30% to 20%. For AML we assume in Europe that the company retains rights, but in the US we assume for both AML and CML that commercialisation is partnered with a 25% royalty rate. Inecalcitol in CLL forms the highest proportion of our sum-of-the-parts valuation at €78m, while CML is €74m and AML accounts for €43m. After the management buyout of Hybrigenics Services, which represented c 80% of the services division revenues, we have removed the proteomics services subsidiary from our valuation and include a forecast of the retained genomics services division, Helixio and Pharma R&D. We include our forecast of the milestone payments from the collaboration with Servier. Preclinical projects and inecalcitol’s value in prostate cancer are excluded.

Financials: FY16 results and rebased forecasts

FY16 revenue grew 66% to €3.6m, mainly due to a €1.5m milestone payment from Servier and restated to reflect the sale of the controlling stake in Hybrigenics Services. Helixio’s FY16 sales increased by 70% from €0.6m to €1m. For FY17 we estimate group revenues broadly unchanged at €3.7m without any Servier milestone payment. This includes our estimated 40% increase in the reshaped service revenues to €1.4m. FY16 operating costs were €7.1m vs €6.1m in FY15 and we forecast an increase in FY17 costs to €8m to cover the Phase II trials. Hybrigenics’ net cash position was €8.5m at end December 2016. We estimate the company is funded into 2018.

Sensitivities: Biotech clinical development

The key sensitivity is the rate of progress in developing inecalcitol in haematological cancers with the usual clinical, regulatory and financial challenges of biotech development. Hybrigenics has sufficient funds to carry out the Phase II trials in AML and CML, but would be reliant on further financing or a partnership to progress into further clinical trials in any or all three haematological indications, and potentially prostate cancer. Our assumptions are based on the company self-funding approval studies of inecalcitol in leukaemia. The sale of the proteomic services division significantly reduces the diversification of its business model and increases the risk profile of the company.

Inecalcitol: Strategic positioning in leukaemias

Hybrigenics has adopted a development strategy with vitamin D3 derivative inecalcitol, initially focusing on adult haematological cancers, based on the anti-proliferative potency and safety profile demonstrated in preclinical studies as well as clinical studies in CLL and prostate cancer. The investment case rests on inecalcitol’s potential to enhance rather than to replace approved therapies, particularly in view of the significantly weakened general health of older leukaemia patients who are unable to tolerate therapies with harmful side effects. Inecalcitol has orphan drug designation for CLL and AML in the US and Europe and the company is pursuing orphan status in CML based on the promising interim data recently published. Our peak sales estimate is US$735m across the three indications. Hybrigenics’ proteomics services subsidiary has been subject to a management buyout and the company offers genomics services through Helixio. With two ongoing clinical trials, the company is focused on biopharmaceutical R&D; in particular on DUB inhibitors and its ongoing collaboration with Servier that could yield up to €12m in further development and regulatory milestone payments until drug registration.

Inecalcitol: Combining potency with safety

Vitamin D plays a role in many cellular mechanisms including cell proliferation and apoptosis as well as inflammation and immunomodulation. Inecalcitol demonstrates up to 15 times the anti-proliferative potency of calcitriol, the active form of vitamin D, on cancer cells in vitro. At the same time, inecalcitol has an excellent safety profile and its chemical structure leads to over 100-fold lower calcium toxicity than calcitriol, a major dose-limiting characteristic of other vitamin D3 derivatives.

Exhibit 1: Clinical pipeline

Indication

Status

Setting

Notes

CML

Phase II ongoing

+ imatinib/stable chronic phase

The efficacy endpoint is the proportion of responders, defined as patients achieving a deep molecular response (DMR) within 12 months of inecalcitol treatment. At interim, 43% of patients who had been on treatment for three months showed improvements to baseline MMR (major molecular response). Additionally 33% of patients who had completed one year in the study achieved a DMR. Target enrolment 42 patients in France.

AML

Phase II ongoing

Newly diagnosed frail or elderly patients ineligible for standard chemo + decitabine

Primary endpoint is overall survival. Designated as an orphan drug in the US and EU. Target enrolment 110 patients in US and France

CLL

Phase II completed

Monotherapy/untreated/
high risk of progression

21 untreated patients dosed with 2mg oral inecalcitol for at least five months; disease progression was halted in 11 patients (52% of cases). Designated as an orphan drug in the EU and US. Next stage Phase III disease progression study.

Castration-resistant prostate cancer (CRPC)

Phase IIa completed

+ docetaxel/all patients

Dose-finding and safety study established daily 4mg oral dose – 40 out of 47 of patients exhibited an 85% reduction in PSA levels within three months, compared to a 65% reduction in PSA levels on docetaxel alone (in external registration study).

Phase IIb proof-of-concept next development stage.

Source: Hybrigenics, Edison Investment Research

Hybrigenics is developing inecalcitol in three haematological cancers: CLL, CML and AML. Exhibit 2 shows the main grouping of haematological cancers divided into the lymphoid and myeloid leukaemias.

Exhibit 2: Overview of leukaemia

Chronic (slow growing)

Acute (fast progression)

Myeloid

Chronic myeloid leukaemia (CML)

Slow growing, abnormal production of myeloid cells

About 10-15% of all newly diagnosed leukaemia

Treatment: generally by targeted therapy, ie Gleevec

Acute myeloid leukaemia (AML)

Group of fast growing diseases, abnormal production of myeloid cells

About 30-40% of all newly diagnosed leukaemia

Treatment: generally chemotherapy, sometimes stem cell transplant

Lymphocytic

Chronic lymphocytic leukaemia (CLL)

Slow growing, abnormal production of lymphocytes

About 30% of all newly diagnosed leukaemia

Treatment: often contains fludarabine; mAbs including Rituxan

Acute lymphocytic leukaemia (ALL)

Fast growing immature lymphocytes

10-15% of all newly diagnosed leukaemia

Treatment: chemotherapy, Gleevec (Ph+ only), transplant

Source: Edison Investment Research

Promising initial data in CML: 43% of patients respond

Inecalcitol is undergoing a Phase II study in patients with chronic myeloid leukaemia (CML). This is an open-label study that plans to enrol 42 patients in France. The study assesses oral inecalcitol administered in combination with oral imatinib in patients with incomplete molecular response after at least two years on imatinib. At February 2017 the trial had enrolled 21 patients and will complete in H218, according to Hybrigenics. The CML programme is built on the back of preclinical data in which inecalcitol in combination with imatinib demonstrated synergistic effects in experiments in vitro by inhibiting the proliferation of CML stem cells, which are involved in relapse. The trial aims to replicate this effect and prolong remission or achieve a functional cure.

The primary endpoint is the proportion of responders measured by the reduction in the expression of the BCR-ABL oncogene. Efficacy in CML can be measured as haematological response, which measures white cells count; cytogenetic response, which tests Philadelphia chromosome in the marrow; and molecular response, which measures expression of BCL-ACR by PCR in circulating blood cells.

Exhibit 3: Definitions of response

Type

Type of response

Haematological response

Partial response (PHR): reduction in white cells, but not to normal levels.

Complete response (CHR): white cells count at or below approximately 12,000 white cells/µl.

Molecular response

Major molecular response (MMR): 3 log reduction in the amount of BCR-ABL protein. BCR-ABL less than or equal to 0.1% in International Scale (IS).

Deep molecular response (DMR): MR4 (4 log reduction, BCR-ABL ≤ 0.01%); MR4.5 (4.5 log or BCR-ABL≤0.0032%) or MR5 (5 log or BCR-ABL ≤0.001%).*

Cytogenetic response

Cytogenetic response (CR or CyR): any reduction in Ph+ chromosome reading.

Major cytogenetic response (MCR or MCyR): 0%-35% of Ph+ cells in the marrow

Complete cytogenetic response (CCR or CCyR): no Ph+ cells can be measured.

Type

Haematological response

Molecular response

Cytogenetic response

Type of response

Partial response (PHR): reduction in white cells, but not to normal levels.

Complete response (CHR): white cells count at or below approximately 12,000 white cells/µl.

Major molecular response (MMR): 3 log reduction in the amount of BCR-ABL protein. BCR-ABL less than or equal to 0.1% in International Scale (IS).

Deep molecular response (DMR): MR4 (4 log reduction, BCR-ABL ≤ 0.01%); MR4.5 (4.5 log or BCR-ABL≤0.0032%) or MR5 (5 log or BCR-ABL ≤0.001%).*

Cytogenetic response (CR or CyR): any reduction in Ph+ chromosome reading.

Major cytogenetic response (MCR or MCyR): 0%-35% of Ph+ cells in the marrow

Complete cytogenetic response (CCR or CCyR): no Ph+ cells can be measured.

Source: Edison Investment Research; *Cross et al. Leukemia. 2012

In February 2017 Hybrigenics presented the first clinical data from the study. At the interim analysis, inecalcitol plus imatinib showed a further decrease from MMR in six of 14 patients at three months (43%). Additionally, three of nine patients (33%) who have completed one year in the study had a DMR.

Comparison with other clinical studies

The Phase III DASISION study one-year MR4.5 was 5% for dasatinib and 3% for imatinib. The two-year MR4.5 rate was 19% for dasatinib and 8% for imatinib.

Exhibit 4: MR4.5 DASISION study

Arm

1 year

2 years

3 years

4 years

5 years

Dasatinib 100mg once daily (n=259)

5%

19%

24%

34%

42%

Imatinib 400mg once daily (n=260)

3%

8%

13%

23%

33%

Source: Edison Investment Research, Cortes et al. Journal of Clinical Oncology. 2016

The ENESTnd Phase III clinical trial comparing two doses of nilotinib vs imatinib in newly diagnosed CML patients showed that at one year 7% and 11% of nilotinib and only 1% of imatinib patients achieved an MR4.5 response. At two years up to 25% of patients on nilotinib achieved an MR4.5, while 9% of patients in the imatinib arm achieved an MR4.5.

Exhibit 5: MR4.5 ENESTnd

Arm

1 year

2 years

3 years

4 years

5 years

Nilotinib 300 mg twice daily (n=282)

11%

25%

32%

40%

54%

Nilotinib 400 mg twice daily (n=281)

7%

19%

28%

37%

52%

Imatinib 400 mg once daily (n=283)

1%

9%

15%

23%

31%

Source: Edison Investment Research, Hochhaus et al. Leukemia 2016

In the absence of a comparator that shows the MR4.5 at different points in time with and without imatinib; and with the limited data disclosed, it is difficult to discern what proportion of the effect is attributed to inecalcitol. Cross-trial comparisons are difficult, but if we assume that patients have been on imatinib for at least two years and, that inecalcitol is added for one year, which is a total of three years, then a 33% MR4.5 is better than 15% at three years in the ENESTnd imatinib arm, and comparable to 32% in the nilotinib arm. Likewise, these data compare better than 24% and 13% in the dasatinib and imatinib arms in the DASISION study, respectively. Therefore, we believe that these preliminary data could be considered positive, while we await full one-year data.

Exhibit 6: Comparison

Arm

3 years

4 years

5 years

Imatinib DASISION

13%

23%

33%

Imatinib ENESTnd

15%

23%

31%

Inecalcitol + imatinib

33%

(imatinib at least 2 years + inecalcitol 1 year)

Source: Edison Investment Research

Value proposition: Increase response to stop treatment

The first-line treatment for CML is tyrosine-kinase inhibitors (TKIs). Most patients on TKIs achieve a lasting molecular response. Moreover, with the advent of second-generation TKIs, such as nilotinib (Tasigna, Novartis) and dasatinib (Sprycel, BMS), more patients can achieve further responses, raising the expectations that survival improves, and second-generation TKIs may potentially achieve a functional cure for the disease. Recent data show that patients who achieve DMRs can safely cease their therapy without relapsing, which is called treatment-free remission (TFR). Even patients who do relapse can still be responsive to other TKIs. Around 40% of patients who stop treatment after achieving stable DMR remain in TFR.

Guidelines from the US National Comprehensive Cancer Network (NCCN) and the European LeukemiaNet (ELN) recommend TKI treatment indefinitely in all patients who respond to treatment. However, long-term treatment with TKIs has been associated with side effects and loss of quality of life. Furthermore, these products have an economic burden. Gleevec’s list price is $120k per year per patient in the US; Sprycel and Tasigna cost about the same. Gleevec’s US patent has expired and generic imatinibs from Teva and Sun Pharma have reached the market, although no information on pricing is available. In Europe, most TKIs cost around $30k per year per patient. Therefore, achieving lasting deep molecular responses that could take the patient off treatment would represent an innovative approach to improve patients’ quality of life and reduce costs. Inecalcitol could fit in this strategy and become an adjunct to other therapies, rather than directly competing with them. We believe that the Phase II initial data show the potential impact of inecalcitol on the CML treatment paradigm due to its benign safety profile and potential to further improve molecular responses leading to discontinuation of treatment and functional cures.

Based on official epidemiology sources, such as the US National Cancer Institute’s (NCI) Surveillance, Epidemiology and End Results (SEER) programme and the European Treatment and Outcomes Study (EUTOS) for CML, we estimate c 14,250 new CML patients per year in the EU and US. We forecast EU/US peak sales for inecalcitol of $257m in CML. The company plans to apply for orphan drug status in the EU and US based on these initial data.

First patients enrolled in Phase II AML study

During H216 Hybrigenics started enrolment in a Phase II study of inecalcitol in patients with acute myeloid leukaemia (AML). The study is a double-blind, placebo-controlled trial that will recruit 110 patients (55 in the US and 55 in France) over 65 years’ old and unfit for chemotherapy. Daily doses of oral inecalcitol (4mg) or placebo will be administered to patients who can only receive monthly cycles of decitabine infusions. The primary endpoint is overall survival and secondary endpoints are response rate and tolerance. The company guides for data read out in H119. Inecalcitol has orphan drug status in Europe and the US.

Preclinical data were presented at the 12th International Congress on Targeted Anticancer Therapies in 2014. Inecalcitol prolonged survival and reduced splenomegaly (increase in spleen size and weight) in FLT3 animal models of AML as shown in Exhibit 7.

Exhibit 7: Preclinical AML data

Source: Hybrigenics

Moreover, in vitro data presented at the American Association for Cancer Research (AACR) annual meeting 2017 in cell lines of AML and multiple myeloma (MM) showed that inecalcitol is able to turn these into less invasive and more functional cells, in addition to its anti-proliferative properties.

Based on updated epidemiology data, we estimate c 40,000 new AML patients in EU and US and peak sales of $119m.

There are a range of treatments in the late stages of development shown in Exhibit 8, including those targeting FLT3, eg midostaurin and quizartinib, in Phase III trials being targeted for treatment of older patients ineligible for chemotherapy.

Exhibit 8: Competing therapies for AML

Product/company

Setting

Status

Notes

Inecalcitol/

Hybrigenics

Patients >65 years

Phase II

French/US placebo-controlled study ongoing. Primary endpoint is overall survival. Target recruitment is 110 patients, half in US and half in France. Results in late 2018 or H119.

Vidaza (azacytidine)/ Celgene

Front-line elderly

Approved in Europe

488-patient study vs conventional care regimens. Median overall survival (OS) was 10.4 months for patients receiving azacytidine compared to 6.5 months for patients receiving CCR. Completed.

Velcade/Takeda + Nexavar/Bayer

Front-line

Phase III

1,250-patient NCI-sponsored study testing various regiments containing bortezomib and sorafenib in parallel in patients with/without mutations. Primary completion date: June 2017.

Vidaza (azacytidine)/ Celgene

CR maintenance

Phase III

460- patient study of oral azacytidine + BSC. Primary completion date: August 2018.

Quizartinib/
Daiichi Sankyo

Relapsed/refractory

Phase III

International Phase III QUANTUM-R trial to treat in FLT3-ITD-positive AML – 363 patients in first relapse. Orphan drug designation in the US and EU and Fast Track designation in the US to treat FLT3-positive patients. Primary completion date: February 2018.

Ivosidenib (AG-120)/ Agios & Celgene

Front-line and relapsed/refractory

Phase I/II

Phase III study in front-line AML in combo with Vidaza to start in H117. First data from ivosidenib Phase I expansion in r/r AML in H117. Phase Ib/II 7+3 study of ivosidenib or enasidenib (AG-221) in combo with chemo in front-line AML ongoing. Phase I/II in combo with Vidaza ongoing in front-line AML. NDA submission by YE17.

PLX3397/
Daiichi Sankyo

Relapsed/refractory

Phase I/II

90-patient Phase I/II trial (patient ≥ 60 years only if unable/unwilling to undergo induction chemotherapy). Primary AML or secondary to an antecedent hematologic disorder. Primary completion in December 2017.

Source: Edison Investment Research, ClinicalTrials.gov

Focus on research and development

Servier collaboration and own programme on track

Hybrigenics and Servier have an ongoing research and development collaboration in the field of deubiquitinating enzymes (DUBs). In particular, the deal involves the validation of one ubiquitin-specific protease (USP) in oncology, screening of lead inhibitors and profiling candidates for further development. Hybrigenics has to date received €4.7m in upfront and research funding and an additional €2m in milestone-related payments for meeting its research targets. Further potential milestone payments of up to €12m until registration are associated with this programme.

The company has its own programme on DUBs and has independently discovered several series of inhibitors of USP7. Furthermore, Hybrigenics has a strong patent position in the field of USP inhibitors, with five patents granted in the US, EU and Japan, as well as other geographies, with protection until 2032. This programme is excluded from our valuation as it is at an early stage.

R&D services refocus

Hybrigenics announced the disposal via management buyout of a 75.8% stake in Hybrigenics Services, its proteomics subsidiary, for €796k. This includes a €196k upfront payment and three potential payments of up to €200k each, depending on the net result levels achieved by Hybrigenics Services in 2018, 2019 and 2020. Hybrigenics Services generated revenues of €3.5m in 2015 and €3.8m in 2016.

The company retains its Helixio division, which offers genomics, sequencing and bioinformatics services across a broad range of sectors and its Pharma R&D activities including pharmaceuticals, agrofood, cosmetics and environmental industries. Retained services revenues were €2.5m in FY16 (including the Servier €1.5m milestone payment) vs €1.2m in FY15.

Potential in additional indications, pending funding

Chronic lymphocytic leukaemia

Phase II data in early-stage untreated patients with CLL at risk of progression were published in 2014 showing that inecalcitol was able to slow the progression of disease in half of patients. Disease progression is defined by the rate of doubling of blood lymphocyte count (BLC). Out of 21 evaluable CLL patients, 11 experienced stabilisation of disease as measured by BLC, including one patient who achieved a 95% decrease in BLC after 10 months of treatment. This programme is awaiting funding before it begins Phase III trials.

While major advances in first- and second-line treatments have been made in CLL, there has been no change in the treatment guidelines for early-stage patients, which is watchful waiting until symptoms appear. Inecalcitol is positioned as a treatment that can slow disease progression and postpone the need for chemotherapy. Despite improvements in efficacy, chemotherapy may cause limiting side effects in some patients. Inecalcitol has orphan drug status in the US and Europe in CLL. Based on official epidemiology sources, we estimate 30,000 new cases of CLL in the US and EU and potential peak sales of $360m.

Prostate cancer

Inecalcitol also has potential in solid tumours, although the focus is currently on haematology. In a Phase IIa trial inecalcitol was shown to lower PSA levels in patients but survival data is needed to assess the value of inecalcitol in this indication. Development of inecalcitol in prostate cancer has been paused, despite its potential, until additional funding is raised or a partnership is agreed upon. The incidence rate of castration-resistant prostate cancer is around 240,000 new cases a year in the EU. However, the competition has advanced since the trial completed seven years ago, so a potential partner might be more likely to focus on haematology.

Sensitivities

The main sensitivity is the successful development of inecalcitol in haematological cancer. Initial data in CML are encouraging, but the study is open label and has no comparator arm, hence further controlled trials will be necessary to ascertain the value of inecalcitol in this indication. Additionally, this would represent a new approach in the CML treatment paradigm and adoption will be subject to clinical efficacy and physicians’ willingness to incorporate it in their practice. Results and progress will also influence Hybrigenics’ ability to attract a partnership for follow-on trials in haematological and solid cancers including resuming development in prostate cancer. Hybrigenics has sufficient funds to carry out the Phase II trials in AML and CML, but would rely on further financing or a partnership to progress into further clinical trials in all three haematological indications, and prostate cancer. We have assumed Hybrigenics self-funds development of inecalcitol in leukaemia to approval, which implies a higher royalty on sales than through an earlier-stage partnership, although with higher costs and greater execution risk.

The sale of the proteomic services division, which represented the bulk of revenues, significantly reduces the diversification of Hybrigenics’ business model and increases the risk profile of the company.

Financials: FY16 results

Hybrigenics reported FY16 revenue growth of 66% from €2.2m to €3.6m, which includes a milestone payment of €1.5m from Servier in H216, recorded as revenue. Following the R&D reorganisation and sale of the majority of its proteomics services division, the company now reports the results of its retained activities, which include the development of inecalcitol, the research on ubiquitin-specific proteases and its genomic services division Helixio. FY16 genomic services sales increased by 70% from €0.6m to €1m. Our service revenue growth forecast is 40% in FY17, reflecting the rapid growth of this division, and we forecast FY17 services revenue of €1.4m. Total group revenue is expected to remain approximately the same in FY17 at €3.7m as we do not project any milestone payments from Servier.

FY16 operating costs reached €7.1m vs €6.1m in FY15 and we forecast that there will be an increase in FY17 costs to €8m due to additional R&D expenditure on the Phase II trials.

Hybrigenics’ net cash position stood at €8.5m as at end December 2016. We estimate this should be sufficient to fund operations into 2018. However, we expect the group to move into a cash shortfall during 2018, which, for the purpose of our model, we have assumed will require new long-term debt of €2m.

Valuation: DCF of €141m

Our risk-adjusted DCF sum-of-the-parts valuation is €141m or €3.9 per share, trimmed from €146m or €4.1 per share, reflecting Hybrigenics’ strategy to develop inecalcitol as an orphan treatment in CML and AML in the US and Europe. We have increased the probability of success in CML from 30% to 40% on the back of the positive interim data. Development of inecalcitol in CLL is paused, despite its potential, because Hybrigenics requires funding or a partner to move development forward in this indication. Therefore, we have lowered the probability of success from 30% to 20% and we look to update it in the future depending on the company’s plans. We include our forecast of the milestone payments from the collaboration with Servier and our new forecast of sales of the genomics services division Helixio. Preclinical projects and inecalcitol’s value in prostate cancer are excluded.

The key assumptions for our DCF valuation are detailed in Exhibit 9.

Exhibit 9: Valuation assumptions for inecalcitol

Status

Launch date

Peak sales ($m)

Risk adjustment

Market penetration

Royalty

Inecalcitol CLL – US

Phase III ready

2023

180

20%

15%

25%

Inecalcitol CLL – EU

Phase III ready

2023

180

20%

15%

N/A

Inecalcitol CML – EU/US

Phase II

2020

257

40%

15%

25%

Inecalcitol AML – US

Phase II

2020

62

30%

15%

25%

Inecalcitol AML – EU

Phase II

2020

56

30%

15%

N/A

Source: Edison Investment Research

Exhibit 10: rNPV valuation

Driver

Value per share (€)

Value (€m)

Inecalcitol CLL – US

0.5

19.5

Inecalcitol CLL – EU

1.6

58.3

Inecalcitol AML – US

0.3

12.3

Inecalcitol AML – EU

0.9

31.1

Inecalcitol CML

2.1

74.2

Milestones

0.3

12.0

Helixio services division

0.1

3.3

Servier collaboration

0.1

2.3

Risk-adjusted expenses including R&D

(0.8)

(29.2)

Tax

(1.4)

(51.1)

Net cash at end FY16

0.2

8.5

Total

3.9

141.2

Number of shares

35.8

Source: Edison Investment Research

The changes to our valuation include:

increasing the probability of success in CML to 40% from 30% due to the positive interim data presented;

lowering the probability of success in CLL to 20% from 30% until development resumes;

a new forecast for the genomics services division Helixio;

adjusting our forecasts, notably estimated risk-adjusted discounted R&D costs for the clinical trials in CML, AML and CLL; SG&A costs for launch in Europe ; and

updating the net cash position for YE16.

In 2017, Hybrigenics is expected to provide an update on the orphan drug designation for inecalcitol in CML in the EU and the US. The Phase II trial is expected to complete in H218. In addition, the company will present results from the Phase II trial in AML in H119.

Exhibit 11: Financial summary

€'000s

2015

2016

2017e

2018e

Year end 31 December

IFRS

IFRS

IFRS

IFRS

PROFIT & LOSS

Revenue

 

 

2,172

3,607

3,670

5,598

Cost of sales

(1,104)

(842)

(1,211)

(1,575)

Gross profit

1,068

2,765

2,459

4,023

EBITDA

 

 

(4,413)

(3,789)

(4,964)

(3,492)

Operating profit (before GW and except)

 

(4,563)

(3,908)

(5,083)

(3,611)

Intangible amortisation

(150)

(119)

(119)

(119)

Exceptionals

0

0

0

0

Share-based payments

(225)

(166)

(174)

(183)

Operating profit

(5,016)

(4,319)

(5,502)

(4,039)

Net interest and other financial items

37

30

152

58

Profit before tax (norm)

 

 

(4,526)

(3,878)

(4,932)

(3,553)

Profit before tax (reported)

 

 

(4,979)

(4,290)

(5,351)

(3,981)

Tax

0

0

0

0

Profit after tax (norm)

(4,526)

(3,878)

(4,932)

(3,552)

Profit after tax (reported)

(4,979)

(4,290)

(5,351)

(3,981)

Discontinued operations

639

(963)

0

0

Net income (norm)

(4,526)

(3,878)

(4,932)

(3,552)

Net income (reported)

(4,340)

(5,254)

(5,351)

(3,981)

Average number of shares outstanding (m)

34.2

35.8

35.8

35.8

EPS - normalised (c)

 

 

(13.2)

(10.8)

(13.8)

(9.9)

EPS - FRS 3 (c)

 

 

(12.7)

(14.7)

(14.9)

(11.1)

Dividend per share (c)

0.0

0.0

0.0

1.0

Gross margin (%)

49%

77%

67%

72%

EBITDA margin (%)

N/A

N/A

N/A

N/A

Operating margin (before GW and except) (%)

N/A

N/A

N/A

N/A

BALANCE SHEET

Fixed assets

 

 

1,718

1,133

923

707

Intangible assets

820

524

405

286

Tangible assets

585

326

228

130

Investments

313

283

290

291

Current assets

 

 

19,584

15,048

8,217

6,725

Stocks

150

55

33

22

Debtors

1,513

546

556

847

Cash

11,716

8,489

3,795

2,024

Other

6,205

3,833

3,833

3,833

Assets held for sale

0

2,125

0

0

Current liabilities

 

 

(4,698)

(4,955)

(2,965)

(2,967)

Creditors

(1,727)

(1,565)

(1,727)

(1,726)

Short-term borrowings

(288)

(91)

(91)

(91)

Other

(2,683)

(1,145)

(1,147)

(1,150)

Liabilities associated with assets held for sale

0

(2,154)

0

0

Non-current liabilities

 

 

(629)

(346)

(346)

(2,346)

Long-term borrowings

(114)

0

0

(2,000)

Other

(515)

(346)

(346)

(346)

Net assets

 

 

15,976

10,881

5,828

2,120

CASH FLOW

Operating cash flow

 

 

(5,304)

(2,593)

(4,790)

(3,773)

Net interest

56

34

152

58

Tax

0

0

0

0

Capex

(548)

(274)

(147)

(147)

Payment of deferred consideration

0

0

0

0

Capitalisation of development costs

0

0

0

0

Expenditure on intangibles

0

0

0

0

Acquisitions/disposals

0

0

0

0

Financing

8,457

0

0

0

Dividends

0

0

0

0

Net cash flow

2,661

(2,833)

(4,785)

(3,862)

Opening net debt/(cash)

 

 

(9,644)

(11,602)

(8,489)

(3,795)

HP finance leases initiated

0

0

0

0

Other

(703)

(280)

91

91

Closing net debt/(cash)

 

 

(11,602)

(8,489)

(3,795)

(24)

Source: Edison Investment Research, Hybrigenics accounts. Note: Accounts have been restated to reflect the sale of a controlling stake in Hybrigenics Services.

Contact details

Revenue by geography

3-5 impasse Reille
75014 Paris
France
+33 (0)1 58 10 38 00
www.hybrigenics.com

Contact details

3-5 impasse Reille
75014 Paris
France
+33 (0)1 58 10 38 00
www.hybrigenics.com

Revenue by geography

Management team

CEO: Rémi Delansorne

CMO: Jean-François Dufour-Lamartinie MD

Rémi Delansorne has been CEO since September 2005 (director since October 2007), having joined Hybrigenics as director of R&D in 2004. Previously he was with Théramex, a French subsidiary of Merck, latterly as director of research in diabetology. He holds a DVM from National Veterinary School of Alfort, France, and a PhD in biology from the Université Pierre et Marie Curie.

Jean-François Dufour-Lamartinie joined Hybrigenics as head of clinical research in 2006. He has broad experience of clinical development, having been a clinician at various cancer research institutes including Institut Gustave Roussy and clinical research director of BioAlliance Pharma, prior to joining Hybrigenics.

CFO: Guillaume Floch

Chairman: Alain Muňoz

Guillaume Floch has been CFO since June 2008. Previously he was head of business planning and performance of Cephalon (France), and financial controller of Zeneus Pharma and Elan France.

Alain Muňoz became chairman of Hybrigenics in July 2015. He also serves on the boards of biopharmaceutical companies Auris Medical, Valneva and Zealand Pharma. Previous roles include chairman at Novagali Pharma and board membership at Erytech.

Management team

CEO: Rémi Delansorne

Rémi Delansorne has been CEO since September 2005 (director since October 2007), having joined Hybrigenics as director of R&D in 2004. Previously he was with Théramex, a French subsidiary of Merck, latterly as director of research in diabetology. He holds a DVM from National Veterinary School of Alfort, France, and a PhD in biology from the Université Pierre et Marie Curie.

CMO: Jean-François Dufour-Lamartinie MD

Jean-François Dufour-Lamartinie joined Hybrigenics as head of clinical research in 2006. He has broad experience of clinical development, having been a clinician at various cancer research institutes including Institut Gustave Roussy and clinical research director of BioAlliance Pharma, prior to joining Hybrigenics.

CFO: Guillaume Floch

Guillaume Floch has been CFO since June 2008. Previously he was head of business planning and performance of Cephalon (France), and financial controller of Zeneus Pharma and Elan France.

Chairman: Alain Muňoz

Alain Muňoz became chairman of Hybrigenics in July 2015. He also serves on the boards of biopharmaceutical companies Auris Medical, Valneva and Zealand Pharma. Previous roles include chairman at Novagali Pharma and board membership at Erytech.

Principal shareholders

(%)

Pradeyrol Development

3.6

Life Science Partners

2.4

Companies named in this report

Celgene (CELG, US), Agios (AGIO, US), Bayer (BAYN, GR), Sankyo (6417, JP).

Edison is an investment research and advisory company, with offices in North America, Europe, the Middle East and AsiaPac. The heart of Edison is our world-renowned equity research platform and deep multi-sector expertise. At Edison Investment Research, our research is widely read by international investors, advisers and stakeholders. Edison Advisors leverages our core research platform to provide differentiated services including investor relations and strategic consulting. Edison is authorised and regulated by the Financial Conduct Authority. Edison Investment Research (NZ) Limited (Edison NZ) is the New Zealand subsidiary of Edison. Edison NZ is registered on the New Zealand Financial Service Providers Register (FSP number 247505) and is registered to provide wholesale and/or generic financial adviser services only. Edison Investment Research Inc (Edison US) is the US subsidiary of Edison and is regulated by the Securities and Exchange Commission. Edison Investment Research Limited (Edison Aus) [46085869] is the Australian subsidiary of Edison and is not regulated by the Australian Securities and Investment Commission. Edison Germany is a branch entity of Edison Investment Research Limited [4794244]. www.edisongroup.com

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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

245 Park Avenue, 39th Floor

10167, New York

US

Sydney +61 (0)2 8249 8342

Level 12, 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

245 Park Avenue, 39th Floor

10167, New York

US

Sydney +61 (0)2 8249 8342

Level 12, Office 1205

95 Pitt Street, Sydney

NSW 2000, Australia

Edison is an investment research and advisory company, with offices in North America, Europe, the Middle East and AsiaPac. The heart of Edison is our world-renowned equity research platform and deep multi-sector expertise. At Edison Investment Research, our research is widely read by international investors, advisers and stakeholders. Edison Advisors leverages our core research platform to provide differentiated services including investor relations and strategic consulting. Edison is authorised and regulated by the Financial Conduct Authority. Edison Investment Research (NZ) Limited (Edison NZ) is the New Zealand subsidiary of Edison. Edison NZ is registered on the New Zealand Financial Service Providers Register (FSP number 247505) and is registered to provide wholesale and/or generic financial adviser services only. Edison Investment Research Inc (Edison US) is the US subsidiary of Edison and is regulated by the Securities and Exchange Commission. Edison Investment Research Limited (Edison Aus) [46085869] is the Australian subsidiary of Edison and is not regulated by the Australian Securities and Investment Commission. Edison Germany is a branch entity of Edison Investment Research Limited [4794244]. www.edisongroup.com

DISCLAIMER
Copyright 2017 Edison Investment Research Limited. All rights reserved. This report has been commissioned by Hybrigenics and prepared and issued by Edison for publication globally. All information used in the publication of this report has been compiled from publicly available sources that are believed to be reliable, however we do not guarantee the accuracy or completeness of this report. Opinions contained in this report represent those of the research department of Edison at the time of publication. The securities described in the Investment Research may not be eligible for sale in all jurisdictions or to certain categories of investors. This research is issued in Australia by Edison Aus and any access to it, is intended only for "wholesale clients" within the meaning of the Australian Corporations Act. The Investment Research is distributed in the United States by Edison US to major US institutional investors only. Edison US is registered as an investment adviser with the Securities and Exchange Commission. Edison US relies upon the "publishers' exclusion" from the definition of investment adviser under Section 202(a)(11) of the Investment Advisers Act of 1940 and corresponding state securities laws. As such, Edison does not offer or provide personalised advice. We publish information about companies in which we believe our readers may be interested and this information reflects our sincere opinions. The information that we provide or that is derived from our website is not intended to be, and should not be construed in any manner whatsoever as, personalised advice. Also, our website and the information provided by us should not be construed by any subscriber or prospective subscriber as Edison’s solicitation to effect, or attempt to effect, any transaction in a security. The research in this document is intended for New Zealand resident professional financial advisers or brokers (for use in their roles as financial advisers or brokers) and habitual investors who are “wholesale clients” for the purpose of the Financial Advisers Act 2008 (FAA) (as described in sections 5(c) (1)(a), (b) and (c) of the FAA). This is not a solicitation or inducement to buy, sell, subscribe, or underwrite any securities mentioned or in the topic of this document. This document is provided for information purposes only and should not be construed as an offer or solicitation for investment in any securities mentioned or in the topic of this document. A marketing communication under FCA Rules, this document has not been prepared in accordance with the legal requirements designed to promote the independence of investment research and is not subject to any prohibition on dealing ahead of the dissemination of investment research.
Edison has a restrictive policy relating to personal dealing. Edison Group does not conduct any investment business and, accordingly, does not itself hold any positions in the securities mentioned in this report. However, the respective directors, officers, employees and contractors of Edison may have a position in any or related securities mentioned in this report. Edison or its affiliates may perform services or solicit business from any of the companies mentioned in this report. The value of securities mentioned in this report can fall as well as rise and are subject to large and sudden swings. In addition it may be difficult or not possible to buy, sell or obtain accurate information about the value of securities mentioned in this report. Past performance is not necessarily a guide to future performance. Forward-looking information or statements in this report contain information that is based on assumptions, forecasts of future results, estimates of amounts not yet determinable, and therefore involve known and unknown risks, uncertainties and other factors which may cause the actual results, performance or achievements of their subject matter to be materially different from current expectations. For the purpose of the FAA, the content of this report is of a general nature, is intended as a source of general information only and is not intended to constitute a recommendation or opinion in relation to acquiring or disposing (including refraining from acquiring or disposing) of securities. The distribution of this document is not a “personalised service” and, to the extent that it contains any financial advice, is intended only as a “class service” provided by Edison within the meaning of the FAA (ie without taking into account the particular financial situation or goals of any person). As such, it should not be relied upon in making an investment decision. To the maximum extent permitted by law, Edison, its affiliates and contractors, and their respective directors, officers and employees will not be liable for any loss or damage arising as a result of reliance being placed on any of the information contained in this report and do not guarantee the returns on investments in the products discussed in this publication. FTSE International Limited (“FTSE”) © FTSE 2017. “FTSE®” is a trade mark of the London Stock Exchange Group companies and is used by FTSE International Limited under license. All rights in the FTSE indices and/or FTSE ratings vest in FTSE and/or its licensors. Neither FTSE nor its licensors accept any liability for any errors or omissions in the FTSE indices and/or FTSE ratings or underlying data. No further distribution of FTSE Data is permitted without FTSE’s express written consent.

Frankfurt +49 (0)69 78 8076 960

Schumannstrasse 34b

60325 Frankfurt

Germany

London +44 (0)20 3077 5700

280 High Holborn

London, WC1V 7EE

United Kingdom

New York +1 646 653 7026

245 Park Avenue, 39th Floor

10167, New York

US

Sydney +61 (0)2 8249 8342

Level 12, 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

245 Park Avenue, 39th Floor

10167, New York

US

Sydney +61 (0)2 8249 8342

Level 12, Office 1205

95 Pitt Street, Sydney

NSW 2000, Australia

Research: Healthcare

Hutchison China MediTech — Future stars are aligning

Despite a strong run over the last 12 months, our increased valuation of $2.7bn suggests the market overlooks HCM’s full R&D potential. Multiple catalysts are on the horizon in 2017/18; notably the China FDA filing for fruquintinib in CRC (full Phase III CRC data [China] at ASCO) and overall survival data from the savolitinib Phase II trial in c-Met-driven PRCC (could support a US NDA submission). Further progress of the early to mid-stage pipeline over time should retain investors focus. Ultimately, HCM’s move to commercialize its innovative pipeline in its domestic market (and longer term in international territories) could provide a major source of uplift.

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