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Fortuno 15 juni 2016 16:15

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Het komt niet vaak voor dat je op een aandeel stuit waarvan je denkt dat de koers op korte-middellange termijn weleens het 100-voudige kan gaan doen.

Immupharma kan zo'n aandeel zijn. Het bedrijf bestrijdt autoimmuunziekten door het auto-immunsysteem te reguleren en niet door het te onderdrukken. Deze platformtechnologie (!) kan bij vele auto-immuunziekten worden ingezet (asthma, rheuma, crohn etc.). Een markt van vele, vele miljarden.

Op dit moment loopt fase 3 onderzoek van Immupharma naar bestrijding van Lupus. Een ziekte waarvoor nog geen echte medicatie bestaat. Een miljardenmarkt op zich.

Er is een erg goed artikel over Immupharma geschreven door Sicilian-kan op een ander BB. Ik kan dat artikel in kwaliteit niet evenaren. Daarom met zijn toestemming hieronder zijn Engelstalig stuk.

Ik hoop dat het anderen evenveel enthousiasmeert als dat het mij gedaan heeft.

Met dank aan Sicilian-kan:

Fortuno 15 juni 2016 16:16

0

(last updated on 26 April 2016: Disclaimer - no information on this thread is intended as investment advice. Always do your own research)

Welcome to the Immupharma – In Phase 3 Lupus Trial Targeting Blockbuster ($1bn+) Revenues thread. Has dosed first US patients. **n.b. A Lupuzor Symposium (Wed 8 June) and a sell-side analyst and media briefing (Thu 9 June) are due imminently In particular Prof Muller will "provide further evidence of the role the P140 molecule can take in the potential treatment of other autoimmune diseases".

Lupus is a disease where the immune system goes wrong. Your body thinks that it is ill when it is not and the overactive immune system attacks healthy tissue. Many drugs have failed lupus trials because they try to suppress the immune system. The problem with this approach is that if you suppress the immune system too little, then the lupus not go away. If you suppress the immune system too much, you weaken the body to other illnesses.

Immupharma’s drug Lupuzor is different. It has a novel mechanism of action aimed at modulating the body’s immune system (rather than suppressing it) so it does not attack healthy cells, without causing adverse side effects. See the video presentation of Prof Sylvaine Muller at vimeo.com/151506805. It also has the potential to halt the progression of the disease in a substantial proportion of patients.

The potential clinical market available to Lupuzor is estimated to be in multiple $bns (billions) per year. See the 2015 Annual Report and the below:

www.immupharma.org/sites/default/modu...

Lupuzor - 100% owned Phase III lupus drug targeting Blockbuster revenues ($1bn+/yr)

The Phase III Trial

7 December 2015 - first US sites opened for recruitment of patients.
15 February 2016 - first US patients dosed
9 March 2016 - first European site opened for recruitment of patients.
12 April 2016 - clinicaltrials.gov reported that 11 sites are now recruiting (5 US, 5 EU, 1 Puerto Rico).
4 May 2016 - confirmation that first European patients have been recruited.

Recruitment in this pivotal Phase III study for Lupuzor(TM) is anticipated to occur in up to 45 investigator sites. 10 sites in United States and 35 in Europe. The aim is to ensure the screening of 270 potential patients, in order to recruit the required 200 patients for the trial.

The completion of patient recruitment is targeted for June 2016, with the primary completion date being June 2017 (final data collection date for primary outcome measure). The study completion date is targeted for December 2017 (i.e. full data being announced).

Updates on the trial can be found at clinicaltrials.gov/ct2/show/NCT025046...

The Phase III clinical study is a relatively small 52-week, randomized, double-blind, parallel-group, placebo-controlled study. There will need to be two 200 patient trials.

Importantly there is a Special Protocol Assessment for the trial from the FDA. This means that (a) the FDA has approved the trial structure and (b) the FDA will accept an efficacy claim from the Phase III trial if the endpoint is met. So a positive outcome in Phase III should lead to FDA approval.

IMM also has fast-track status from the FDA for Lupuzor. This means that the FDA will review any application for approval within six months.

Blockbuster Potential ($1bn+/yr)

If Lupuzor's Phase III trial meets its endpoints then a blockbuster market opportunity opens up for IMM:

• Decision Resources suggests $4bn for lupus drugs generally by 2022 www.pharmatimes.com/Article/13-11-11/...

• ReportBuyer suggests $2.6bn for lupus drugs generally by 2018 www.reportbuyer.com/product/2070064/d...

• GlobalData suggests $1.1bn for lupus drugs generally by 2022 healthcare.globaldata.com/media-cente...

• IMM states that Lupuzor has "multi-billion dollar sales potential"hTTp://www.immupharma.org/sites/default/modules/immu/downloads/imm%20update%20interims%20oct.pdf and has previously indicated $1bn to $4bn potential per year

There is pretty much an open goal for IMM to score into at the moment. Only one lupus drug has been given approval in the past 40-50 years - Benlysta from Glaxo. However, Benlysta only just scraped through clinical trials and the FDA and has many key failings. (a) Benlysta failed to be approved by NICE and the German regulators and only passed 13:2 at the FDA; (b) showed slim efficacy at 52 weeks and did not show efficacy at 76 weeks missing its secondary endpoint; (c) has failed to show efficacy on blacks / African-Americans, who have a high risk of lupus; (d) has much more severe and frequent side effects than Lupuzor; (e) is very expensive for a drug showing slim efficacy, with the US price being $35,000, whereas Lupuzor is targeting $10,000 to $20,000 per patient; (f) is administered by infusion taking an hour whereas Lupuzor is subcutaneous (though a subcutaneous trial was successful at the end of Phase 3 with similar efficacy over placebo as the infusion).

It is important to note that despite Benlysta's failings, Glaxo bought out HGSi, which owned 50% of Benlysta for $3.6bn with Benlysta being the only drug HGSi had on the market and with Benlysta struggling to make an impact on the market. HGSi had two other Phase III drugs in the pipeline.

The blockbuster market is therefore open to a new drug with good efficacy and a good safety record. Lupuzor has the potential to meet both these criteria.

Current Phase 3 SLE competition is very limited. There are just two other new drugs in Phase 3 for SLE. These are Blisibimod (Anthera Pharmaceuticals) and Anifrolumab (Astrazeneca). For information:

Blisibimod's trial is targeting only those patients with high lupus activity (SLEDAI >=10; 6-10 is moderate and 11-19 is high)

Anifrolumab's trials are due to complete after Lupuzor's trial. In Phase IIb, anifrolumab had a low response rate of 34.3% and a surprisingly low placebo rate of 17.6%. Just like epratuzumab, which also had a low Phase 2 placebo rate, I expect the placebo rate to rise in Phase 3. Anifrolumab is also associated with dose dependent side effects. Herpes zoster (placebo: 2%, 300mg: 5.1%, 1000mg: 9.5%) and influenza (placebo: 2%; 300mg:6.1%; 1000mg: 7.6%). They are taking the lower dose into Phase III.

In my view, Lupuzor is therefore one of very few at the moment, not one of very many. It also has significant potential safety and efficacy advantages over both the other candidates in Phase 3 and should report Phase 3 results before one of them.

Fortuno 15 juni 2016 16:17

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Previous Trial Results

Phase IIa trial results showed 50% of patients on the lower dose had a 50% reduction in SLEDAI scores.

The first phase IIb trial results (in moderate to severe patients) showed the following on its best dose:

- 67% were SLEDAI responders compared to 41% in placebo after 12 weeks
- 62% were SRI responders compared to 39% in placebo after 12 weeks

The SRI (the test used by Benlysta and both other trials in Phase 3) is clinically significant (p=0.016) and 23% above placebo. Contrast with Benlysta's Phase 3 trial results - 14% over placebo at 52 weeks in its first trial; 10.3% over placebo at 52 weeks in its second trial; 6.1% over placebo at 78 weeks in its second trial; and in a more recent subcutaneous trial (the previous were infusion) 12.3% over placebo at 52 weeks.

Results at 24 weeks were affected by IMM announcing the success of Lupuzor in interim analysis to the stock exchange just before Cephalon signed the deal. When the successful interim analysis was announced to the market, there were still placebo patients in the trial who would have been influenced by this news. 22 patients were recruited during this period and many more had already not completed the 24 weeks. Whilst the best dose SRI responder rate settled at 69.1%, the placebo rate shot up to 56.5%, a score that I have not seen in any other lupus trial and is much higher than the interim data, suggesting that the release of the positive trial results had a significant effect upon the 24 week placebo score. This is discussed in the BMJ article by Dr Zimmer, Dr Muller and others, in which it is said that:

"It has to be mentioned that in groups 1 and 2 of the interim analysis (the active groups), the 12-week period provided 88% and 83% of the total SLEDAI responders versus 62% in the placebo group, indicating that the disclosure effect was huge"

In my view, the story that IMM presents about the Phase IIb data is convincing. Whether the story is proven to be correct in the Phase 3 trial, we will have to see.

ard.bmj.com/content/early/2012/11/20/...

A second Phase IIb trial took place with a different excipient. An excipient should be an inactive bulking agent that is inert / neutral on the results. However the second Phase IIb used an excipient that was not inert / inactive and which according to a peer reviewed study "virtually shuts down the immunomodulatory properties of the P140 peptide [Lupuzor] in MRL/lpr mice". See e.g.hTTp://lup.sagepub.com/content/early/2014/03/18/0961203314525249.full.pdf In my view, the second Phase IIb trial results can be ignored and the Phase IIa and first Phase IIb results using the correct excipient should be relied upon.

Partnership and Commercialisation

IMM retains 100% of Lupuzor (though it must pay up to 15% of the monies it receives to the CNRS for the work that they have done).

On 22 January 2015 announced that it had entered into a collaboration with Simbec-Orion, a CRO, who will perform the trial. Simbec-Orion was created in 2014 through a merger completed through the provision of funds raised from the Wales Life Sciences Fund LP, a £100m fund managed by Professor Sir Christopher Evans' Arthurian Life Sciences Limited. Sir Christopher Evans has built companies worth over £3bn, floated 20, employed over 4,000 people and raised over £1.2bn from investors and governments across 30 countries. He is also a Non-Executive Director of Simbec-Orion. Simbec-Orion invested in the last placing.

Lupuzor was previously partnered with Cephalon (a then top 20 pharma since taken over by TEVA). An option deal was agreed before the first Phase IIb results were announced and $45m was received by IMM for the option and subsequent signing on fee, with $500m milestones and royalties, thought to be in the high teens +, or 18-22% depending on where you read. However when Cephalon were taken over by TEVA in 2011, Immupharma reclaimed 100% of Lupuzor as TEVA already had a Lupus candidate that they were seeking to use in other indications as well and IMM held a change of ownership and a non-compete clause.

As for commercialization in the future, IMM stated in 2016 that “There will be a number of routes to market Lupuzor which are open for consideration upon receipt of approval by the FDA, which the Directors believe could be: a global licensing deal, with the partner offering Immupharma royalties on sales; subject to further financing, Immupharma could partner with local distributors whilst controlling the manufacture of the drug through Polypeptide, a world-leader in peptide manufacturing and a longstanding partner of Immupharma, thus over the longer term, retaining a higher margin revenue stream; or the Directors could explore the sale of the asset or the Company, with cash returned to shareholders. The prime objective of any strategy would be to ensure long term shareholder value.”

Fortuno 15 juni 2016 16:17

0

Method of Action

Lupuzor's approach is novel and is unlike other lupus treatments in trials. It has been shown to behave as an immunomodulator and not as an immunosuppressant. As it does not suppress the whole immune system, Lupuzor's side effect profile is much lower. Also the drug specifically targets lupus. Lupuzor also has a selective form of autophagy (cell degradation of unnecessary or dysfunctional cellular components). Full details of the MoA can be seen in the below link – the first is a video presentation by Prof Muller, the inventor:

vimeo.com/151506805

www.lupuzor.com/Lupuzor_Research_and_...

Other Indications

A new patent has been filed (co-owned with CNRS) to cover other autoimmune indications - some of which have the potential for Orphan Drug designation.

Filed in December 2011 (so patent life to 2031) there is a patent at the EPO targeting:

Lupus (Target market size $1bn-$4bn)
Rheumatoid Arthritis / Juvenile Arthritis (Market size $16bn)
Mixed Connective Tissue Disease
Sjogren's Syndrome (Market size $0.5bn)
Multiple Sclerosis (Market size $14bn)
Insulin Dependent Diabetes (Market size $22bn)
Crohn's Disease (Market size $3.5bn)
Bullous Diseases (Target market size $1.6bn for Bullous Pemphigoid)

register.epo.org/application?document...

It is also worth noting that a previous Edison report states that they "understand that a majority of Phase IIb patients showed resolution of the arthritis measure (four point score...)".

The CNRS recently announced that "What we have learned from our research may also enable us to treat other autoimmune diseases, such as rheumatoid arthritis or Crohn's disease". Lupus is a potential blockbuster ($1bn+/year) market, but Rheumatoid Arthritis is in multiples of that, so this could become interesting in due course.

IPP-204106 - 100% owned cancer drug entering Phase II and targeting Blockbuster revenues

Trial Results and Pre Clinical Results

‘In vivo’ studies showed that the majority of tumours were completely eradicated and survival time increased without additional treatment.

A Phase IIa safety trial with an earlier formula of this drug was conducted only on patients who had already failed other cancer treatments and who had metastases.

21% of patients with progressive disease stabilised for more than 6 months; one of the first patients to be tested was still alive 20 months later.

A revised formulation was then trialled, using a new nano or micro or polyplexed nucant has that has been shown to be 10x more potent in pre-clinical studies than the original.

On 11 February 2015, IMM stated in a brief update that the trial had achieved its primary objective in demonstrating the maximum tolerated dose with chondroitin sulfate as 9mg/kg. In preclinical studies a 1mg/kg equivalent human dose with chondroitin sulfate in a combination therapy using the cancer drug Gemcitabin demonstrated a massive reduction in tumour volume in mouse pancreatic cancer. ImmuPharma can now, from a regulatory perspective, commence a Phase II study in pancreatic cancer using the optimum human dosage. A further update on this new Phase II study will be given in due course.

Nucant Platform

The nucant platform is a specific family of peptides for cancer and ophthalmology, which contains IPP-204106, Immupharma’s lead compound for cancer and other indications. There is the potential for phase II studies in cancer (see above), age-related macular degeneration or diabetic retinopathy (see below) in 2016.

Pre Clinical Pipeline

Immupharma has a very interesting pre-clinical pipeline. In particular:

- Urelix, derived from the CNRS collaboration, with a new patented breakthrough peptide technology platform mimicking long natural peptides improving their stability and giving greater efficacy. The first therapeutic area being targeted is diabetes with glucagon-like peptide -1 agonists, a class of drugs for the treatment of Type II diabetes, as well as initiating the development of novel peptides as glucagon antagonists - one of the novel approaches to treat Type I and Type II diabetes. The market potential for GLP1 is >$10bn per year. A non-refundable grant of c€400k was received in October 2014 to develop the Urelix technology and a further €200k has since been received, with application to diabetes and control of protein / protein interactions (cancer). Immupharma and CNRS have filed a new co-owned patent controlling this breakthrough peptide technology.

- IPP-203101, a novel class of antibiotics based on the fact that bacteria (and other microorganisms) have electrically charged cell membranes whereas human cells do not. It is believed to be very unlikely that a bacterium can modify the fundamental properties of its membrane structure in such a way that IPP-203101 would not interact with it. The potential is for IPP-203101 to be able to effect cell death in a manner that the bacteria cannot circumvent through mutation. In vitro data shows stability in plasma of over 5 days, so it may be able to be used as a single injection.

- IPP-201007, a new molecular series with potential application in inflammatory/allergic conditions such as asthma and rheumatoid arthritis.

- IPP-102199, being developed as a morphine replacement, with major advantages such as longer pain relief and reduced opioid side effects such as respiratory depression and dependency. In preclinical studies, IPP-102199 demonstrated efficacy over 24 hours when administered orally as a single dose. When given intravenously, IPP-102199 also shows activity for 24 hours and therefore may have the potential to be given just once a day. ImmuPharma has developed IPP-102199 using its proprietary Peptide-to-Drug- Converting Technology (PDCT), a key novel approach that allows peptides to be delivered orally and retain their efficacy, applied to met-enkephalin.

- Opthalmology. New patents were also recently awarded for an “optically pure” version of the Nucant family. The composition of matter patent provides longer exclusivity, additional protection of the Nucant program and a multitude of other indications in addition to cancer. The Nucant program has shown some modulation of angiogenesis with multiple applications in cancer as well as in non-cancerous but highly critical clinical indications including ophthalmology. ImmuPharma has been awarded a grant to further investigate the Nucant’s potential in age-related macular degeneration diabetic retinopathy and other ophthalmological indications.

N.b. IMM's peptide collaboration with the CNRS is exclusive and enables low cost research. It is "Immupharma's research engine". The CNRS is the "largest fundamental research organization in Europe with over 30,000 employees and a budget of €3.3bn". The CNRS provides access to many scientists and physicians. In return, the CNRS gets up to 15% of the monies that IMM receives from commercialising the targets that the CNRS has generated.

Fortuno 15 juni 2016 16:17

0

Director and Institutional Shareholdings

19.94% - Robert Zimmer (President and CSO) - 24,287,371
14.69% - Lanstead Capital - 17,893,456
9.22% - Aviva Investors - 11,232,848
4.15% - Alto Invest - 5,053,548
2.93% - Dimitri Dimitriou (CEO) - 3,567,430
2.89% - Richard Warr Deceased (former Chairman) - 3,518,968
2.34% - Hargreaves Landsdown - 2,849,180
2.22% - Pictet & Cie - 2,698,500

[23% - Shares held by Directors]
[56.76% - Shares held by those with 2% or more, n.b. the 2.34% of Hargreaves Landsdown will be nominees]

Total shares in issue - 121,781,219

Directors and Key Scientists

Dimitri F Dimitriou, Chief Executive Officer
Former Senior Director, Worldwide Business Development at GlaxoSmithKline
Former Senior Director, European Business Development at Bristol-Myers Squibb

Dr Robert Zimmer, President and Chief Scientific Officer
Has developed a substantial number of products for Roche, GlaxoSmithKline, Abbott, Searle, Sanofi-Aventis and Lilly.
Former director and head of research and development at SkyePharma

Tim McCarthy, Chairman
Chairman of Incanthera, Harvard Healthcare and Expedeon Holdings.
Former CEO and Finance Director of a number UK listed companies, including Alizyme and Peptide Therapeutics Group
Fellow of the Association of Chartered Certified Accountants

Sylvanne Muller, Research Director at CNRS
Dr Muller is a Research Director at the CNRS, where she is the winner of the CNRS Medal of Innovation for her discoveries made on the mechanism of action of Lupuzor and its applications to other autoimmune diseases.
Made 23 patented discoveries and is widely published.
Key inventor of Lupuzor.

Nicholas Kostopoulos, Responsible for fundraising and business development activities.
Was the responsible person for FDA approval at Debiopharm SA for a peptide-based prostate cancer drug, licensed to a major pharmaceutical company pursuant to a $500 million agreement negotiated by Mr. Kostopoulos.
Principal at The BioAlliance Practice, an international consultancy located in Washington D.C., focused on the commercialization of breakthrough medicines in North America.

Tracy Weimar, Vice President, Operations & Finance
Former Director, Worldwide Business Development at GlaxoSmithKline

Dr Stephane Mery, Non-Exec Director

CEO of Contronics Ltd, which designs and sells laboratory monitoring equipments,
Recently, a Partner at Beringea LLP, a $400m US/UK venture capital fund
Previously, Fund Manager/CEO of the Bloomsbury Bioseed Fund behind the birth of successful companies such as Spirogen (sold to MedImmune), Abzema (listed on AIM), and Canbex (recently sold to Ipsen).
Prior to this, Associate Director, Worldwide Business Development, for SmithKline Beecham (GSK) where responsible for the negotiation of several major in-license deals and acquisitions.

Dr Franco di Muzio

Former Executive Vice President of Bristol Myers Squibbs' medical equipment and products division, Weck International Inc., in charge of Europe, Asia, Middle East and Africa.
Former Area Managing Director and Head of all Glaxo Wellcome's (now GSK) business in the Middle East, Africa and Turkey.

Scientific Advisory Board

Dr Daniel Wallace
Former chairman of the Lupus Foundation of America
On Board of Directors for Lupus Research Institute
Author of leading lupus textbook and five others
Has the largest clinical lupus practice in the US
The Wallace Rheumatic Disease Research Center has run over 30 clinical trials for lupus, RA etc.

Prof David Isenberg
Chair of the British Isles Assessment Group (which sets the BILAG scoring system for clinical trials)
Past President of the British Society for Rheumatology
Won Evelyn Hess Prize from Lupus Foundation of America

Prof Vibeke Strand
Participated in the development of all the approved biologic agents and synthetic DMARDs in RA and SLE of the past 20 years.
Participated in the preparation of INDs for over 25 biologic and pharmaceutical agents.
Served on Advisory Panels for Amgen, Novartis, SmithKline Beecham, Astra-Zeneca and many others.
Has ran a consulting practice offering clinical research and regulatory strategy expertise to pharmaceutical and biotech companies for over 20 years.

Prof Cees Kallenberg
Written over 500 articles in international peer-reviewed journals.
On editorial boards of several journals in clinical immunology, nephrology and rheumatology.

Dr Lee Simon
Former Division Director of Analgesic, Anti-inflammatory and Ophthalmologic Drug Products within the Center for Drug Evaluation and Research at the FDA.
Principal for 9 years in SDG LLC, a consulting firm helping companies to create successful drug development programs through good designs and using insightful regulatory strategy

Cash Position

£8.4m raised in Q1 16 before expenses (£7.7m net), to cover the current Phase III trial and use the proceeds to fund working capital requirements through to 2018

hsprod.investis.com/ir/imm/ir.jsp?pag...

n.b. Under the Lanstead deal, IMM will receive monthly payments from Lanstead for the shares that they have issued them. If the share price averages over the 34.667p benchmark price, IMM will make more than the £4.43m estimated. If the share price is at double that for the month, IMM receive double that month. Conversely, if the share is at half the benchmark price for the month, IMM receive half that month. Note this is not an equity line of credit. Lanstead have all the shares. There is no fresh dilution each month and Lanstead do not sell every month, see e.g. AFC.

As part of the fundraising exercise, ImmuPharma also received confirmation of advance assurance from HM Revenue and Customs that it is a qualifying holding for the purposes of the Venture Capital Trust rules and a qualifying company for the purposes of the Enterprise Investment Scheme.

Shares in Issue

End 2010 - 81,171,744 shares in issue
End 2011 - 81,532,463 shares in issue
End 2012 - 81,532,463 shares in issue
End 2013 - 82,282,463 shares in issue
End 2014 - 88,622,463 shares in issue
End 2015 - 88,622,463 shares in issue
Currently in April 2016 - 121,781,219 shares in issue

*n.b. the Phase 3 trial underway and running costs until 2018 are now fully funded, see hsprod.investis.com/ir/imm/ir.jsp?pag...

Also, the Landstead deal merely effects the amount of cash received by IMM; it does not affect the number of shares in issue as they took their shares like any other placee.

My Lupuzor NPV Spreadsheet

**n.b. do not use without reading the warnings in the header and the instructions at uk.advfn.com/cmn/fbb/thread.php3?id=2...

The link for the spreadsheet is below:

www.dropbox.com/s/p5xlffp55newn93/Cop...

Recent Broker Notes

15 Dec 15, Panmure Gordon - 150p target price, currently under review following successful Phase 3 funding

See www.hl.co.uk/shares/shares-search-res...

Older GECR notes available at:

www.gecr.co.uk/latest-research/2014/1...

www.gecr.co.uk/latest-research/2014/1...

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