The Cross-Border Biotech Blog

Friday Science Review: May 25, 2012

John Holyoake — Fri, 25 May 2012 11:38:15 +0000

Most people take for granted that given a little resolve at the gym they can induce their muscles to grow, however, most people have probably not considered the complexity of the underlying cellular and biochemical processes. In response to exercise or injury, normally quiescent muscle satellite cells are activated and divide to produce progeny myogenic precursor cells that will themselves undergo multiple rounds of division before differentiating and fusing to the multinucleated muscle myofiber, thereby increasing the size and strength of the muscle. Key to the regulation of the satellite cell function is expression of the paired box transcription factors Pax3 and Pax7. These transcription factors are highly related (>85% sequence identity) and play overlapping, but mostly nonredundant roles in the specification and progression of the adult satellite cell lineage. Lineage tracing has suggested that Pax3 is required in cells that contribute to embryonic myoblasts and to the endothelial lineage, but Pax7 cells contribute to fetal myoblasts.

Given their sequence similarity, researchers at the University of Ottawa investigated how the functional differences were achieved. By profiling the global gene expression of satellite cell-derived myoblasts, alongside determining the genome-wind binding sites of Pax3 and Pax7, they showed that Pax3 and Pax7 have intrinsic differences in DNA binding and it is the differential binding that drives the differential downstream gene activation. Specifically, they showed that Pax3 and Pax7 are both able to activate gene expression by binding to combined prd/hbox motifs, but Pax7 can also activate gene expression by binding to the hbox motif alone. Due to this difference in binding ability, over 400 genes are regulated by Pax7, that are not subject to regulation by Pax3 and these genes have diverse functions from cell adhesion to muscle cell differentiation. This work adds to the transcriptional network underpinning muscle cell differentiation and also cautions us by showing how large functional differences can occur in transcription factors with only small differences in sequence.

Other publications:

Hyperphosphorylation and cleavage at d421 enhance tau secretion. PLoS One. Université de Montréal
Structural basis for substrate specificity and catalysis of human histone acetyltransferase 1. PNAS. Structural Genomics Consortium, Toronto
Muramyl Dipeptide Induces NOD2-Dependent Ly6C(high) Monocyte Recruitment to the Lungs and Protects Against Influenza Virus Infection. PLoS One. Laval University

Q1 2012 in Canadian Healthcare

wschnarr — Thu, 24 May 2012 15:36:45 +0000

Investors are looking for positive events, share price increases and yield from their various Canadian healthcare investments. This quarter’s review looks at delivery on these objectives during Q1 2012. Click here to download the 2012 Q1 Equicom Healthcare Review (pdf).

Friday Science Review: May 18, 2012

John Holyoake — Fri, 18 May 2012 11:30:26 +0000

The development and application of large scale studies of pathways, metabolites and interactions is clearly hugely important for biomedical advances and today’s paper from the University of Toronto and the University of Ottawa is concerned with acetylomics (a relatively recent addition to the rapidly growing omeome).

Lysine acetylation of histones has long been known to be involved in regulation of gene expression. However, acetylation has only recently come to be appreciated as having a wider role outside of histones and may be as extensive a post-translational modification as phosphorylation, with over 2500 mammalian proteins being subject to acetylation. Normal cell proliferation, growth, and differentiation requires the function of lysine acetyltransferases (KATs) and lysine deacetylases (KDACs) to maintain the appropriate levels of histone acetylation and abnormal function of these proteins is found in cancer. Therapeutically, KDACs are the targets of the histone deacetylase inhibitors (e.g. Vorinostat) and also include Sirtuin-1, the proposed target for the much hyped Resveratrol.

In their study, the Andrews lab and collaborators determined a network of 463 synthetic dosage lethal interactions for two classes of KDACs in budding yeast, thereby identifying which cellular pathways were subject to regulation by the different KDACs. The identified genes were enriched for diverse cellular processes, indicating that acetylation has a wide, and currently under-appreciated, role within cells that means we should hope to hear a lot more from acetylomics in the future (whether you be a fan of that particular neologism or not).

Other publications:

TLR Tolerance Reduces IFN-Alpha Production Despite Plasmacytoid Dendritic Cell Expansion and Anti-Nuclear Antibodies in NZB Bicongenic Mice. PLoS One. Toronto Western Research Institute
Translational Homeostasis via the mRNA Cap-Binding Protein, eIF4E. Molecular Cell. McGill University
Multiple roles of integrin-linked kinase in epidermal development, maturation and pigmentation revealed by molecular profiling. PLoS One. University of Western Ontario

Monday Biotech Deal Review: May 14, 2012

Jacob Cawker — Mon, 14 May 2012 18:33:47 +0000

Welcome to your Monday Biotech Deal Review for May 14, 2012. Highlights from the previous week include the $5 million private placement announced by Lorus Therapeutics and other equity financing announcements, but otherwise the week has generally been a slow one. Read on to learn more.

Investments

Lorus Therapeutics Inc. (TSX: LOR) intends to complete a $5,000,000 private placement of 15,625,000 ($0.32) units, each comprised of one common share and a (2-year, $0.45) warrant with a 20-day, $0.90 trigger. PowerOne Capital Markets Limited will receive a finder’s fee of 6% of the gross proceeds and (2-year, $0.32) finder’s warrants equal to 6% of the units sold to the finder’s subscribers, comprised of one common share and a (2-year, $0.45) warrant. Proceeds will be used to for R&D and for general and administrative purposes.

Amorfix Life Sciences Ltd. (TSX: AMF) announced a $1,000,000 non-brokered private placement of 2,500,000 ($0.40) units, each comprised of one common share and a half (2-year, $0.80) warrant with a 20-day, $1.00 trigger. Amorfix may pay finder fees of up to 8% of the gross proceeds and issue finder warrants, having the same terms as the warrants, to acquire shares equal to up to 8% of the units sold. Proceeds will be used for R&D and for general corporate purposes.

Calyx Bio-Ventures Inc. (TSXV: CYX) has entered into an agreement with Canaccord Genuity Corp. to place 6,000,000 ($0.25) units for proceeds of $1,500,000. Each unit will comprise one common share and a (2-year, $0.40) warrant. Calyx will also conduct a $500,000 non-brokered private placement under similar terms. Proceeds will be used for general working capital purposes. Calyx has also cancelled its previously announced $3,500,000 private placement.

Other Commercial Developments

ProMetic Life Sciences Inc. (TSX: PLI) has signed agreements for the co-development and co-exclusive worldwide commercialization (excluding China), of a plasma-derived biopharmaceutical product targeting a rare medical condition. The deal includes the granting of manufacturing rights by ProMetic to HBI of plasma-derived biopharmaceuticals using ProMetic’s proprietary PPPS™ with both parties sharing profits equally. The $10 million from HBI will fund the development program up to regulatory approval. HBI will have rights to ProMetic’s proprietary PPPS™ as well as training and technical support to manufacture plasma-derived biopharmaceuticals in a Taiwanese facility to be built and operated by HBI. Prometic will manufacture the drug in its Laval facility and by HBI in its planned facility in Taiwan.

Immunovaccine Inc. (TSXV: IMV) has entered into a research collaboration with an animal health company to develop next generation companion animal vaccines. Immunovaccine will combine multiple vaccine candidates provided by its research partner with the company’s proprietary DepoVax adjuvanting vaccine technology. The resulting vaccine products, which are expected to deliver long-lasting, single-dose protection against several of the most common infectious diseases effecting dogs and cats, will then be advanced through veterinary studies in several indications by Immunovaccine’s research partner.

Special thanks to Keldeagh Lindsay for help with this week’s Monday Biotech Deal Review!

Friday Science Review: May 11, 2012

John Holyoake — Fri, 11 May 2012 11:20:26 +0000

The tumour suppressor p15^ink4b is a cyclin-dependent kinase (cdk) inhibitor, which functions to cause cell cycle arrest and whose functional presence in tumour cells is often lost through mutation or deletion. The expression of p15^ink4bcan be rapidly induced by transforming growth factor beta (TGF-β) and regulation of p15^ink4b levels occurs primarily at the level of transcription. DNA methylation is one of the mechanisms known to repress transcription of p15^ink4b, however, the mechanism by which DNA methylation is reversed for the regulation of transcription is relatively poorly understood. In this week’s Molecular Cell paper, the Torchia lab at the University of Western Ontario sought to determine the mechanism of DNA methylation and demethylation of the p15^ink4b in response to TGF-β.

Using chromatin immunoprecipitation-sequencing (ChIP-seq), they showed that the p15^ink4b gene is a target for the ZNF217/CoREST complex and that along with the action of specific DNA (cytosine-5)-methyltransferase enzymes e.g. DNMT3A, the p15^ink4b gene is hypermethylated and repressed. Overcoming the repression in response to TGF-β induced signaling was shown to require removal of the DNMT3A/ZNF217/CoREST complex and replacement by SMAD2/3, the CBP acetyltransferase, and TDG or MBD4. Base excision repair then occurred, demethylating the DNA and thereby removing the transcriptional repression. They further showed that ZNF217 overexpression, a feature of some cancers, was shown to inhibit recruitment of the demethylation complex.

While focused on the specific regulation of p15^ink4b, these results add more generally to our knowledge of methylation-based epigenetic regulation and the important association of abnormal DNA methylation patterns with malignant transformation.

Other publications:

Monomeric site-specific nucleases for genome editing. PNAS. University of Western Ontario
TRADD contributes to tumour suppression by regulating ULF-dependent p19(Arf) ubiquitylation. Nature Cell Biology. University of Toronto

The Partnering Process – Deal Structure: Part 18 of Valuation and Other Biotech Mysteries

Jeremy Grushcow — Wed, 09 May 2012 12:00:31 +0000

[Ed. This is the eighteenth part in Wayne's series. You can access the whole thing by clicking here. Please leave comments or questions on the blog and Wayne will address them in future posts in this series.]

Assuming that a partnering deal is signed, what are the usual financial components?

Up-front cash usually has no conditions and is a non-dilutive financing. Big pharma generally does not want equity as it just clutters up their balance sheets and is an even bigger problem if the partnership gets terminated.
Clinical and regulatory milestone payments are fairly standard. The basic milestones are the initial U.S. and E.U. approvals but may include approvals of additional indications if they increase the market potential.
Sales milestone payments have become more common in the last decade. If the pharma partner does not believe the market potential, milestones can be included for reaching certain annual or cumulative sales milestones.
Royalties on sales are generally no longer a simple X% on net sales. They can be tiered, increasing after annual or cumulative sales milestones are reached.
If there is an R&D program, who conducts it and who pays for it?
Who executes and pays for the clinical and regulatory programs?
Some companies would like to retain or have an option on some sales and marketing rights in specific territories. These rights may cease to exist if there is a change of control at the smaller company.

The only way to learn about deal structures is to create a fictional deal, make the spread sheet and start looking at the impact of structural changes on the product NPV. The following assumptions have been used to create the attached Excel workbook.

Product assumptions:

Small molecule chemotherapeutic
Currently in the middle of a Phase 3 trial (only one needed for approval)
Phase 3 for a second clinical indication will be started after initial approval
Assume 10 years of market exclusivity, followed by generic competition
Approval in second half of year 2
Sales and marketing at full speed starting in year 3
No sales & marketing synergy with other products
No R&D costs

Partnership Terms:

Up-front payment of $250 million
Biotech pays for completion of initial Phase 3
Pharma pays for second Phase 3
Pharma has all sales and marketing responsibilities
Milestone payments
- FDA approval $50 M
- EU Approval $50 M
- Sales reach $1 billion annually $50 M
- Royalty on sales
  - Before annual sales reach $1 B 20%
  - After annual sales reach $1 B 25%

There are four sheets in the attached workbook. Sales assumptions are the same in all models – sales peak at $1.65 B in year 12 followed by generic competition which reduces sales to $100 M by year 16 (last year of the model).

Internally developed at pharma: net product cash flow over 16 years is $6.03 B with an NPV of $2.256 B (10% discount rate).
Internally developed at biotech: net product cash flow over 16 years is $5.598 B with an NPV of $2.039 B. The basic difference in the assumptions is that the biotech company will have higher costs to build a company and achieve the same sales results. It is possible that a private company could do this and just dividend the cash flow out to its small shareholder base. However, it is likely that a public company would try to grow through R&D and acquisitions or be acquired.
Partnership – pharma perspective: pharma is paying $250 M up-front to acquire an exclusive option on a potential product cash flow of $3.890 B with an NPV of $1.292 B.
Partnership – biotech perspective: the biotech company is mitigating corporate financial risk and the product specific risks of clinical failure and market competition for $250 M up-front. Including corporate costs, it will receive a net product cash flow of $1.718 B with an NPV of $776 M. These reductions from the go-it-alone scenario, when viewed in isolation, seem to be too much to give up. However, this analysis needs to include a per share analysis which would take into account shareholder dilution from equity financings to fund the building of the company. If equity financings are done before the Phase 3 data, the dilution could be substantial if the market is sceptical about the product. If the equity or debt financings are delayed until after the Phase 3 data, it could delay the product launch and slow the sales growth.

This is not meant to be a perfect, detailed model, or even realistic. I have never seen a company release saying ‘we did it once, we are unlikely to repeat this success, so we are going to dividend the cash flow’, although this action might be in the best interests of shareholders. This is a model where you can question and change assumptions and see what the impact is on the cash flow and NPV. Do this yourself – I will look at some of the questions and options in the next blog post.

Monday Biotech Deal Review: May 7, 2012

Jacob Cawker — Mon, 07 May 2012 11:00:06 +0000

Welcome to your Monday Biotech Deal Review for May 7, 2012. Highlights from the previous week include the announcement by Valeant of its agreement to acquire assets from University Medical Pharmaceuticals Corp. for approximately $64M as well as the announcement of Merus’ $10M bought deal private placement and the completion of Allon Therapeutics’ $10M brokered private placement. Read on to learn more.

Investments

Merus Labs International Inc. (TSX: MSL, NASDAQ: MSLI) has entered into an agreement with a syndicate of underwriters co-led by Canaccord Genuity Corp. and Clarus Securities Inc. who have agreed to purchase, on a bought deal basis 5,556,000 ($1.80) common shares for proceeds of $10,000,800 with a (30-day, 15%) over-allotment option. Proceeds will be used for general corporate purposes.

Allon Therapeutics Inc. (TSX: NPC) has completed the previously announced $10 million brokered private placement of 15,612,500 units and 24,387,500 subscription receipts convertible upon shareholders approval into units (covered here), both priced at $0.25. Each unit consists of one common share and a (5-year, $0.40) warrant. Bloom Burton & Co. acted as the placement agent and will receive cash commission and 1,176,906 ($0.25) agent’s warrants.

M&Eh

Valeant Pharmaceuticals International, Inc. (TSX: VRX, NYSE: VRX) has agreed to acquire certain assets from University Medical Pharmaceuticals Corp., for approximately $64 million plus potential milestones based upon attainment of future revenue targets. Total revenue in 2011 from the acquired assets was approximately $32 million. The transaction is expected to close by mid-year, subject to certain closing conditions.

Licensing and Other Commercial Developments

Lorus Therapeutics Inc. (TSX: LOR) has entered into a global license with Genentech, a member of the Roche Group (OTCQX: RHHBY), in respect of certain patents owned by Genentech for IL-17E, a recently identified anticancer cytokine. Detailed financial terms were not disclosed.

Abattis Biologix Corporation (CNSX: FLU) has entered into an exclusive distribution agreement with Hedley Enterprises Ltd. to purchase, resell and distribute Abattis’ line of natural products in Canada.

Friday Science Review: May 4, 2012

John Holyoake — Fri, 04 May 2012 11:25:44 +0000

The innate immune system is the first line of defense against infection of the host organism by pathogens and in this system, type I interferons are a critical component in limiting viral replication. Indeed, type I interferons are already marketed or in development for their anti-viral and immune modulating activities.

Levels of type I interferons are subject to control and rapid induction in response to the recognition of a pathogen by the host organism’s pattern-recognition receptors (e.g. Toll-like receptors – topically a struggling area of development with Idera’s recent phase II failure of a TLR9 inhibitor for advanced head and neck cancer). Production of the type I interferons is rapidly stimulated through a cascade that includes regulation of both transcription and translation, with the transcriptional activator NF-kB being an important site of regulation. A paper in Nature Immunology from a international consortium of researchers led by the Sonenberg lab at McGill University presents data showing that phosphorylation of the translation factor eIF4E is a key mechanism in regulating NF-kB’s ability to activate type I interferon production. Using mice in which the Ser209 phosphorylation site in eIF4E is removed, they showed indirect enhancement of NF-kB activity through decreased translation of NF-kB’s inhibitor IkBa. Furthermore, they showed that in these mice the replication of three different RNA viruses was impaired and that the mice were more resistant vesicular stomatitis virus (VSV) infection associated neurological damage.

Currently Mnk1 and Mnk2 are the only known kinases to phosphorylate eIF4E in mice, with Mnk2 being constitutively active and Mnk1 being activated in response to mitogens, growth factors and hormones, which places Mnk1 in the cascade initiating response to pathogen detection. Earlier this year researchers at the Child and Family Research Institute at the University of British Columbia identified Mnk1 as mediating Trastuzumab (Herceptin) resistance in HER2-positive breast cancers, which excitingly identifies Mnk1 as an unexploited potential target for multiple therapeutic categories, including cancer, viral infections and immune modulation.

Other publications

A programmable droplet-based microfluidic device applied to multiparameter analysis of single microbes and microbial communities. PNAS. University of British Columbia
Innate immune response to rift valley Fever virus in goats. PLoS Negl Trop Dis. National Center for Foreign Animal Disease, Canadian Food Inspection Agency
Trappin-2/Elafin Modulate Innate Immune Responses of Human Endometrial Epithelial Cells to PolyI∶C. PLoS One. McMaster University
Inflammation-Driven Reprogramming of CD4(+)Foxp3(+) Regulatory T Cells into Pathogenic Th1/Th17 T Effectors Is Abrogated by mTOR Inhibition in vivo. PLoS One. McGill University
Co-Expression of α9β1 Integrin and VEGF-D Confers Lymphatic Metastatic Ability to a Human Breast Cancer Cell Line MDA-MB-468LN. PLoS One. University of Western Ontario
Early steps in oxidation-induced SOD1 misfolding: Implications for non-amyloid protein aggregation in familial ALS. J. Mol. Biol. University of Toronto

Healthcare in the U.S. – The New Normal

aztecchris — Fri, 04 May 2012 02:39:11 +0000

Following the release of the new U.S. bioeconomy strategy, and as we head toward this year’s BIO Convention in Boston, Deloitte is presenting a webcast that may be of interest on how the U.S. healthcare system will deal with an aging population and increasing cost pressures:

Health Sciences Consolidation: Industry’s Response to the New Normal

The webcast will discuss factors driving the future of consolidation in the following sectors:

Biotech and Pharmaceutical Manufacturers
Hospitals
Commercial Health Insurance

Click here to register for the webcast.

Monday Biotech Deal Review: April 30, 2012

Jacob Cawker — Mon, 30 Apr 2012 22:47:21 +0000

Welcome to your Monday Biotech Deal Review for April 30, 2012. It was a slow week last week, with a couple of private placement closings, a business unit purchase and some commercial activity. Read on to learn more.

Investment

biOasis Technologies Inc. (TSXV: BTI) has closed its previously announced $2,484,000 non-brokered private placement of 2,160,000 ($0.15) units (covered here), each comprised of one common share and a (1-year, $1.30) warrant. Finder’s fees of $143,290 were paid in connection with the financing. Proceeds will be used as working capital.

Innovotech Inc. (TSXV: IOT) has announced a $750,000 private placement of 2,343,750 ($0.32) units, each comprised of one common share and a (3-year, $0.40) warrant. Proceeds will be used to support marketing of its veterinary and human test kits and to support efforts to gain regulatory approval of its agricultural industry products.

Critical Outcome Technologies Inc. (TSXV: COT) has completed the final tranche of its previously announced $1,800,000 non-brokered private placement offering with the issuance of 11,250,000 ($0.16) units, each comprised of one common share and one (1.5-year, $0.30) warrant. Finder’s fees of $116,270 and 726,686 compensation (1.5-year, $0.30) warrants were paid in connection with the placement.

M&Eh

Warnex Inc. (TSXV: WNX) has completed the previously announced sale of its Analytical Services division to NEOPHARM LABS Inc. (covered here), whereby Warnex will realize cash proceeds of $300,000, and NEOPHARM will assume certain specific liabilities related to the division. Proceeds will be used to support its working capital requirements and to reduce outstanding debt.

Other Commercial Developments

ProMetic Life Sciences Inc. (TSX: PLI) announced that it has received a $1.9 million follow-on purchase order pursuant to an existing long-term supply agreement entered into with a US based biopharmaceutical company, relating to the supply of a proprietary affinity adsorbent developed and manufactured by ProMetic’s UK subsidiary, with deliveries to be completed during 2012. ProMetic has also announced that its UK subsidiary, ProMetic Biosciences Ltd, has signed an agreement with a European biotechnology manufacturing company, whereby ProMetic will develop an affinity resin biosimilar product and its related manufacturing process. ProMetic will receive initial service revenues of $1.4 million with work commencing immediately.

Special thanks to Keldeagh Lindsay for help with this week’s Monday Biotech Deal Review!