Welcome to your Monday Biotech Deal Review for October 15, 2012. Thanks to Thanksgiving for the Canadians and Columbus day for the Americans out there, this week’s post covers the last two weeks of activity. Biggest of the weeks’ stories, however, is Aeterna Zentaris Inc.’s $15 million public offering, closing in mid October. Read onwards to see just how busy this fall the market is shaping up to be. Read more of this post
What happens to the genome of pathogenic bacteria when they are forced to adapt after being confronted by an antibiotic, or after colonizing a new host species? This was the question posed by the Kassen lab at Carleton University. In their study, published in PLoS Genetics, they exposed Pseudomonas aeruginosa, an opportunistic pathogen and the major pathogen in the lungs of cystic fibrosis sufferers, to antibiotics in CF-lung mimicking culture conditions and then used by whole-genome sequencing to follow the genomic basis of the bacteria’s adaptation.
As might be expected, they found changes in antibiotic resistance genes that correlated with the degree of antibiotic resistance of the particular experimental isolate. However, they also found other co-occurring mutations that played a role in antibiotic resistance, but that had different associated fitness costs, suggesting a wide range of compensatory mutations. Separately, the study was able to add to the body of evidence suggesting that cyclic-di-GMP signaling plays a role in the adaptation of the bacteria to CF-lung-like conditions – a signaling pathway that promotes the adoption of a biofilm phenotype rather than the motile planktonic phenotype.
Ultimately, the study shows that adaptation of an opportunistic pathogen to conditions reproducing its common host environment results in a mixture of expected and unexpected genetic adaptations. These adaptations represent new targets for therapies, but also illustrate the heterogeneity facing patients and clinicians as they try to address these infections in the clinic.
Welcome to your Monday Biotech Deal Review for September 31, 2012. This week’s big news is yet another acquisition by Valeant, this time for the U.S rights and inventory of an age-related macular degeneration treatment from QLT Inc. Find more details on this story and others by clicking through. Read more of this post
Saccharomyces cerevisiae is a mainstay model organism for molecular biology, where dissection of its signaling pathways and interaction networks are used to build models that can be extrapolated to other higher organisms. Closer to home, S. cerevisiae shares many conserved features with other yeast species, such as Candida albicans, which can be opportunistic human pathogens. The virulence of C. albicans has been correlated to its ability to switch between budding yeast to filamentous forms, an ability that is shared by S. cerevisiae. Therefore, understanding the genes involved in the different morphologies of S. cerevisiae, which includes distinct forms of filamentation, can therefore lead to an increased understanding of the pathogenesis of opportunistic fungal infections – a growing problem amongst immunocompromised patients
In an international collaboration, led by the Boone lab at the University of Toronto, a global gene deletion approach was used to explore the genes required for the filamentous growth programs. In their paper published in Science, they show that unique genes appear to underlie each filamentation program, but that some key genes are important across filamentous growth. These core genes include MFG1 (YDL233w), whose gene product acts as a regulator of filamentous growth by binding to Flo8 and Mss11, transcription factors previously found to have morphogenetic roles. With the identification of MFG1 as a key regulator of filamentation, the potential for a novel therapeutic strategy to prevent the invasion of human tissues by filamentous fungal species like C. albicans arises.
Welcome to your Monday Biotech Deal Review for September 24, 2012. A busy week in investment stories includes Valeant’s launch of unsecured notes through its subsidiary VPI Escrow Corp, and MedX Health Corp.’s plans to offer 15,000,000 in common shares. Read on to learn more. Read more of this post
Left-sided congenital heart disease (LS-CHD) is one of the most commonly seen forms of cardiac malformations. Affected individuals suffer from a spectrum of cardiac issues that include bicuspid aortic valves, aortic valve stenosis, narrowing of the aorta and underdevelopment of the left side of the heart (hypoplastic left heart syndrome). Several lines of evidence indicate that LS-CHD is due to genetic factors, but the specific genetic causes are not currently known. An international collaboration, headed by the Andelfinger lab at the Université de Montréal, set out to explore the role of structural genomic variations by searching for copy number variants present in only affected individuals and not other family members.
Their study, reported in PLOS Genetics, revealed 25 new candidate genes for LS-CHD. The genes had diverse functions and included the SMC1A gene, involved in sister chromatid cohesion, MFAP4, believed to be involved in in cell adhesion or intercellular interactions, and CTHRC1, which is involved in vascular remodelling. Together it builds a picture that suggests broad alterations in angiogenesis may be the root cause of at least some of the incidences of LS-CHD. This work is part of the first steps in determining the detailed molecular pathophysiological mechanism of LS-CHD, an important part of understanding the diversity of patient outcomes and of developing therapies.
[Ed. This is the twentieth 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.]
I am starting the final part of this blog series with a description of the main players in the capital market – what do they do, who do they interact with and how do they generate revenue. These blogs will be written for the person who has little or no knowledge of capital markets. For simplicity, I am only going to deal with equities (stocks) in the public market.
Welcome to your Monday Biotech Deal Review for September 17, 2012. This week’s big news includes Valeant’s plans to syndicate an additional $1,000,000,000 of incremental term B loans, and Cangene’s sale of 3 plasma centres to U.S-based Grifols. Read on to learn more. Read more of this post
Welcome to your Monday Biotech Deal Review for September 10, 2012. This week’s highlights include Zymeworks Inc.’s completion of a common share offering, as well as their achievement of a major research milestone with Merck. Read on for more. Read more of this post
This week saw the publication of two important papers on protein-protein interactions. The first paper, from a collaboration led by Andrew Emili at the University of Toronto, was published in the journal Cell and details a census of soluble protein complexes from human cells. In a second complementary paper, published in Nature and led by Jack Greenblatt also at the University of Toronto (and also involving their next door neighbours, the Emili lab), the first global, high-confidence physical interaction map of membrane proteins from Saccharomyces cerevisiae was developed.
Both of these studies produced a wealth of information and provide important resources to identify candidate disease genes, as well as to predict the function of individual proteins within their respective complexes. Indeed, the human cell census identified over 300 previously un-annotated protein complexes, that comprised over 1,000 proteins, some of which are have already been linked to human disease. Similarly the membrane protein study identified more than 1,700 membrane protein-protein interactions and 500 putative protein complexes that involved a membrane protein. On this later point, it is important to remember that membrane proteins represent the majority of drug targets, but have been notoriously difficult to study due to their amphipathic nature.
In addition to the identification of new protein complexes, both papers allowed the exploration of the evolutionary conservation of protein complexes across different species that emphasizes a generally high degree of conservation, but that could ultimately reveal the dangers and limitations of using simpler organisms as models of human diseases.
Welcome to your Monday Biotech Deal Review for September 3, 2012. A slow week was capped by today’s announcement that Valeant Pharmaceuticals International Inc. will acquire dermatology specialist Medicis Pharmaceuticals Corporation. The deal, which pushes Valeant’s total 2012 acquisition spending to over $3.5 billion, continues Valeant CEO Michael Pearson’s strategy of “using M&A as a surrogate for R&D.” Read on to learn more. Read more of this post
Welcome to your Monday Biotech Deal Review for August 27, 2012. Highlights from the previous two weeks include Miraculins Inc’s grant of stock options and distribution agreement with London Drugs, Microbix Biosyetem’s licensing of a thrombolytic biopharmaceutical to Zydus Cadila, and BIOREM’s closing of its private placement. The Monday Deal Review for August 13, 2012 also marked the last Review authored by Jacob Cawker. We’d like to thank Jacob for his hard work and years of service! For more about me, please see my Bio, here. Read on to learn more. Read more of this post
Reduced blood flow to organs and peripheral tissue, as might be expected, leads to cell necrosis and death. The nature of the resulting ischemic disease depends upon the specific tissue affected and spans the range from acute conditions such as acute coronary syndrome or acute kidney injury, to chronic conditions such as peripheral artery disease and angina. Despite the development of both pharmacological and surgical treatment strategies, ischemic disease remains a leading cause of morbidity and mortality. As such, therapies that will reduce ischemia by promoting the regeneration of damaged vasculature are an active area of active research and cell-based therapies represent one avenue being pursued.
In a paper in Stem Cells, researchers at the University of Western Ontario show that by selecting for a rare population of aldehyde dehydrogenase expressing cells from human umbilical cord blood they could promote vascular regeneration in an animal model of ischemic disease. This rare population of cells (<0.5%) is enriched for early myeloid and stem cell-associated cells and displays a pro-angiogenic transcription profile, including the hallmark angiogenic signaling factors ANGPT1 and VEGFA. In vitro cell culture efficacy was demonstrated in experiments that showed that this cell population was able to promote human umbilical vein endothelial cell (HUVEC) survival and tube-like cord formation, both being indicators of pro-angiogenic activity. Interestingly, permanent engraftment of the cells was not required for the vascular regeneration, which increases the clinical development potential by potentially avoiding the need for long-term immune suppression of a patient receiving this allogeneic cell therapy approach.
Public Canadian healthcare companies raised over $1 billion in equity and convertible debt financings in the first half of 2012. Before anybody wonders whether another biotech boom has suddenly appeared, a closer look at the details shows a different reality.
Large equity and convertible debt financings by profitable Canadian healthcare service companies in the first half of 2012 totaled $1,048 million. These are profitable companies, three of which do monthly distributions to shareholders. These companies fit the current risk profile of many investors, who are looking for profits, value and yield.
SXC Health Solutions $541.8 million
Chartwell Seniors Housing REIT $339.3 million (equity and convertible debt)
HealthLease Properties REIT $110.0 million (IPO)
Leisureworld Senior Care $ 56.4 million
The total for the rest of the sector was about $288 million for equity and convertible debt deals closed in H1 2012. A financing over $10 million indicates that a company, especially one developing a novel therapeutic, may have a chance to plan its future, as opposed to just survive. This list includes:
YM BioSciences $80.5 M
Novadaq Technologies $40.3 M
Oncolytics Biotech $21.3 M
Bioniche Life Sciences $20.0 M (debt)
BELLUS Health $17.3 M (includes plan of arrangement proceeds)
Merus Labs $17.3 M (equity plus debt)
Removing these large financings leaves about $127 million for the remaining over 100 companies in the sector to share. A small amount of additional funding came from exercise of warrants, government grants and milestone payments from partners.
The financing numbers in this post were compiled from the Q2 2012 Canadian Healthcare Review (pdf), co-authored by myself and Ross Marshall, Senior Vice President, The Equicom Group Inc., a wholly-owned subsidiary of TMX Group Inc.
Welcome to your Monday Biotech Deal Review for August 13, 2012. Highlights from the previous two weeks include the announcement of an interim order for a plan of arrangement between QHR Technologies Inc. and Open EC Technologies and the announcement of a support agreement for the takeover of Life Bank by Insception Biosciences. Read on to learn more. Read more of this post
Antibiotic resistance is an increasingly pressing public health problem. While the prevalence of resistance is increasing, there is a simultaneous dearth of newly approved or in development drugs. For those that are in development the majority are natural products or derivatives thereof. Most of these represent improved variants of marketed compounds rather than a new mechanistic class, which increases the risk of the rapid appearance of resistance. The small pipeline and current lack of diversity therefore means the identification of novel antibiotics is an important task.
Cationic antimicrobial peptides (CAMPs) represent one such class and are produced by all living species. These peptides have varied structures, but share the feature of a segregation of cationic and hydrophobic resides and it is this gross physiochemical property that underlies the antibiotic effects. Multiple mechanisms can be involved in the bactericidal activity, including membrane disruption, binding of DNA and other cellular components. However, the ability to translate the promise of CAMPs into antibiotics is hampered by their pharmacokinetic properties and especially their susceptibility to degradation by serum proteases.
Various strategies are available to address the stability problems of potential peptide therapeutics and this week’s paper by the Schweizer lab at the University of Manitoba focuses on examining the potential of the incorporation of peptoid residues into CAMP’s to improve their stability. Encouragingly their peptoid analogues had similar activities to the parent peptides, again supporting the idea that CAMPs work through gross physical chemical properties rather than specific structural features. The next step for the researchers is to show that the retained activity is bolstered by improved serum stability.
Welcome to your Monday Biotech Deal Review for Monday July 30, 2012. Highlights from the previous weeks include the closing of the $13 million public offering by Trimel Pharmaceuticals and $7.5 million loan, as well as the M&A activity involving Functional Technologies Inc. and Medifocus Inc. Read on to learn more. Read more of this post
TDP-43 and its C. elegans ortholog, TDP-1 are DNA and RNA binding proteins that have multiple functions in repressing transcription, splicing pre-mRNA and regulating translation. TDP-43 is found to be a constituent of stress granules, cytosolic RNA/protein aggregates that form in response to cellular stress, be it from heat, oxidative or osmotic.
TDP-43 has also been found to be mutated and accumulated in multiple neurodegenerative disorders, including ALS (Lou Gehrig’s disease), frontotemporal dementia (a form of pre-senile dementia second in prevalence only to Alzheimer’s disease) and chronic traumatic encephalopathy (including dementia pugilistica).
Given TDP-1/TDP-43’s role in cellular stress response the Parker lab at the Université de Montréal asked whether TDP-1 participated in C. elegans’s cellular stress response and longevity pathways and whether it was through participation in the Insulin/IGF-signaling (IIS) pathway, a major axis of stress-response signaling and longevity in worms.
They found that the tdp-1 gene is responsive to stress and participates in the Insulin/IGF signaling pathway to regulate lifespan, as well as to respond to oxidative stress. While worms that lack tdp-1 were more sensitive to external stresses, over-expression of tdp-1 was itself toxic. Furthermore, tdp-1 expression was induced by the introduction of mutant TDP-43 due to increased oxidative stress and that this led to increase neuronal degradation and reduced lifespan. This leads to the model that tdp-1 was intended to protect from unfavourable conditions, but is now becoming aberrantly activated and is contributing to proteotoxicity and oxidative stress in the cell. If this malfunction is present in humans it may explain why TDP-43 is found to be associated with an increasing number of neurodegenerative conditions and would support the exploration of TDP-43 as a therapeutic target.
Oncolytic viruses are a promising therapeutic approach that may finally be approaching the market; Amgen’s recently acquired OncoVEX GM-CSF is in phase III for melanoma with results expected in 2013 and Canada’s own Oncolytics has recently completed the first stage of its phase III trial for the treatment of platinum-refractory head and neck cancers.
For tumour types that are permissive to these viruses much of the promise arises from the specific replication in cancer cells and subsequent lysis. However, another activity that can help improve complete responses and prevent recurrence even when the virus has been cleared from the patient is the induction of antitumor immunity. This immunity is greatly stimulated by the viral replication and lysis process. Aiming to harness this effect, the recent paper in Molecular Therapy by researchers at the University of Ottawa describes an approach to generate a broad anti-tumour immunity against a multitude of tumour antigens through the use of an infected cell vaccine (ICV) platform, which is even applicable for tumours that are not permissive to oncolytic viruses.
The oncolytic VSV-Δ51 virus is able to induce a strong anti-tumour immunity in tumour cell lines, but only when viral replication occurs in the tumour cells. To overcome this, the researchers chose an ex vivo approach, whereby infection of isolated tumour cells with their oncolytic virus construct (the VSV-Δ51 virus, but expressing GM-CSF similar to the BioVEX approach) could be ensured in vitro by a high multiplicity of infection. A vaccine could then be prepared from this population of infected cells. With this approach mice were protected from subsequent tumour challenge and the induced innate and adaptive immune response was robust enough to control the growth of established tumours.
This approach offers a personalized vaccine comprising the full range of a patient’s tumour-specific antigens improving the hope for complete response and effective control of recurrence, albeit with a significant commercialization challenge arising from the inherently unscalable manufacturing, operational complexity and high production costs that is currently being faced by Dendreon’s Provenge.
Welcome to your Monday Biotech Deal Review for July 9, 2012. Highlights from the previous two weeks include the announcement of a $13.25 million prospectus offering by Trimel Pharmaceuticals, and the announcement of a $200 million exchange offer by Angiotech on its Senior Floating Rate Notes due 2013. Read on to learn more. Read more of this post
While there are a surprisingly low number of genes in the human genome, 95% of the multi-exonic genes are subject to alternative splicing and therefore the role of alternative splicing in permitting increased cellular and functional complexity should be more widely appreciated.
In different cell types and in response to different conditions, coordinated splicing regulation leads to the specific use of alternative exons and these regulated exon networks can be assumed to play important roles in specific processes and pathways – why else would it occur and be conserved. However, while this regulated behaviour is well known, there is a current lack of understanding of the functional effects imparted by the tissue-regulated alternative exons. A desire to fill in some of this gap motivated the research by a collaborative trio of labs at the University of Toronto. In their Molecular Cell paper, they show that proteins containing regulated exon networks tend to have more interactions in protein-protein interaction networks and that these regulated exons, together with their flanking constitutive exons, are enriched in sequences predicted to be highly disordered.
In a specific example of an alternative exon network regulated by nSR100/SRRM4 (neural-specific Ser/Arg-repeat related protein of 100 kDa), which is responsible for the inclusion of ~11% of brain specific exons, they show that the inclusion of the regulated exons could result in more or fewer protein-protein interactions, depending on the specific gene. Therefore, introduction of a regulated exon and the corresponding additional protein segment does not merely have an additive effect on the range of interactions in which an alternatively spliced protein can engage. Continuing on to a deeper level of detail, the authors show that the inclusion of one of these regulated exons in Bin1 promotes the interaction with the GTPase Dnm2 and that this interaction was needed for efficient endocytosis in neural cells, linking the splicing regulation all the way to cellular function.
Changes in exon splicing are known to be both causes and consequences of multiple human diseases, including tauopathies, spinal muscular atrophy and familial dysautonomia; adding to the functional understanding of alternative splicing will surely allow the identification of more, and the increased chance for the development of a treatment.
Welcome to your Monday Biotech Deal Review for June 25, 2012. Highlights from the previous week include the closing of the second tranche of Medifocus’ private placement for gross proceeds of $3.3 million. Read on to learn more. Read more of this post
On the heels of the U.S. government’s recent report: National Bioeconomy Blueprint , Battelle and BIO have released: State Bioscience Industry Development 2012.
The report highlights how the bioscience industry has excelled in terms of job growth. Even during tough economic times and an uneven recovery of the global economy, the industry has generally been an employment generator, well above the U.S. national average.
The report goes on to examine the bioscience industry by state. To read the report, click here
The Dick lab at the Campbell Family Institute of the Ontario Cancer Institute has been instrumental in the field of cancer stem cells. The central tenet of the cancer stem cell hypothesis is that there is a small population of cells within a tumour that are able to self-renew and also differentiate into the full range of cell types found within that tumour. In addition to their role at the head of the tumour cell hierarchy, these cancer stem cells (also known as cancer initiating cells, or tumour initiating cells) have increased resistance to chemotherapeutics, leading to an unfortunate ability to cause both relapse and metastasis.
In their Cancer Cell paper, the Dick lab and collaborators investigated the genes that are involved in controlling this combination of abilities. They determined that the proteins ID1 and ID3 were responsible for controlling the self-renewal of colon cancer stem cells. ID1 and ID3 are members of the DNA-binding protein inhibitor family of proteins that heterodimerize with basic helix-loop-helix transcription factors to prevent their ability to bind DNA. ID1 and ID3 appeared to be exerting their effect by increasing levels of p21, a cell-cycle inhibitor and regulator of self-renewal. p21 itself has previously been linked to protecting cancer cells from stress and DNA damage and it was also found that knocking down ID1 and ID3 led to increased sensitivity to oxaliplatin, thereby linking the phenomenon of increased resistance to chemotherapy and self-renewal.
As an official blog site for BIO 2012, Cross Border Biotech had the opportunity to participate in a fantastic new program known as the “BIO Buzz Center” which enables official bloggers to do webcasts over BIO’s website. During the convention, traffic to BIO’s websites surges – with the audience increasing by 2-3 times the normal size therefore increasing visibility.
Not being shy of the camera I jumped at the opportunity and had the privilege of interviewing Mr. Sanj Singh, President and CEO of Ade Therapeutics
Aside from the fact that my mike level was a bit low and I probably should have hit the makeup chair before taping, the 4 minute interview went very well.
A big thank-you to Sanj, Tracy Wemett and Gayle Kansagor for making this happen.
In light of the Canadian government’s review of the R+D tax credit regime in Canada and the hand wringing around the fallout should the recommendations from the Jenkins report be implented, it was refreshing to hear about the State of Maryland’s approach.
The Maryland government decided to create a unique approach to tax credits for early stage bio and tech companies resulting in “InvestMaryland”. The program has been highlighted in the “BIOtechNOW” event daily : BIOtech_Issue1_17 (2) from the BIO 2o12 convention.
The state program has been well received and local governments like Montgomery county have stepped up to provide additional support .
Welcome to your Monday Biotech Deal Review for June 18, 2012. Highlights from the previous week include the $10 million subscription receipt financing by Allon Therapeutics, the elimination of $11.8 million in debt by MedMira and the syndication of $600 million in debt by Valeant under its existing senior secured credit facilities. Read on to learn more. Read more of this post
BIO 2012 has officially kicked off in the beautiful city of Boston.
Social Media has moved front and centre during the convention with a full range of bloggers and tweeters. This year BIO is re-broadcasting blog posts via: http://convention.bio.org/ . Cross Border Biotech is listed as an official blog site so please check back for the latest updates and news from the convention floor. Speaking of convention floor, the Canadian Pavilion (booth 735) occupies a very large piece of real estate (7200 sq. ft.) and although not officially open is attracting a steady flow of people. The Pavilion houses companies from every province looking to promote, connect and partner.
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