Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘Biotech Strategy’

Bone is a tissue in constant state of remodeling by osteoclasts (cells responsible for bone resorption) and osteoblasts (cells responsible for new bone formation).

Osteoporosis is a disease of progressive bone loss that is associated with increase risk of fractures.  Particularly debilitating are hip fractures in the elderly that are costly to treat and also lead to increased death and reduction in quality of life.  It’s estimated that osteoporosis affects 44 million people in the United States over the age of 50.

Most treatments for osteoporosis inhibit bone resorption e.g. bisphosphonates (alendronate, risedronate, ibandronate, zoledronic acid).  By inhibiting or reducing bone resorption, there is a lower amount of bone loss.

Recent research published in the November 2011 issue of the journal Nature Medicine has highlighted a new potential target for osteoporosis drug development that acts on osteoblasts and promotes bone formation.

In a series of elegant experiments, Takako Negishi-Koga and colleagues found that osteoclast-derived Semaphorin 4D (Sema4D) inhibits bone formation.

They found that the transmembrane protein Sema4D is expressed by osteoclasts and inhibits osteoblastic bone formation. In other words, Sema4D is a critical mediator of osteclast-osteoblast communication. 

They reported that:

In osteoblastic cells, Sema4D stimulation decreased the expression of cadherin-11 at the cell-cell contact region suggesting that Sema4D stimulates cell motility through an impairment of cell-cell adhesion, which in turn results in the reduction in bone-forming activity.

Osteoclast-derived Sema4D inhibits bone formation: 

The binding of Sema4D to its receptor Plexin-B1 on osteoblasts resulted in the activation of the small GTPase RhoA, which inhibits bone formation by suppressing insulin-like growth factor-1 (IGF-1) signaling and by modulating osteoblast motility. 

The implication of these findings is that blocking Sema4D could promote osteoblastic bone formation without affecting osteoclastic bone resorption.  The researchers successfully tested this hypothesis using an antibody to Sema4D.

They concluded that:

These results suggest that the blocking Sema4D–Plexin-B1 interaction is a new and potentially effective strategy for increasing bone formation in humans.

This preclinical work using an animal model is highly promising and suggests that as we learn more about the bone microenvironment, new therapeutic and molecular targets for drug development may emerge.

ResearchBlogging.orgNegishi-Koga, T., Shinohara, M., Komatsu, N., Bito, H., Kodama, T., Friedel, R., & Takayanagi, H. (2011). Suppression of bone formation by osteoclastic expression of semaphorin 4D Nature Medicine, 17 (11), 1473-1480 DOI: 10.1038/nm.2489

Biotech Strategy Blog is 1 today!  I can’t believe that a year has gone by so quickly!  Before moving on to year 2, I thought a brief review might be interesting.

What have been the top posts on Biotech Strategy Blog this past year?

In terms of total visitors per post:

  1. Results from NEJM Lucentis v Avastin AMD CATT clinical trial
  2. AUA Results from PIVOT study show no benefit from radical prostatectomy in low risk early stage patients
  3. ASCO 2011 Cabozantinib (XL184) may be an exciting new prostate cancer drug
  4. Merck’s capthepsin-K inhibitor odanacatib in osteoporosis
  5. Update from AACR on new prostate cancer drugs to watch

For those who like metrics:

  • Highest number of reads per month was in May (19,927)
  • Year to date there have been 79,179 visitors
  • Most visited day was September 22, 2011 (2136 reads)

What have been some of the other posts that I enjoyed writing about?

My top 5 (not in rank order) would be:

  1. Alpharadin will be new treatment option for prostate cancer
  2. Patient advocacy session at European Hematology Assocation EHA Congress shows impact of drug adherence on outcome
  3. How nanotechnology may revolutionize the detection of traumatic brain injury using a sensor that changes color
  4. Innovation in Nanotechnology will lead to improved drug delivery, diagnostics & imaging
  5. Insights of the decade

Finally, I have produced 4 videos that you can watch on the biotechstrategy channel on YouTube.

It’s been a busy but enjoyable year. Biotech Strategy Blog is still a work in progress.  If you have enjoyed a particular series of posts or would like me explore a topic or theme in the future, do email me or post a comment.

Academic institutions are now bringing pharma/biotech companies together and facilitating rational combination trials that make solid scientific sense.

Combining at least two targeted drugs looks to be increasingly necessary in order to develop innovative new cancer treatments, where turning off one target may stimulate another, thus both need to be targeted for there to be an overall effect.

However, one company may not have all the pathways and drug targets covered by their portfolio.  The result is that companies may have to work together in combination trials with each providing one drug from their portfolio.

That was one of the key messages I took from Gordan Mills (UT MD Anderson Cancer Center) in his recent video interview with Sally Church from Pharma Strategy Blog:

Sally Church’s video interview with Professor Mills is well worth watching if you have not already done so.

Not only are universities and research institutions well placed to judge the scientific merits, but as Mills points out they can facilitate things as an independent third party and actively help bring partnerships together.  Given that combination therapies may be needed in order to turn off different parts of signaling pathways and cross-talk, I think we are likely to see more of this approach.

It’s going to be new territory for many companies – how to enter into a potential joint venture or alliance? However, if it results in a therapy that works, it is going to be win-win for all parties. It may also improve efficiency in drug development and lead to better use of patients in early stage development.

Some examples of where this is happening already in oncology include AstraZeneca and Merck with their MEK-AKT approach and GSK (MEK) with Novartis (PI3K), to name a couple.  This is a new trend we are likely to see more of in the future.

I can see universities hiring alliance managers who have industry experience to ensure these collaborations run smoothly.

The topic of the industry/academia interface in rational cancer drug development will also be discussed in a plenary session at the forthcoming American Association for Cancer Research (AACR) meeting on Molecular Targets and Cancer Therapeutics (November 12-16, 2011) in San Francisco.

How academia can better help the pharma/biotech industry bring innovative, rational drug combinations to market is a topic that I think we will be reading more about in coming months.

In a letter to the science journal Nature, published online on August 21, 2011, scientists from Northwestern University in Chicago report findings that could help develop drugs for patients with Amyotrophic Lateral Sclerosis (ALS), more commonly known as Lou Gehrig’s disease.

ALS is a progressive, fatal, degenerative motor neurone disease, which results in the inability to walk, get out of bed, move arms, hands, swallow or chew. Unlike Alzheimer’s disease, cognitive functions are not usually impaired, making it a particularly nasty disease when faced with awareness of disease progression.

According to Wikipedia, ALS is one of the most common neuromuscular diseases worldwide, with 1 or 2 people in every 100,000 developing ALS each year.

One of the characteristics of ALS and other neurodegenerative disease is the accumulation of protein aggregates or inclusions. Amyloid-ß plaques and intracellular tau neurofibrillary tangles are common in Alzheimer’s disease, for example.

By contrast, in ALS, a hallmark of the disease pathology is the presence of ubiquitin-positive, protein aggregates in spinal motor neurons.

The new research from Northwestern University shows how a mutation in UBQLN2, the gene that encodes ubiquilin 2, may be the cause of ALS in some patients.

The UBQLN2 mutation results in a failure to properly encode the protein, ubiquilin 2, a member of the ubiquitin-like protein family known as ubiquilins. The result is that normal protein degradation through the ubiquilin pathway is impaired, leading to cellular deposits and abnormal protein aggregation.

How did the team at Northwestern discover this insight?

Using DNA sequencing they looked at a five-generation family with 19 affected by ALS and sought to identify the causative gene in the transmission of this disease.  They found that a mutation in UBQLN2, the gene that encodes ubiquilin 2 was the key difference in those family members with or without ALS.

They subsequently tested the hypothesis that UBQLN2 mutations were causative of ALS using clinical data from 40 individuals in 5 families with UBQLN2 mutations. Interestingly in eight patients with the UBQLN2 mutation and ALS, dementia was also present suggesting a possible link between ubquilin 2 inclusions and dementia.

The team explored this correlation by examining brain autopsy samples of 15 cases without UBQLN2 mutations, of which 5 had experienced dementia as well as ALS. They found no ubiquilin 2 pathology in the hippocampus of the 10 ALS patients without dementia, but did find it in the 5 that had experienced both ALS and dementia. They noted:

The correlation of hippocampal ubiquilin 2 pathology to dementia in ALS cases with or without UBQLN2 mutations indicates that ubiquilin 2 is widely involved in ALS-related dementia, even without UBQLN2 mutations.

They also observed that:

We did not observe obvious differences in the distributions of wild-type and mutant ubiquilin2.

The authors concluded:

These data provide robust evidence for an impairment of protein turnover in the pathogenesis of ALS and ALS/dementia, and possibly in other neurodegenerative disorders as well.

These interesting findings by the Northwestern group were reported in Nature, and while promising, must be treated with caution for several reasons:

  1. It is still early-stage preliminary research on a small group of subjects.
  2. The exact function of ubiquilin 2 is not well understood.
  3. Not all ALS patients have the UBQLN2 mutation
  4. If the UBQLN2 mutation is not present in all ALS patients, then this mutation is not the sole means by which ALS develops.
  5. UBQLN2 may not be the only mutation involved in the pathophysiology of ALS.

The data from Northwestern does, however, offer hope that in the future, gene therapy or new treatments could be developed that stop or slow disease progression. Targeting the ubquilin pathway and the UBQLN2 mutation may, for example, prevent the abnormal protein turnover and aggregation that leads to impaired signaling and loss of function seen in ALS.

Further research into pathogenic pathways could lead to new targets for drug development, not only for the treatment of ALS but also dementia, and other neurodegenerative disorders.

ResearchBlogging.orgDeng, H., Chen, W., Hong, S., Boycott, K., Gorrie, G., Siddique, N., Yang, Y., Fecto, F., Shi, Y., Zhai, H., Jiang, H., Hirano, M., Rampersaud, E., Jansen, G., Donkervoort, S., Bigio, E., Brooks, B., Ajroud, K., Sufit, R., Haines, J., Mugnaini, E., Pericak-Vance, M., & Siddique, T. (2011). Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia Nature DOI: 10.1038/nature10353

Story source:  LA Times & Fierce Biotech

Richard Hsu (@hsutubeesq), a Silicon Vally technology lawyer and partner at King & Spalding has a new blog that I’d like to recommend.

Named “The One Page Blog”, it aims to showcase Richard’s knowledge of IP and technology law using one page posts. Most of the posts have a downloadable PDF with a useful framework or summary. A picture tells a thousand words.

I particularly like Richard’s recent post on how to analyze a confidentiality agreement. The model Richard proposes will be useful to lawyers who are not IP-experts or those who need to talk to their lawyers about some of the issues that should be considered.

The challenge I find with a non-disclosure or confidentiality agreement is always one of negotiating an agreement that is fair and reasonable to both parties. Typically the boilerplate I receive from biotechnology and pharmaceutical companies is far too much in their favor. Redlining and negotiation then follows!

Richard’s blog also has a 48 second video entitled “making my own magnetic rubik’s cube.” It is excellent and a standard I aspire to as I seek to do more video blog posts:

I look forward to more posts and video from the “The One Page Blog.”

I recently returned from a few days in Boston & Cambridge, so today, in memory of the late Alastair Cooke and his Letter from America, broadcast for 58 years from 1946 to 2004, I wanted to share with you my “Letter from Boston”.

New England is the No 1 biotechnology region on the East Coast of the United States and the Boston/Cambridge area of Massachusetts is the hub.

What makes Boston/Cambridge so attractive as a biotech region?  Amongst many, I’d suggest 3 factors stand out to me:

  1. Access to World-Class Science with an Entrepreneurial Focus.  With over 50,000 students in the Boston/Cambridge area it is a city with a focus on higher education.  Harvard, MIT, Boston University, Northeastern, Tufts, Massachusetts General Hospital are but a few of the many research institutions.  However, what strikes me about the researchers in Boston/Cambridge area is the entrepreneurial focus they have.  The idea of starting up a company, commercializing an innovation or finding the application of science is something a lot of people want to do.  This entrepreneurial focus is key to the success of industry/academic colloboration in the area.
  2. Critical Mass of Industry infrastructure. There’s a range of companies in the Boston/Cambridge area. From start-ups such as Blueprint Medicines to more established companies such as Ariad, Vertex and Millennium-Takeda, what Boston/Cambridge offers is a critical mass of talent and people. Those working in the area have sufficient opportunities to move to new companies and positions, that it’s not a major career risk to move to the area.  There’s also a lot of early stage infrastructure such as the Novartis Institute of Biomedical Research that bridges the gap between basic research and early stage commercial development.
  3. Geographic Location. Finally, what stands out for me is the excellent location that Boston has. You can easily reach New York’s investors and analysts, Washington Policy Makers or New Jersey big pharma without too much difficulty. At the same time, Boston is easily accessible for European companies, and the travel time to London can be less than going to the West Coast.

Pfizer recently announced further R&D investment in the Longwood Medical area, Harvard are building a new science campus in Allston and Vertex recently broke ground on a new headquarters in the South Boston innovation district.

For biotechnology companies at all stages of development there are a lot of opportunities in the Boston/Cambridge area.

Although I had to leave BIO 2011 early due to illness, I did shoot some video during the time I was at the meeting, and have now put this together into a short 2 minute video that you can watch below.

This post wraps up my coverage of the 2011 BIO international convention in Washington DC. Next week, I’ll be writing more about innovative science and new products in the pipeline that have caught my attention.

A happy holiday weekend to everyone in North America.

What is innovation? Like “strategy” and “leadership” it’s a term we frequently use, something we all seek in the biotech/pharma industry, yet it’s hard to define, even harder to develop or predict.

What is the future for innovative medicines in our industry’s pipeline? was the title of a session that I attended yesterday afternoon at BIO 2011, the annual meeting of the Biotechnology Industry Association (BIO) in Washington DC.

BIO 2011 Innovation Pipeline SessionModerated by John Mendlein, the panel contained some R&D heavy weights:

  • Tom Daniel, President of Research & Early Development, Celgene
  • Charles Homcy, Venture Partner, Third Rock Ventures
  • Moncef Slaoui, Chairman R&D, GlaxoSmithKline
  • Doug Williams, Executive VP, R&D, Biogen Idec

Several people in the audience live tweeted the key messages of the speakers, and I encourage you to review them, if interested.  The take homes that I took from this session were:

Innovation can be incremental or major breakthroughs

Many people think of innovation as a major breakthrough. Well worn clichés such as “ground breaking”, “game changing” come to mind.  In pharma, I’d cite imatinib (Glivec®/Gleevec®) in CML as an example.  In the consumer world, the Dyson vacuum cleaner jumps out to me.  Something completely redesigned and made better = innovation.

However, incremental change can also be innovation if it has an impact.  Take a new drug formulation that instead of daily dosing moves it to monthly doses and in the process improves patient compliance and adherence.  That’s incremental innovation.

“Incremental versus major breakthrough” reminds me of scientific research.  Most published papers are incremental, only rarely is there a major paradigm shift and landmark study.  Only a few PhD students undertake truly novel research, instead the majority pursue incremental avenues associated with their supervisor’s interests. An oversimplification perhaps but there’s some truth to it.

Understanding science enables Innovation

Companies should focus their energies on disease mechanisms where the basic science has reached an inflection point of knowledge i.e. there is enough information for us to apply. This is why the work of research organizations such as the National Institutes of Health (NIH) is so important. In an area where there is the disease knowledge emerging, you can then put together a team of people who understand the science and biology of the disease.  This does not guarantee innovation, but allows the identification of opportunities and in my view “enables innovation.”

Innovation will come from focus on molecular pathology of disease

Drug development is no longer focused on treating symptoms but on the underlying mechanism of a disease.  Medicine itself is moving in this direction with personalized medicine and drugs that target specific mutations of genes e.g crizotinib in lung cancer.  In a complex world of overlapping pathways (cancer and inflammation was the example cited), drug development innovation is going to come from understanding the molecular pathology of a disease. The terms “translational medicine” was not used in the session, but this is what comes to mind.  Understanding science is key to success.

What is the future for innovative medicines in our industry’s pipeline? The panelists didn’t actually answer this question directly, but my view is that it is promising.

One of the “Super Sessions” at the forthcoming 2011 Biotechnology Industry Organization (BIO) international convention is a presentation of the highlights of Ernst & Young’s 25th Annual Biotechnology Industry Report.

The 97 page report, available online, offers a useful summary of metrics around financing, deals and sector performance.

As the report notes, one of the key issues that biotech companies continue to face is access to funding in order to sustain innovation.  Many biotechnology executives I spoke to at the recent American Society of Clinical Oncology (ASCO) meeting in Chicago confirmed how difficult access to capital remained.

The E&Y report confirms this anecdotal evidence. In their report they note that the 80/20 rule that we are all familiar with applied to biotechnology funding in 2010, with 20% of US companies obtaining 82.6% of the capital!

Given this ratio, it’s not hard to see why so many small biotech companies have struggled for funds.  However, what would have been more interesting to learn about is what were the characteristics of the 20% that led them to successfully obtain more than 80% of the funding? In other words what are the learnings for emerging biotech companies seeking capital?

The report also notes that biotech’s share of available VC funding fell from 18% in 2009 to 12.2% in 2010, as VC’s invested in other market segments such as media and technology.  One only has to look at the recent market interest in LinkedIn to see that investing in web 2.0 companies is back in fashion again, although with the subsequent share price drop it might be considered to be a little akin to Tulip mania.

Another key funding point that the E&Y report picks up on, is that many VC’s now invest in tranches with milestone or contingency based payments.  The result of this “risk sharing” is a lowering of available working capital.  The consequence for biotech companies is that less upfront R&D investments can be made. Instead they may be forced to go after fewer indications and not pursue all available opportunities.

Ernst & Young also interviewed several biotech CEOs about how they planned to sustain innovation, and two strategies emerged:

  • Prove that what you are doing benefits patient outcome
  • Do more with less i.e. improve efficiency

They are not mutually exclusive, and as the report points out, these are the challenges faced by all life science companies.

It will be interesting to see at BIO 2011 how industry executives view the current state of the biotechnology industry and how innovation can be sustained.

error: Content is protected !!