ThisAugust, Pharmaceutical Manufacturing and Packing Sourcer (PMPS) will publish an article by AsisChem scientists Guillermo Morales, Bryan Roland, and Emile Bellott, entitled: “Working With Synthesis” ( August, 2010, p70 )  Some of our findings and main points are summarized below:

For the past two decades, the industry buzz has been about ‘pipeline productivity’. The well-known graphic showing exponentially increasing drug R&D expenditures by the pharmaceutical industry, in parallel with level or declining new drug approvals, year-by-year, has been a popular talking point at industry meetings and conferences.

Against this backdrop, the pharma industry has evolved dramatically in response to competitive pressures.

  

	1990's	2000's
Industry Competitive Environment	• Increasing globalization • Emphasis on blockbusters	• Globalization • Cost containment • More emphasis on niche drugs
Pharma Business Model	In-house development	Partner or acquire majority of pipeline
Emerging Companies	Drive toward IPO	• Drive toward partnering event • Lean operating model • Emergence from academic research
Drug Discovery Paradigm	• Combichem and screen • Structure-based design	Post genomics era - rationale – based discovery
Medicinal Chemistry	Emphasis on pharmacology	• Increasing emphasis on druggability and optimizing properties
Chemistry CRO's	Little competition	• Intense competition • Continuing growth • Emphasis on cost, skill, and intangibles

 

Drug prices face continued pressure, as the most visible out-of-pocket healthcare expense by most households. This will intensify the incentives driving the use of generic drugs and constrain pricing and use of innovative therapies.

One major area that will continue to be affected by the new sense of cost consciousness is discovery and development.

Diminished margins will only serve to accelerate the move by large pharma and biotech toward M&A and the consequent dismantling of redundant R&D operations. Analyst presentations by these large companies emphasize a goal of outsourcing more than half of the discovery pipeline through collaborations and deal-making with small innovator companies.

These small emerging companies, based on academic inventions and funded by venture capital typically emphasise a lean and flexible business model, using CROs and CMOs for all but their core scientific competencies.

As pricing constraints lead to business models that rein in cost, the use of CROs and CMOs will increase. A recent report predicts that the CRO market will more than double in the five years from 2009 to2014. At the same time, the center of gravity will continue to shift towards providers in the developing world, increasing use of manufacturing sources in emerging markets. The growth of this geographic shift in manufacturing sources will result in cost-saving potential, as well as an enhanced opportunity to penetrate high growth areas.

Our article concludes that this is a time of intense opportunity and growth for chemical synthesis outsourcing CRO's. As a consequence of the pool of talented scientists with former large pharma background, the best CRO's are positioned to become trusted collaborators who not only complete the technical aspects of the projects , but also help guide the program definition and development path.

Staying sharp and flexible, the successful CRO's bring solid infrastructure; highly skilled personnel; advanced knowledge in synthesis, medicinal chemistry, and computational methods; excellent problem solving; and project management skills. In addition, the leading CRO's bring additional services in ADME/Tox, and in vitro and in vivo biological assays.

 

Please use the "contact us" link in the AsisChem web site to request a reprint of the full article.

 

W look forward to meeting you at the fall 2010 ACS National Meeting, in Boston - August 23-26

Dear Bryan,

This summer has been very busy for us with exciting new projects and lots of travel.  We been to Detroit, Cleveland, New Jersey and New York all in the past couple of weeks, but for your convenience we will be attending these conferences:

ACS meeting in Boston from August 22 to 26 and ChemOutsourcing conference in New Jersey, from September 14 to 16.

If you are available to meet with us during any of these occasions, you can contact Mel Bellott and we would be happy to set aside the time to discuss your Medicinal Chemistry and Custom Synthesis needs.

 

Staphylococcus aureus is a type of bacteria commonly found on the skin that is relatively harmless unless it gets into the bloodstream, where it can cause blood poisoning and create abscesses in organs such as the heart and brain.

MRSA, or Methicillin Resistant Staphylococcus aureus, can be particularly dangerous because it is resistant to treatment with most antibiotics. Read More

 

Higher concentrations of clusterin, a protein in the blood plasma, appears to be associated with the development, severity and progression of Alzheimer's disease, according to a report in the June issue of Archives of General Psychiatry, one of the JAMA/Archive journals.

Individuals with Alzheimer's disease display several findings in their blood ans cerebrospinal fluid that may reflect neuropathological changes.   Read More

 

For someone with a severe, incurable lung disorder such as cystic fibrosis or chronic obstructive pulmonary disease, a lung transplant may be the only chance for survival. Unfortunately, it's often not a very good chance. Matching donor lungs are rare, and many would -be recipients die waiting for the transplants that could save their lives. 

Specialists in the emerging field of tissue engineering have been hard at work on this for years. But they've been frustrated by the problem of coaxing undifferentiated stem cells to develop into the specific cell types that populate different locations in the lung.  Read More

 

The Chemistry of Fireworks

 

 

 

June 2010 Newsletter

Dear Bryan,

Last month Mel Bellott from AsisChem was invited to UCSF to give a seminar on Drug Discovery.  His presentation used case studies and examples to show how chemistry is involved from beginning-to-end.  The talk illustrated some of the important opportunities and pitfalls along the way to advancing a new drug candidate.   Due to the overwhelming positive response, we are giving a webinar on June 23 at 10:30 AM PST.  To find out more please visit our registration page.

 

Molecular Imaging Reveals Origin of Acid Reflux Disease

Molecular imaging has uncovered what may be to blame for acid reflux disease, a painful and potentially dangerous illness that affects a sizeable percentage of the population. A study presented at SNM's 57th Annual Meeting provides further evidence that the disease of the digestive system is brought on by a lack of tone, or motility, in the esophageal muscles that clear and keep stomach acids and other gastric contents from backing up into the esophagus.  Read More

 

Ancient Viral Invasion Shaped Human Genome

Scientists at the Genome Institute of Singapore, a biomedical research institute of the Agency for Science, Technology and Research, and colleagues have recently discovered that viruses that "invaded" the human genome millions of years ago have changed the way genes get turned on and off in human embryonic stem cells. The study provides definite proof of a theory that was first proposed in the 1950's by Nobel Laureate in physiology and medicine, Barbara McClintock, who hypothesized that transposable elements, mobile pieces of the genetic material, such as viral sequences, could be "control elements" that affect gene regulation once inserted in the genome.   Read More

 

Scientists Break Barrier to Creating Potential Therapeutic Molecules

Scientists from The Scripps Research Institute have created a novel technique that for the first time will allow the efficient production of a molecular structure that is common to a vast array of natural molecules. This advance provides a means to explore the potential of this molecular substructure in the search for new therapies.  Read More

 

The Safety Song

 

 

  ... AsisChem has developed a seminar  "Medicinal Chemistry and The Roles of Chemistry in Drug Discovery" to show you how to handle the chemistry in your early-stage drug program.


Chemistry is called "The Central Science"  This name was popularized by a late twentieth century chemistry textbook.  People call it the Central Science because understanding of atoms and molecules is built upon the laws of physics and mathematics.  Biology and life processes represent the next rung up the ladder.  The next higher order of conceptual aggregation is built on an understanding of molecules, their properties, and interactions.

In the discovery and development of small-molecule drugs, chemistry is an essential element, every step of the way.  From target validation - to filing an IND - there are tasks that involve chemistry, chemists, chemical synthesis, and chemical testing.

Last month we were invited to UCSF, along with our partner, Apredica, to give a seminar on Drug Discovery --

 

Our piece "Medicinal Chemistry and The Roles of Chemistry in Drug Discovery" used case studies and examples to show how  chemistry is involved from beginning-to-end.  The talk illustrated some of the important opportunities and pitfalls along the way to advancing a new drug candidate.

The final case study described the (published) development of a new non-nucleoside reverse transcriptase inhibitor ( NNRTI ) at Pfizer-UK.

The path wasn't always linear -- they had to take steps forward and back in order to arrive at the final drug candidate, which is now in clinical trials.  Their progress, in terms of IC50, LogP, and half life are shown in the graph.  The Japanese Proverb says: "Fall seven times, get up eight."  Attendees learned how the development team followed this up-and-down prescription, to meet its objectives:

•Improve Half-life
•Improve potency
•Maintain good side effect profile
•Maintain activity against viral mutation
•Create novel IP
•Easily accessible analogs

Due to the overwhelming positive response, we will make our presentation at other universities, and will also present a webinar in June,  for everybody who couldn't attend in person.

 

 

 _______________________________________________________________________

The Japanese proverb says "Fall seven times, get up, eight"

This is particularly true in the practice of drug discovery.  As I was preparing for this Friday's seminar, that we will give jointly with Apredica, at UCSF.  I had occasion to review an example of lead-optimization and nomination of a clinical candidate.  This series of three papers, that I choseto discuss as a case study, went from a discontinued clinical compound -to a novel NCE - to clinical candidate.

 ( see: series of papers by Mowbray, et al., Bioorganic & Medicinal Chemistry Letters, 2009 )

On paper, it sounded so easy...  If only they knew in advance, where they would end up.  From the starting point, to the candidate spanned hundreds of compounds, and many man-hours of synthetic and analytical effort.  

All this was done according to a plan that divided the molecule into three zones, for trial of various substituents.  [ Recall that Julius Caesar said that "All Gaul is divided into three parts" ]

LogP got worse, while half life in human liver microsomes got better.  Then the opposite occurred in the next wave.  then back again, as they "fell down" and "got up" many times, in a pitched battle of man vs nature.

In the end, they got it right.  Log P was superbly low.  Half life and predicted clearance were in a good range, and in vitro tox was clean.

 

( Please see our blog entry of January 26, 2010 on Lipinski's Rules, LogP and other Physicochemical properties that affect drug properties and activity. )

 

WE are particularly pleased to inaugurate our seminars at UCSF, the premier US institution of academic drug development.  As we noted in the March 9 Blog entry,  there is increasing interest in academic sources of drug discovery, as the models  for innovation, entrepreneurshipand the industry evolve  in the new decade.

 

 

Hear all about it this Friday, April 23, 2010, at 12:00 in 212 Byers Hall,  at the UCSF Mission Bay campus, San Francisco.

Medicinal Chemistry – The Roles of Chemistry in Drug Discovery(AsisChem- Emile Bellott)
and
Drug-like Properties -- Why early in vitro ADME is Important (Apredica - Bob Annand )

 

 

 

 

 

 

On the next day, we had an opportunity to visit with a colleague at the technology licensing office of a major research university.  I had previously worked with him, when my former companies licensed in  drug candidates for development.

 The timeline from discovery through proof of concept in man, is aptly named the ‘valley of death’, because this part of the program is the most risky element of drug development. In the prevailing view of drug discovery and development, the economic value of a program (pipeline asset) increases over time, as the program is ‘de-risked’. A favorable value proposition sets the stage for monetizing the asset, through licensing, partnering or sale. In the classic large company business model, this would not be a problem, as planned and measured resources are applied to meet specified milestones.

 In a tight capital environment and with industry focus on relatively de-risked programs, the ‘valley of death’ has become a problem for academic innovators. University technology transfer offices have emphasised proactive business development, to appeal to potential interested partners, for licensing and development. They expect to see additional animal data, market projections, and a solid IP position, with freedom to operate.

Major research universities and teaching hospitals have responded strategically, by creating ‘accelerator funds’. These funds award competitive translational grants to principal investigators, to help advance their programme towards its commercial potential. In a typical scenario, the technology office provides mentorship, expert advisors, program planning and other advice, as well as support in contracting and project management activities.

Reflecting the new realities of the competitive environment, selection of candidate programs follows priorities similar to those that an innovator drug company would employ. Projects must show a clear path to market and estimation of commercial potential, if successful.  Universities are attempting to utilise other non-dilutive sources of funds, such as targeted philanthropy and government small business grants, whenever possible in support of the acceleration effort.

 

 

 A View From The Top

 

It's always a pleasure to visit Manhattan. The city is awesome.

We had an opportunity to visit several prospective clients and to renew acquaintances with an existing academic client who is starting a new company and wants to work with us on their synthesis – which we pioneered with them. The basis of the company is a license from an academic institution.

Maybe it's fate or kharma, but the underlying theme of the visit was licensing, ventures, and venture capital.

On the 9^th, I attended VC Outlook-BIO, a reception and panel discussion in the offices of Goodwin Proctor LLP, in the 23^rd floor of the New York Times Building. This panel covered the latest situation briefing on capital and start-ups, with emphasis on the biotech / medical sectors.

As the Wall Street Journal expounded, that very morning, capital continues to be tight. The outlook for emerging companies is challenging, because the total raised by venture capitalists in the US was down substantially due to the realities of the financial markets.

 

 View Inside The Lobby of The New York Times Building

 

In 2009, total VC investments were $17.7Bn, down 31 percent from the year before. Life sciences were somewhat more fortunate – VC investment was down 11 percent year to year. Furthermore, in light of continuing shortfall of capital intake, the VC industry is preserving capital for existing portfolio companies and private equity investments. Early stage deals, while still happening are more difficult. The profile of investments and funds is also shifting towards higher growth locales such as asia.

For start-ups the picture is complicated by the fact that the emphasis is on relatively de-risked opportunities and programs that have a shorter path to market. VC's are more risk averse, today, and frequently invest in start-up companies that are based on programs in-licensed from large pharmas. In-licensed academic technologies may appear less attractive in some cases, because the academic institutions are placing a high expectation on royalty streams.

Large biotech and pharma firms, who are relatively cash-rich are concentrating on later stage programs where there is a proof-of concept. In the larger biotech and pharmaceutical firms, the goal is to externally source up to 50 percent of their discovery pipelines. This provides a ready exit strategy for cash-starved mid and late stage smaller enterprises, for whom the traditional IPO route is not viable in the present and near-term economic climate.

The last and most poignant question is the fate of start-ups. The old axiom that there's always money for a good idea is slim comfort, indeed. On the academic side, large companies are helping nascent programs get through the “valley of death” by increasing investment in academic programs and licensing opportunities.

The panelists emphasized that access to capital for startups will continue to be constrained for the forseeable future. They offered several important criteria for investment opportunities that they would find attractive:

1. A “disruptive” game changing technology or therapy

2. The quality of the team

3. A straightforward value proposition

4. A clearly delineated path to the market

5. First in class or best in class therapeutic

6. Lower technical and operational risk

7. Lean and efficient business model

 

 

 

March 2010 Newsletter

Greetings!

Conference season is fully underway and we at AsisChem are getting right into the mix.  Coming up this month we will be at the American Chemical Society in San Fransisco from March 21st through March 25th.  If anybody is interested in learning about our progress since the last ACS meeting we would love to meet with you.  You can contact Mel Bellott to discuss details. 

We Dig Chemsitry

WINSTON-SALEM, N.C. - Not getting enough sleep does more damage than just leaving you with puffy eyes. It can cause fat to accumulate around your organs - more dangerous, researchers say, than those pesky love handles and jiggly thighs.

A new study by researchers at Wake Forest University School of Medicine reveals how extremes of sleep - both too much and too little - can be hazardous to your health - especially for young minority women, a group most affected by obesity and chronic metabolic disease.  Read More

Doctors treat millions of children with Ritalin every year to improve their ability to focus on tasks, but scientists now report that Ritalin also directly enhances the speed of learning.
 
In animal research, the scientists showed for the first time that Ritalin boosts both of these cognitive abilities by increasing the activity of the neurotransmitter dopamine deep inside the brain. Read More

How You Think About You Age May Affect How You Age

WEST LAFAYETTE, Ind. - The saying "You're only as old as you feel" really seems to resonate with older adults, according to research from Purdue University.

"How old you are matters, but beyond that it's your interpretation that has far-reaching implications for the process of aging," said Markus H. Schafer, a doctoral student in sociology and gerontology who led the study. "So, if you feel old beyond your own chronological years you are probably going to experience a lot of the downsides that we associate with aging.  Read More

 

I know there are projects that need custom synthesis, medicinal chemistry or chemical consulting.  Why wait any longer submit an inquiry or use our Ask-A-Chemist service! 

Sincerely, 

Bryan Roland, Director - Project Management 
Bryan.Roland@asischem.com 

 

This is the most popular newsletter in our history.  I suppose it makes sense: who doesn't like chocolate or roses?  Hope valentine's day goes off without a hitch for everyone!

-----------------------------------------------------------------------

February 2010 Newsletter 

Greetings!

February is here and with it Valentine's Day.  Bad food, long waits and poor service.  But if you get past all of the force feed love there is a lot of chemistry.  The video touches on some interesting chemistry with chocolate and roses. Enjoy.

Chemistry of Chocolate and Roses

New "Suicide" Molecule Halts Rheumatoid Arthritis

CHICAGO --- A researcher from Northwestern University Feinberg School of Medicine has invented a novel way to halt and even reverse rheumatoid arthritis. He developed an imitation of a suicide molecule that floats undetected into overactive immune cells responsible for the disease.

Whimsically referred to as Casper the Ghost, the stealthy molecule causes the immune cells to self-destruct. Read More 

Tobacco Plant-Based Treatment Thwarts West Nile Virus

A new therapeutic made from tobacco plants has been shown to arrest West Nile virus infection, according to a new study by Arizona State University scientist Qiang Chen and his colleagues.

Chen, a researcher at Arizona State University's Biodesign Institute and professor in the College of Technology and Innovation, on the Polytechnic campus, is the first to demonstrate a plant-derived treatment to successfully combat West Nile virus after exposure and infection. The research appears in this week's issue of the Proceedings of the National Academy of Sciences (advanced online edition). Read More 

 

I know there are projects that need custom synthesis, medicinal chemistry or chemical consulting.  Why wait any longer submit an inquiry or use our Ask-A-Chemist service! 

Sincerely, 

Bryan Roland, Director - Project Management 
Bryan.Roland@asischem.com