BMS 2011: Victory from the jaws of defeat

PLAVIX® is soon to go the way of LIPITOR® i.e., a multibillion drug with an expired patent. The loss of exclusivity on the 7 billion dollar anticoagulant is expected to result in a 13% loss in sales revenue for Bristol-Myers Squibb in 2012. Despite the impending revenue bust, Forbes named BMS the “Best Big Drug Company in 2011.”  Pfizer, Abbott and Lilly all enjoyed a very respectable + 15%  increase in stock price in 2011 but BMS achieved an almost incredible +32%.  As usual, innovation made the difference. Two BMS new drugs, YERVOY® and ELIQUIS® are expected to be leaders in their respective classes.

YERVOY(iplimumab injection), has been shown to extend the life of metastic melanoma patients an average of 10  months. It is the first oncology drug to achieve that goal. Iplimumab is a monoclonal antibody which binds CTLA4, a protein that inhibits T-cell activity. Enahnced T-cell activity can increase immune response to certain tumors.

ELIQUIS (apixaban) was shown to be more efficacious than warfarin in reducing the risk of death in patients with atrial fibrillation.Warfarin is the gold standard for this indication. Apixaban is a direct factor Xa Inhibitor. Factor Xa acts by cleaving prothrombin into thrombin, a major step in the coagulation cascade. Oral administration, predictable, outcomes and a reduced need for patient monitoring are some noteworthy advantages of ELIQUIS.

YERVOY was submitted for regulatory approval in May 2011. An NDA for ELIQUIS, already approved in the EU, was submitted to FDA in November 2011 and granted a  priority review status.

It seems the market is responding not only to the novelty of these products in their respective therapeutic areas but to the BMS business strategy. YERVOY was  obtained with the $2.4 billion acquisition of Medarex in 2009. ELIQUIS was developed and commercialized in collaboration with Pfizer, a global leader in the cardiovascular therapeutic field. Innovation in both science and business  is a combination that’s hard to beat.

Key Article http://www.forbes.com/sites/matthewherper/2011/12/26/the-best-big-drug-company-of-2011/

A notable year for personalized medicine

Personalized medicine has long been considered the probable next step in the evolution of pharmaceutical development. Knowledge of the  human genome can and has been used to optimize the treatment of disease and to provide specific cures for specific patients. The coupling of pharmaceuticals with corresponding diagnostics makes sense from a treatment standpoint and also provides a business opportunity. One Pharma highlight of 2011 was that two significant personalized medicine products were approved. XALKORI® (crizotimib) was approved for use in ALK (anaplastic lymphoma positive kinase) and ZELBORAF® (vemurafenib),  for melanoma . Both drugs  were developed for diseases attributable to readily detectable genetic mutations.  Both drugs were approved with corresponding diagnostic kits

XALKORI, supplied by Pfizer, is a kinase inhibitor. In approximately 5% of NSCLSC patients, chromosomal rearrangement leads to formation of the EML-ALK fusion gene. The increased kinase activity results in carcinogenesis. XALKORI has demonstrated excellent remission rates in clinical studies of patients with positive ALK. The Vysis ALK Break Apart FISH Probe Kit  is used to identify suitable candidates for XALKORI treatment by detecting the mutation in tumor cells.

ZELBORAF  is a BRAF Kinase Inhibitor. A mutation of the BRAF gene can be found in over 50% of  patients with melanoma. ZELBORAF was co-developed by Roche and Plexxikon. It too is accompanied by a diagnostic kit; the cobas 400 BRAF V600 Mutation Test. ZELBORAF has been demonstrated to be a useful ameliorative treatment for late stage melanoma patients.

Both approvals are encouraging and significant advances in personal medicine. Although not without its critics, mostly for issues of patient privacy, personalized medicine holds the promise of improved health care in the future – and this year could be a noteworthy first step  in that direction.

Recoverable magnetized microspheres to remove toxins

Interesting concept  - but probably many practical issues- antibody coated magnetized nanoparticles that can be recovered after binding with toxin in blood stream
.=fhttp://www.technologyreview.com/biomedicine/39181/?mod=chfeatured&a=f

Ready to Drug the Undruggable ?

Who would disagree that one of the key challenges of pharmaceutical scientists today is developing bioavailable oral dosage forms for poorly soluble compounds?  Over the years, various approaches have led to a number of  success stories in this area. These successes came in part due to the establishment of new scientific collaborations, new tools and enhanced knowledge.

In vitro tissue culture testing  became a somewhat useful tool for screening bioavailability of new molecules. Peyer's patches, tight junctions and absorption enhancers became widely used targets and mechanisms for enhancing oral absorption.   Practical nanoparticle  and amorphous formulation systems were  developed . A fruitful collaboration among formulation scientists,  biologists and chemists was nurtured . The anatomy and physiology of the gastrointestinal tract was incorporated into the knowledge base of the various scientific disciplines involved in drug research and development and an agreed upon classification system for drug molecules that ranks drugs according to their probability of  having poor bioavailability (BCS) was established. It appears though, that another challenge for pharmaceutical scientists has been steadily progressing over the past several years; development of drugs and delivery systems for undruggable targets.

The term “undruggable” means different things to different researchers but when used in the context of drug discovery it mostly refers to drug targets that range form not easily to impossibly difficult to access by conventional therapeutic agents. There may be no enzyme to inhibit, no surface receptor that exists or is suitably specific, no really efficient way of treating the disease except by inhibiting the synthesis of the target protein within the cell. The figures usually quoted are that approximately 70 -80% of  potential drug targets are undruggable. The implications are clear; there is a vast  untapped “gold mine” for treatment of disease. If this hurdle is eliminated, the impact on pharmacotherapeutics could be huge. Cancer is  an area for which reaching undruggable targets may be the most rewarding. One example is TGF-β which is a growth factor over expressed in certain tumor cells. Over expression of TGF in tumors leads to immnunosuppression and effectively allows the tumor to become more invasive as well as less likely to be eliminated by the immune system. Inhibiting its synthesis, specifically in tumor cells, would decrease their lethality. Many other examples exist.

There are  variety of methodologies use to reach undruggable targets. Lipid systems (nanoparticles, liposomes), polymeric systems, lipidated peptides , and stapled peptides (AILERON Therapeutics) are among them. The field is in it early stages if one considers the usual timeframe needed for drug development. It seems, very likely that undruggable target research will continue and grow. The goal of reaching three to four times the therapeutic targets we can reach today is an almost irresistible one for those in serious pursuit of treating disease.



In light of the new challenge of “drugging the undruggable”, the present paradigm for pharmaceutical scientists must change throughout R&D , not just for the molecular biologist. Knowledge of intracellular trafficking mechanims should be given high priority by all disciplines. The challenges  of cellular uptake and targeting must be understood and a multidisciplinary approach must be taken to solve the various issues. The barrier of endosomal release, for instance, could be examined by scientists who have achieved success in increasing bioavailability of poorly absorbed compounds. Molecular biologists, drug delivery experts and formulators must seriously join forces. Bioavailability itself, must not be limited to comparitive blood levels  but to the amount and time course for a  drug to be taken up by the cells and reache its intracellular target.

As with oral absorption enhancement, collaborative scientific efforts, development of new tools in research and development and expansion of the relative knowledge base to all involved disciplines will be critical. The challenges are formidable, the re-think process a challenge itself, but the rewards promise to be great for patients and researchers alike.

Drawings compiled from::

http://bio-and-chem.blogspot.com/2009/07/what-is-digestive-system-digestive.html
http://www.dna-sequencing-service.com/

RA – bad indication for Merck this week

Rheumatoid arthritis was a bad indication for Merck this week. The pharma giant agreed to pay $950 million to offset allegations  of off  label promotion of VIOXX® for RA . The huge settlement, one of the largest for a pharmaceutical company, will be used to settle civil lawsuits and  pay a criminal fine (violation of the FDC Act). If you have been following along, VIOXX Sales reps were more or less caught red-handed as their notes revealed plans to discuss RA treatment with physicians.

More bad news related to RA came to Merck this week as AMGEN’s pending etanercept patent (licensed from ROCHE) was approved.  This put a damper on Merck’s deal to license Hanwha Chemical’s etanercept with the hopes of scoring big in the biosimilar market. This obviously doesn’t bode  well for Merck  but may also be an unfortunate precedent for any company interested in developing biosimilars. It sounds like more legal battles ahead but perhaps they will be worth it. ENBREL© (AMGEN’s etanercept ) has consistently been a multibillion dollar drug and one of the  best selling biotherapeutics on the market.

Pharma R&D Costs Increase-Fewer Drugs in Late Stage Development

In 2011, fewer drugs reached the later stages of development than in 2010. In addition, there were more late stage failures. These were the key findings of a recently issued report by Deloitte LLP. In the twelve Big Pharma companies which were evaluated, late phase projects decreased from 270 to 220 in 2011. It was suggested that greater discretion  regarding development project selection was responsible for the decline , however,  there was also a notable increase in late stage failures.  Merck, Sanofi and Glaxo were among the companies that discontinued programs late in development. It would be reasonable to expect that greater discretion in selecting  Phase III programs would lead to fewer failures but apparently this wasn't the case, at least in the short term. It will be interesting to observe if the “brain power” drain Big Pharma is going through will have long term effects on success rate of development programs

http://www.bloomberg.com/news/2011-11-21/drugmakers-returns-on-research-fall-as-pipeline-projects-fail.html