BioScience Biz

Drug Industry Needs "Open Innovation" Says J&J's Stoffels

The Health Blog just reported on a conversation with J&J's head of drug R&D, Paul Stoffels, on what the drug industry needs to do to survive in a difficult economic and regulatory environment.  Here is what he said as reported by HB.

Drugmakers’ struggle for survival boils down to finding new medicines to replace the old. The key, Stoffels told the Health Blog, is “open innovation,” or looking outside of companies for innovation and then collaborating with biotechs or academics on promising compounds.

 

“All simple diseases have been solved,” Stoffels said. “The next-generation drugs, therapies, are much more complex… You need much more information and science than what you can get out of your own internal labs.”

Stoffels said he learned the value of external partners “the hard way and also the good way.” When his first HIV drugs — developed in-house — were tested in patients, they didn’t work. He realized he didn’t know enough about the clinical complexity of HIV.

He sought the help of hospitals and other institutions working with patients. A 10-year collaboration led to two J&J HIV medicines — Prezista and Intelence — now on the market.

Others in the industry also have acknowledged that external partnerships will be important for developing innovative drugs moving forward. Critics say the drug industry has no choice but to look to biotechs or academic for help, given companies’ weak internal pipelines and stagnant R&D spending.

The future of the drug industry, Stoffels told the Health Blog, is “building networks where together with a number of different groups you come up with solutions to solve different medical needs.”

PRESS RELEASE: First human embryonic stem cell therapy trial approved by FDA

California's Menlo Park-based Geron Corporation announced today that the U.S. Food and Drug Administration (FDA) granted clearance of the company's Investigational New Drug (IND) application for the clinical trial of the world's first human embryonic stem cell (hESC)-based therapy in patients with acute spinal cord injury.

Geron plans to initiate a multi-center Phase I clinical trial that is designed to evaluate the safety of the therapy in patients with spinal cord injuries.

"The FDA's clearance of our...IND is one of Geron's most significant accomplishments to date," said Thomas Okarma, Ph.D., M.D., Geron's president and CEO. "This marks the beginning of what is potentially a new chapter in medical therapeutics - one that reaches beyond pills to a new level of healing: the restoration of organ and tissue function achieved by the injection of healthy replacement cells. The ultimate goal for the use of (the stem cell therapy) is to achieve restoration of spinal cord function by the injection of hESC-derived oligodendrocyte progenitor cells directly into the lesion site of the patient's injured spinal cord."

"The neurosurgical community is very excited by this new approach to treating devastating spinal cord injury," said Richard Fessler, M.D., Ph.D., professor of neurological surgery at the Feinberg School of Medicine at Northwestern University. "Demyelination is central to the pathology of the injury, and its reversal by means of injecting oligodendrocyte progenitor cells would be revolutionary for the field. If safe and effective, the therapy would provide a viable treatment option for thousands of patients who suffer severe spinal cord injuries each year."

The Stem Cell Clinical Program

Patients eligible for the Phase I trial must have documented evidence of functionally complete spinal cord injury with a neurological level of T3 to T10 spinal segments and agree to have the cells injected into the lesion sites between seven and 14 days after injury. Geron has selected up to seven U.S. medical centers as candidates to participate in this study and in planned protocol extensions. The sites will be identified as they come online and are ready to enroll subjects into the study.

Although the primary endpoint of the trial is safety, the protocol includes secondary endpoints to assess efficacy, such as improved neuromuscular control or sensation in the trunk or lower extremities. Once safety in this patient population has been established and the FDA reviews clinical data in conjunction with additional data from ongoing animal studies, Geron plans to seek FDA approval to extend the study to enable access to the therapy for as broad a population of severe spinal cord-injured patients as is medically appropriate.

Preclinical Evidence of Safety, Tolerability and Efficacy

Geron submitted evidence of the safety, tolerability and efficacy of its hESC therapy, GRNOPC1, to the FDA in a 21,000-page IND application that described 24 separate animal studies requiring the production of more than five billion GRNOPC1 cells. Included in the safety package were studies that showed no evidence of teratoma formation 12 months after injection of clinical grade GRNOPC1 into the injured spinal cord of rats and mice. Other studies documented the absence of significant migration of the injected cells outside the spinal cord, allodynia induction (increased neuropathic pain due to the injected cells), systemic toxicity or increased mortality in animals receiving GRNOPC1.

In vitro studies have shown that the GRNOPC1 hESC therapy is minimally recognized by the human immune system, which allows a low-dose of immunosuppression drugs.

Also included in the IND application were published studies in animals that showed that administration of the GRNOPC1 hESCs significantly improved movement of animals with spinal cord injuries when injected seven days after the injury (Journal of Neuroscience, Vol. 25, 2005). Histological examination of the injured spinal cords treated with GRNOPC1 showed improved axon survival and extensive remyelination surrounding the rat axons. These effects of GRNOPC1 were present nine months after a single injection of cells. In these nine-month studies, the stem cells were shown to migrate and fill the lesion cavity, with bundles of myelinated axons crossing the injury site.

Production and Qualification of GRNOPC1 hESCs

GRNOPC1 cells are produced using current Good Manufacturing Practices (cGMP) in Geron's manufacturing facilities. Geron's cell production process and clean-room suites have been inspected and licensed by the state of California. The cells are derived from the H1 human embryonic stem cell line, which was created before August 9, 2001 and is on the list of former President Bush's approved human enbryonic stem cells. Studies using this line qualify for U.S. federal research funding, although no federal funding was received for the development of Geron's therapeutic product or to support the upcoming clinical trial.

Induced pluripotent stem cells steal the limelight from embryonic stem cells, by Steven S. Clark

Recent stem cell headlines are all about how adult cells can be reprogrammed into induced pluripotent stem cells (iPS), which was recently hailed as the biggest scientific breakthrough of 2008.  All of this attention to iPS cells and hardly a word about embryonic stem cells (ESCs)—have ESCs lost their luster since scientists figured out how to reprogram adult cells back to the primordial stem cell state?

In reality, iPS cells have been around longer than ES cells.  In cloning the sheep Dolly in 1996, Scottish scientist Ian Wilmut took a single adult cell and injected its nucleus into a sheep egg from which the nucleus had been removed.  The cellular environment of the egg reprogrammed the nucleus of the adult cell so that it was able to give rise to Dolly. 

Last year, the laboratories Jamie Thomson at the University of Wisconsin-Madison and of Shinya Yamanaka, from Kyoto University, reported that this reprogramming could be done by simply expressing only three or four genes in an adult cell.  More recently reprogramming has been used by Harvard professor, Kevin Eggan, to derive iPS cells from patients with ALS (Lou Gehrig’s disease) and by UW-Madison professor, Clive Svendson, to derive iPS cells from patients with another neurodegenerative disease, spinal muscular atrophy (SMA).  Both iPS cell lines were then used to grow the defective neurons in the lab giving the scientists their first access to the very cells that caused the respective neurodegenerative diseases.  This creates a powerful research tool that will enable researchers to study the disease process and find ways to halt it. 

“Clinical trials” using iPS cells

The benefits of iPS cells don’t stop there.  Madison, Wisconsin-based Cellular Dynamics International (CDI) recently produced one of the world’s first commercial stem cell products, ESC-derived cardiomyocytes.  These are functional heart cells that CDI produces and sells to pharma companies for drug and toxicity testing.  But CDI also has a robust research effort to efficiently produce iPS cells, possibly without having to introduce exogenous genes into the adult cells.

“We have a large scale research activity to create a vector-free methodology for no integrated DNA (in the iPS cells),” said Chris Kendrick-Parker, Chief Commercial Officer at CDI.  The company is now filing patents and Kendrick-Parker was not at liberty to say if CDI has developed a DNA-free method for inducing iPS cells.  However, he did say that the company is “looking at all options.”

Kendrick-Parker believes that CDI will soon switch exclusively to using iPS cells to develop heart and other cell types for sale to pharma and researchers.  The advantage of iPS cells he said is that they can be used to produce adult tissues from people representing different ages, ethnic types and sexes as a way to model the human heterogeneity in tissue culture.  This way, “drug companies can actually recapitulate (in tissue culture) what happens in clinical trials,” Kendrick-Parker said.   

For this to happen, Kendrick-Parker says that CDI and other companies will use iPS technology to make a library of iPS cells from a wide range of people in order to reflect the genetic heterogeneity of the population.

Most investigational or even post-market drugs fail due to liver or cardiotoxicity in a subset of people, which is “why pharma is so interested in these (iPS-derived) models,” said Kendrick-Parker.  The cells should allow drug makers to identify organ-specific toxicities before clinical trials begin, thereby saving much time and money bringing a new drug to market, only to have it fail.  For example, having iPS-derived cardiomyocytes from a large patient population might have identified, early on, the cardiotoxicity of Vioxx, saving Merck & Company a great deal of money getting the drug to market and in subsequent litigation fees.

iPS cells in the clinic?

But what about using iPS cells to directly treat disease?  After all, they have been widely touted as the great ethical hope for stem cell therapy since they don’t involve destroying human embryos. 

Currently, iPS cells are made by expressing a few genes in an adult cell, which turns back the cells' developmental clock to an embryonic-like state from which they can become any of the body's 220 different cell types. Yet, the genes used to reprogram adult cells are, themselves, associated with cancer, so iPS cells made this way will not be used clinically.

However, last November, Thomson opined that in about six months, it will be possible to make iPS cells without having to resort to oncogenic gene expression.  While this will eliminate the immediate problem to using the cells clinically, they still face significant hurdles before being used to treat specific diseases.  In fact, Thomson also suggested that there may be problems with iPS cells, saying that there are “dark clouds on the horizon”.

Eric Forsberg, Director of the WiCell Research Institute, explained that reprogramming of adult cells is extremely inefficient, meaning that for some reason, it is only the rare adult cell that can be successfully re-programmed.  This suggests that other unknown factors affect the ability of each cells’ genome to be reset to an embryonic state. 

Researchers also know that reprogramming is incomplete.  The genome clock is not completely reset and this Incomplete reprogramming likely plays a role in the health problems that cloned animals have—Dolly had arthritis and was euthanized due to progressive lung disease.  This raises the possibility that tissues developed from reprogrammed iPS cells might not function normally.

Forsberg pointed out that the extent to which a person’s genome is reset can vary from person to person and this could mean that each person will require an individualized reprogramming regimen in order to create iPS cells for therapeutic use.  But, it is unlikely that the FDA would approve such an individualized protocol—they like uniformity and conformity in therapeutic protocols, not different protocols for different people

Thus, while iPS cells provide enormous potential for learning how human disease develops and progresses and for cost-effective development of new and safer drugs, they are still a long ways from the clinic.  In fact, ESCs will likely find clinical use before iPS cells do.

Embryonic stem cells after a decade of hope…or was it hype? By Steven S. Clark

As we reach the ten year anniversary of UW-Madison Professor, Jamie Thomson’s, discovery of how to grow human embryonic stem cells (ESCs), one wonders whether this has been worth the controversy that ensued over the destruction of human embryos in order to obtain the stem cells.  After all, no therapies have come from the discovery, so were opponents correct that this research was not only unethical, but also irrelevant?

While there have been no headline-grabbing ESC-based therapies, the technology is surely changing the way that medicine will be done.  This was illustrated by recent events in Madison, including the World Stem Cell Summit held last September and a more recent celebration of the ten-year anniversary of Thomson’s discovery, put on by the Wisconsin Academy of Arts and Sciences.  The Anniversary event featured keynote talks by Thomson and Michael West, CEO of BioTime, Inc., and founder of Geron, a West Coast stem cell company.

Thomson sounded his usual cautionary note, saying that it will be very difficult to use ESCs to directly treat disease.  But, he also said that even if they never make it into the clinic; ESCs will profoundly affect the future of medicine.  ESCs give us laboratory access to human tissues that we had not been able to get at before.  This lets scientists see what goes wrong with the specific cell types that cause Parkinson’s and cardiovascular diseases, diabetes and other maladies.  This, Thomson said, will lead to the development of new drugs and therapies to treat and prevent such diseases.  

Thomson also explained that the different cell types that can be derived from ESCs enables researchers to directly test new drugs on different human tissues.  He suggested that this will both dramatically reduce the number of animals used in drug and toxicity testing and allow more precise assessment of new drug efficacy and toxicity.  

This was put into perspective at the Stem Cell Summit, by John McNeish, head of Pfizer’s Regenerative Medicine efforts. He said that 10-16% of all new drugs fail during Phase I clinical trials alone due to cardiotoxicity.  Many more drugs fail due to liver, kidney and other organ-specific toxicities.  Overall, about 92% of new drugs that enter clinical trials fail due to lack of efficacy or to toxicity, according to the FDA’s web site. This means that potential drug toxicity is inefficiently measured in current animal models, making drug makers gamble early on that their new drugs won’t show organ-specific toxicity—a gamble that they lose nine times out of ten.  ESC technology, therefore, promises to provide tissues on which to test and eliminate potentially toxic drugs much earlier in the development pipeline, potentially saving billions in drug development costs, according to the FDA.  

ESC-derived research tools are entering the marketplace

Thomson and others from the UW-Madison, recently founded Cellular Dynamics International, or CDI, to grow different tissues from ESCs.  According to Tim Kamp, a UW-Madison cardiologist and CDI co-founder, the company now sells heart cells to Roche and Covance for drug testing purposes.  CDI grows the heart cells in-house and then sells them as research tools. Thus, they retain control of the ESCs and the developmental process, while providing a renewable stream of cellular tools that researchers can purchase.  At this time, CDI only markets heart cells, said Kamp.  But, according to Chris Kendrick-Parker, CDI Chief Commercial Officer, the company has agreements with, or is talking to the “all of the top 20 pharma companies” to provide cells for toxicity testing.

Besides CDI, the Menlo Park biotech company, Geron Corp., and San Francisco’s Vistagen Therapeutics also use ESCs to produce cells from the heart, pancreas, liver and other organs for similar purposes.  The European company, Cellartis provides AstraZeneca with ESC-derived liver cells for toxicity testing, but only at very low numbers that are not useful for high-throughput-screening of new drugs.  Cellartis also provides Pfizer with embryonic cells to test for birth defects.  Clearly, ESCs as drug testing and research tools is a growing international market, which Pfizer stem cell expert, John Hambor, said at the Stem Cell Summit, currently stands at $1.5 billion and is predicted to grow 20% annually in the foreseeable future.

Clinical trials on the horizon?

Michael West is more optimistic than Thomson that ESC-based therapies will soon happen.  He cited the very high interest in the technology shown by several biotech and pharmaceutical companies as the driving force that soon will propel ESCs into the clinic.  

Some biotechs already are pushing hard to begin clinical trials of ESC-based therapies. For instance, last Spring, Geron submitted an Investigational New Drug application (IND) to the FDA for permission to undertake the first ESC clinical trial to treat spinal cord injuries.  According to a company press release, the trial had been in the works for four years, but the FDA issued a Clinical Hold because they have not yet established ensure safety and efficacy guidelines for ESC-based therapies.  According to an article last May in the science journal, Nature, there also is speculation that President Bush’s objection to ESC research helped force the FDA to put the trial on hold.

Geron also is planning ESC clinical trials for heart disease, while Advanced Cell Technology in Los Angeles has indicated that it is close to submitting an IND to use ESCs to treat macular degeneration.  San Diego’s Novocell, with funding from Johnson & Johnson, is preparing for ESC clinical trials to treat diabetes.

So, ten years after Thomson’s discovery, ESCs are just now entering the market as research tools for drug and toxicity testing and clinical trials loom on the horizon.  At this point, the holdup is so the FDA can figure out how to monitor the trials.  Furthermore, with the Obama administration, political constraints on the FDA to approve ESC-based trials will likely be removed next year.