From bench to bedside
How to overcome the valley of death
By Michael Seringer
The fact that 90% of compounds in clinical trials fail to receive Food and Drug Administration approval doesn’t fully account for the magnitude of the drug discovery challenge. Getting a new drug to the patient is exceedingly hard. Investigators must obtain FDA approval of an investigational new drug (IND) application before a lab even gets the opportunity to attempt human trials. Researchers too often underestimate the complexity of the preclinical IND-enabling studies, dooming their intellectual property and making it another victim to the preclinical “valley of death,” where promising research dies.
Innovative science is not enough to advance patient care. This preclinical challenge must be successfully overcome, yet few scientists have the expertise to do this. Creating a team dedicated to help biomedical scientists successfully traverse the valley of death is essential for bringing a significant discovery to the clinic.
Creative medicinal chemistry
The first test for any drug therapy occurs during the medicinal chemistry stage and determines if the compound is novel, effective and specific for the target. Many scientists find compounds that can attack their targets, but these are often already-known chemicals. The lack of composition of matter patent claims will prevent most sponsors from capitalizing further preclinical work.
Thus, the first step in overcoming the valley of death is to hire medicinal chemistry expertise that can take the known compound and modify it into something novel. Then, in collaboration with the scientist, the medicinal chemist will modify the novel compound to make it more specific and potent for the original target.
The great promise of the investment the nation has made in biomedical research can only be realized when universities recognize that a great discovery is not enough; it needs help reaching patients.
Once this medicinal chemical work generates these critical compound characteristics, the challenge of producing the drug in large quantities using good manufacturing process (GMP) begins. GMP can present challenges in the chemistry, manufacturing and controls (CMC) of therapies, according to Robert Hromas, MD, FACP, dean of the Joe R. and Teresa Lozano Long School of Medicine and vice president for medical affairs at The University of Texas Health Science Center at San Antonio. Hromas believes CMC is both a potential challenge and an opportunity to create additional intellectual property. He suggests an example of this is the development of DT2216, a first-in-class cancer-fighting molecule currently in Phase 1 clinical trials at the Mays Cancer Center at UT Health San Antonio.
“DT2216 was approximately a 30-step synthesis,” Hromas said. “It took a year and more than $1 million to get that down to fewer steps and to go from three purification steps to one. During this time, we discovered our compound was not soluble in water, and so we formulated it in a lipid nanoparticle that permitted it to be given intravenously to patients.”
This innovative approach to addressing the challenge in formulating the cancer drug resulted in new intellectual property. Hromas believes the manner of delivery will continue to yield new intellectual property as labs apply increasingly complex and novel solutions to large and poorly soluble compounds.
The already-complicated manufacturing process is made more difficult by the need to produce drugs in bulk for animal trials. Scaling up manufacturing may present additional obstacles for investigators by requiring innovative processes that take time and increase costs. However, this also creates novel intellectual property that can extend the patent protection for the compound.
Thus, universities can hire formulation expertise as well as medicinal chemists to help cross the valley of death. These new faculty must be evaluated differently than other research faculty. Their goal is not to obtain extramural research grants but to generate novel compounds and new formulations.
Preventing problems in patients
Once the compound has successfully made it through the GMP synthesis and formulation stage, it is halfway to the investigational new drug goal of a successful FDA IND application. The next phase critical to overcoming the preclinical valley of death is planning, developing and managing successful animal trials. Investigators should spend time thoughtfully designing animal trials and defining key endpoints before they invest in good laboratory practice (GLP) studies. Given the significant cost of GLP studies, investigators must determine the levels of the drug in the bloodstream over time, called pharmacokinetics, and then also at the disease target, termed pharmacodynamics. Once both the pharmacokinetics and pharmacodynamics half-life values are defined, investigators must assess absorption, metabolism and excretion of the drug.
At this point, non-GLP research conditions can be used on mouse models at a fraction of the cost. Because many compounds end up failing the pharmacokinetics and pharmacodynamics stages of development, it is better to discover problems before engaging a high-priced GLP toxicity study. Universities seeking to overcome the valley of death can sponsor these inexpensive non-GLP animal studies to help select the best novel compound and the most successful formulation. Such data indicating low off-target toxicity and excellent pharmacokinetics and pharmacodynamics help recruit investors to sponsor the GMP synthesis and the GLP animal toxicity studies.
“There are lots of cancer drugs that fail because of a toxic metabolite that destroys a normal organ,” Hromas said. “Before you go into costly GLP mammalian studies, you need to understand the absorption, metabolism and excretion as well as the pharmacokinetics and pharmacodynamics of the compound being investigated.”
GLP toxicity studies required by the FDA are very expensive. The required two mammalian species of models used to determine animal pharmacology and toxicity can cost millions of dollars before a drug candidate is approved to be tested on humans.
Determining the maximally tolerated dose in different animal models can prove problematic. Sometimes one animal species is more sensitive to the compound than another.
“DT2216 lowered dog platelets more than human or rat platelets,” Hromas said. “We showed the FDA that dog platelets express much higher levels of several proteins that are important for DT2216 action than rat and human platelets, suggesting that human platelets should be more like rat platelets and less sensitive to DT2216 than dog platelets. This critical finding was very important to win the FDA approval of our IND application.”
Strategies such as coordinating non-GLP mouse studies before the stringent FDA GLP testing, along with a focus on innovating the manufacturing and formulating the therapy, are also critically important. To make the transition through animal studies into human trials, investigators must follow a parallel business-oriented path. Partnerships, funding and business strategy are all required to get the compound to human trials.
The business of discovery
It is well known that shepherding a drug to human trials is expensive and complex. A GLP toxicity study can easily cost a few million dollars to obtain FDA approval of an IND. Once an IND is obtained, it is far easier to attract financial support for further studies because the drug has been significantly de-risked. Investigational researchers have three main models of funding available to support the preclinical studies of their intellectual property for an FDA investigational new drug.
The first model is a traditional licensing of the compound from a university by an established pharmaceutical or biotech company. This alleviates much of the risk for the research investigator and university. This model has become rare, as larger pharmaceutical corporations prefer to buy small biotech companies that have completed both Phase 1 safety and Phase 2 efficacy trials in humans. While this can ensure the drug has a future in clinical care, and there is much less risk of failure, the purchase price is usually quite high.
The second model relies on venture capital and private equity investors who will fund a company that the original investigator or the university has started. This ensures the financing of the compound usually through human Phase 2 effectiveness trials, where the larger pharmaceutical corporations might become interested.
Like the traditional licensing model, venture capital and private equity come at a cost. Often, the goals of such entities and medicine don’t align, as venture capital or private equity are focused more on a profitable exit from the deal than creating a successful therapy. Investigators will lose control of their company as the founders’ goals take a back seat to the goals of the investment firms financing the discovery.
“If you can keep control of the company yourself, you can make the best decisions on what will help people,” Hromas said. “Venture capital is not beholden to medicine, science, patients or you. They are only beholden to their investors.”
The third model retains both control and ownership for founders but is inherently more difficult and riskier. By bootstrapping their own small company and relying on grants, friends, family and small investors, investigators can retain ownership and control.
“The third model is what has been successful here. The scientist brute-forces the company to an FDA IND,” Hromas said. “The university spins off the intellectual property to the scientist’s own company. The scientist then relies on friends, family and local small investors to build a team, allowing them to maintain control and ownership of the company as they work toward an FDA IND.”
While the brute-force bootstrapping of intellectual property is a more difficult path, that path is more frequently in the best interest of the compound, the patient and the investigator, Hromas said.
The essential role of collaboration
Developing and maintaining good relationships with key partners is another important job for the investigator-turned-entrepreneur. From choosing a non-GLP lab to working with a company on effective formulation and drug delivery, the new biotechnology entrepreneur has important choices to make in developing partnerships. Investigators need to develop strong networking skills as they reach out to teams that have a proven compound for insights into crucial partner relationships.
Creating a team dedicated to help biomedical scientists successfully traverse the valley of death is essential for bringing a significant discovery to the clinic.
One advantage San Antonio investigators have is the long history of nonprofit biomedical technology development based in the area. The University of Texas at San Antonio — UT Health San Antonio’s sister institution — Southwest Research Institute and Texas Biomedical Research Institute all have proven records of drug development.
UTSA and Southwest Research Institute both have strong medicinal chemistry and Southwest Research Institute has a long history of GMP chemical synthesis and formulation. Texas Biomed has long been a leading GLP testing facility. This history, combined with biomedical science at UT Health San Antonio and UTSA, has created a vibrant community of investigational researchers and fueled the rapid growth of all these research institutions.
“We have all the pieces in San Antonio to put together great drug development,” Hromas said. “UT Health San Antonio and UTSA can define novel targets for intervention in human disease, UTSA and Southwest Research Institute can do the chemistry, Southwest Research Institute the GMP synthesis in bulk and formulation, the animal testing can be done at Texas Biomed, and we can do the clinical trials right here at UT Health San Antonio.”
Improving the percentage of drugs that make it to human trials will require research institutions to better navigate the valley of death. Too many compounds fail to earn an FDA investigational new drug approval because investigators are unprepared for the difficulties in formulation or manufacturing in bulk — or they pick the wrong business partner. Likewise, good therapies with great potential are too often lost to missteps in funding, licensing, testing or poor business decisions.
The great promise of the investment the nation has made in biomedical research can only be realized when universities recognize that a great discovery is not enough; it needs help reaching patients, and there are concrete steps any university can make to help a discovery reach its potential.