© AVARAND/SHUTTERSTOCKThis past August, the US Food and Drug Administration (FDA) approved an intravenous antibiotic called oritavancin (Orbactiv) to treat skin infections, some 20 years after the pharmaceutical company Eli Lilly began developing it. The drug candidate had completed Phase 1 and was in Phase 2 and 3 clinical trials when, in 2001, the company discontinued its antibiotic program and sold oritavancin to the biotech InterMune for a base payment of $50 million, with an additional $15 million paid out in 2003. InterMune conducted more Phase 1 trials to clarify details of the drug’s safety and dosing. They also worked with Eli Lilly to complete a second major Phase 3 trial that the pharma giant had begun. But then, citing a desire to focus more narrowly on liver and lung drugs, InterMune sold the drug to

Targanta Therapeutics in 2005. By 2007, the company had paid InterMune $4...

Targanta was the first company to submit a new drug application (NDA) for oritavancin. After completing additional Phase 1 and Phase 2 trials, company executives filed the NDA in February 2008. Ten months later, the FDA rejected the drug, claiming it had failed to demonstrate sufficient proof of efficacy and safety.

Oritavancin again changed hands in 2009, when The Medicines Company, a biotech focused on providing drugs to acute or intensive-care hospitals, acquired Targanta for a base $42 million paid to shareholders. Five years of supplemental clinical trials and FDA consults later, oritavancin was resurrected as an FDA-approved treatment for gram-positive bacterial skin infections. With added payments owed to former Targanta shareholders and other parties based on oritavancin’s success, The Medicines Company could end up spending an additional $89 million on the drug.

Clive Meanwell, chairman and CEO of The Medicines Company, says he wasn’t deterred by oritavancin’s 0-1 record with the FDA, even crediting the rejection with preparing the drug for its ultimate success. “The experience of having strong feedback from a regulatory agency can be very positive, even if their viewpoint was negative.”

The experience of having strong feedback from a regulatory agency can be very posi­tive, even if their viewpoint was negative.—Clive Meanwell,
The Medicines Company

A drug’s march to the clinic can appear straightforward. But many successful treatments have convoluted histories, involving regulatory rejections, changed indications, and often multiple developers. Below, The Scientist explores stories of drug failures and rebirths, involving medicinal compounds that powered through multiple clinical trials to prove their worth for their intended disease, as well as compounds that ended up being useful for something else entirely.

Regulatory travails

FDA rejections are frustrating, to say the least. And the financial setbacks can be devastating. After an investment of millions or even billions of dollars, notice from the FDA that the drug candidate has failed to meet benchmarks for efficacy, safety, or standards for manufacturing can sound the death knell, spelling the end of a drug or even a company.

It is common for drugs to bounce back from FDA rejection, however. One study found that, among 52 drugs and biologics evaluated by the FDA between 2007 and 2009, only around half initially met approval. But by 2013, the FDA had approved 11 additional drugs following resubmission (Clin Pharmacol Ther, 94:670-77, 2013). And at the time this article went to press, nearly 70 percent of the original 52 submissions had gained approval.

Some therapies even survive multiple rejections. The drug-dispensing eye implant Iluvien was rejected by the FDA three times before being approved in September for diabetic macular edema. Iluvien’s final application was bolstered by safety data from users in the U.K. and Germany, where the implant had already been approved.

Meanwell views the FDA as a collaborator rather than an obstacle. “If you’re not agreeing on something, then . . . explaining the basis for that disagreement becomes an important part of the dialog,” he says. “At the end of the day, we’re treating patients here.”

In the case of oritavancin, the FDA walked The Medicines Company through new guidelines for testing drugs for acute bacterial skin infections. Making more short-term endpoints, for example, could help better reveal efficacy, as skin infections can sometimes resolve spontaneously over longer periods of time. Meanwell points out that FDA employees are usually quite knowledgeable and competent and can actually aid in study design. “It’s a scientific dialog,” he says.

“The leadership of the FDA is well aware that trust building is a critical component of regulation,” Meanwell adds. “The drug companies themselves have to embrace that idea, too. When both sides do that it can be a very successful interaction.”

Rewards of repurposing

Not every drug on the market is approved for its originally intended indication. Refocusing what was likely a long and expensive project can be difficult, but drug makers must decide when a drug has missed too many benchmarks to make it for its original indication. To help recoup the costs, they are also on the lookout for previously undetected potential for treating other disorders.

Some well-known drugs are, in fact, repurposed failures. Viagra was originally meant to manage blood pressure and chest pain as a result of angina, or reduced blood flow to the heart. In a Phase 2 trial, the drug failed to show efficacy for treating angina, but male participants in a Phase 1 trial reported that they had sustained erections when they took the drug, prompting Pfizer to develop it for erectile dysfunction. The same compound, sold as Revatio, was more recently approved as a treatment for pulmonary arterial hypertension.

Azidothymidine (AZT), initially intended by its developers to treat cancer, was more proficient at keeping HIV viruses from replicating. And thalidomide, infamous for the birth defects it caused in babies born to women who took the drug for morning sickness, is now an approved therapy for leprosy and multiple myeloma.

Some companies have even popped up for the sole purpose of searching for novel therapeutic uses for drugs. (See “Teaching an Old Drug New Tricks,” The Scientist, April 2011.) Pennsylvania-based Melior Discovery, for example, has contracts with drug companies such as Pfizer, AstraZeneca, and Janssen to screen their compounds in around 40 animal models for human diseases, ranging from epilepsy to arthritis. In some cases, companies simply pay Melior to screen their drug libraries. In other cases, Melior does the screening for free, and owns any intellectual property generated during the screening process, unless the drug companies buy it back.

Melior also works to discover new uses for compounds to develop and license on its own, forming a new corporate entity for each major candidate. Melior’s CEO and cofounder Andrew Reaume notes that compounds shown to be safe in humans but that have not been approved for any indication are the most attractive for repurposing. “You get all the benefits of knowing they are safe and well tolerated to some extent,” he said.

The drugs must be old enough that they are, or are about to be, free of a composition-of-matter patent, which requires that companies selling the compound for a new indication license the product from the patent holder. But older drugs were also subject to different regulatory standards when they first started clinical development. The sweet spot is drugs that were discontinued in the 1980s and ’90s, says Reaume, as they are just old enough to be off patent. To gain exclusivity, companies repurposing old drugs can seek method-of-use patents that give them exclusive rights for particular indications. Additionally, any compound approved by the FDA for the first time gets five years of market exclusivity.

Melior’s most advanced clinical candidate, MLR-1023, sensitizes the body to insulin by activating the enzyme Lyn kinase. MLR-1023 was originally developed by Pfizer for the treatment of gastric ulcer and went through Phase 2 trials before the drug’s development was discontinued around 1980 because it did not improve patients’ ulcers. It sat on the shelf until Melior ran it through its drug discovery platform. “Not only was it useful potentially in diabetes, but the way in which it worked, if it held up, would be quite an important contribution to diabetes,” says Reaume. “It’s a novel mechanism.”

After three years of gathering promising data on MLR-1023, Melior managed to strike a deal with Pfizer to get access to the drug’s dossier—the collection of papers describing the drug’s preclinical and early clinical trial data. They found that, simply by chance, five of the 74 patients that had been enrolled in a Phase 2 gastric ulcer trial had diabetes, and four of those five patients had been given MLR-1023. Even better, the patients all routinely had their blood glucose measured. The people with diabetes who took the drug showed dramatically lower blood glucose levels. In November 2013, Melior licensed MLR-1023 to the Korean drug company Bukwang, which is now testing the drug in people with type 2 diabetes in a Phase 2 clinical trial.

Reaume says that working with previously failed drugs benefits from a rich trove of past data that can shed light on the drugs’ safety profile and mechanisms of action. And since the drugs have undergone some human testing, they can sometimes skip Phase 1 safety trials.

However, developing regulatory strategies for resurrected drugs does bring its own challenges, as it is not always clear which stages of the testing process can be cleared with preexisting data. “Every case for us is a bit different,” says Reaume. “It always requires some clarification with the agency in order to establish a development path.” The FDA’s requirements will vary depending on how significantly the drug’s dosage, duration of use, and indication have changed, according to FDA public affairs specialist Tara Goodin. “If these factors differ significantly from those of the previous studies, more safety and other information may be needed before the sponsor can proceed with Phase 2 studies.”

Academic expertise

The National Center for Advancing Translational Sciences (NCATS) in Bethesda, Maryland, is also hoping to develop new uses for unapproved compounds by bringing pharmaceutical companies and academics together. As part of its New Therapeutic Uses program, NCATS convinced a group of pharmaceutical companies, including AstraZeneca, Sanofi, and Pfizer, to make public limited information about drugs that had significant clinical data available but had not been approved. The companies included information about the drugs’ original purposes, safety, and mechanism of action.

NCATS then invited academic researchers to look through the list of drugs for compounds they thought might be relevant to the diseases they were studying. If a researcher is interested in testing a drug on a new patient population, she can file a preliminary application with NCATS. If the application makes the first cut and if the relevant pharmaceutical company supports the proposed collaboration, the researcher can apply for NCATS funding. NCATS funded nine projects in 2013, the program’s inaugural year, including studies aimed at treating Duchenne muscular dystrophy, Alzheimer’s disease, and alcoholism. “The goal for each project is to actually repurpose a drug,” said Christine Colvis, director of drug development partnership programs at NCATS.

One winning proposal was for a collaboration between Eli Lilly and Indiana University School of Medicine psychiatrist Alan Breier. After running a schizophrenia research program at the National Institute of Mental Health, Breier spent 11 years at Eli Lilly, eventually becoming the vice president and chief medical officer. He retired from pharma six years ago and accepted a full professorship at Indiana University.

Looking through the NCATS failed-drug database, Breier was intrigued by an Eli Lilly compound called LY500307. The compound is similar to estrogen, but binds and activates only one of the two kinds of estrogen receptors in the human body. LY500307 was developed to treat prostate enlargement in older men, but a large international study demonstrated that, while the compound was safe, it did not shrink the prostate.

Breier had been vaguely aware of the compound during his time at Eli Lilly, but only now did he realize that LY500307 might be useful for treating schizophrenia. It has long been apparent that exposure to estrogen tempers some symptoms of schizophrenia. However, estrogen supplements can cause sexual problems, breast enlargement, and other unwanted symptoms in men. And premenopausal women who take high doses of estrogen are at increased risk of uterine cancer and heart disease. LY500307 binds and activates estrogen receptor beta, which is present at high densities in brain regions associated with schizophrenia. But unlike estrogen, LY500307 does not bind estrogen receptor alpha, which is more prevalent at sites associated with unwanted side effects. Breier is now testing LY500307 in men with schizophrenia in a Phase 1b/2a trial, intended both to test the safety of relatively high doses of the compound and to determine how effectively it treats schizophrenia.

By sharing data on unused compounds and funding their development, NCATS allows researchers to think creatively about what to do with old drugs that might otherwise just sit on the shelf. Information about past research on the drugs gives groups a head start down a new clinical path, and the pharmaceutical companies provide access to a clinical-grade supply of the drug. If the NCATS-funded Phase 2a clinical trials of a compound are successful, the companies will get first dibs on licensing the intellectual property generated by the academic researchers so they can move the drug to market.

The program is “based on partnership and shared expertise,” said Breier. “It’s really a way that groups can work together and advance the development of new treatments.”

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