Turning Failure into Success?

Every year, the NIH spends some $30 billion on biomedical research. The private sector – including the medical device industry, big pharma and the biotech sector –  chips in another $70 billion. What do we get for this investment? According to comedian Chris Rock, we don’t get many cures. As he puts it, “[Doctors] ain't cured anything in a long time, man, you know, diseases are piling up, man…..….Some diseases, they just gave up on… Like blindness. ….You go to a doctor, tell him you're blind, he says, "Hey why don't you get this dog to drag your blind ass around."

Chris Rock’s critique of lack of progress can equally well be made about central nervous system (CNS) diseases like Parkinson’s and Alzheimer’s. Despite impressive advances in basic science, there have been no groundbreaking clinical solutions since the discovery of L-dopa, 45 years ago. To the contrary, researchers and patients have faced setback after setback – such as the series of failed neurotrophic factor trials for PD (by Amgen, Ceregene, and Phytopharm) and the disappointing performance of the latest Alzheimer drugs bapineuzumab, solanezumab, and gammagard.

Such setbacks have made the mighty pharmaceutical industry increasingly risk averse; they’re reluctant to bear the enormous costs (on average about $1.3 billion and 15-18 years per drug) of developing CNS medicines. Instead, according to Richard Wyse of the UK-based Cure Parkinson’s Trust, many pharmaceutical companies seem to prefer making cosmetic refinements to existing drugs. “So, a “new” drug might be slightly longer acting, or it might be pink rather than blue…such efforts don't have the patients' interests in mind.”

If the pharmaceutical industry has lost enthusiasm, and if government funded research lacks the necessary urgency and focus to deliver “cures,” says Wyse, then “it's up to charities like Cure Parkinson’s Trust and the Michael J Fox Foundation to set the global research agenda.”

Easier said than done. Whether you’re the NIH, big pharma, or a Parkinson’s charity, discovering safe and effective new drugs is an inherently risky business. According to Princeton health economist Uwe Rheinhardt, it’s “like drilling for oil. You hit a lot of dry holes before you hit a gusher. So, the cost of all the failures has to be charged, ultimately, to the successful drug.” So, for every blockbuster like Lipitor, there are dozens of compounds that turn out to be ineffective – in essence, pharmacological dry holes. But what if they weren’t really worthless? What if a drug designed to do one thing (e.g. treat diabetes or cancer) turned out to work against a neurodegenerative condition like PD. Then since the FDA had already approved the compound as safe for human consumption, it should be simpler, quicker, and cheaper test its efficacy in patients. That’s the provocative idea behind drug “repurposing,” the subject of an exciting initiative reported by Brundin et al in the Journal of Parkinson’s Disease.

The idea is not new. In 1952, clinicians noticed that patients given a TB drug called iproniazid were “inappropriately happy.” In 1958, the drug was reborn, or “repurposed,” as one of the first ever antidepressants. A better-known example involves Pfizer. In the 1980s, the company tested a new angina medicine called UK-94, 480 in the Welsh town of Myrthyr Tydfil. The drug was a bust. It did little to combat angina. Pfizer prepared to declare failure, to rack up another “dry hole.” But then something surprising happened. Men in the trial reported a surprising side effect of the drug – enhanced erections. Pfizer repurposed UK-94, 480 from an angina medication to an erectile dysfunction drug, called Viagra…and made billions..

Over the years, a number of drugs have been repurposed, like Viagra. Thalidomide, a tragic failure as a morning sickness drug, now treats complications of leprosy. The hypertension drug Minoxidil turned out to control hair loss. And aspirin has an ever-growing list of uses--painkiller, blood thinner, anti-inflammatory, diabetic cataract preventer etc. A couple of years ago, Cure Parkinson’s Trust decided to apply the concept systematically to PD. It assembled an international team led by neuroscientist Patrik Brundin with a clearly articulated goal: to screen thousands of FDA approved drugs (and OTC supplements) for anti-Parkinson’s activity, and test the medicines in patients via a worldwide clinical trial network. These small “learning trials” were to be run in parallel, hence the name “Linked Clinical Trials (LCT) initiative.

In the first phase of the LCT project, researchers identified 72 candidate compounds used against a wide range of conditions including type 2 diabetes, hypertension, thalassaemia and cancer. A cut-down list of 26 was analyzed by an international committee of neuroscientists with a wide range of expertise in PD. After evaluating the many exotic biochemical agents involved (GLP-1 agonists, Metformin, iron chelators, a statin, a fibrate, an ACE inhibitor, an Angiotensin Receptor Blocker, mTOR inhibitors, PARP inhibitors, a Kinase inhibitor, a Microtubular stabilizer, a Retinoid, and a SIRT1 activator) for safety and passage across the blood-brain-barrier, the committee ranked the drugs in order of priority to be used in small “affordable” learning trials, funded by a variety of sources

The top five choices included three type 2 diabetes drugs (Exenatide, Liraglutide, and Lixisenatide), an iron chelator (Deferasiros) and a statin (Simvastatin). Will drug repurposing fill the void left by the commercial drug industry and kick start translational research in PD? It’s early days. In the first learning trial that’s made it into print, Iciar Aviles-Olmos et al report that Exenatide (an injectable diabetes medication) produced a statistically significant effect in an open label trial PD trial. One problem with the trial was that there was no "placebo" given to the control group, due to the excessive expense of making injection pens containing a non-active substance. Future larger trials will have to address whether Exenatide actually modifies PD progression. And Exenitide is just the first of 26 potentially effective medicines.

Just because this approach is “affordable” and fast doesn’t guarantee success. A decade ago, the National Institute of Neurological Disorders and Stroke (NINDS) started something similar, setting up the Committee to Identify Neuroprotective Agents for Parkinson's (CINAPS). CINAPS looked for existing FDA-approved drugs that were neuroprotective for PD, which they tested – albeit rather slowly –  at multiple centers in NIH’s Exploratory Trials in Parkinson's Disease (NET-PD) program. So far, none of the repurposed candidates have proved effective. A large NET-PD study testing a purified form of creatine reported negative results this month.

Another big uncertainty about this approach involves intellectual property. Many of the candidates in the LCT initiative are owned by pharmaceutical companies. This means, as the authors’ admit, “that the future funding of any prioritized candidate might be influenced by ownership.” Should a repurposed drug (or group of repurposed drugs) ultimately prove highly successful against PD, one must hope that the pharmaceutical companies behave reasonably. Some readers may recall what happened when the drug company Questor repurposed the anti-inflammatory ACTHAR gel for infantile spasm (a rare form of epilepsy). In that case, the company hiked the price for a 5-milliliter vial from $50 to $28,000. Such profiteering would undercut the value of this promising strategy in Parkinson’s disease.

Last comment on by Lucinda McGuire,

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Submitted by Lucinda McGuire, on

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