Funding for psychiatric drugs growing scarce
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Suicide is the tenth leading cause of death in the United States, ranking a remarkable second among 15- to 34-year-olds and fourth among 35 to 54-year-olds. In 2014, approximately 43,000 Americans lost their lives to suicide.

People with depression are at significantly higher risk for suicide. About 6.7 percent of adults in the United States experience major depression, and approximately 2.6 percent of the adult population have bipolar disorder. The need for a new treatment is especially strong among patients with bipolar depression, who have 20 to 30 times the suicide rate of the general population. The death of actor Robin Williams in 2014 from suicide related to bipolar disorder brought increased attention to this risk.

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Nevertheless, most large pharmaceutical firms have abandoned research and development of new psychiatric drugs, including those that would treat depression and suicidal thoughts. In the past 10 years, the number of psychiatric drug studies has gone down a staggering 70 percent.

The days when we could look into the pipeline and see promising new drugs like Prozac, Zyprexa and Abilify offering new hope for these vulnerable patients are long gone. One reason is that all of these multibillion-dollar medications — $3B, $5B and $7.4B, respectively — are now generic. It is very difficult for Big Pharma to develop new drugs that are significantly different from these now generic blockbuster drugs. And if a new drug is not seen as a significant improvement, insurers are likely to restrict paying for them.

But generics are not the only barrier to innovation. Psychiatric studies, especially in depression, carry above-average risk (high placebo response), which makes them challenging to undertake. Another key risk factor is an increased risk of suicide, as patients may develop these thoughts when being treated with antidepressants; hence, antidepressants actually carry a warning in their label about this risk. Wanting to avoid this added risk in their studies, pharmaceutical firms have excluded patients at risk of suicide from virtually all their clinical studies. Today there is no approved medicine to prevent suicidal thoughts or actions in patients with depressive disorders.

Many patients in a desperate quest to alleviate their unresolved depression and/or suicidal thoughts have turned to physicians willing to prescribe off-label ketamine, which is only approved as an anesthetic. This trend was prompted by studies showing that ketamine can reduce depression and suicidal thoughts in the short term. A key receptor here is the NMDA receptor, which appears to have an effect on both depression and thoughts of suicide although the effect on thoughts of suicide is somewhat independent of improvements in depression. 

In response, a few pharmaceutical companies started studying ketamine and some of its derivatives with NMDA receptor activity, foremost as potential therapies for treatment-resistant depression.

Johnson & Johnson is developing an intranasal form of esketamine (a ketamine derivative) for treatment of unipolar treatment-resistant depression. Allergan acquired biotech Naurex for $560 million last year because that company had an injectable ketamine-like product called rapastinel in development, also targeted at treatment-resistant unipolar depression. Both drugs are now in Phase III trials. However, ketamine and most of the drugs targeting the NMDA mechanisms carry the risk of addiction and potentially hallucinations. Ketamine is a scheduled drug, and is known to be abused in the party scene, and the impact of using ketamine and its derivatives over the long term is not yet known. 

In contrast to all other firms, our start-up NeuroRx is focused on the needs of the bipolar segment, specifically on the reduction of suicidal thoughts. We estimate that up to half of all suicides may be related to bipolar disease. Our lead drug, NRX-101, is a proprietary fixed-dose combination of two already approved drugs: D-cycloserine (an antibiotic that at higher dosages has NMDA activity) and lurasidone (approved for the treatment of bipolar depression and schizophrenia).  

An exploratory clinical study showed that starting patients on an infusion of ketamine and then transferring them for up to 8 weeks to an oral combination that included the two drugs reduced suicidal thoughts by 75 percent and depression by 50 percent.  Our hope is that this combination will provide an oral outpatient alternative to extend the effect of ketamine and its derivatives, which will likely have to be administered in a clinic-like setting, either because they are infusions or because of their potential for abuse. (The two substances in NRX-101 are not scheduled drugs). A 505(b)(2) route of development and clinical program for NRX-101 will begin within the next few months. The 505(b)(2) route allows firms to draw on the data of previously approved medicines, thereby decreasing the cost and risk of development.

The development of ketamine and ketamine-like drugs to treat depression was triggered by the scientific findings of pioneering investigators, including Dr. Daniel Javitt and the chair of our scientific advisory board. The finding that thoughts of suicide could be reduced by these substances may herald a new era of much-needed clinical investments in the field, especially as patients at risk for suicide have been excluded from virtually all studies.

Just getting to such a point in which clinical data point toward a clinical path can take decades within industry and academia. Further acknowledging this a potential novel path was a 2015 report by the APA Research Task Force on Novel Biomarkers and Treatments, which identified rapastinel (the drug Allergan acquired) and D-cycloserine (a component of NRX-101) as promising future alternatives. As most big and small pharma have turned away from psychiatry, perhaps our approach may present a new business model for the field. It might even be possible to drive suicide down the list of leading causes of death. 

Robert Besthof, a biopharmaceutical executive with over 25 years of covering global marketing of medicines and crafting the investment path for the advancement of drug pipelines, is Chief Commercial & Patient Officer at NeuroRx. He previously worked for Eli Lilly, Wyeth, Pfizer, and Deutsche Bank.


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