Treating the Fentanyl Epidemic

The primary challenge we face against the epidemic spread of fentanyl is the long-standing stigmatization of individuals with substance abuse issues. There is limited appreciation that addiction is a chronic, relapsing disease – no different from other chronic conditions – that affects all socioeconomic and demographic stratifications. And it is, at least in part, stigma that has contributed to a lack of investment in this area by healthcare-related venture capitalists. 

Currently, there are only three molecules approved for the treatment of opioid use disorder (OUD), of which the last novel molecule was approved in 1981. And though these approved treatments do have a long history of safe use, the growing number of overdose-related deaths via fentanyl suggests there is room for improvement. Today, we suffer from a notable lack of therapeutic options; in other words, we are ill-equipped to deal with the scale of the problem.

In the US, fentanyl accounts for over 90 percent of all opioid-related overdose deaths – a rise attributed to fentanyl (and fentanyl analogs) replacing heroin as the primary opioid in the illicit drug supply. What was once an opioid crisis is now very clearly a fentanyl crisis. In most cases, the primary instances of harm, overdose, and fatalities are associated with illicitly produced fentanyl. It is often found in illegal drugs, and the dose varies considerably; even slight alterations in batch-to-batch amounts can result in unpredictable effects (including overdoses or death).

For international crime organizations, fentanyl possesses two notable benefits: it’s cost-effective and incredibly potent. To be specific, fentanyl is roughly 10 percent of the cost of heroin and can induce life-threatening respiratory depression in as little as 2-3 minutes, drastically undercutting heroin’s 30 minute countdown. Thus, the time window for administering life-saving treatments, such as naloxone (sold as Narcan), is significantly shorter.

There is also evidence to suggest the epidemic could spread beyond US borders.  Following a ban on poppy cultivation – the primary source of heroin production – in Afghanistan in 2022, the door has opened for the growth of illicit synthetic opioids. We’re now seeing scattered reports of fentanyl-related deaths from countries across the Eastern and Southern hemispheres, as well as in the Baltic states and Brazil (and others) that have certainly intensified this concern. Statistics and reports only tell half the story, and many of us have been touched personally by addiction. Cessation Therapeutics was founded to help change the story. One of our most promising therapeutic candidates – CSX-1004 – has just entered a phase Ia, first-in-human study.

CSX-1004 is a human monoclonal antibody directed against fentanyl – and fentanyl analogs – and works by sequestering fentanyl molecules as they enter the bloodstream, effectively neutralizing them in the blood before they reach the brain, and preventing them from exerting harmful effects. Moreover, because CSX-1004 prevents fentanyl from reaching the brain, CSX-1004 can also block all the effects of fentanyl, including the respiratory depressant effects that lead to life-threatening overdose, as well as the euphoric feeling (or “high”) people receive from fentanyl. In a primate model, we demonstrated that a single dose of CSX-1004 blocks the respiratory depressant effects of potentially lethal doses of fentanyl for up to one month.

CSX-1004 is restricted to the bloodstream; thus it does not have intrinsic abuse potential or opioid-related side effects, contrary to other medications for OUD. And because it acts differently than other medications for OUD, CSX-1004 could be used not only as a stand-alone agent, but also in combination with other medications to yield the best outcomes in patients with OUD. We are now working closely with the FDA on further development and recently received Fast Track designation for the molecule. 

We are also developing a fixed-dose, subcutaneous formulation of CSX-1004 – known as CSX-1004 SQ – that will provide a formulation to be incorporated into a broad range of healthcare settings. Cessation and its academic collaborator, McLean Hospital/Harvard Medical School, recently received a $14.7 million grant from the National Institute on Drug Abuse (a division of NIH) to spearhead its subsequent progression.

Yet, despite these promising developments, substance abuse is drastically neglected by the private sector. There are still no FDA-approved medications for the treatment of stimulant use disorder, a condition characterized by the problematic use of stimulants, such as cocaine, methamphetamine, and prescription stimulants (amphetamine, methylphenidate). And though there are three approved medications for alcohol use disorder, they have only modest efficacy. Additional treatments are sorely needed. Nicotine use, though not often appreciated as a substance use disorder, also suffers a dearth of pharmaceutical treatment options – and those that are available have modest efficacy and/or tolerability issues.

Though NIDA has been a massive supporter of drug development efforts, we still require much more investment and attention from private investors. In contrast, there are dozens of approved medications for major depression (another chronic CNS disorder), and despite the availability of safe and effective treatment options, there continues to be massive investment in this space. I can only hope that a greater understanding of addiction will eventually reduce the stigma and encourage additional investment in this domain.