Indivior Inc., a global specialty pharmaceutical company with a 20-year legacy of leadership in patient advocacy and health policy, has built a global portfolio of treatments for opioid use

disorder (OUD) and a pipeline of product candidates to address other chronic conditions and co-occurring disorders of addiction, including alcohol use disorder (AUD) and schizophrenia. All

along, the company has also invested in education programs on evidence-based treatment models that have helped revolutionize modern addiction treatment. Indivior’s goal is to transform the

perception of addiction from a global human crisis to a chronic disease that should be recognized and treated. The year 2017 marks 20 years since the publication of the first World Drug

use translated into an estimated 28 million years of healthy life lost worldwide as a result of premature death and disability. Opioids (opiates and prescription opioids) were the most

harmful drugs in this context, accounting for 12 million disability-adjusted life years (DALYs), or 70% of the negative health impact associated with drug use disorders (DUDs) worldwide. In

the United States alone, the misuse of opioids, together with a significant increase in heroin and fentanyl use, accounted for approximately 25% of the estimated number of drug-related

deaths in 2015. Overdose deaths in the United States were mostly driven by opioids and increased in number from 16,849 to 52,404 annually during the 1999–2015 period. Despite this state of

affairs, access to treatment of DUDs and related conditions remains limited, and currently fewer than one in six persons with DUDs receives treatment. According to Christian Heidbreder, CSO

of Indivior, “approximately 200,000 premature deaths worldwide can be attributed to the use and misuse of opioids. This figure clearly shows the rapidly evolving public health crisis that

requires pioneering scientific solutions. Indivior’s research and development is totally dedicated to the development of innovative therapeutics that move the international community one

step closer to new treatment options that help patients with DUDs worldwide improve their quality of life and well-being.” ADDRESSING THE DRUG USE DISORDER CHALLENGE Indivior’s core guiding

principle—focus on patient needs to drive decisions—incentivizes research and development (R&D) that advances treatment innovation in the face of the growing global addiction crisis.

Indivior has a long history of supporting the addiction treatment community and has been involved in manufacturing and supplying buprenorphine, a μ-opioid receptor (MOR) partial agonist and

κ-opioid receptor antagonist, for patients since 1996 as a treatment for OUD. Indivior’s focus on putting the patient first helps define the company’s R&D mission: stabilizing drug

delivery, decreasing dosing frequency, increasing treatment adherence and retention, decreasing diversion and misuse, improving management of overdose, and treating the comorbidities of

addiction. Indivior’s science is constantly expanding the mechanistic understanding of addiction to promote the development of novel approaches to treatment and new methodologies to support

measurements of clinical response. To keep this promise, Indivior has recently invested in the construction of a state-of-the-art R&D Centre of Excellence in Hull, UK. EXPANDING ACCESS

TO OPIOID USE DISORDER TREATMENT Indivior is developing RBP-6000, a new investigational buprenorphine sustained-release formulation that uses the ATRIGEL delivery system, which consists of a

polymeric solution of a biodegradable poly-(DL-lactide-co-glycolide) co-polymer dissolved in _N_-methyl pyrrolidone (NMP), a water-miscible biocompatible solvent. After subcutaneous

injection, NMP interacts with body fluids that replace the NMP as it diffuses out of the polymer matrix, triggering polymerization, which traps buprenorphine inside and forms an amorphous

solid depot _in situ_ . The depot releases buprenorphine over a one-month period by diffusion as the polymer biodegrades (FIG. 2). RBP-6000 was designed to provide sustained plasma levels of

buprenorphine that translate into high and sustained MOR occupancy in the brain over a one-month period to suppress withdrawal symptoms and reduce the subjective and objective effects of

opioid agonists. RBP-6000 was granted Priority Review Designation and is currently under review by the US Food and Drug Administration. The results of Indivior’s pivotal US phase 3 trial in

subjects with moderate to severe OUD as part of a complete treatment plan that included counseling and psychosocial support showed that treatment with RBP-6000 significantly reduced illicit

opioid use compared to placebo over a 6-month period. Treatment outcomes were consistent across other clinical endpoints, including control of craving and withdrawal symptoms. Furthermore,

exposure-response analyses predicted correlation among buprenorphine plasma concentration, whole-brain MOR occupancy, abstinence, withdrawal, and opioid craving. The safety profile of

RBP-6000 was consistent with the known profile of transmucosal buprenorphine, with the addition of injection-site reactions. ADDRESSING THE ALCOHOL USE DISORDER CHALLENGE AUD is a chronic

disease with a multifactorial etiology that is characterized by excessive drinking, alcohol craving, loss of control of alcohol intake, tolerance, and physical dependence, with a risk of

potentially life-threatening alcohol withdrawal syndrome. According to the World Health Organization, the worldwide average level of alcohol consumption in 2016 was 6.4 L of pure alcohol per

person aged 15 years or older2. This alcohol consumption resulted in about 3.3 million deaths, or 5.9% of all global deaths, and was responsible for 139 million DALYs, or 5.1% of the global

burden of disease and injury2. These findings highlight the need for continued and increased efforts to reduce the harmful use of alcohol. Decades of research have focused on the way

alcohol enhances inhibitory γ-aminobutyric acid (GABA)-mediated neurotransmission, including the characterization of drugs such as baclofen that target the GABA system3. True to its vision

and mission, Indivior is developing arbaclofen placarbil, a novel transported prodrug of _R_ -baclofen, the more active of the two baclofen enantiomers, that is designed to be well absorbed

by the large intestine, thus allowing less frequent dosing and reduced fluctuations in the plasma. Results of an ongoing phase 1/2 clinical study of the bioavailability of arbaclofen

placarbil will be available in early 2018. ADDRESSING DRUG USE DISORDER PSYCHIATRIC COMORBIDITIES Epidemiological and clinical studies have shown that psychiatric disorders are highly

comorbid with DUDs. For example, nearly half of patients diagnosed with schizophrenia, a chronic disorder characterized by a lifelong pattern of acute psychotic episodes superimposed on

chronically poor psychosocial adjustment, have co-occurring DUDs4. Therefore, adherence to antipsychotic pharmacotherapy is a key aspect of treatment, and long-acting injectable

antipsychotics may facilitate improvements in medication compliance, thereby reducing the risk of relapse and potentially facilitating the management of comorbid DUDs. Indivior is developing

a once-monthly sustained-release formulation of risperidone (RBP-7000) using the ATRIGEL delivery system for the long-term treatment of schizophrenia. The results of a pivotal phase 3 trial

to assess the efficacy, safety and tolerability of RBP-7000 in subjects with acute schizophrenia showed clinically significant reductions in the symptoms of acute schizophrenia over an

eight-week treatment period5. EXPANDING TREATMENT OPPORTUNITIES ON BEHALF OF PATIENTS Indivior continues the work of changing societal attitudes toward DUDs, revising their status from

marginalized conditions to treatable diseases. Indivior contributes to widening access to quality treatments by educating health care professionals on treatment options and making sure

patients know that treatment is available. The global challenge of DUDs also means that there are many more countries and addiction areas into which Indivior can expand to meet unmet patient

needs. Indivior invests in prospective health economics and outcomes research as part of clinical development plans to better understand patient outcomes beyond clinical efficacy and safety

(e.g., improvement in health status and health-related quality of life, medication satisfaction, decreased health care resource utilization, improvement in employment status and health

insurance, and decreases in comorbid drug use and psychiatric associations). Indivior is also focusing on new molecular targets with mechanisms of action involved in craving; these are

likely to be useful across DUDs. More collaborative research efforts will be required on the pharmacogenomics of DUDs, including learning how to characterize and quantify pharmacotherapy

response (e.g., efficacy, nonadherence, treatment duration, concurrent medications use) and how to define patients’ characteristics (e.g., differential diagnosis, illness course,

comorbidities). Indivior believes that these concerted efforts may ultimately result in the reduction and cessation of drug use by the patient, thereby preventing future harms associated

with the abuse of drugs and improving the quality of life and well-being of patients with DUDs. “The inherent complexity and multi-dimensional nature of DUDs require a deep understanding of

their neurobiological underpinnings,” said Heidbreder. “Equally important are partnerships and collaborations that allow us to understand patients’ unmet needs and ccelerate the development

of new medications. Indivior’s mission is to facilitate these coordinated efforts to offer innovative solutions and ltimately prevent and treat DUDs and their comorbidities. Patients are

waiting.”