Bio-MD™ Opioids: Abuse-resistant Opioid Prodrugs

Signature Therapeutics’ proprietary abuse-resistant opioid prodrug technology – the Bio-MD™ platform - is designed to improve the care of patients with chronic pain while reducing the human and economic costs associated with prescription opioid drug abuse. Our opioid prodrugs are chemically stable molecules that provide pain relief similar to currently approved opioid drugs. However, unlike commonly used opioid drugs, our prodrugs resist the usual extraction and tampering techniques used by addicts to abuse prescription opioid drugs via injection or snorting, as well as chewing and crushing. Administered intravenously, our opioid prodrugs do not release opioid and do not produce any appreciable opioid effects. Consequently, our opioid prodrugs offer the benefits of effective pain relief with a substantially reduced potential for abuse.

The Opioid Abuse Epidemic

The abuse and misuse of prescription opioid drugs has reached epidemic proportions in the United States. Despite efforts to develop opioid drug formulations that are resistant to tampering, abusers have matched the advances in pill/tablet formulation technology with new ways to abuse these drugs. Most opioid drugs currently on the market can be physically manipulated (crushed, cut, grated, ground, heated, dissolved) to yield active opioid that can be injected, snorted, smoked, or taken orally.

Increased sales of prescription opioid drugs over the past decade have been matched by a parallel increase in the number of opioid overdose deaths. In 2003, the number of deaths related to prescription opioid drugs exceeded the number of deaths due to cocaine and heroin combined. Since that time, the number of deaths related to prescription opioid drugs has increased annually, rising to more than 16,000 in 2010 alone. The Centers for Disease Control and Prevention (CDC) considers the prescription drug abuse crisis in the United States to be an epidemic. Similarly, the Office of National Drug Control Policy describes prescription drug abuse as “the Nation’s fastest-growing drug problem.”

In addition to causing significant morbidity and mortality, abuse of prescription opioid drugs is associated with high economic costs. The average direct health care costs for opioid abusers is eight times higher than the average for non-abusers. The economic impact of prescription drug abuse is $72.5 billion each year in health care costs alone.

Despite the substantial human and economic costs associated with the abuse of prescription opioid drugs, these medications are essential for improving the care and outcomes for the 100 million adults living with chronic pain in the United States. It is estimated that the cost of medical treatment and lost productivity associated with chronic pain is $560-$635 billion annually.

Clearly, improved abuse-resistant opioid drugs are essential for managing chronic pain and reducing the toll of prescription opioid drug abuse. In 2011, President Obama put forth a plan to respond to America’s prescription drug abuse crisis. Included in this plan is a call for the Food and Drug Administration (FDA) and other federal agencies to expedite development of abuse-deterrent formulations of opioid medications and other drugs that have a potential for abuse. A Citizen’s Petition submitted to the FDA in May 2013, calls on the FDA to take action that fosters a transition to abuse-deterrent opioid drugs and improves access to addiction treatment.

We believe that our Bio-MD™, abuse-resistant opioid prodrug technology has the potential to meet the medical needs of patients living with chronic pain, while providing a solution to the national epidemic of prescription opioid abuse.

Bio-MD™ Prodrug Technology

Unlike currently approved opioid pill/tablet formulation approaches, the molecular structure of Signature Therapeutics’ novel prodrug technology provides a chemical barrier to parenteral abuse as well as the extended-release profile. A representative Bio-MD opioid prodrug structure is shown here.

The prodrug portion of the molecule decreases the affinity of the molecule for the opioid receptor as well as the permeability of the molecule to enter the central nervous system, resulting in minimal opioid effects, as shown. The prodrug remains intact when the compound is injected, snorted, or smoked.

Bio-MD opioids are bioactivated molecular delivery systems. When administered orally, trypsin in the gastrointestinal tract releases the amino acid portion of the prodrug and provides the initial step in the process of opioid drug release. The pharmacokinetic profile is controlled by a subsequent reaction within the molecule itself that releases free opioid.

 

When subjected to common methods of tampering, our prodrugs do not release appreciable amounts of active opioids.

 

Our Bio-MD™ abuse-resistant opioid prodrug technology is protected by issued and pending patents in the United States and other countries that cover compositions of matter, methods of manufacture, and methods of use. We believe that this patent estate provides broad protection of our proprietary technology, and will protect our morphone-class prodrugs and codone-class prodrugs until at least 2027 and 2030, respectively.

Prodrug Data

Signature Therapeutics has conducted early-stage clinical trials of PF329, our proprietary, extended-release prodrug of hydromorphone. In two phase 1 studies, PF329 has demonstrated safety, dose proportionality, and a clinically beneficial extended release profile.

 

In these studies, PF329 was safe and no food effect was observed.

Fisher et al, First-in-Man Evaluation of HM Prodrug, an Abuse-Resistant Prodrug of Hydromorphone, Journal of Pain 2012;13:7

(400) First-in-man evaluation of PF329, a abuse-resistant pro- drug of hydromorphone

D Fisher, J Magruder, A Konstantatos, and P Hodsman; PharmacoFore, Inc., San Carlos, CA
PF329, an abuse- and tamper-resistant prodrug of hydromorphone, is being de- veloped by PharmacoFore for treatment of chronic pain. When administered orally, PF329 is cleaved by gastrointestinal trypsin to hydromorphone and inac- tive fragments. PF329 is not active at the opioid receptor and does not convert to hydromorphone systemically. Unlike formulation approaches for abuse-re- sistance, PF329 is not affected by chewing or crushing. A first-in-man study was conducted in healthy, monitored, subjects at Nucleus Network Limited (Melbourne, Australia), with approval from their IRB. Part 1: 51 fasted subjects received a single oral dose of Dilaudid" (0.5-24 mg) or PF329 (1-48 mg). Part 2: 12 subjects received 16-mg PF329 either fasted or after a high-fat meal (cross- over design). All doses were in solution. Subjects received naltrexone before (Part 1) and 12 hours after study drug administration (Parts 1, 2). Plasma was sampled for 72 hours and assayed for PF329, hydromorphone, and PF329 frag- ments. Hydromorphone Cp peaked < 1 hour following hydromorphone and at 3-4 hours following PF329; hydromorphone Cmax was markedly lower follow- ing PF329. With PF329, hydromorphone AUC was dose proportional; variability in dose-normalized Cp was low. Naltrexone did not affect hydromorphone AUC. A high-fat meal increased hydromorphone AUC 10%, but did not affect Cmax or Tmax. Population pharmacokinetic modeling indicated that 80% of PF329 was converted to hydromorphone (based on AUC); this fraction did not vary with PF329 dose. PF329 was detected in most subjects but reached as- say LOQ quickly; PF329 fragments were detected transiently. Adverse events were mild-moderate and consistent with exposure to hydromorphone and naltrexone. In summary, PF329 conversion to hydromorphone is dose-propor- tional over a broad range of doses, with low variability. Conversion to hydro- morphone delays Tmax and decreases Cmax. Future clinical trials will confirm that PF329’s hydromorphone time profile is efficacious in chronic pain. Supported by PharmacoFore, Inc.    

In dog studies, our proprietary, extended-release prodrug of oxycodone (PF614), demonstrated an extended-release profile similar to that of OxyContin® (oxycodone controlled release)*.

*OxyContin is a Registered Trademark of Purdue Pharma, L.P.

Our proprietary Bio-MD™ prodrug technology is broadly applicable to classes of drugs used in indications other than pain management. Studies conducted in animals confirm the release characteristics of several other medications based upon the Bio-MD™ platform, including extended- and immediate-release versions of dexamphetamine, a drug that is used for the treatment of ADD and ADHD.

PF614: Prodrug of Oxycodone

PF614, our lead abuse-resistant opioid drug is a proprietary prodrug of oxycodone. Extended-release oxycodone had $2.8 billion in sales in 2012, and is subject to tampering and abuse that is associated with a significant number of deaths. We have demonstrated safety and efficacy of our hydromorphone prodrug, PF329, in phase 1 clinical trials. We have selected PF614 as our lead abuse resistant opioid drug, however, because oxycodone is more frequently abused than hydromorphone and there is an urgent need for improved abuse-resistant oxycodone drugs. We are developing PF614 to have an analgesic profile that is similar to oxycodone while providing a level of tamper resistance that is not feasible with other oxycodone products.

In preclinical studies, PF614 demonstrated an extended-release profile similar to that of OxyContin® (oxycodone controlled release)*.

*OxyContin is a Registered Trademark of Purdue Pharma, L.P.

We are preparing to advance PF614 into human clinical trials by mid-2014.

Commercial Opportunity

Prescription opioid medications constitute a multi-billion dollar annual market. In 2012, sales of these products were $8.5 billion in the United States and $11.7 billion globally. Annual sales of several extended-release opioid formulations are very robust, including oxycodone ($2.8 billion), oxymorphone ($600 million), morphine ($350 million) and hydromorphone (>$100 million). Effective opioid medications are essential for improving the lives of the 100 million U.S. adults living with chronic pain.

Despite the clear medical need for prescription opioid drugs, the availability of these drugs is associated with a growing epidemic of abuse and misuse. Prescription opioid abuse resulted in more than 16,000 deaths in 2010 in the United States, and the economic impact of prescription drug abuse is $72.5 billion each year in health care costs alone. To address this epidemic, President Obama has called on several federal agencies to expedite the development of abuse-deterrent opioid drugs. The US FDA has committed itself to pushing the US market for opioid drugs in the direction of ever-increasing barriers to abuse and misuse of the prescription drugs.

Several abuse-deterrent opioid products are currently marketed or in late-stage clinical development, but they fall short of being resistant to abuse. Current pill/tablet formulations designed to deter abuse are susceptible to simple extraction techniques and fail to prevent abuse when doses are crushed.

Signature Therapeutics’ proprietary Bio-MD™ platform effectively resists chewing, crushing, injection, and inhalation; fails to release active opioid when subjected to simple extraction; and resists simple kitchen chemistry approaches that can be used to abuse other unprotected and abuse-resistant opioid pill/tablet formulations. Our technology is broadly applicable to all known opioids, as well as other medications that have the potential for abuse. This higher level of abuse-resistance that our drugs demonstrate, coupled with the growing desire that multiple federal agencies have expressed the desire to transition to more abuse-resistant opioid drugs, favorably positions our opioid prodrugs in the competitive landscape of abuse-resistant opioid products. We believe that novel opioid drug products based on our Bio-MD™ technology will be well positioned to capture significant proportions of their respective markets, creating value for patients, our partners, and our investors.