Moderate-to-Severe Pain

Market

According to the U.S. National Institutes of Health, pain affects more Americans than diabetes, heart disease, and cancer combined, with chronic pain being the most common cause of long-term disability. The U.S. economic impact of acute and chronic pain exceeds $100B per year. The global market for pain relievers exceeds $50B.

Opioid drugs remain one of the most widely prescribed drug classes in the world. Due to their unparalleled efficacy, the use of opioid agonists will likely continue to be the dominant therapy for treating a wide spectrum of pain conditions in a growing population of patients dealing with acute or chronic pain issues.

The market opportunity is expected to be much larger as it is well understood that pain is severely undertreated.

Unmet Need

From 1994 to 2003, the number of prescriptions for controlled substances rose from 22M to 354M annually. With this increase, the abuse of prescription drugs has surpassed abuse of illicit drugs. The two categories of prescribed drugs most subject to abuse are those prescribed for pain and ADHD (Attention-Deficit Hyperactivity Disorder).

In the United States, the abuse of prescription medicines is more prevalent than the abuse of cocaine, heroin, and methamphetamine. The number of admissions for misuse of prescription painkillers to hospital emergency room rose from some 40,000 in 1994 to over 300,000 in 2008.

Prescription drug abuse and addiction are major burdens to American society, resulting in significant costs, illness, and deaths. Over 48 million Americans will abuse prescription drugs in their lifetimes; in 2005, such abuse cost the US government $468B.

An unintended consequence of the current efforts to limit abuse of pain drugs has been the undesired impact on medical practice and patient care. While opioid drugs Medications made from, artificially developed from, or containing opium, a potent pain-killing substance that is derived from poppy pods. Examples of opioid medications include morphine, codeine and hydrocodone. remain the choice for the effective treatment of moderate-to-severe pain, fears of opioid drug misuse and abuse, as well as prosecution for prescribing them, lead to under-treatment of pain. At least 30 percent of patients with moderate chronic pain and more than 50 percent with severe chronic pain fail to achieve adequate pain relief. Studies of cancer patients’ pain control consistently reveal that up to half of patients receive inadequate analgesia, and 30 percent do not receive appropriate drugs for their pain. This phenomenon is demonstrable both in Western countries as well as in Third World settings.

Unrelieved pain also puts patients at risk. For example, uncontrolled pain after surgery increases heart rate, systemic vascular resistance, and circulating catecholamines (“fight or flight” hormones released by adrenal glands). These reactions place patients at risk of angina, stroke, bleeding, and other complications.

Signature Therapeutics' Solution

Bio-Activated Molecular Delivery™ Technology

The issues of (i) providing effective pain management and (ii) the widespread and increasing prescription opioid drug abuse are intertwined. An unintended consequence has been the significant under-treatment of patients with moderate-to-severe pain. These issues highlight the need for a robust drug technology capable of effectively treating pain while resisting abuse.

We have created a novel Bio-Activated Molecular Delivery™ (also referred to as Bio-MD™) technology designed to effectively deter prescription drug abuse at a molecular level. This technology does not involve the reformulation of existing opioid drugs in physical matrices that are easily circumvented by simple extraction methods. Our opioid Bio-MD systems are “activated” to release clinically effective opioid drugs only when exposed to the correct physiologic conditions (i.e., ingested).

When developing our abuse-resistant technologies, we focused on (i) key patient benefits while (ii) significantly reducing the risk of abuse. Our drug design principles include:

• Reduce barriers to pain therapy: Address the worldwide under-treatment of pain by providing a treatment option for moderate-to-severe pain while substantially decreasing global prescription drug abuse.
• Do no harm to patients: Patients should not be treated as abusers. Unlike certain alternative approaches to opioid drug abuse, our drugs do not expose patients to aversive agents or opioid antagonists that could cause them harm.
• Protect from inadvertent overdose: If a patient crushes or chews a competitor’s pill to ease ingestion, the patient could be exposed to more than the prescribed dose and/or undesirable and unnecessary adverse effects. Patients and physicians should be confident that the dose prescribed is the dose the patient will receive, whether or not the patient crushes or chews the pill.
• Long-lasting pain relief: Provide abuse-resistant opioid drugs that offer extended relief.
• Reduce side effects: Control systemic opioid drug exposures, so that patients will experience fewer side effects. In addition, discover and develop a complementary medicine, PF05, which further reduces opioid-associated side effects.
• Protect from multi-pill overdose: Patients and physicians should be confident that the patient will not be at risk of harm from accidentally or intentionally swallowing too many pills at the same time. This is accomplished with our MPAR™ (oral overdose protection) technology.
• Improved physician-monitored patient care: Provide more effective pain treatment via strengthening the important relationship between patients and their prescribing physicians. The combination of our Bio-MD and MPAR™ technologies limit the opioid drug blood levels achieved when multiple pills are ingested simultaneously. If a patient needs additional pain relief, the patient will revisit his or her physician to determine the appropriate adjustment to their pain management treatment.

Other companies have created formulations of existing prescription opioid drugs to deter abuse; however, these approaches are easily defeated via tampering, and in some cases they expose patients to additional risks. In contrast, we believe our technology poses no additional risk to patients and offers an unprecedented level of abuse resistance via all common routes of abuse:

•  Injection (“shooting”) or inhalation (“snorting” or smoking)
  
  • No “high” can be achieved because our Bio-MD systems:
    • Are essentially inactive in the blood
    • Do not readily cross the blood-brain barrier
    • Do not convert to active drug in the systemic circulation
    • Provide substantial chemical barriers to extracting active drug in vitro
• Oral
  • Systemic exposure of active opioid drug
    • Lowered to avoid “high”
    • Not increased by chewing, crushing, or dissolving tablets
    • Minimally increased after swallowing multiple pills simultaneously
      • Complementary MPAR technology

We believe that our new drug technologies will 1) provide the best treatment option for moderate-to-severe pain; 2) reduce the worldwide under-treatment of pain; 3) substantially decrease prescription opioid drug abuse; and 4) for the first time ever, provide protection against oral overdose.

MPAR™ (oral overdose protection) Technology

Patients often “mis-use” their opioid prescriptions by deciding to significantly escalate their dose. This high-risk misuse can eventually lead to abuse behavior (e.g. doctor shopping, early refills, addiction, etc.). Abusers often attempt to obtain a euphoric effect by ingesting multiple opioid tablets at the same time. With conventional opioids, this practice produces progressively higher amounts of opioid drug in the abuser’s blood stream to afford the desired “high”, or, all too frequently, the undesired lethal effect.

With regard to death from injury, poisoning is the second leading cause overall, and the leading cause for people aged 35–54 years, surpassing both firearm-related and motor-vehicle-related deaths in this age group. Drug poisonings are the largest category of poisoning, and opioid-related deaths are among the fastest increasing types of drug poisoning deaths. Opioid drugs Medications made from, artificially developed from, or containing opium, a potent pain-killing substance that is derived from poppy pods. Examples of opioid medications include morphine, codeine and hydrocodone. were involved in almost 40% of all poisoning deaths Deaths resulting from accidental or intentional overdoses of a drug, being given the wrong drug, taking the wrong drug in error, or taking a drug inadvertently. Poisoning deaths also include those involving biological or other toxic substances, gases, or vapors. in 2006, up from about 20% in 1999. About one-third of opioid-related poisoning deaths involved no other drugs.

Signature Therapeutics' MPAR technology complements our Bio-MD technology by providing multi-pill abuse resistance – taking away the incentive to abuse with multiple pills, including self-escalating the dose, and protecting from oral overdose. MPAR is uniquely applicable to drugs with our Bio-MD system’s mechanism of activation. When several doses of our MPAR-protected drugs are co-ingested, the systemic exposure (i.e., blood levels) of the opioid drug is dramatically limited. In other words, the exposure from taking 10 pills simultaneously can be limited to the exposure of 2 to 3 “unprotected” pills.

Figure 1 The red line depicts the maximum exposure (Cmax) following escalating multi-doses of an unprotected opioid. The blue line depicts the Cmax from equivalent escalating multi-doses with the protection of our MPAR™ technology.

We are further extending our technology to provide protection from serious adverse events, including fatality, resulting from drug-drug interactions (e.g. simultaneous ingestion of opioid drugs with benzodiazepines, which are prescribed for insomnia, anxiety, seizures, panic, and agitation).

Application of Our Technology

We are initially applying our technology to the full range of opioid drugs. Our portfolio of abuse-resistant opioid drugs includes:

• Bio-Activated Molecular Delivery™ and MPAR™ technologies
  • PF03: hydromorphone, oxymorphone, morphine
  • PF06: oxycodone, hydrocodone
  • PF16: tapentadol

We have further extended the technology to create abuse-resistant drugs for the treatment of ADHD, another category of drugs that is highly susceptible to abuse.

Because our opioid Bio-MD™ systems release known, active drugs, we believe that commercial launch can be achieved more rapidly than higher risk programs that have novel mechanisms-of-action and/or require late stage studies to demonstrate human proof-of-concept.

We have completed a Phase 1 human proof-of-concept study of our initial lead drug, extended-release hydromorphone (HM) Bio-MD™ system (PF329). The Phase 1 hPOC study demonstrated that PF329 is safe, that it releases HM in a dose-proportional manner, and that the delivery process is efficient. Time-to-maximal-plasma-concentration of HM following administration of PF329 is approximately two hours, which is slower than that of immediate-release HM and more rapid than the published data for Exalgo®, a commercial, once-per-day HM product. By delivering PF329 in solution in this study, Signature Therapeutics demonstrated that the extended-release profile is intrinsic to the molecule; that is, the Bio-MD™ technology does not involve the reformulation of existing opioid drugs in physical matrices that are easily circumvented by simple extraction methods. PF329's pharmacokinetic profile appears optimal for twice-daily dosing.

Partnering

We expect to enter a worldwide partnership for full development and commercialization of our opioid Bio-MD systems based on human proof-of-concept of our lead hydromorphone Bio-MD system, PF329. This partnership may involve an ongoing research collaboration focused on applying our proprietary technology to other opioids, developing our MPAR technology and, potentially, developing PF05 to reduce opioid side effects.