Elite Pharmaceuticals Inc (ELTP)

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How Pharma Copes with the Pain of Developing Abuse-Deterrent Opioids

https://citeline.com/wp-content/uploads/2015/02/Jan-2015_Abuse-Deterrent-Opioids_HeidiChen.pdf

With the wide availability of generic opioid analgesics, such as oxycodone and hydromorphone, the abuse of prescription opioids has become a major public health problem in the US. Consequently, in January 2013, the FDA released draft guidance for drug makers that mandates inclusion of abuse- deterrent technology for new opioid products. Data from Pharmaprojects and Trialtrove were analyzed to explore the current development for opioid analgesics with abuse-deter- rent technology in order to gain insight into the front runners of this competitive area, their characteristics, and the top sponsors on the verge of becoming market leaders.

One of the most common approaches in abuse-deterrent technology is the development of new formulations of extended-release opioids, or tamper resistant properties that render the drugs difficult to crush, grind, and dissolve for injection or nasal insufflation by potential abusers. The reformulation approach for approved opioids, with their proven efficacy and acceptable safety profiles, is an attractive develop- ment pathway that requires primarily safety and bioequivalence studies and leads to an abbreviated clinical program.

Pharmaprojects profiles for the current reformulations applied to the opioid compounds, and their abuse-deterrent technologies, are captured in Figure 1. The majority of reformulations involve modified-release of the opioid over time (immediate-release, <24 hour-release) or fixed-dose combinations that render the drug more resistant to crushing or abuse. Other abuse deterrent technologies, such as transdermal patch and transmucosal delivery technologies, are a small niche that may offer an alternative to oral or injectable routes of administration without compromising the physical integrity of the compound.

Besides rendering the opioid resistant to physical manipulations, reformulations can be designed to alter how the drug binds to opioid receptors, thereby, reducing the potential euphoric effect and discouraging abuse behavior. One example is the use of naltrexone in fixed-dose combination with an opioid. Naltrexone acts as an opioid receptor antagonist by blocking opioid receptors in the brain and produces a “withdrawal” rather than a euphoric effect. The specific details of how drug developers incorporate abuse-deterrent technology are usually considered proprietary, but may be disclosed more widely once these new drugs reach the market.

Trialtrove data profiles the clinical trials of the top 10 sponsors for abuse-deterrent opioids, illustrating that nearly 60% of the 109 trials are Phase I studies because most of these drugs are reformulations of marketed opioids. These programs require fewer clinical trials and focus primarily on bioequivalence and the effectiveness of tamper-resistant technologies. Purdue Pharma, whose Oxycontin was the market leader prior to generics reaching the market, is the top sponsor by number of sponsored trials. Aside from Pfizer and Johnson & Johnson, the majority of the sponsors are considered “boutique” firms with a vested interest or specialty in pain therapeutics. These smaller pharmaceutical companies have a focus on proprietary controlled-release and tamper proofing technologies, which are combined with the marketed opioids, to facilitate generation of new pain medications.

The table summarizes the notable clinical-stage candidates of abuse-deterrent opioids, many of which are sponsored by the top 10 companies. Clearly there is a healthy pipeline of both pre-registration and Phase III programs.

After the FDA published its guidance on abuse-deterrent opioids in January 2013, the October 2013 approval of Zohydro ER, a 12hr controlled-release formulation of the highly potent opioid hydrocodone without anti-abuse protection, caused heated debates, as critics voiced concerns that this approval puts patients at unnecessary risk. The FDA stood by its decision that the requirement of abuse-deterrent properties for all new opioid drugs was not feasible at the time. Today, Zogenix continues to fill their pipeline with new Zohydro ER candidates. Their hydrocodone bitartrate (extended-release) is a pre-reg- istration stage compound utilizing Alkermes’ Spheroidal Oral Drug Absorption System as the deterrent technology, and a second hydrocodone bitartrate (extended-release) formulated with Altus’ proprietary Intellitab drug delivery platform is in Phase I development. If approved, Zogenix intends to transition the currently marketed Zohydro ER to the modified formulation of Zohydro ER that has been designed to have abuse deterrent properties. Zogenix’s strategy of releasing Zohydro ER first, followed by the “upgraded” versions containing abuse-deterrent properties, may give Zogenix an advantage by extending patent protection on the drug.

In addition, Purdue, who completed pivotal trials for Hysingla ER in early 2014 with positive results, was granted priority review by the FDA for this compound. Since acquiring Cephalon’s hydrocodone bitartrate, Teva’s CEP-33237 has shown a consistent safety profile and efficacy in patients with chronic low back pain. Pfizer’s naltrexone + oxycodone FDC (AL-02) completed its pivotal phase III trials in 2014 and is ready to advance towards NDA submission. Elite Pharmaceuticals has a rich pipeline of abuse-deterrent opioids, most of which are in Phase III development. In early December 2014, Elite reported successful results from a pivotal study of its twice- daily naltrexone+oxycodone FDC. Elite Pharmaceuticals plans to submit a NDA filing, which places it in direct competition with Pfizer’s FDC candidate.

Since the FDA released its draft guideline for development of abuse-deterrent opioids in January 2013, considerable industry development produced a first wave of new therapeutics to reach the registration stage. The relative ease with which this approved class of effective pain drugs can be reformulated, and the huge unmet need of reducing the risk of opioid abuse, has contributed to this robust wave of development by many sponsors. The FDA has since met with industry sponsors to discuss new approaches to pain management, but development of novel classes of pain drugs remains at an early stage. In recent FDA news, CDER disclosed its 2015 priorities, including issuing final guidance on abuse-deterrent opioid formulations as one of its front burner priorities. As we await the much anticipated final guidance in 2015, Citeline will be looking closely at how the FDA will shape the opioid market. Hopefully, these steps will enable access to effective pain medications while reducing the risk of prescription drug abuses that have now reached near epidemic proportions.