Our most advanced product candidate, KP201/APAP, is an immediate release (IR) combination of KP201, our prodrug of hydrocodone, and APAP (acetaminophen). We are developing KP201/APAP for the treatment of acute moderate to moderately severe pain.
KP201/APAP is designed to be an abuse-deterrent opioid product that offers equivalent efficacy to the existing standard-of-care, IR hydrocodone/APAP combination products such as Vicodin, Norco and Lortab. KP201 combines hydrocodone with the ligand benzoic acid and is designed not to release its hydrocodone component until it is metabolized in the GI tract following oral administration.
We designed KP201/APAP to deter tampering and abuse by selecting a molecular structure that prevents the release of the opioid upon crushing, physical manipulation and the application of other commonly employed extraction techniques. This approach to abuse-deterrence at the molecular level contrasts with other abuse-deterrent technologies, which are formulation-based, combining the opioid drug with another drug or in an abuse-deterrent capsule or physical matrix.
We believe our molecular-based approach to abuse-deterrence may be more effective than many formulation-based approaches as we believe the KP201 prodrug does not release hydrocodone effectively upon intranasal administration and has very poor solubility in blood, water and other solvents, thus rendering it unsuitable for intravenous (IV) administration.
Key Product Features of KP201/APAP
If approved by the FDA, KemPharm believes KP201/APAP may have many valuable product features and may provide significant benefits to patients, physicians and society, compared to other FDA-approved and widely prescribed IR hydrocodone/APAP combination products:
Molecular-based abuse-deterrent technology. Unlike formulation-based opioid abuse-deterrent approaches, KP201/APAP incorporates KemPharm’s LAT platform technology to create its abuse-deterrent properties at the molecular level. This may provide a higher barrier against attempted abuse than many existing formulation-based approaches.
No generic equivalent product. KP201 is a new molecular entity (NME) prodrug with a new chemical name, benzhydrocodone, and if approved, KemPharm expects it will have a lower prescribed milligram strength than the therapeutic equivalent amount of hydrocodone bitrate used in existing IR hydrocodone/APAP combination products. These differences will mean there will be no generic equivalent product for KP201/APAP in most states, making substitution difficult at the pharmacy.
Composition-of-matter patent protection. KP201/APAP is protected by a U.S. composition-of-matter patent on KP201 that will expire, after utilizing all appropriate patent term adjustments but excluding possible patent term extensions, in 2031.
KP201/APAP Human Abuse Liability Program Design and Data Review
The KP201/APAP human abuse liability program was designed by KemPharm to assess key abuse-deterrence criteria as specified by the FDA. The program included three clinical trials, KP201.A01, KP201.A02 and KP201.A03, as well as three distinct trials designed to evaluate the tamper-resistant properties of KP201/APAP.
Results from the KP201.A01 oral human abuse liability trial, which was designed to measure hydrocodone exposure, drug likability and the safety of KP201/APAP, as compared to Norco®, when taken orally at 4, 8 and 12 tablet dosages, indicated that KP201/APAP resulted in lower exposure to hydrocodone at the two highest dose levels for the trial, as well as lower incidence of hypoxia across the same dosage levels, in each case compared to Norco®, suggesting the potential for improved safety.
Results from the KP201.A02 intranasal human abuse liability trial, which was designed to determine the relative bioavailability, abuse potential, and safety of equivalent doses of crushed and intact KP201/APAP as compared to Norco®, indicated that KP201/APAP, when insufflated, reduces peak hydrocodone exposure (Cmax), delays the time to achieve peak exposure (Tmax), and significantly decreases in exposure to hydrocodone (AUC0-2h) at early time points typically associated with an increased safety risk.
Data from the KP201.A03 intranasal human abuse liability trial, which was designed to compare the amount of hydrocodone released from KP201 and from hydrocodone bitartrate (HB) (both without APAP) after insufflation, demonstrated a statistically significant reduction in Cmax, a delay in Tmax, and a significant decrease in total exposure to hydrocodone especially at early time points typically associated with increased drug liking, abuse and safety. Secondary endpoints related to drug liking, pupillometry and ease of snorting also showed significant differences between KP201 and HB, with KP201 demonstrating lower drug liking, less pupil dilation and higher difficulty of snorting than HB.
Lastly, results from three distinct trials designed to evaluate the tamper-resistant properties of KP201/APAP indicated that KP201 remains mostly intact in its inactive prodrug form when being subjected to various chemical manipulation techniques used commonly by opioid abusers. The trials demonstrated that efforts to extract and hydrolyze KP201/APAP were less efficient compared to HB/APAP tablets. Under the more than 1,000 conditions tested, KP201/APAP released less hydrocodone compared to the hydrocodone released from the HB/APAP tablets in every case, usually only yielding the inactive prodrug, KP201. Additionally, KP201/APAP is difficult to prepare for injection and it does not appear to be possible to smoke either KP201 or KP201/APAP.
KP201/IR
KP201/IR is an acetaminophen (APAP)-free formulation of its immediate release (IR) hydrocodone product, KP201. We expect this highly differentiated product candidate to feature the same abuse-deterrent properties demonstrated by KP201/APAP, our most advanced product candidate.
Based on current development timelines, KemPharm anticipates a potential New Drug Application (NDA) filing for acetaminophen-free KP201 in 2017. KP201/IR would be the first IR, acetaminophen-free hydrocodone option available to physicians.
KP511/ER
KP511/ER is an extended release (ER) formulation of KP511, KemPharm’s NME prodrug of hydromorphone, which the company is developing for the treatment of moderate to severe pain. KP511/ER is designed to be an abuse-deterrent opioid product that offers equivalent efficacy to approved ER hydromorphone products.
KemPharm’s prodrug, KP511, combines hydromorphone with one or more ligands and can be formulated in both IR and ER dosage forms. KP511 is designed not to release its hydromorphone component until it is metabolized in the GI tract following oral administration. We believe KP511 is highly tamper-resistant and is stable under conditions that can potentially defeat many formulation-based abuse-deterrent technologies.
KemPharm plans to seek approval of KP511/ER under the 505(b)(2) NDA pathway. Based on preclinical data, we believe that KP511 may release hydromorphone after oral administration in humans in a manner that is comparable to the appropriate approved hydromorphone drug.
Key Product Features of KP511/ER
Based on our preclinical data, KemPharm believes KP511/ER, if approved by the FDA, may have valuable product features and provide significant benefits to patients, physicians and society when compared to FDA-approved hydromorphone products:
Molecular-based abuse-deterrent technology. KP511/ER utilizes KemPharm’s LAT platform technology to create its abuse-deterrent properties at the molecular level, and the company believes it may have abuse-deterrent characteristics similar to KP201/APAP.
Oral overdose protection. In preclinical studies, KemPharm observed that hydromorphone blood levels in rats increased more slowly and to a lesser extent after oral administration of increasing excessively large doses of KP511, as compared to increasing equimolar oral doses of hydromorphone hydrochloride. We also observed that the study animals began dying from the increasing excessively large oral doses of hydromorphone hydrochloride, but never died from an equimolar oral dose of KP511. Based on the molecular structure of KP511, KemPharm believes it may be possible that the metabolic processes of releasing hydromorphone from the prodrug become saturated at excessively large oral doses. If confirmed by further studies, this could potentially mean that KP511 and KP511/ER may reduce the risk of oral overdosing by a unique mechanism that is inherent in the prodrug molecule itself.
KP606/IR
KP606/IR is an immediate release (IR) formulation of KP606, KemPharm’s NME prodrug of oxycodone, which the company is developing for the treatment of moderate to severe pain.
KP606/IR is designed to be an IR abuse-deterrent opioid product that offers equivalent efficacy to approved oxycodone products KP606 combines oxycodone with one or more ligands. We have currently formulated an IR dosage of KP606 and plan to develop an ER dosage.
KemPharm currently anticipates human proof-of-concept data for KP606/IR in 2017 and plans to seek approval of KP606/IR under the 505(b)(2) FDA pathway.
KP746
KP746, KemPharm’s NME prodrug of oxymorphone, is designed to be an abuse-deterrent opioid product that offers equivalent efficacy to approved oxymorphone products.
Based on preclinical studies of KP746, KemPharm believes that the prodrug may offer enhanced bioavailability at typical therapeutic doses and abuse-deterrent features in comparison to standard oxymorphone. Specifically, based on preclinical studies, KemPharm believes KP746 may be highly tamper-resistant and may be stable under conditions that can potentially defeat many other abuse-deterrent technologies, suggesting greatly reduced intranasal bioavailability and minimal to no release of oxymorphone when administered intravenously.
KP746 applies KemPharm’s Ligand Activated Therapy (LAT) platform technology and has the potential to be the first approved prodrug of oxymorphone.
