LIMITX Products in Development

LIMITX technology is intended to address an oral Excessive Tablet Abuse (ETA) or accidental consumption of multiple tablets and provide a margin of safety during accidental over-ingestion of tablets. LIMITX is also expected to exhibit barriers to abuse by snorting and injection. The patented LIMITX technology works by neutralizing stomach acid with buffering ingredients as increasing numbers of tablets are swallowed and relies on stomach acid to play a role in the release and subsequent systemic absorption of the active ingredient from micro-particles contained in the tablets. The FDA’s 2015 Guidance singles out immediate-release combination products with acetaminophen as being predominately abused by the oral route and that reducing nasal snorting of these products may not be meaningful.

Status

We have completed 3 proof-of-concept clinical studies on the LIMITX Technology. We currently have the following products in development utilizing our LIMITX Technology:

  • Immediate-release hydrocodone bitartrate/APAP (LTX-03)
  • Immediate-release hydromorphone HCl (LTX-04)
  • Immediate-release oxycodone HCl (LTX-01) & (LTX-02)
  • Immediate-release non-opioid drug (LTX-09)

Acura has changed its emphasis as it regards to the LIMITX Technology from LTX-04 to LTX-03 due to the larger market size for this product as well as the prevalence of excessive oral abuse of the hydrocodone bitartrate/APAP Tablets.

LTX-03

Study AP-LTX-300 (Study 300) – Study 300 demonstrated rapid release of drug from the micro-particle formulation providing expected therapeutic drug levels in the bloodstream for a single dose. A single dose of LTX-03 formulated without any buffer achieved a peak blood concentration (Cmax) of hydrocodone at 82% of the marketed reference drug. Comparatively, the Cmax of acetaminophen in LTX-03 from the same non-buffered dose was 63% of the reference drug. The acetaminophen Cmax was 100% of the reference drug across all doses in the study indicating the non-buffered LIMITX cohort was apparently unduly affected by the over-encapsulation of tablets used in Study 300. We believe these results indicate the potential for an improved Cmax for each drug when over-encapsulation is eliminated.

Study 300 was a parallel design, open label, pharmacokinetic buffer dose ranging study for 56 fasted healthy subjects. The study was comparing the LTX-03 tablet (10mg hydrocodone bitartrate/325mg acetaminophen) to a Norco® tablet with the same strength. The buffer that was included in the LTX-03 tablets was a fraction of what was previously used in studies 400 & 401 and was to be given to the subjects in an incremental number of buffering units ranging from 0 (no buffer) to 5 buffer doses. The buffer doses (if any) and the LTX-03 tablet were placed in a capsule (over-encapsulated) so that the test would replicate all subjects receiving a single dose of LTX-03. The purpose of this study was to determine the highest buffer level that allowed for the full release of hydrocodone bitartrate at a single tablet dose before the buffering effect is observed. In addition, acetaminophen blood levels were also analyzed and compared to the positive control.

Study 300 was not able to determine the definitive amount of buffer required to be placed in a LTX-03 tablet. This was due to erratic releases of the drug from the over-encapsulated tablets that were used in this Study.

Based on these results, another study without over-encapsulation is necessary which should guide us on the final formulation of LTX-03 tablets, which will combine the hydrocodone micro-particles, acetaminophen and buffer ingredients into a single tablet.

Study AP-LTX-301 (Study 301) – Study 301 was performed without over-encapsulation of tablets and took place in December 2017. Study 301 was an open-label, parallel design pharmacokinetic study testing our LIMITX formulation LTX-03 in 72 fasted healthy adult subjects randomized into 9 groups. One group was administered a single Norco® 10/325mg tablet, which is the marketed reference drug. The remaining 8 groups were administered a single LTX-03 tablet with differing (increasing) buffer amounts starting with no buffer (Formulations A through H).

Study 301 was conducted to examine bioequivalence (BE) to generate information for future registration studies. The study results demonstrated a trend toward BE for both active ingredients (hydrocodone bitartrate and acetaminophen) in LTX-03 formulations A through E. Formulation E had BE ratios for hydrocodone of 0.89 and 0.97 for Cmax and AUC (Area Under the Curve) respectively. Both hydrocodone BE confidence intervals were below the acceptable lower BE range of 0.80 at 0.74 and 0.79 for Cmax and AUC, however, the acetaminophen BE ratios for Formulation E were 1.15 and 1.03 for Cmax and AUC respectively. While the acetaminophen AUC’s met the BE standards, the Cmax upper confidence interval of 1.61 was above the acceptable upper BE range of 1.25. We believe that bioequivalence of this formulation may be achieved by reducing data variability that can be achieved through an adequately powered crossover study design with sufficient numbers of subjects in the study. Formulations F through H of LTX-03 which were the higher buffer level tablets measured in increasing reduction in hydrocodone Cmax culminating in a 34% Cmax reduction associated with Formulation H, the highest buffer level evaluated. The Cmax for acetaminophen did not decline in Formulations F through H in Study 301.

In summary, we believe that Study 301 identified a formulation that optimizes the balance between providing therapeutic blood levels of drug for pain relief at a single tablet dose while retarding the bioavailability of drug when higher buffer levels are ingested.

We intend to proceed in the development of LTX-03 to clinical development for a New Drug Application (NDA). During the first quarter of 2018, we submitted an IND (Investigational New Drug Application) for LTX-03 to the FDA which became effective in April 2018. During the second quarter of 2018, we have commenced the scale-up of the commercial manufacturing process as to-be-marketed formulations are required for all NDA development work, however, we may run additional exploratory studies before manufacturing scale-up is complete to further understand the LIMITX Technology.

LTX-04

Study AP-LTX-400 (Study 400) and AP-LTX-401 (Study 401) – Studies 400 and 401 tested LTX-04 in the presence of buffer compared to a marketed reference drug and both demonstrated a reduction in Cmax at the buffer level tested. Study 400 demonstrated a 45% and 50% reduction in Cmax for LTX-04 at two different buffering strengths. The Cmax reduction for LTX-04 improved to 59% with an 8 tablet dose. The results of Study 401 confirmed these findings with a 48% reduction in Cmax at a single tablet dose and a 65% reduction for a 7 tablet dose.

Study 401 also had an experimental arm in which LTX-04 at a 7 tablet dose included an agent known to increase gastric emptying time in an effort to retain the excess buffer ingredients in the stomach for a longer period of time. The exploratory arm demonstrated an increase in time to Cmax in the bloodstream (lnTmax) to slightly over 2 hours compared to 43 minutes for reference and 73 minutes for LTX-04 alone. Peak concentration of drug in the bloodstream (lnCmax) for the exploratory arm was 3.74 ng/mL compared to 6.73 for hydromorphone and 2.49 for LTX-04 alone. We believe the exploratory results support that the LIMITX technology is affecting the amount and timing of drug in the bloodstream as we manipulate the stomach acidity.

Studies 400 and 401 were cross-over design pharmacokinetic studies in 56 and 64 health adult subjects, respectively. Study 400 tested LTX-04 against a marketed reference drug at doses of 1, 2, 3, 4, 6 and 8 tablets. Doses of LTX-04 at 1 through 3 tablets included two test articles containing different levels of buffer. Study 401 dosed 1 and 7 tablet doses with LTX-04 tested at a single buffer level.