PRECLINICAL
PHASE 1
PHASE 2
PHASE 3
Molecule: Onzotrigine (LTG-001)
Acute Pain: Demonstrated highest analgesic effect seen in abdominoplasty trial
Onzotrigine (previously referred to as LTG-001) is a novel, non-opioid, orally bioavailable small molecule that selectively and potently inhibits NaV1.8 in development as a potential treatment for moderate to severe acute pain. We received positive data for onzotrigine in a randomized, placebo and comparator-controlled trial in 343 patients undergoing abdominoplasty. These results were published in The New England Journal of Medicine.
Based on our discussions with the FDA, this trial may serve as one of the two pivotal adequate well-controlled trials required to demonstrate efficacy to support approval for the treatment of moderate to severe acute pain, including postoperative pain. This trial met the primary endpoint of SPID48 with high dose of 450mg / 300mg BID of onzotrigine achieving statistically significant pain reduction of 62.1 points compared to placebo. High dose of onzotrigine also achieved 50% greater analgesic effect than Vicodin, the opioid comparator used in the trial. High dose onzotrigine achieved meaningful pain relief at 52 minutes post-dose. The opioid comparator arm did not achieve meaningful pain relief until 83 minutes post-dose. 52.3% of patients receiving high dose onzotrigine remained opioid-free during the 48-hour treatment period. Onzotrigine has been generally well-tolerated to date. We plan to initiate a placebo-controlled Phase 3 trial in participants undergoing bunionectomy and an open-label Phase 3 safety trial.
Status: Abdominoplasty Trial Completed; Phase 3 Bunionectomy and Safety Trial Planned
Molecule: LTG-321
Chronic Pain: Potential first-in-class in osteoarthritis pain
LTG-321 is our next-generation candidate for the inhibition of Nav1.8, initially being developed for the treatment of chronic musculoskeletal pain, starting with osteoarthritis. LTG-321 is structurally distinct from onzotrigine. LTG-321’s differentiated profile may enable a lower effective dose and once daily dosing, characteristics we believe are particularly important for a chronic-use setting. We have completed a randomized, double-blind, placebo-controlled Phase 1 clinical trial of LTG-321 in healthy volunteers. The trial enrolled four single ascending dose cohorts and four multiple ascending dose cohorts to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of LTG-321 in healthy volunteers. The results from the Phase 1 trial showed that LTG-321 exhibited dose-proportional exposure across all doses tested.
As part of our Phase 1 trial, we also conducted a randomized, double-blind, placebo-controlled within-participant crossover CPT to evaluate the pharmacodynamic effects of LTG-321, which showed high increase in pain tolerance threshold and continued activity out to 24 hour post-dose assessment.
We intend to investigate LTG-321 as a treatment for chronic pain, and have initiated a Phase 2 trial of LTG-321 in patients with osteoarthritis (OA) of the knee. The Phase 2 trial is a randomized, double-blind, placebo-controlled within-patient crossover trial in approximately 120 patients with OA of the knee.
Status: Phase 1 SAD / MAD and Cold Pressor Test Completed; Phase 2 Trial Initiated
Molecule: Onzotrigine IV
Acute Pain: Designed to allow IV to oral therapy transition
In addition to developing onzotrigine as an oral twice-daily therapy, we are also developing onzotrigine as a potential IV therapy to enable the transition from the postoperative period to patient discharge in hospital settings. We have completed bioavailability studies for the onzotrigine IV formulation, with preliminary data indicating approximately 100% bioavailability. We are currently evaluating dosing regimens and plan to seek regulatory feedback on the clinical development strategy.
Status: Bioavailability Study Completed
Molecule: LTG-418
Potential for improved potency, novel formulations
Our earlier stage Nav1.8 pipeline consists of next-generation Nav1.8 inhibitor molecules, which may provide effective pain management medicines at a lower dose than other Nav1.8 inhibitors. LTG-418 is a next-generation drug candidate for inhibition of Nav1.8 being developed for the treatment of acute and chronic pain. LTG-418 is structurally distinct from onzotrigine and LTG-321 and is predicted to have a dose which will be substantially lower than the expected doses for onzotrigine and LTG-321. We believe the predicted lower dose with LTG-418 is one of the features that may enable additional opportunities for other formulations and routes of administration including gels, patches, eye drops, inhalers and injectables, expanding our reach within the pain market and offering patients therapeutic options beyond oral and IV delivery. Suitable tolerability was demonstrated in completed 14-day non-GLP toxicology studies in both rats and non-human primates.
Status: Drug Candidate Selected
Additional Discovery
We are also in discovery of additional ion channel modulators involved in peripheral transmission of pain that represent potential complementary mechanisms of action to Nav1.8 inhibition for additional pain relief, including in other chronic pain etiologies like neuropathic pain.
Publications
The New England Journal of Medicine: Phase 2b Trial of a Nav1.8 Inhibitor for Acute Pain
Read the full publication here.