TQ-1021 (Topical Mepivacaine)
TQ-1021 is a proprietary topical dosage form of the local anesthetic mepivacaine for the treatment of painful peripheral neuropathies, such as painful diabetic neuropathy, postherpetic neuralgia and painful HIV-associated neuropathy. We expect that TQ-1021 will be used alone or in combination with oral therapies such as Lyrica® and Cymbalta® for the treatment of neuropathic pain. TQ-1021 will compete in the same market segment as Lidoderm® patch, which had U.S. sales of $770 million for 2009. By 2018, the market for neuropathic pain drugs across seven major markets (US, Japan, France, Germany, Italy, Spain and the UK) is variously projected to grow to $5.5 billion (Datamonitor) or $9.7 billion (Decision Resources).
We have received two orphan drug designations for mepivacaine, one each for the treatment of painful HIV-associated neuropathy and postherpetic neuralgia. In addition to the 7-year market exclusivities, each orphan drug designation provides a 50% R&D tax credit with a 17 year carry forward, transferability of assets and tax credits and exemption from NDA user fees.
We have developed several gel and cream formulations of TQ-1021 with robust skin permeability and stability. The dosage forms are undergoing further ex vivo and in vivo diffusion and permeability assessments. Pharmaceutical development of a patch dosage form is also underway.
Pharmacologic Rationale for Topical Mepivacaine
A limited number of treatments are available for PHN and even fewer have been approved by the FDA. Lidoderm® patch was approved in 1999, Neurontin® in 2002, Lyrica® in 2004 and Qutenza® in late 2009. Many patients obtain no relief from these agents and seldom is pain relief complete.
Lidoderm® provides only modest pain relief in patients with PHN, with a number need to treat (NNT) of 4.4 patients for one patient to obtain ≥ 50% relief from ongoing pain (steady pain), and a NNT of 8.4 patients for one patient to obtain ≥ 50% relief from allodynia (pain from non-painful stimulus). This is a lower efficacy response than other drugs, including antiepileptics (NNT=3.2), antidepressants (NNT = 2.1) and OxyContin® (NNT = 2.5). The effect size for reduction of ongoing pain for Lidoderm® is 0.4, while the effect size for OxyContin® is 0.75. Effect sizes of 0.2, 0.5 and 0.8 are considered small, medium and large, respectively.
Mepivacaine has a number of potential advantages over lidocaine including: (i) intrinsic vasoconstrictor effects, thereby reducing the rate at which drug is cleared away from peripheral (skin) sites of pain generation and (ii) the lowest potential for neurotoxic effects on developing or regenerating primary cultured neurons with lidocaine having the highest neurotoxic potential in this model (Radwan et al., Anesth Analg 2002; 94:319-24).
Efficacy of Topical Mepivacaine in Preclinical Models of Pain
We have evaluated the analgesic efficacy of topical mepivacaine in a number of validated analgesic models, including the HIV viral envelope protein (gp120) model of painful HIV-neuropathy, a combined antiretroviral (ddC)/gp120 model of painful HIV-neuropathy and the radiant heat tail-flick assay. The results of our studies indicate a robust analgesic effect of topically applied mepivacaine.
Topical Mepivacaine Reverses Mechanical Allodynia
in Painful HIV Neuropathy Model
Topical Mepivacaine Reverses Thermal Hyperalgesia
in Painful HIV Neuropathy Model
Formulation Rationale for Topical Mepivacaine
TheraQuest is developing gel and patch formulations of mepivacaine for application to the skin. In addition to its low efficacy, Lidoderm® patch provides poor adhesion, particularly over highly contoured and hairy skin surfaces. Patients using Lidoderm®sometimes resort to application of adhesive tapes, bandages and skin fasteners to secure the patch to skin. Additionally, use of a patch may be problematic for the treatment of distal painful neuropathy such as painful diabetic neuropathy and painful HIV-neuropathy which primarily involve the feet. This is due to the absence of a large, contiguous flat surface to assure patch adhesion, the need for footware, and the need to have a clear and unobstructed view of the feet for daily inspection in patients with diabetes who have poor wound healing.
Compared with Lidoderm® patch, TQ-1021 gel can be expected to provide:
- More suitable dosage form for application to the extremities
- Improved skin contact
- More efficient drug delivery
- Potentially improved efficacy
- Improved prescriber and patient acceptance
Compared with Lidoderm® patch, TQ-1021 patch can be expected to provide:
- Improved skin adhesion
- Longer application(Lidoderm® is 12 hours on & 12 hours off)
- More efficient drug delivery
- Increased compliance
- Improved prescriber and patient acceptance
We have developed and tested a number of stable semisolid dosage forms (microemulsion, gel and cream) of mepivacaine for application to the skin. The formulations demonstrate robust in vitro and ex vivo diffusion and permeability and stability under ICH conditions. The semisolid dosage forms of mepivacaine are ready for GMP manufacture and human testing. Further development work on a patch formulation is under way.
Cumulative Skin Permeation of Mepivacaine Gel
Intellectual Property and Market Exclusivity
We have received an orphan drug designation for the treatment of PHN and painful HIV neuropathy, each of which is associated with a 7-year marketing exclusivity. This exclusivity will run concurrently with the 3 year Hatch-Waxman exclusivity. In the E.U, we believe TQ-1021 may be eligible for 10-year data exclusivity. In addition, TheraQuest has filed a method of use and pharmaceutical composition patent application for topical mepivacaine. We intend to cement our market exclusivity through additional patents and through the introduction of line extensions.