FX006 is a novel, non-opioid, sustained-release, intra-articular formulation of triamcinolone acetonide (TCA) targeting moderate-to-severe osteoarthritis (OA) pain. The Food and Drug Administration (FDA) has put patient enrollment in a Phase 2b safety and tolerability study on a clinical hold due to the development of a knee joint infection, which occurred in one enrolled patient.1 In a completed Phase 2b dose-ranging trial, clinically meaningful and significantly better pain relief was obtained with FX006 versus the current injectable standard of care, immediate-release TCA. In addition, synovial fluid pharmacokinetic studies following a single intra-articular injection of FX006 showed therapeutic concentrations of the drug in joint fluid for at least 12 weeks.2 A Phase 3 international, multi-center, randomized, blinded, single-dose study in 462 patients with OA of the knee is planned. The study will have three arms, a 40 mg dose of FX006, placebo and a 40 mg dose of immediate-release TCA. The primary objective of this trial is planned to provide the second pivotal efficacy dataset against placebo at 12 weeks before submitting a New Drug Application (NDA). The trial will provide a key comparative dataset against immediate-release TCA. Anticipated NDA filing could be in 2016.
Odanacatib is a once-weekly cathepsin K inhibitor, which is currently in Phase 3 clinical trials to treat postmenopausal osteoporosis.3 The Long-Term Odanacatib Fracture Trial (LOFT) randomized 16,713 women age 65 years and older who had a diagnosis of osteoporosis and had become menopausal at least five years prior. All women received vitamin D 5,600 IU a week and up to 1,200 mg/day of calcium. Patients were randomized to receive weekly odanacatib 50 mg (n=8,357) or placebo (n=8,356). Odanacatib-treated patients had a 54% relative risk reduction of new and worsening radiographically assessed vertebral fractures, a 47% relative risk reduction of clinical hip fractures, a 23% relative risk reduction of clinical nonvertebral fractures and a 72% relative risk reduction of clinical vertebral fractures (P<0.001 for all). Progressive increases in bone mineral density (BMD) were seen over five years in the total hip and lumbar spine. The change in BMD from baseline at Year 5 was 9.5% for total hip and 11.2% for lumbar spine (P<0.001 for both).
In the odanacatib-treated group, 12 patients developed morphea-like skin lesions that resolved or improved following drug discontinuation. According to the Mayo Clinic, morphea is a localized or limited form of scleroderma, which usually appears on the abdomen, but can affect the face (which can make patients concerned about their appearance), arms and legs.4
Other adverse effects in odanacatib-treated patients included 92 individuals who developed atrial fibrillation compared with 80 placebo-treated patients. Stroke was also more common in odanacatib-treated patients (n=109 [1.4%] vs. n=86 [1.1%]), and atypical femoral shaft fractures (n=5 [1.1%] vs. none for placebo-treated patients). The NDA is anticipated to be submitted in 2015.5
TNX-102 SL (cyclobenzaprine HCl 2.8 mg sublingual) is a sublingual pain management agent being investigated to treat fibromyalgia.6 In the recent Phase 2b BESTFIT (BEdtime Sublingual TNX-102 SL as Fibromyalgia Intervention Therapy) trial as a chronic bedtime fibromyalgia treatment, TNX-102 failed to meet the main goal of reducing patient pain by Week 12 of the study. Fibromyalgia patients did, however, have improved sleep quality while taking the agent, with a small amount (30%) experiencing pain reduction. The manufacturer is regrouping and may plan trials around TNX-102 to focus on sleep quality improvement as an indication rather than pain management. Another potential use is in treating post-traumatic stress disorder, potentially by enhancing sleep quality, as well.
Atypical fractures continue to be associated with bisphosphonates.7 According to Schilcher et al in their recent cohort analysis of long-term bisphosphonate use, for patients with osteoporosis, the benefits of bisphosphonate treatment outweigh the risk during the first years of treatment. However, for patients without osteoporosis and with only a moderate BMD decrease, the benefit of bisphosphonate use is likely to be smaller than the risk. Their team evaluated radiographs from over 5,300 men and women aged 55 years and older who had a femoral shaft fracture. Of these, 172 had atypical fractures according to the American Society for Bone and Mineral Research criteria (women: 160, men: 12).
The age-adjusted relative risk of an atypical fracture with bisphosphonate use was 55% and 54% among women and men, respectively. Among women the absolute and relative risks were three times higher than in male bisphosphonate users. Fracture risk among women increased with longer duration of bisphosphonate use. The multivariable-adjusted odds ratio with four to five years of current use was 100 times higher than with nonuse. Use of glucocorticoids or proton pump inhibitors along with bisphosphonates did not modify the risk of atypical fractures. In the patients with atypical fracture, bisphosphonate agents included alendronate (n=120), risedronate (n=16) and ibandronate (n=2).
Michele B. Kaufman, PharmD, CGP, RPh, is a freelance medical writer based in New York City and a pharmacist at New York Presbyterian Lower Manhattan Hospital.
- Flexion Therapeutics Inc. Flexion Therapeutics announces clinical hold of FX006 Phase 2b clinical trial in osteoarthritis of the knee. Press Release. Sept. 17, 2014. http://ir.flexiontherapeutics.com/releasedetail.cfm?ReleaseID=871411.
- Flexion Therapeutics Inc. Flexion Therapeutics to start FX006 Phase 3 pivotal trial in 2014; Following FDA meeting, development plan advanced by one year. Press Release. Sept. 3, 2014. http://ir.flexiontherapeutics.com/releasedetail.cfm?ReleaseID=868967.
- Barber J. Merck & Co.’s osteoporosis drug odanacatib hits main goal in Phase III study. First Word Pharma. Sept. 15, 2014. http://www.firstwordpharma.com/node/1235141#axzz3DUBpT59Y.
- Mayo Clinic staff. Diseases and conditions: Morphea. Mayo Clinic. Oct. 5, 2012. http://www.mayoclinic.org/diseases-conditions/morphea/basics/definition/con-20028397.
- Merck announces data from pivotal Phase 3 fracture outcome study for odanacatib, an investigational oral, once-weekly treatment for osteoporosis. Press Release. Sept. 15, 2014. http://www.mercknewsroom.com/news-release/research-and-development-news/merck-announces-data-pivotal-phase-3-fracture-outcomes-st.
- Tonix Pharmaceuticals Holding Corp. Tonix Pharmaceuticals reports top line results from Phase 2b BESTFIT Trial of TNX-102 SL in patients with fibromyalgia. Press Release. Sept. 29, 2014. http://content.stockpr.com/_news/tonixpharma/2014-09-29_Tonix_Pharmaceuticals_Reports_Top_Line_Results_Fro_854.pdf.
- Schilcher J, Koeppen V, Aspenberg P, et al. Risk for atypical femoral fracture during and after bisphosphonate use. N Engl J Med. 2014;371:974–976.