Osteoarthritis

Emerging drugs in osteoarthritis


Osteoarthritis is progressing as one of the major growing health conditions, with recent estimates suggesting that approximately 250 million people worldwide are affected 1.  In the next 20 years it is predicted this figure will increase by around 50% 2.

Based on data from the Australian Institute of Health and Welfare there has been a 47% rise in total knee replacements from osteoarthritis from 2003-04 to 2012-13 3.

Osteoarthritis is a disease involving the whole joint, with a multifactorial etiology, including mechanical stress, ageing process, genetic predisposition and underlying anatomical disorders.

The development of symptoms and disease progression is highly variable between individuals.

At the molecular level, its pathogenesis incorporates increased activities of inflammatory chemokines and cytokines, synovitis, and changes in bone turnover and mineralisation.

A need for new drugs

Conservative management of osteoarthritis based on recent guidelines involves a combination of weight management, physical therapy, gait modification with aids as core treatment, and medications as adjuncts.

To date, available medications are of palliative nature in the management of osteoarthritis, predominantly in the form of analgesics. Whilst non-steroidal anti-inflammatory drugs are of benefit, it is often not recommended in many individuals due to potential cardiovascular, gastrointestinal and renal side effects 5.

This is further complicated as osteoarthritis is predominantly associated with the ageing population group, who are regularly troubled with multiple health co-morbidities.

Given the disease burden, development of disease modifying osteoarthritis drugs (DMOADs) is an important focus, in an attempt to impact both disease progression and symptom management.

Managing pain a priority

The management of pain in clinical practice remains a challenge and development of novel therapies to address this imperfectly met need also remains a research priority.

Targets for potential treatment are based on pain management and prevention/slowing of structural joint progression.

There are a multitude of medications currently in phase 2 and 3 trials. Some are reformulations of existing compounds, in particular, sustained release formulation of triamcinolone acetonide (FX006). An exploratory dose ranging study showed significant analgesic effect compared with an immediate release suspension after 4 weeks 6.

Intra-articular hyaluronic acid, to date, has not shown to have a significant difference in comparison to placebo 4. Despite this, a phase 3 trial assessing Hydros TA, a dual mode viscosupplement with triamcinolone and Hydros hydrogel beads is currently being completed.

A novel non-steroidal anti-inflammatory drug formulation of a non-selective COX-2 inhibitor and a carbonic anhydrase (Polmacoxib) aims to reduce associated gastrointestinal and cardiovascular side effects 7. 

Monoclonal antibodies against nerve growth factor (Tanezumab) showed initial promise in both osteoarthritis and other pain syndromes such as back pain8.

The trials were put on clinical hold due to concerns regarding secondary joint failure resulting in accelerated osteoarthritis requiring joint replacement surgery.

This suggests that completely extinguishing pain in persons with osteoarthritis may alter the innate self-protective mechanism that one develops in response to avoidance of pain, leading to potential for increased harm. Interestingly, after analysis of the positive non-clinical data by the FDA, the trials will resume towards the end of this year (2015).

Towards disease modifying drugs 

Looking at potential agents for structural modifications, there are a multitude of focus areas and these can be broadly divided into groups based upon their purported targets including agents targeting the inflammatory pathways, cartilage catabolism and anabolism (growth and breakdown), and subchondral bone remodeling.

Within the inflammatory pathways, the main targets are IL-1b and TNF-a; biological agent targets typically used in rheumatoid arthritis. Most osteoarthritis trials with TNF-a inhibitors have been disappointing, perhaps not surprisingly, given the lower degree of inflammation in osteoarthritis.

Many IL-1 agents also failed to demonstrate significant response in pain reduction. A phase 2 trail of ABT-981 (anti-IL-1a/b), is currently under recruitment, given the positive phase 1 findings 9. Other inflammatory targets include inducible nitric oxide synthase, vascular adhesion protein-1, bradykinin B2 receptor.

In regards to cartilage catabolism and anabolism – this includes bone morphogenetic protein-7, with its recombinant protein, Eptotermin alfa showing potential in its phase 1 studies, with a trend towards symptomatic improvement at the 12 week follow-up.10

Early studies of fibroblast growth factor-18 have demonstrated improvement in tibiofemoral cartilage volume and reduction in joint space narrowing at the 1 year interval.11, 12.

The commercial use of platelet-rich plasma and stem cells are concerning. Whilst theoretically, they may be ideal in their possible ability for cartilage repair, the exact mechanism of action remains uncertain. They are confounded in the lack of standardization of study protocols with widely varied preparations of these and lack of randomized controlled trials against placebos.

Stem cell clinical trials are in force, with majority in phase 2-4. However, to date, no results are posted. We do not recommend current utilisation of these agents.

The usage of osteoporosis medications, including bisphosphonates and strontium to target subcondral bone remodeling are based on their inhibitory effect on osteoclasts, however mixed results are seen with bisphosphonates 13, 14 and whilst strontium may be of benefit 15, its tempered by apprehensions regarding its associated cardiovascular side effects.

Calcitonin also promotes inhibition of bone resorption via its effect on osteoclasts. Significant improvements have been in seen pain and function 16, a more recent phase 3 trial was terminated due to concerns with prostate cancer occurrence.

Exciting times for osteoarthritis research

Osteoarthritis is a chronic, complex disease. There remains an unmet need for effective and safe therapeutic options. These are exciting times in osteoarthritis research, but the development of DMOADs are hampered by the ability to demonstrate significant positive effects to date.

The disease itself is slow in progression, thus clinical trials spanning a couple of years are unlikely to show significant changes over time. The disease itself is largely mechanically driven; targeting disease process at the molecular level is likely to be insufficient.

The application of multi-drug regimens targeting different mechanisms may be a more appropriate consideration. Focus towards modification in early disease is key, where changes are likely to be more reversible.

References

  1. Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2163-96.
  2. Hunter DJ, Schofield D, Callander E. The individual and socioeconomic impact of osteoarthritis. Nat Rev Rheumatol. 2014;10(7):437-41.
  3. http://www.aihw.gov.au/arthritis-and-musculoskeletal-conditions/.
  4. McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Berenbaum F, Bierma-Zeinstra SM, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage. 2014;22(3):363-88.
  5. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA. 2006;296(13):1633-44.
  6. Bodick NL, J.; Willwerth, C.; Kumar, A.; Bolognese, J.; Schoonmaker, C.; Hunter, D.; Clayman, M.D. Safety and efficacy of FX006 in patients with osteoarthritis of the knee. Osteoarthritis and Cartilage. 2014;22(Supplement):S376-77.
  7. Skarke C, Alamuddin N, Lawson JA, Cen L, Propert KJ, Fitzgerald GA. Comparative impact on prostanoid biosynthesis of celecoxib and the novel nonsteroidal anti-inflammatory drug CG100649. Clin Pharmacol Ther. 2012;91(6):986-93.
  8. Lane NE, Schnitzer TJ, Birbara CA, Mokhtarani M, Shelton DL, Smith MD, et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N Engl J Med. 2010;363(16):1521-31.
  9. Wang SXM, J.K.; Kosloski, M.P.; Liu, W.; Saltarelli, M.J., Karsdal, M. Interleukin-1 dual variable-domain immunoglobulin reduces multiple inflammatory markers in knee osteoarthritis patients. Ann Rheum Dis. 2014;73(Supplement 2):756.
  10. Hunter DJ, Pike MC, Jonas BL, Kissin E, Krop J, McAlindon T. Phase 1 safety and tolerability study of BMP-7 in symptomatic knee osteoarthritis. BMC Musculoskelet Disord. 2010;11:232.
  11. Mastbergen SC, Saris DB, Lafeber FP. Functional articular cartilage repair: here, near, or is the best approach not yet clear? Nat Rev Rheumatol. 2013;9(5):277-90.
  12. Lohmander LS, Hellot S, Dreher D, Krantz EF, Kruger DS, Guermazi A, et al. Intraarticular sprifermin (recombinant human fibroblast growth factor 18) in knee osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2014;66(7):1820-31.
  13. Bingham CO, 3rd, Buckland-Wright JC, Garnero P, Cohen SB, Dougados M, Adami S, et al. Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study. Arthritis Rheum. 2006;54(11):3494-507.
  14. Spector TD, Conaghan PG, Buckland-Wright JC, Garnero P, Cline GA, Beary JF, et al. Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized, controlled trial [ISRCTN01928173]. Arthritis Res Ther. 2005;7(3):R625-33.
  15. Reginster JY, Badurski J, Bellamy N, Bensen W, Chapurlat R, Chevalier X, et al. Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial. Ann Rheum Dis. 2013;72(2):179-86.
  16. Karsdal MAA, P.; John, M.R.; Loeffler, J.; Arnold, M.; Azria, M.; Byrjalsen, I.; Riis, B.J.; Christiansen, C. Oral calcitonin demonstrated symptom-modifying efficacy and increased cartilage volume: results from a 2-year phase 3 trial in patients with osteoarthritis of the knee. Osteoarthritis and Cartilage. 2011;19(Supplement 1):S35.

 

Already a member?

Login to keep reading.

OR
Email me a login link
logo

© 2022 the limbic