Are oral Tumor Necrosis Factor inhibitors (TNFi) effective?

Oral TNF Inhibitors for Inflammatory Diseases

Currently, there are no FDA-approved oral TNF inhibitors available for clinical use, though small molecule oral TNF inhibitors are in development with promising early results.

Current Status of TNF Inhibitors

TNF inhibitors (TNFi) are a cornerstone therapy for several inflammatory conditions, including:

• Rheumatoid arthritis (RA)
• Ankylosing spondylitis (AS)
• Psoriatic arthritis (PsA)
• Inflammatory bowel disease (IBD)

Available TNF Inhibitors

All currently approved TNF inhibitors are administered parenterally 1:

• Monoclonal antibodies:
  • Infliximab (IV)
  • Adalimumab (SC)
  • Golimumab (SC)
  • Certolizumab pegol (SC)
• Fusion protein:
  • Etanercept (SC)

Emerging Oral TNF Inhibitor Development

Research into oral TNF inhibitors is ongoing:

• SAR441566 is a small molecule TNF inhibitor that has advanced to Phase 1 clinical trials 2
• This compound stabilizes an asymmetrical form of soluble TNF, compromising downstream signaling
• It aims to provide a more convenient oral alternative to injectable biologics 2

Comparative Effectiveness of Current TNFi

TNF inhibitors have demonstrated significant efficacy in inflammatory conditions:

• In RA, they produce significant improvements in all measures of disease activity compared to placebo 1, 3
• In AS, TNFi are strongly recommended for patients with active disease despite NSAID treatment 4
• For PsA, TNFi are recommended over other oral small molecules for patients with active disease 4

Treatment Algorithms Based on Current Guidelines

For Ankylosing Spondylitis:

1. First-line: NSAIDs (trial of at least 2 different NSAIDs at maximal doses)
2. Second-line: TNF inhibitors or IL-17 inhibitors (secukinumab or ixekizumab)
   • TNFi are conditionally recommended over IL-17 inhibitors 4
3. Third-line: Tofacitinib (oral JAK inhibitor) only after failure of biologics 5

For Rheumatoid Arthritis:

1. First-line: Conventional DMARDs (methotrexate preferred)
2. Second-line: TNF inhibitors or other biologics/JAK inhibitors
   • For MTX-inadequate responders, guidelines don't specify preference between TNFi or other mechanisms 4

For Psoriatic Arthritis:

1. First-line: Conventional DMARDs
2. Second-line: TNF inhibitors (preferred over other biologics for most patients)
3. For TNFi failures: Consider switching to another TNFi or different mechanism (IL-17i, IL-12/23i) 4

Special Considerations

• Concomitant IBD: Monoclonal antibody TNFi (not etanercept) are strongly recommended 4
• TNFi failure:
  • For primary non-response, switching to IL-17 inhibitors is conditionally recommended 4
  • For secondary non-response, switching to a different TNFi is conditionally recommended 4
• Contraindications to TNFi:
  • Heart failure or demyelinating disease: Consider IL-17 inhibitors 4
  • Tuberculosis or chronic infection: Consider sulfasalazine 4

Future Directions

The development of oral TNF inhibitors could potentially transform treatment paradigms by:

• Improving patient convenience and adherence
• Potentially reducing costs compared to biologics
• Offering an alternative administration route for patients who prefer oral medications

However, until oral TNF inhibitors complete clinical trials and receive regulatory approval, parenteral TNF inhibitors remain the standard of care for appropriate patients with inflammatory conditions.