Is Tachyphylaxis a Concern in Anti-VEGF Therapy?

Anti-VEGF agents may fail over the long term.

John Hwang, MD, MBA • Julie Gasperini, MD • Amani A. Fawzi, MD

Tachyphylaxis, a phenomenon wherein repeat administration of a drug is associated with a decreased therapeutic response, is a well-described pharmacologic entity that is associated with drugs such as infliximab,¹ brimonidine² and oxymetazoline.³ Long-term therapy with such agents has been associated with initial treatment success, followed by a diminution of biologic effect.

A number of studies have suggested the occurrence of tachyphylaxis during anti-VEGF therapy. Keane et al.⁴ first recognized a potential tachyphylactic response in a study evaluating the effect of ranibizumab on retinal morphology in neovascular AMD patients. Their study demonstrated an initial robust response to ranibizumab with a reduction of subretinal fluid and retinal edema to nadir. However, continued treatment with ranibizumab led to an attenuated response and an increase in subretinal fluid. Schaal et al.⁵ demonstrated a similar phenomenon in a study evaluating OCT volumetric change following intravitreal bevacizumab injections in neovascular AMD patients. The authors demonstrated that repeat intravitreal bevacizumab treatments were associated with decreased bioefficacy, suggesting possible tachyphylaxis. These findings were further corroborated by Forooghian et al,⁶ who identified a subset of neovascular AMD patients who developed tachyphylaxis following an initial response to bevacizumab therapy.

The etiology of tachyphylaxis is thought to be multifactorial and may include cellular and metabolic mechanisms that ultimately lead to diminished therapeutic efficacy.^1-3,7 Cellular adaptations may include changes in surface receptor expression, alterations in signaling pathway feedback and development of a systemic immune response. Chronic VEGF blockade may alter the expression pattern of surface receptors and modify the quantity and/or sensitivity of receptors. Long-term suppression may also augment feedback to other angiogenic signaling pathways or pathways acting downstream of VEGF.

Production of VEGF may also be upregulated by macrophages within CNV tissue,⁸ and the response to anti-VEGF treatment may be dependent on the composition and structural integrity of the CNV lesion.⁶ Both ranibizumab and bevacizumab contain murine antibody components, which may elicit systemic immune reactions with repetitive treatment. Bevacizumab levels have been detected systemically with intravitreal treatment⁹ and may be recognized as an antigen by the immune system. Antibodies active against ranibizumab have been isolated following intravitreal injections and rise progressively in patients undergoing chronic intravitreal therapy.¹⁰ Metabolic tolerance may arise from alterations in pharmacokinetics with changes in drug absorption, distribution and metabolism.

The timing of onset of tachyphylaxis remains unclear and is presumably highly individualized. In our experience at the Doheny Eye Institute, some patients developed tachyphylaxis quickly after two intravitreal injections, whereas others maintained a sustained therapeutic response even after 10 intravitreal treatments. Forooghian et al.⁶ suggest that tachyphylaxis generally occurs after eight intravitreal bevacizumab injections, occurring approximately 100 weeks following initial treatment. Schaal et al.⁵ demonstrated that approximately three intravitreal injections of bevacizumab are required to decrease efficacy to 50% of the initial response. Individual susceptibility to tachyphylaxis is likely highly variable and advances in pharmacogenetics may prove helpful in elucidating risk profiles.

POTENTIAL REMEDIES

A number of approaches have been proposed to combat tachyphylaxis, such as higher drug dosage, drug-free intervals, combination therapy with drugs from a different class, and treatment with different members within the same class of drugs.

Increasing the drug dosage can be achieved by increasing the frequency of administration or by increasing concentration of drug therapy and may mitigate both cellular and metabolic tolerance. However, Forooghian et al.⁶ described limited benefit with administration of double-dose bevacizumab (2.50 mg) in five of six patients who demonstrated tachyphylaxis. The single patient who demonstrated initial improvement with double-dose treatment was unable to maintain the early gains with subsequent treatment.

Drug-free intervals have been identified by the pharmacologic literature as effective strategy for reversing drug-induced changes in receptor expression patterns and signal pathway feedback. While drug-free intervals may not be a viable option in the face of active neovascular lesions, it provides theoretical support favoring a “treat and extend” approach rather than a fixed monthly treatment schedule.

Combination approaches with different-class drugs have been employed to reduce tachyphylaxis. In rheumatoid arthritis, infliximab is administered in combination with methotrexate to avoid development of tachyphylaxis to the murine component of infliximab.¹¹ A similar strategy may be employed with ranibizumab and bevacizumab, which both contain murine components that may elicit systemic immune reactions. Schaal et al.⁵ reported greater success in treating neovascular AMD with combination triamcinolone (4 mg) and bevacizumab (1.25 mg) compared to double-dose bevacizumab (2.50 mg), and suggested that combination therapy may be an effective approach to blunting tachyphylaxis. Development of novel therapeutic targets for treatment of neovascular AMD — such as hypoxia-inducible factor, integrins, angiopoetins, the complement cascade, erythropoietin and pigment epithelium–derived growth factor — may add to the armamentarium of combination treatment options.

Finally, switching therapy within the same class (ie, ranibizumab and bevacizumab) appears to be an effective approach to managing tachyphylaxis. We performed a retrospective review of 26 eyes that developed tachyphylaxis (defined as a decrease in therapeutic response following an initial positive response) during the course of therapy with ranibizumab or bevacizumab at the Doheny Eye Institute from September 2006 to April 2009 (Figure 1). We found that switching to a different anti-VEGF agent was associated with a positive response in 13 of 16 (81%) eyes initially treated with ranibizumab and eight of 10 eyes (80%) initially treated with bevacizumab (Figures 2 and 3). The majority of eyes (21 of 26 eyes) experienced a therapeutic benefit from switching anti-VEGF agents. Notably, half of the eyes (10 of 21 eyes) demonstrated complete resolution of fluid, whereas the other half (11 of 21 eyes) showed improved but persistent exudative disease, requiring continued treatment at last follow-up.

Figure 1. Summary of findings. Twenty-six eyes of 25 patients met the inclusion criteria for the study.

Sixteen of the 26 (62%) eyes were initially treated with ranibizumab for choroidal neovascularization secondary to age-related macular degeneration. Fifteen eyes had occult lesions and one eye demonstrated predominantly classic choroidal neovascularization. After an initial positive morphologic response to ranibizumab, these eyes developed apparent tachyphylaxis and therapy was switched to bevacizumab. Thirteen of the 16 eyes demonstrated a positive therapeutic response and eight eyes showed a response after a single injection. Six eyes ultimately had complete resolution of subretinal fluid. Three eyes failed to respond to bevacizumab and all of these eyes had occult lesions.

Ten of the 26 (38%) eyes were initially treated with bevacizumab. Occult lesions were observed in seven patients and predominantly classic lesions in three patients. The treatment regimen was changed to ranibizumab for apparent tachyphylaxis to bevacizumab. Eight of the 10 eyes demonstrated a positive therapeutic response and six eyes responded after a single injection. Four eyes ultimately had complete resolution of subretinal fluid. Two eyes failed to respond to ranibizumab.

Figure 2. Tachyphylaxis to ranibizumab. A 65-year-old Caucasian female with neovascular age-related macular degeneration patient presented with (A) subretinal fluid and a large serous pigment epithelial detachment and achieved (B) complete resolution of subretinal fluid and decrease in pigment epithelial detachment size following three intravitreal ranibizumab injections. The patient subsequently experienced (C) recurrence of subretinal fluid and tachyphylaxis, (D) and despite six additional ranibizumab injections there was continued subretinal fluid and pigment epithelial detachment. At this point the patient was switched to bevacizumab, which resulted in (E) complete resolution of subretinal fluid following six bevacizumab injections.

Figure 3. Tachyphylaxis to bevacizumab. An 85-year-old Caucasian male with neovascular age-related macular degeneration presented with (A) cystic retinal edema, subretinal fluid, and a fibrovascular pigment epithelial detachment. He underwent treatment with two rounds of bevacizumab with (B) improvement in retinal edema and resolution of subretinal fluid. Despite three additional treatments with bevacizumab, (C) the cystic retinal edema worsened and tachyphylaxis was suspected. The patient was switched to ranibizumab and achieved (D) complete resolution of cystic retinal edema after three treatments of ranibizumab.

Most eyes responding to a switch in anti-VEGF agents demonstrated a positive response after a single intravitreal treatment (14 of 21 eyes) although two injections were required for six cases and three injections for one case. The average duration of follow-up in this study was 13 months (ranging six to 28 months). Patients were evaluated approximately every four or six weeks if being treated with ranibizumab or bevacizumab, respectively.

Interestingly, 22 of 26 eyes (85%) with tachyphylaxis had occult CNV, suggesting that these lesions may be more susceptible to tachyphylaxis. Pigment epithelial detachments (PEDs) were present in the majority of occult CNV cases (19 of 22 eyes) but resolution of PEDs with anti-VEGF treatment was achieved in only two eyes, which is consistent with prior reports in the literature that suggest that PEDs regress more slowly than subretinal fluid or cystoid macular edema.^4,12

CONCLUSION

In summary, tachyphylaxis is a well-recognized pharmacologic entity by which repetitive administration of a drug results in an attenuated biologic effect through cellular and metabolic tolerance.

Tachyphylaxis occurs in a subset of neovascular age-related macular degeneration patients undergoing treatment with ranibizumab and bevacizumab, and may have a predilection to occult CNV lesions.^4-6 Pharmacologic approaches for addressing tachyphylaxis include combination therapy with different-class drugs, drug-free intervals or increased drug dosage. Our findings presented here suggest that switching anti-VEGF agents is a viable approach to combat tachyphylaxis with positive response and a reduction in exudative activity in the majority of patients upon switching. RP

REFERENCES

1. Svenson M, Geborek P, Saxne T, et al. Monitoring patients treated with anti-TNF-alpha biopharmaceuticals: assessing serum infliximab and anti-infliximab antibodies. Rheumatology. 2007;46:1828-1834.
2. Brown SM, Khanani AM, McCartney DL. The effect of daily use of brimonidine tartrate on the dark-adapted pupil diameter. Am J Ophthalmol. 2004;138:149-151.
3. Vaidyanathan S, Williamson P, Clearie K, Khan F, Lipworth B. Fluticasone reverses oxymetazoline-induced tachyphylaxis of response and rebound congestion. Am J Respir Crit Care Med. 2010;182:19-24.
4. Keane PA, Liakopoulos S, Ongchin SC, et al. Quantitative subanalysis of optical coherence tomography after treatment with ranibizumab for neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci. 2008;49:3115-3120.
5. Schaal S, Kaplan JG, Tezel TH. Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration? Ophthalmology. 2008;115:2199-2205.
6. Forooghian F, Cukras C, Meyerle CB, et al. Tachyphylaxis after intravitreal bevacizumab for exudative age-related macular degeneration. Retina. 2009;29:723-731.
7. Hoffman BB, Taylor P. Neurotransmission: the autonomic and somatic motor nervous systems. in: Goodman LS, Hardman JG, Limbird LE, Gilman AG, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001:115-154.
8. Tatar O, Yoeruek E, Szurman P, et al. Effect of bevacizumab on inflammation and proliferation in human choroidal neovascularization. Arch Ophthalmol. 2008;126:782-790
9. Bakri SJ, Snyder MR, Reid JM, et al. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology. 2007;114:855-859.
10. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.
11. Wilkinson N, Jackson G, Gardner-Medwin J. Biologic therapies for juvenile arthritis. Arch Dis Child. 2003;88:186-191.
12. Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology. 2006;113:363-372.