Safety surveillance in the anti-VEGF era: Myths and misconceptions

ByScott W. Cousins, MD

Although anti-vascular endothelial growth factor (VEGF) agents have been shown to prevent vision loss caused by the neovascularization or wet form of AMD,^1-3 the need for repeated intravitreal injection of these angiogenesis inhibitors and the potential for local and systemic adverse effects warrant careful evaluation of their safety profiles. This article reviews myths and misconceptions about pharmaceutical safety in general, provides well-known examples of each principle and applies each concept to the anti-VEGF class of drugs.

Myth or misconception No. 1:

Most important drug toxicities are identified during phase 3 pivotal trials

False: Most serious drug toxicities are discovered during post-marketing surveillance; for example, rofecoxib (Vioxx, Merck & Co., Inc.) was removed from the market following re-analysis of data obtained from post-marketing surveillance. Merck submitted a new drug application for Vioxx in 1998, at which time no cardiovascular safety signals were observed. Following approval of Vioxx in 1999, safety issues became apparent.⁴ The pharmaceutical company touted potential cardioprotective effects of a comparator drug naproxen when an imbalance in serious cardiovascular thrombotic events became apparent in previously submitted studies and post-marketing surveillance studies. However, when the FDA applied additional statistical analyses to the Vioxx Gastrointestinal Outcomes Research (VIGOR) study, it concluded that rofecoxib 50 mg was associated with an increase in cardiovascular thrombotic events compared with naproxen. Results from a separate phase 4 study confirmed the increased risk of myocardial infarction (MI) and stroke for rofecoxib 12.5 mg and 25 mg compared with placebo after 18 months of treatment. ⁵ The product was withdrawn from the market in 2004. But 5 years were necessary to develop the safety data required to justify the drug’s withdrawal from the marketplace.

Extrapolating the idea that safety signals may not appear until after FDA approval to the anti-VEGF class of agents should lead to the consideration of potential systemic events, particularly cardiovascular toxicities, in patients treated with these drugs. A high-risk analysis of 701 patients treated with pegaptanib (Macugen, [OSI] Eyetech) and 222 sham-treated patients in the VISION (VEGF Inhibition Study in Ocular Neovascularization) study revealed an overall incidence of Antiplatelet Trialists’ Collaboration (APTC) events in 2.4% and 3.1% of patients, respectively; furthermore, the overall incidence of cardiovascular/thrombotic events was 4% (28/701) in pegaptanib-treated patients and 5% (11/222) in sham-treated patients.¹

Rates of cerebrovascular events and MI were determined after 2 years of ranibizumab (Lucentis, Genentech) or sham treatment in the MARINA trial (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD).⁶ Cumulative rates were 4.6% in the ranibizumab 0.3-mg group (11/238), 4.2% in the 0.5-mg group (10/239) and 3% in the sham group (7/236). The majority of events occurred during the second year of treatment, which supports the search for a safer maintenance arm (Figure). Ranibizumab is most efficacious during induction of treatment, and a safe treatment strategy may involve using a separate agent for long-term maintenance therapy. Clinical trials under way are exploring the efficacy of induction with a nonspecific anti-VEGF agent such as ranibizumab or bevacizumab (Avastin, Genentech) followed by maintenance with the specific anti-VEGF agent pegaptanib.^7-8

Phase 3 trials may yield subtle safety signals. An example may be the non-ocular hemorrhagic events reported in the ANCHOR and MARINA trials. An apparent lack of safety signals may be misleading because the frequency of a particular adverse event is dependent on widespread drug use. Large-scale studies with sufficient power need to be conducted to evaluate the safety of these agents.

Figure: MARINA - 1 year vs. 2-year safety data

Cumulative rates of cerebrovascular events and myocardial infarctions

Figure courtesy of Scott W. Cousins, MD

Myth or misconception No. 2:

Most drug reactions are reversible. Alternatively, they are so severe that they are fatal.

True, but misleading: Many serious adverse reactions can cause lifelong disability. An example of this phenomenon is the widespread development of birth defects when thalidomide was prescribed to pregnant women as an antiemetic and/or sedative in the 1950s and 1960s. A lack of testing to discover the drug’s teratogenicity highlighted the inadequacy of testing methodologies that were implemented at the time.

The law of unintended consequences suggests that unrecognized biological activities can result in untoward effects. Vasoactive drugs are especially powerful in their effects. Anti-VEGF agents are potent vascular agents that have the potential to cause MI and strokes, conditions that are often disabling if not fatal.

VEGF was originally theorized to be a permeability factor but was quickly identified as an angiogenic factor as well. Now it is recognized that VEGF serves a major role in healthful physiological processes as well, especially maintaining capillary fenestrations, neuroprotection and many others. Blocking all of the biological actions of VEGF in the retina may have unintended consequences. For example, I have observed geographic atrophy in the eyes of some of my patients who have been treated chronically with anti-VEGF therapy. Although this complication might be caused by the natural history of neovascular AMD, blockade of all VEGF isoforms might contribute by altering the choriocapillaris fenestrations or blocking neuro-protection from VEGF.

Ophthalmologists should be vigilant of the unintended effects that anti-VEGF agents can have in their patients. Adverse events can vary in severity from mild to severe.

Myth or misconception No. 3:

“Innocuous” drugs that have stood the test of time are safe.

False: Even seemingly innocuous medications like over-the-counter (OTC) drugs can have serious toxicities that are not recognized until formally analyzed by post-marketing research. Although phenylpropanolamine (PPA) was introduced into OTC cold remedies in the 1930s and used in appetite suppressants since the 1960s, case reports linking it to blood pressure elevations did not emerge until 1982,^9-10 and it was not until 2000 that a case-control study linked PPA exposure to hemorrhagic stroke.¹¹ These findings demonstrate the logical fallacy “absence of proof proof of absence.”

The implication as it relates to anti-VEGF agents is the importance of designing post-marketing surveillance studies with the appropriate powers and parameters for the evaluation of safety. Bevacizumab is used off-label for the treatment of AMD, and appropriate safety testing in the AMD population is not required. The Bascom Palmer Eye Institute has performed a surveillance study in which physicians self-reported minimal adverse reactions with the use of bevacizumab in their patients.¹² These results, however, do not seem credible. Approx-imately 75% of patients with AMD already have APTC high-risk factors. ¹³ Even without treatment, cardiovascular events will occur in approximately 3% of this population. How much anti-VEGF treatment increases the risk of cardiovascular events has yet to be determined. In the absence of formal reporting mechanisms, researchers and physicians may fail to identify increased risks for serious adverse events for decades.

Myth or misconception No. 4:

Because patients with AMD are old, they will probably die before experiencing a serious adverse event. Therefore, we do not have to be as concerned with safety.

False: Patients with AMD have reasonably long life expectancies, and they are getting longer. Their lives should not be impaired with safety concerns when precautions can be taken.

Myth or misconception No. 5:

Intravitreally injected drugs do not get into the blood. Therefore, systemic toxicities will not occur.

False: Intravitreal drugs achieve physiological blood levels. A normal plasma level of VEGF in a healthy adult is approximately 0.1 ng/mL. ¹⁴ According to the package label, a single intravitreal injection of pegaptanib 3 mg, which is 10 times the approved dose, achieves plasma levels of approximately 80 ng/mL, has a half-life in the order of hours and achieves 90% clearance in 1 to 2 days. ¹⁵ An animal study showed that, in monkeys, bilateral intravitreal injections of ranibizumab 0.5 mg yielded plasma levels of 150 ng/mL, a half-life in the order of days and a 90% clearance rate that took a week.¹⁶ According to Karl Csaky, MD, from the National Eye Institute (personal communication, September 2006), bevacizumab achieves high plasma levels (100’s ng/mL) following a 1.25-mg intravitreal injection in adults; the half-life is in the order of weeks, and blood levels have been detected for up to a month after intravitreal injection. When systemic anti-VEGF levels exceed physiologic VEGF levels, these anti-VEGF agents have the potential to cause systemic adverse reactions. Ophthalmologists should understand the magnitude of risk among individual agents and assess the risk in the therapeutic choice among individual patients.

Conclusion

Many questions remain unanswered in terms of defining the safety issues of anti-VEGF agents. Although one can theorize that pegaptanib may be safer than nonselective ranibizumab and bevacizumab due to its selective inhibition of VEGF-165, post-marketing surveillance systems are not yet in place to sufficiently address this issue. There is no “safety” precedent in ophthalmology because anti-VEGF agents are the most potent systemically acting drugs to become available and none of the current clinical trials are sufficiently powered to detect safety issues. Duke University is designing a multifactorial surveillance system that will work with industry, academia and the government in an attempt to better track the safety of anti-VEGF agents.

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