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Posts tagged ‘Macular degeneration’

The FDA earlier this week issued a safety alert to doctors that repackaged bevacizumab (Avastin®) had caused serious eye infections in 12 patients in Florida. The New York Times today reports that five patients at the Veterans Affairs Medical Center in Los Angeles have gone blind as a result of an eye infection following injection of compounded Avastin.

I have written previously about the Lucentis v Avastin debate and the results in the Comparison of Age-related macular degeneration treatment trial (CATT) published earlier this year in the New England Journal of Medicine.

It is not good news that contamination has occurred while compounding bevacizumab (Avastin) from sterile100mg/4mL single use preservative-free vials into individual 1mL syringes.

Genentech/Roche may see this news as reinforcing their position that ranibizumab (Lucentis®) should only be used, since it comes in the correct dose for injection in the eye. However, this ignores the reality caused by the fact that Lucentis is approximately 40x the cost of compounded Avastin ($1950 versus $50).

This week’s news does not support the proposition that intravitreal injection of bevacizumab is not safe and effective for the treatment of AMD, nor any suggestion that pharmacies properly accredited and experienced in aseptic techniques are not qualified to do this. Pharmacists compound drugs everyday.

As the FDA notes in their alert:

“Health care professionals should be aware that repackaging sterile drugs without proper aseptic technique can compromise product sterility, potentially putting the patient at risk for microbial infections.  Health care professionals should ensure that drug products are obtained from appropriate, reliable sources and properly administered.”

However, there is no evidence to suggest that the pharmacies who undertook the Avastin compounding that led to the infection were not “appropriate, reliable sources and properly administered.”

The New York Times notes that the the contaminated Avastin came from the pharmacy at the main campus of the V.A. Greater Los Angeles Healthcare System.  There is no mention of whether the VA pharmacists did the compounding themselves or sourced the drug elsewhere.

According to a news report in the Florida SunSentinel, the pharmacy identified as the source of the infection in Florida is InfuPharma. This is not a retail pharmacist in the high street, but a specialist compounding pharmacy that advertises sterile preparations for numerous products. Licensed pharmacists run this specialist company and looking at their website they do appear to be experienced in this area.

Endophthalmitis is a serious eye infection that may lead to loss of vision. The contamination should not have occurred.  These incidents should not, however, be blown out of proportion in the Lucentis v. Avastin debate.

Sadly, infections and contamination happen in hospitals and the healthcare industry all the time. Even the FDA approved manufacturing facilities of pharmaceutical companies have experienced problems in recent years.  Last summer, BMS experienced issues with sterile manufacturing standards at their Puerto Rico plant following FDA inspections.  Earlier this week, Baxter announced they had filed a lawsuit against Teva for indemnification over a hepatitis C outbreak following reuse of oversize propofol vials.

The news of serious eye infections with repackaged Avastin must, therefore, be put in context. There are countless patients around the world who have benefited from intravitreal injections of Avastin for treatment of their age-related macular degeneration (AMD). The issue raised by the infections in Florida and Los Angeles is whether there is adequate inspection and certification of compounding pharmacies, and whether there is a need for more State regulation and inspections in this area.

Disclosure:  I have written freelance articles for Pharmacy Today, the magazine of the American Pharmacists Association.

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Breaking news:

The New England Journal of Medicine have just published online the results of the Comparison of Age-related macular degeneration treatment trial (CATT) comparing the efficacy of FDA approved ranibizumab (Lucentis) to off-label bevacizumab (Avastin); a trial that has important commercial importance given the comparative costs of an intravitreal injection of around $1950 (Lucentis) vs. $50 (Avastin).

Key Study Results

Based on 1208 patients randomly assigned in the single-blind noninferiority trial, primary outcome was mean change in visual acuity between baseline and 1 year. This was equivalent between the two drugs.

Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively.

Secondary outcome measures included the incidence of ocular and systemic side effects, the results show some similarities and differences:

Rates of death, myocardial infarction and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20).

The proportion of patients with serious adverse events (primarily hospitalization) was higher with bevacizumab than with ranibizumab (24.1% vs 19%)

The conclusion of the study is that:

At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered to the same schedule”

However, here is the potential ‘get out’ for Genentech:

Differences in rates of serious adverse events require further study.

The investigators note that the difference in serious adverse events may be due to:

“chance, imbalances in baseline health status that were not included in the medical history or multivariate models, or a true difference in risk.”

i.e. they don’t know.

What the results from the CATT study mean is that Avastin and Lucentis are similar, but different. That is not a surprising result given that they originate from the same anti-VEGF monoclonal antibody.  However, they are not identical.

Clearly, if I were a patient, the additional 5% risk of serious adverse events would have to be weighed against the cost benefits. For those who are uninsured or unable to afford Lucentis, receiving Avastin may be an informed decision worth taking.  As the investigators note:

One of the many factors that contribute to the selection of a drug for a patient is cost.  A single dose of ranibizumab costs 40 times as much as a single dose of bevacizumab.  This cost differential has important economic implications when extrapolated to the more than 250,000 patients who are treated for neovascular AMD annually in the United States.

I look forward to hearing the animated discussion of these results at the ARVO annual meeting in Fort Lauderdale on Sunday.

ResearchBlogging.orgThe CATT Research Group (2011). Ranibizumab and Bevacizumab for Neovascular Age-Related Macular Degeneration New England Journal of Medicine DOI: 10.1056/NEJMoa1102673

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Human eye cross-sectional view. Courtesy NIH N...Image via Wikipedia

VEGF Trap-Eye is a formulation of VEGF Trap (aflibercept) and is an anti-angiogenic agent that can be injected into the eye to stop the proliferation of blood vessels. Regeneron (REGN) are co-developing it with Bayer (BAY) and it is currently in clinical trials for the treatment of wet Age-Related Macular Degeneration (AMD), Diabetic Macular Edema (DME) and Central Retinal Vein Occlusion (CRVO).

Phase II DME clinical trial results presented at the
Angiogenesis 2010 meeting in Miami showed the primary endpoint of a
statistically significant increase in visual acuity over 24 weeks compared to
the standard of care (laser treatment) was met.

There are high levels of vascular endothelial growth factor (VEGF) associated with DME, so the news that VEGF Trap-Eye has biological activity in this disease is positive.What makes this data promising is the fact that DME is the leading cause of blindness in adults under 50 and there are 370,000 Americans with clinically significant DME with 95,000 new cases a year.

The ability to treat DME by an eye injection, rather than use an expensive laser will make it easier to treat the disease. It will be interesting to see what how the cost of treatment with VEGF Trap-Eye compares to laser therapy procedures, should the agent make it to market.

The recent pricing issue faced by Genentech with its VEGF inhibitors Lucentis
(eye indications) and Avastin (oncologic indications) are also relevant because
Regeneron are developing VEGF-Trap in cancer with it’s partner sanofi-aventis
(a client).

For VEGF Trap-Eye, Regeneron retains all U.S. marketing
rights, while Bayer has rights to market ex-US in return for a 50/50 profit
share with Regeneron.The results so far look promising and aflibercept looks like an interesting agent well worth watching as the development moves forward.

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