Lucentis sets new high standard for treatment of neovascular AMD

I mentioned in the last blog that Lucentis® has set a new high standard for the treatment of neovascular AMD. To match the results with Lucentis, any new treatment should be as good as or better than the following results:

1. 95% of patients should not lose 15 or more letters of vision at one year.
2. 90% of patients should not lose 15 or more letters at two years
3. The entire group of treated AMD patients should gain 6.6 letters or just over one line of vision at two-years of follow-up
4. A third of the treated patients should gain 15 or more letters, (three lines), of vision at one year.
5. 40% of treated patients should be 20/40 or better.

The downsides to Lucentis are:

1. It has to be injected into the eye once a month.
2. After it’s stopped, the leakage, edema, and vision loss often return.
3. Although it stops choroidal neovascularization from growing it usually doesn’t destroy it permanently.
4. It’s expensive.

Genentech sponsored the PIER study to see if fewer injections of Lucentis would work as well as monthly injections. Patients initially received three monthly doses of Lucentis followed by injections only every three months for one year. The patients didn’t do quite as well as those who got monthly injections:

1. 90% of patients didn’t lose 15 letters at one year.
2. The entire group had about the same vision at one year that they started with instead of a gain of 6.6 letters.
3. 13% gained fifteen or more letters of vision.
4. 30% were 20/40 or better.

Retinal doctors felt that they could improve these results if they followed patients carefully and re-injected Lucentis on an “as needed” basis. Phil Rosenfield from Miami reported on a study in which patients received three monthly injections and then were followed every month thereafter. They received another injection if fluid recurred on the OCT, the vision decreased, or if there was a new hemorrhage or area of neovascularization. This treatment plan appeared to work as well as giving injections every month for a year and has the benefit of the patient often needing fewer injections.

Another strategy to reduce the number of injections needed to control the neovascularization is to use a combination of Avastin® or Lucentis® followed by PDT. PDT can close neovascularization permanently but it can also cause damage to the normal vessels in the choroid, later regrowth of neovascularization, and vision loss. PDT alone is not as good as Avastin or Lucentis alone. But now retinal doctors are trying a combination treatment, Avastin or Lucentis followed 1-2 weeks later by low dose PDT. Usually the light dose used in the PDT is one-half or even less of the normal dose. It’s hoped that this lower light dose will limit the damage caused by PDT. The goal is to close the abnormal blood vessels permanently but get the same visual results as with Avastin or Lucentis alone.

There were four papers reporting on this combination treatment. The combination treatment did reduce the number of injections. The visual results were close to but not quite as good as with Avastin or Lucentis alone. This treatment could be considered in patients who have recurrent fluid despite numerous injections. Retinal doctors are working hard to get the right recipe of Avastin or Lucentis with PDT and maybe even intraocular Kenalog. The right recipe may have the same visual result as Avastin or Lucentis alone but require fewer treatments and result in permanent closure of the abnormal blood vessels.

From Paris- The 24th Annual Meeting of the American Association of Retinal Specialists

From Paris- The 24th Annual Meeting of the American Association of Retinal Specialists and the 6th Annual Meeting of The European Vitreoretinal Society, Cannes, France

The two-year results from the MARINA study were reported again and, in a word, très bien. Two years after study entry, 95% of patients, who were injected monthly with 0.5mg of Lucentis®, (ranibizumab), met the efficacy endpoint, which meant they didn’t lose 15 or more letters of vision. On average the entire group gained 6.6 letters or just over one line of vision. A third of the treated patients gained 15 or more , (three lines), of vision and 40% were 20/40 or better. The one-year results from the ANCHOR study were similar. These results are now the high standards against which new treatments will be measured.

Retinal experts all over the world have had a lot of experience using Avastin®, (bevacizumab), to treat neovascular AMD before Lucentis® was approved. Experts in Europe are still using Avastin® since Lucentis® has not yet been approved. There were a number of studies reported at this meeting which concluded that Avastin® was very close to or as good as Lucentis®. Most retinal experts in the hallway opined that Avastin® was as good. The studies that were reported however, were nonrandomized and had limited follow-up. It’s easy to get mesmerized by the initial, “WOW,” effect when the patient returns with no fluid and improved vision after an injection of either drug. I must admit that I haven’t seen much difference between the two drugs but, like everyone else at the meeting, believe a randomized, controlled study testing the two drugs, head to head, is needed. Such a trial is in the works.

Lucentis® and Avastin® cause resolution of most of the fluid within and under the retina within days after injection in almost every patient. Patients may still have some fluid one month after injection but it’s usually much less than pre-injection. This remaining bit of fluid almost always resolves with additional injections. Either drug is an excellent treatment. It’s hard to imagine another drug that would be better at getting rid of fluid and stopping the growth of the neovascular membrane. A drug would have to have the same visual results and also do one of the following to be better than Lucentis®:

1. Be administered less often.
2. Be cheaper,
3. Cause involution of the CNV so that therapy could be stopped.
4. Cause better visual acuity results by limiting scarring beneath the retina.
5. Prevent the CNV from developing in the first place, (the best treatment)

Retinal experts are working feverishly on 1-3 above. Pharmaceutical companies are working on nos. 3-5. In the next blog, I’ll discuss “as needed” therapy for Lucentis® or Avastin® and combination treatments.

Avoiding Plaquenil in AMD

I received the following question:
Do you still advise that Plaquenil, (hydroxychloroquine) not be used in someone with AMD?

I still advise against it especially if someone has bonafide AMD. There are exceptions to any rule but recent studies have shown that the outer retina is damaged with Plaquenil before we see any visible signs in the fundus or on fluorescein angiography. Lai and colleagues found abnormal multifocal electroretinograms (MERGs) in patients taking Plaquenil who otherwise looked normal. The MERG improved slightly in those who stopped the drug and worsened in those who continued taking it.1 An excellent editorial by Marmor talked about the difficulties in using the finicky MERG to determine if Plaquenil should be stopped.2

This August, Kellner et al. showed autofluorescence abnormalities in the macula before any visible changes. In four patients, the MERG was abnormal even before the autofluorescence.3 Marmor correctly pointed out that the MERG was abnormal in patients who had normal vision and no symptoms.

My point is that hydroxychloroquine is causing changes in the outer retina before we can see any visible damage and these are the same layers that are damaged in AMD. I have no evidence and have done no study, but it seems advisable to avoid this drug if possible in people with AMD.

References

1. Lai TY, Chan WM, Li H, Lai RY, Lam DS: Multifocal electroretinographic changes in patients receiving hydroxychloroquine therapy. American journal of ophthalmology 2005, 140(5):794-807.
   
2. Marmor MF: The dilemma of hydroxychloroquine screening: new information from the multifocal ERG. American journal of ophthalmology 2005, 140(5):894-895.
   
3. Kellner U, Renner AB, Tillack H: Fundus autofluorescence and mfERG for early detection of retinal alterations in patients using chloroquine/hydroxychloroquine. Investigative ophthalmology & visual science 2006, 47(8):3531-3538.