Avastin Lucentis Update 49 A Follow up on Infections from Intravitreal Injections

In my last posting (Avastin/Lucentis Update 48), I wrote about the problems with Avastin injections, that appeared to be caused by non-sterile/non-aseptic techniques during re-packaging Avastin from 4 ml bottles into much smaller doses (0.05ml) in tuberculin syringes.

A colleague, who is a compounding pharmacist, pointed out to me that other things can cause contamination of the eye during intravitreal injections besides using non-aseptic techniques during aliquoting and re-packaging of Avastin into injectable syringes.

He sent me a copy of a report from Medscape Medical News that was published online following a meeting of the American Academy of Ophthalmology and Middle East Africa Council of Ophthalmology 2010 Joint Annual Meeting, held during last year’s AAO Meeting.

Here are excerpts from that report:

Intravitreal Injections Expose Patients to Streptococcus More Often Than Eye Surgery

Kathleen Louden
October 20, 2010
Medscape Medical News

Streptococcus is isolated much more frequently from endophthalmitis cultures after intravitreal injection (IVI) of antivascular endothelial growth-factor agents than after ocular surgery, results of a meta-analysis show.

Ophthalmologists should consider using additional sterile techniques during these injections to prevent exposing patients to the sight-threatening complication of streptococcal endophthalmitis, said study author Colin McCannel, MD, associate professor of ophthalmology from the Jules Stein Eye Institute at the University of California at Los Angeles.

"If we can prevent some of the worst cases of endophthalmitis, I think it's worth the effort," Dr. McCannel told Medscape Medical News.

To confirm his impression that reports of Streptococcus organisms seemed more frequent than should be expected after IVI, Dr. McCannel analyzed the American medical literature from 2005 through 2009. He found 16 articles that reported the causative organism in post-IVI endophthalmitis. As expected, endophthalmitis was rare, occurring in 54 of 105,531 injections. Only 26 were culture-positive, according to the abstract. Most of the causative organisms were coagulase-negative Staphylococcus, he said.

However, cultures yielded Streptococcus organisms 30.8% of the time (8 of 26), which Dr. McCannel said is "3- or 4-fold higher" than the incidence reported in the literature for acute postoperative endophthalmitis. The postoperative incidence of streptococcal endophthalmitis ranges from 0% after vitrectomy to 8.2% to 9% after cataract surgery, he reported.

Likely Source of Infection

This finding led him, he said during an interview, to do "some detective work" to try to find the possible source of these streptococcal infections. He found several studies in the anesthesia literature reporting streptococcal meningitis after dural puncture, a procedure that, according to Dr. McCannel, has a working distance between physician and patient similar to that of IVI. Analysis found that the causative organisms in most of those cases came from the treating physician's oral flora, which was aerosolized during talking.

Consequently, the Centers for Disease Control and Prevention in Atlanta, Georgia, recommended in 2007 that spinal procedure operators wear a surgical mask during the procedure (MMWR Morb Mortal Wkly Rep. 2010;59:65-69).

Ophthalmologists "often have to give directions to the patient during injections, and sometimes there is small talk," Dr. McCannel said. "The patient's eye is probably being showered with these microscopic droplets. We may be contaminating the injection field or the needle."

Recommendations

If other studies validate his findings, the ophthalmic community should decide whether to recommend wearing a surgical mask during IVI, he said. He told the audience that he does not wear a mask because "it would be burdensome to take it on and off" during the brief injections.

Another precautionary strategy that Dr. McCannel suggested was to avoid talking, coughing, or sneezing during the injections. He said he asks his ophthalmic technicians to instruct the patient before the procedure that "the injection is not the time to ask questions" and to refrain from talking. If he needs to instruct the patient, he said he speaks away from the patient.

A panelist at the session who did not participate in the study, Joan W. Miller, MD, said in an interview that the study findings have the potential to change clinical practice. Dr. Miller, professor and chair of ophthalmology at Harvard Medical School in Boston, Massachusetts, said she will consider changing her IVI techniques to try to prevent the spread of Streptococcus.

"Not talking on the [injection] field is probably sufficient precaution," she told Medscape Medical News.



My friend, the compounding pharmacist, went on to say,  “I wish we had more visibility into what [really] happened in TN and FL and the pharmacies that prepared those compounds. It is even more critical that physicians look to do their diligence when choosing a pharmacy to provide these sterile compounds to patients. Because of our strict quality control and assurance procedures we have created an environment that focuses on quality.”

“As you may be aware OMIC, the ophthalmology insurance carrier, has been recommending to physicians that the best practice is to seek out compounding pharmacies that have been accredited by PCAB, the Pharmacy Compounding Accreditation Board.  Being accredited by PCAB gives confidence to physicians and consumers that products are prepared in accordance with the United States Pharmacopeial Convention's standards. Chapter 797 of the USP clearly outlines the facility, environment and testing necessary to provide sterile compounded products.  Without an accreditation body like PCAB, there is no reliable third-party verification that a pharmacy meets the USP 797 standard.”

Stem Cells in Ophthalmology Update 5 Gene Defects Common in Induced Stem Cells

As the senior editor, John Gever, of MedPage Today reported, following the publication of three studies about induced pluripotent stem cells in the March 3rd, issue of Nature, “The road to regenerative medicine based on induced pluripotent stem cells (iPSCs) may have developed a giant pothole, with new studies showing that the cells are prone to several types of genetic defects.”

The three studies showed that the reprogramming process and subsequent culture of pluripotent stem cells in vitro can induce genetic and epigenetic abnormalities in these cells. The authors of the studies and the editorialist said that the results raise concerns over the implications of such aberrations for future applications of pluripotent stem cells.

Point mutations, copy number variations, and abnormal DNA methylation patterns all appear to crop up during generation of iPSCs. The frequency of such defects significantly exceeds what is normally found in human embryonic stem cells or in fibroblasts, the somatic cells from which iPSCs are usually derived.

"The studies raise concerns over the implications of such aberrations for future applications of iPSCs," wrote Martin F. Pera, PhD, of the University of Southern California in Los Angeles, in an accompanying editorial commentary. But he noted that it remains unknown whether the genetic "reprogramming" undertaken to generate iPSCs from fibroblasts is itself responsible for the genetic defects. Perhaps, Pera indicated, such defects "would be common to any experimental situation in which a cultured cell is subjected to strong selection and replication pressures in vitro."

Each of the three studies focused on a different type of genomic defect.

Kun Zhang, PhD, of the University of California San Diego, and colleagues from several other institutions looked at rates of point mutations in 22 iPSC lines and in the fibroblasts from which they were generated. The average number of mutations in protein-encoding genomic regions in each cell line was close to six. "Every single stem cell line we looked at had mutations. Based on our best knowledge, we expected to see 10 times fewer mutations than we actually observed," Zhang said.

All of the 22 iPSC lines had at least one "nonsilent" mutation that affected the resulting protein. One line showed 12 such alterations leading to mutated proteins. The mutations took different forms, the researchers reported, including splice variants and nonsense mutations.

In addition, they wrote, the abnormalities "were enriched in genes mutated or having causative effects in cancers."

Another of the Nature papers, by investigators from the Samuel Lunenfeld Research Institute in Toronto and elsewhere, examined gene copy-number variations that arise in iPSCs. Samer Hussein, PhD, of the Lunenfeld Institute, and colleagues found that these variations -- which included deletions as well as multiple copies -- were present in 37% of the iPSC lines they analyzed. Such variations were present in just 15% of fibroblasts and 25% of human embryonic stem cells (ESCs). The defects may be less significant in practical applications, however, relative to the point mutations. Hussein and colleagues reported that the highest rates of copy-number variations in iPSCs were seen in early-passage cells, whereas rates dropped with additional passages.

"Most of these novel CNVs rendered the affected cells at a selective disadvantage," the researchers explained. "Expansion of human iPSCs in culture selects rapidly against mutated cells, driving the lines towards a genetic state resembling human ESCs."

The third paper investigated what authors Joseph Ecker, PhD, of the Salk Institute for Biological Studies in La Jolla, Calif., and colleagues called "aberrant epigenomic reprogramming."

DNA methylation patterns help regulate gene expression and are variable during life as well as transmissible during reproduction. Ideally, causing an adult cell to revert to a stem-cell state would also involve reestablishing stem cell-like methylation patterns. Ecker and colleagues therefore generated whole-genome methylation profiles of five iPSC lines along with undifferentiated human ESCs, somatic cells, and differentiated iPSCs and ESCs.

They found that the reprogramming of methylation patterns in iPSCs was generally successful when looked at across the entire genome. "Overall, this process generates an iPSC methylome that, in general, is very similar to that of ESCs," they wrote. But in their base-by-base analysis, Ecker and colleagues discovered hundreds of differentially methylated regions compared with ESCs. Some of these were on the megabase scale, which apparently were "repeatedly resistant to reprogramming."

There were detectable differences in cell appearance or function as a result, the researchers noted. Moreover, whereas cells with copy-number variations failed to survive multiple passages, the abnormal methylation patterns did not appear to affect cell survival, as differentiated iPSCs retained the abnormal patterns.

That these aberrations "cannot be erased by passaging and are frequently transmitted through cellular differentiation has immediate consequences for the derivation and use of iPSCs," Ecker and colleagues warned.

In his "News and Views" commentary, Pera pointed out that these are not the first studies to warn of genomic irregularities in iPSCs. Two previous analyses, one published in 2010 and another earlier this year, also documented abnormal chromosome numbers and gene copy-number variations in the cells. These and the new Nature studies raise a number of questions about the future of iPSC research, Pera contended. Perhaps the most important, he wrote, "is the biological significance of the changes."

He indicated that missing or duplicated chromosomes would clearly disqualify cells from use in therapy, as would a high frequency of mutations in genes associated with cancer or known genetic disorders. "However, the many subchromosomal changes, copy-number variations, or point mutations that are not obviously associated with known disease-related genetic abnormalities pose challenges to interpretation," Pera argued.

He suggested that high-throughput functional genomics may be the best approach to resolving the problems -- which need to be addressed before iPSCs can become a basis for human disease treatments.

All three studies were supported by government and foundation grants. No commercial funding was reported.

The three studies are:

Gore A, et al, "Somatic coding mutations in human induced pluripotent stem cells" Nature 2011; 471: 63-67.

Hussein S, et al, "Copy number variation and selection during reprogramming to pluripotency"  Nature 2011; 471: 58-62.

Lister R, et al, "Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells" Nature 2011; 471: 68-73.

And the accompanying editorial:

Pera M, "The dark side of induced pluripotency" Nature 2011; 471: 46-47

Source:
MedPage Today, John Gever, Senior Editor
March 2, 2011

In addition, Healthzone Canada published a lengthy review of the Toronto study: “Toronto Scientists Report Roadblock in Stem Cell Field”; and a press release from the UC San Diego Health System“Mutations Found In Human Induced Pluripotent Stem Cells”, reported in depth on the study from the scientists and colleagues from the University of California, San Diego:

For more on “induced pluripotent stem cells “(iPSCs) and the three other types – "embryonic stem cells" (embryonic SCs, or human embryonic stem cells hESCs), "adult stem cells" (adult SCs) and "parthenogenetic stem cells" (hpSCs), please see my Primer on the Use of Stem Cells in Ophthalmology.

CATT Study Update 12 Status of WorldWide Studies

With the anticipated arrival of the one-year results of the CATT Study this Spring, I thought it would be appropriate to update where the other worldwide studies stand.

During the Retina Subspecialty Day sessions, held prior to the recent 2010 AAO Meeting in Chicago, Daniel Martin, MD provided an update on the various comparative studies underway around the world between Avastin and Lucentis. Here are Dr. Martin’s comments, as reported by the Market Scope team in the November issue of Ophthalmic Market Perspectives.


Daniel Martin, MD, updated comparative studies of Lucentis and Avastin, describing the ongoing clinical trials and noting that results will begin to become available soon. One-year results of the much-awaited CATT study will be available in the spring of 2011.

IVAN, the trial sponsored by the National Health Service in the UK, is similar to CATT but smaller and its recruitment is now complete.

The German study VIBERA is examining a higher dose of Avastin and will be fully enrolled sometime in 2011.

MANTA in Austria began in mid-2008 and is likely to complete enrollment by the end of 2010.

LUCAS, the Norwegian study, uses a treat and extend strategy and is more than halfway enrolled, and France's GEFAL study began in the fall of 2009 and is halfway to its enrollment goal.

For more on full coverage of the 2010 AAO Meeting, please contact Market Scope, for complete subscription information to their monthly Ophthalmic Market Perspectives newsletter.

Avastin Lucentis Update 12 The Controversy Makes the Front Page of the WSJ

On February 22nd, Marilyn Chase of the Wall Street Journal’s staff, in a front page article, reported on the controversy both within Genentech and outside, between retinal specialists, on the use of either the high-priced, FDA approved for AMD Lucentis, and the much lower-priced but off-label use of the FDA approved (for colorectal cancer) Avastin for treating "wet" age-related macular degeneration. I would like to claim at least a little credit for the story, as I urged Ms. Chase (and a number of other investigative reporters) to take a look behind the rumors that some medical and pharmaceutical companies were trying to stop the upcoming NEI/NIH trial to compare the effectiveness of Avastin versus Lucentis, after posting my Update No. 9: A Disturbing Report... on December 2nd.

Following Ms. Chase’s story on Genentech that appeared in the Journal on January 11th, I wrote her with a link to my posting above. Then following the posting of the White Paper, Why Avastin vs Lucentis Matters, prepared by a group of retinal specialists alarmed by the public health implications of the high cost of Lucentis to society (Update No. 11 – published February 10th), I again urged Ms. Chase to pursue the cause. The result was yesterday’s story.

Because of Copyright laws, I will only publish excerpts of Ms. Chase’s story. Anyone wishing to see the complete article can go to http://www.wsj.com/ (if you are a subscriber to the online edition of the Journal), or send me an email and I will be happy to respond with a copy of the story.

BLIND AMBITION

Genentech's Big Drug For Eyes Faces a Rival

Intended for Other Use, Cheaper Injection Is One of Its Own Products

By MARILYN CHASE (February 22, 2007; [WSJ] Page A1)

SAN FRANCISCO -- For some of her patients at risk of blindness, retinal specialist Anne Fung injects the drug Lucentis, which costs nearly $2,000 a shot. For those who have less health coverage, she offers a shot of another drug, Avastin, that costs around $40.

The two drugs are both made by Genentech Inc. They work similarly. Doctors say both can be effective in preventing or even reversing vision loss. But only Lucentis is approved by the Food and Drug Administration to treat eye problems.

...The Lucentis-Avastin showdown has thrown the pharmaceutical world into a tizzy. Genentech, fearful that a potential billion-dollar-a-year product could be headed down the tubes, is urging doctors to stick to Lucentis and its proven efficacy in treating age-related macular degeneration. Doctors are weighing benefit and cost -- and often choosing to roll the dice with Avastin, although it is approved only as a cancer treatment, to ensure that less well-off patients get treatment.

Now the federal government is hoping to settle the dispute by funding a head-to-head comparison of the two biotechnology drugs, the first such trial by the National Institutes of Health. If Avastin works as well as Lucentis, the government's Medicare program for the elderly could save $1 billion or more a year, officials say.

The mutiny by doctors nationwide against a high-priced drug -- and Washington's willingness to go to bat for them -- is triggering alarms in the drug industry. "Industry doesn't want an equivalency trial where there could be decisions on coverage. They are terrified," says William L. Rich, director of health policy at the American Academy of Ophthalmology, which backs the NIH trial.

...For Genentech, the world's second-largest biotechnology company by revenue after Amgen Inc., the stakes are high. Lucentis was a surprise hit after its June 30 launch, logging $10 million in sales on its first day and $371 million in the second half of 2006. Eric Schmidt, an analyst at Cowen & Co., estimates the figure could reach $900 million this year and rise to $1.3 billion by 2011.

Genentech has refused to provide any funding or drugs for the NIH trial, scheduled to start in April. The Biotech Industry Organization says the NIH should be studying cutting-edge science, not comparing two approved drugs. Genentech's head of business development, Joseph McCracken, adds: "If I were trying to decide how to spend NIH's money, I might not think this is the best way."

...Doctors are using Lucentis and Avastin to treat "wet AMD," a type of the disease in which overgrowth of blood vessels and leakage of fluid cause gross swelling of the macula, a part of the retina.

...Avastin fights cancer by halting the growth of blood vessels that sustain tumors. The FDA approved it as a cancer treatment (for colorectal cancer) in 2004.

More than a decade ago, research suggested that taming vessel overgrowth might also be used to treat diseases of the eye. But based on early tests in monkeys using a similarly sized molecule, Genentech thought the Avastin molecule was too big to penetrate the retina. Its scientists spent two years re-engineering it to create Lucentis, which then underwent seven years of testing.

...In July 2005, Genentech reported the results of a big Phase III study of Lucentis before a hushed crowd of 2,000 at a medical meeting in Montreal. The studies showed it halted blindness in 90% of people with AMD and improved vision in 30%.

"There was an audible gasp," recalls George Williams, chairman of ophthalmology at the Beaumont Eye Institute in Royal Oak, Mich. Lucentis "was so much better than anything else." Previously the disease was treated with less-effective drugs, photodynamic therapy and lasers -- "like using a blowtorch to stop weeds," says Dr. Fung in San Francisco.

The only problem: Approval would take another year.

Then came an apparent solution: At the same meeting, Philip Rosenfeld, a professor at the Bascom Palmer Eye Institute of the University of Miami Medical School, presented a case of a patient who had been going blind and was injected with Avastin. The patient's retinal scans dramatically improved a week after treatment and vision began to regain sharpness over six months.

It was a review of this meeting, the July 2005 American Society of Retina Specialists held in Montreal, by Lynne Peterson in her Trends-in-Medicine newsletter, that piqued my interest, and started my journey in reporting on the Avastin (and later Lucentis) phenomenon, beginning with my posting of January 31, 2006, Avastin: A New Hope for Treating AMD.

Over the following year plus, that initial posting was followed by an additional 12 reports on the status of the two drugs in treating wet AMD. See the Author’s Notes at the end of this posting for a complete listing and links to each story.

...Rather than wait until Lucentis was approved by the FDA, many doctors grasped at the next best thing. With the help of compounding pharmacists who siphoned tiny doses of Avastin into small syringes, eye doctors tried it in thousands of patients. In large doses for cancer, Avastin costs $55,000 a year. The dose used in the eye costs just $20 to $100.

"People thought we were cowboys, but we were doing it in our patients' interests," says Robert Avery, an ophthalmologist in Santa Barbara, Calif. "When people are going blind, they're willing to take risks."

Even after Lucentis received FDA approval last year (June 30, 2006), many doctors stuck to Avastin because a comparable Lucentis injection costs $1,950. "This is a public-health issue," says Dr. Rosenfeld of Miami. "I believe in profit but things are out of proportion."

See also the above mentioned White Paper: Why Avastin vs Lucentis Matters, for more discussion on the public health issues on the costs to society of the continued use of the high-priced Lucentis.

...Last month, the American Society of Retina Specialists found in a survey that doctors preferred Avastin over Lucentis 76% to 9% for their Medicare patients. Even when patients had supplemental insurance policies that covered the patient's cost, the margin was 51% to 43%.

Genentech argues Lucentis is the only product shown to safely restore vision and Avastin remains unproven as an eye treatment. "I've seen anecdotal reports. They're impressive. But they're still single-case reports," says Susan Desmond-Hellmann, the company's president of product development. She cites the mom test: "If my mom had [AMD], I'd want her to get the drug that is safe and effective."

...Genentech, in justifying the cost of Lucentis, says its trials of the drug included more than 6,000 patients who received vision tests, retinal scans and monthly doctor checkups. It was "one of the more expensive clinical trials we've run," says Ronald Park, team leader for pricing. He notes that older drugs for AMD cost nearly $1,000 a dose without improving vision. Lucentis "is a breakthrough drug for a very bad disease," says Dr. Park.

The company also reasons that Lucentis could prevent disability, falls, broken hips and depression associated with blindness. The elderly blind "become more dependent on those they love to drive, get food, help around the house. Until you've seen someone who was independent go blind -- and I've treated these folks -- you don't understand how terrible this can be," Dr. Park says. The American Academy of Ophthalmology this month said blindness costs the health-care system more than $2 billion a year including nursing-home care.

Finally, Genentech says it is happy to help those who can't afford Lucentis. Since Lucentis's approval last summer, 15,000 patients have called the company's assistance programs asking about the drug, a spokeswoman says.

...With billions of dollars at stake and medical questions unanswered, the National Eye Institute plans to start a two-year trial in May or June to compare safety and efficacy of Avastin versus Lucentis. While the NIH has previously run tests comparing newer brand-name drugs against older and cheaper generics, this is the first time it is pitting two brand-name biotech drugs against each other, says Dr. Ferris, the eye institute's clinical director. He says the government must conduct the study because it needs to ensure that the widespread use of Avastin is safe.

Daniel Martin, chair of ophthalmology at Emory University School of Medicine, is leading the NIH trial and has selected 45 test sites for it. He offers his own mom test. "If I were treating your mom, you'd want me to know which drug is better," he says. "And if they're equal, why not use the less-expensive one?"

However, funding for the trial remains uncertain. In part because the government has to purchase all of its Lucentis and Avastin supplies, the eye institute says it can't afford to fund the trial on its own and is seeking help from Medicare.

Barry Straube, chief medical officer of the Center for Medicare and Medicaid Services, says he welcomes the trial as a guide for reimbursement policy, but lawyers for the agency have said it lacks legal authority to use the Medicare trust fund for such research expenses. Dr. Martin says the NIH has awarded $16.2 million for the trial and he'll seek additional funds elsewhere if needed.

Officials at the center, which administers Medicare, project that Lucentis could over time cost taxpayers more than $1 billion a year and possibly as much as $3 billion annually. Dr. Straube says he would be pleased if that figure can be reduced. "Not only are we interested in preserving the Medicare trust fund, but we're sensitive to the higher co-insurance payment Medicare beneficiaries would have to pay," he says.

Genentech says some of the projections of the Medicare impact are too high, noting analysts' estimates that this year's total sales will fall short of $1 billion.

For the moment, the company's data suggest Lucentis has captured about 55% of the market in new cases of AMD. Doctors' surveys suggest Avastin has captured much of the rest. That "unique situation," Executive Vice President Ian Clark recently told analysts, "will challenge our rate of growth of Lucentis in 2007."

Author’s Note on Avastin

Since posting the original article on January 31, 2006, I have now added twelve updates on this important drug for treating age-related macular degeneration. In addition to the posting you are reading, here is a listing (with links) to the others:

Avastin: A New Hope for Treating AMD (January 2006)

Avastin Update: Medicare not Likely to Cover its Use (March 2006)

Avastin Update II: AAO supports Medicare Coverage for Off-label Avastin Use (April 2006)

ARVO 2006: A Further Update on Both Avastin and Lucentis for Treating AMD (May 2006)

Avastin/Lucentis Update 4: FDA Approves Lucentis for Treating Wet AMD (July 2006)

Avastin Update 5: NIH Considers Comparing Lucentis and Avastin (August 2006)

Avastin/Lucentis Update 6: Latest Results Published in NEJM and Another Call for a Trial Between Them (October 2006)

Avastin/Lucentis Update 7: BREAKING NEWS – NEI/NIH Will Fund Comparative Study (October 2006)

Avastin/Lucentis Update 8: A Report of the Latest News from the 2006 AAO Meeting (November 2006)

Avastin/Lucentis Update 9: A Disturbing Report about the Upcoming Trial Between Avastin and Lucentis (December 2006)

Avastin/Lucentis Update 10: A Review of the Current Status of These Drugs for Treating AMD (January 2007)

Avastin/Lucentis Update 11: A White Paper on Why Avastin vs Lucentis Matters (February 2007)

Stem Cells in Ophthalmology Update 12 Updated Table of Company Participants

When I first wrote about stem cells in ophthalmology (Primer) in September 2010, I was able to identify six companies participating. Since then, and with the help of a few friends, I can now identify eleven companies using stem cells to treat ophthalmic diseases. Since I believe access to knowledge is very important, here is my revised table of companies using stem cells in treating ophthalmic diseases.

Please let me know of any corrections or omissions.

(An easier to read pdf file of this table is available from the author via email request.)

Stem Cells in Ophthalmology Update 26 First Wet AMD Patient Treated With RPE Derived from iPS Cells

Earlier this week, it was reported that Masayo Takahashi, an ophthalmologist at the RIKEN Center for Developmental Biology (CDB) in Kobe had appeared in front of a 19-member health-ministry committee for the safety of the clinical use of stem cells. She was flanked by Shinya Yamanaka, the biologist who first created iPS cells. Yamanaka shared the 2012 Nobel Prize in Physiology or Medicine for his breakthrough and now heads the Center for iPS Cell Research and Application in Kyoto. Takahashi was seeking approval to implant a retinal pigmented epithelial (RPE) sheet made from induced pluripotent stem (iPS) cells into a human patient.

Takahashi and her collaborators had shown in monkey and mice studies that iPS cells generated from the recipients' own cells did not provoke an immune reaction that causes them to be rejected. There had been concerns that iPS cells could cause tumours, but Takahashi's team found that to be unlikely in mice and monkeys.

To counter further fears that the process of producing iPS cells could cause dangerous mutations, Takahashi's team had performed additional tests of genetic stability. Guidelines covering the clinical use of stem cells require researchers to report safety testing on the cells before conducting transplants. The health ministry said that no problems were found and that the human trial could commence.

Only four days later (Friday, September 12th), the first patient was treated with the implanted sheet of RPE cells. She derived them from the patient's skin cells, after producing induced pluripotent stem (iPS) cells and then getting them to differentiate into retinal cells.

This is a major first for the stem cell and regenerative medicine fields.

Takahashi and her collaborators have been using induced pluripotent stem (iPS) cells to prepare a treatment for age-related macular degeneration. Unlike RPE derived from embryonic stem cells (i.e., as being done by Advanced Cell Technology), iPS cells are produced from adult cells, so they can be genetically tailored to each recipient. They are capable of becoming any cell type in the body, and have the potential to treat a wide range of diseases. The CDB trial will be the first opportunity for the technology to prove its clinical value.

A Japanese woman in her 70s is the world's first recipient of cells derived from induced pluripotent stem cells, a technology that has created great expectations since it could offer the same advantages as embryo-derived cells but without some of the controversial aspects and safety concerns.

In a two-hour procedure starting at 14:20 local time, a team of three eye specialists lead by Yasuo Kurimoto of the Kobe City Medical Center General Hospital, transplanted a 1.3 by 3.0 millimeter sheet of retinal pigment epithelium cells into an eye of the Hyogo prefecture resident, who suffers from age-related macular degeneration.

The procedure took place at the Institute of Biomedical Research and Innovation Hospital, next to the RIKEN Center for Developmental Biology (CDB) where ophthalmologist Masayo Takahashi had developed and tested the epithelium sheets.

Afterwards, the patient experienced no effusive bleeding or other serious problems, as reported by RIKEN.

Another important element to this story is that Japan has a clinical translation pipeline that is now faster with recent changes in regulations than that of the US. For example, this and future iPS cell-based transplants were approved as part of a clinical study, a type of clinical research mechanism that doesn't exist in the US. It is safe to say that the same technology with the same research team and outstanding level of funding would still be at least a few years away from their first patient in the US due to the different regulatory scheme.

As noted by Dr. Paul Knoepfler, in his writeup about the procedure:

 “The patient is clearly a brave hero. The team transplanted a huge (from a bioengineering perspective) 1.3 x 3.0 mm sheet of RPEs into the retina of the patient, who did not have any clear immediate side effects from the procedure. Keep in mind again that this sheet was made indirectly from the patients own skin cells so it is an autologous (or self) transplant, a notion that 10 years ago would have seemed entirely like sci-fi.”

“This is not only a huge milestone, but also an astonishingly fast translation of iPS cell technology from the bench to the bedside.”

 “Also, on the positive side we have the encouraging results from the ongoing clinical trials from Advanced Cell Technology (ACT) using a similar approach to macular degeneration, but employing human embryonic stem cells to make the RPEs.”

“For the vision impaired and the broader stem cell field, it is heartening to have two such capable teams working to cure blindness with pluripotent stem cells.”

Sources:

1.Next-generation stem cells cleared for human trial: Japanese team will use 'iPS' cells to treat patient with degenerative eye disease, Nature, David Cyranoski, September 10, 2014.

2. Japanese woman is first recipient of next-generation stem cells: Surgeons implanted retinal tissue created after reverting the patient's own cells to 'pluripotent' state, Nature, David Cyranoski, September 12, 2014.

3. Stem cell landmark: patient receives first ever iPS cell-based transplant, Knoepfler Lab Stem Cell Blog, Paul Knoepfler, Septermber 12, 2014.

Avastin Lucentis Update 50 A Possible Break in the Dam

News has just come out of England that Novartis may discount the price of Lucentis to off-set the gains made by Avastin in the treatment of wet AMD. As Nick Smith of APM Health Europe wrote yesterday, Novartis is considering cutting the price of Lucentis because of the gains being made by doctors using Avastin to treat AMD.

Here is Nick’s story...and as we hear more, we will bring you the news:

Novartis UK may cut Lucentis price to compete with off-label Avastin in AMD
by Nick Smith, APM Health Europe

LONDON, Oct 4 (APM) - Novartis on Tuesday indicated it may discount Lucentis (ranibizumab) in age-related macular degeneration (AMD) to curb the off-label use of Roche's Avastin (bevacizumab) in the UK.

In a statement to APM following earlier press reports that Novartis may take such a step, the company said: "We recognize the cost pressure within the National Health Service" adding it was "working with the Department of Health and NICE ... exploring all options, to help make Lucentis available for as many as possible of the patients who could benefit from this treatment."

Novartis gave no further indication of what steps it might be prepared to take to boost sales volume but did highlight that NICE had found the drug cost-effective in AMD.

PATIENT ACCESS SCHEME

It did not mention the patient access scheme, then known as a 'risk-sharing' scheme, which was used to discount the drug to gain approval.

The company agreed to pay the cost of the drug beyond 14 injections in August 2008, (APMHE 12490) but this did not stop the UK government undermining the agreement by asking NICE if it could examine Avastin for cost-effectiveness in the indication, despite the fact it is not licensed for the use.

Early take up of Lucentis seemed slow, leading to some sales figures coming below analysts' expectations.

However, an ever-wider global market, ageing population and innovative pricing schemes has helped the company turn this around and second quarter sales reached the equivalent of 310 million euros.

ns/ra

CATT Study Update 14 One Year Study Results Show Equivalency Between Avastin and Lucentis

The Comparison of AMD Treatment Trials (CATT Study) one-year results were released today in the New England Journal of Medicine (NEJM). As anticipated, the two anti-VEGF drugs, Avastin and Lucentis, both produced by Genentech, showed equivalent results in the four-arm head to head study. The 43-center, single-blind, noninferiority trial of 1208 patients with neovascular age-related macular degeneration, showed no significant difference either on a monthly injection schedule, or on an as needed injection schedule.

The National Eye Institute (NEI) launched the CATT Study in 2008 to compare Lucentis and Avastin for treatment of wet AMD. The study has now reported the one-year results for 1,185 patients treated at the 43 clinical centers in the United States. Patients were randomly assigned and treated with one of four regimens for a year. They received Lucentis monthly or as needed, or Avastin monthly or as needed. Enrollment criteria required that study participants had active disease.

Patients in the monthly dosing groups received an initial treatment and then had an injection every 28 days. Patients in the as needed groups received an initial treatment and were then examined every 28 days to determine medical need for additional treatment. As needed groups received subsequent treatment when there were signs of disease activity, such as fluid in the retina. Ophthalmologists involved in patient care did not know which study drug a patient was getting, to make sure that the data was not affected by how anyone felt about the treatment.

Change in visual acuity served as the primary outcome measure for CATT. Thus far, visual acuity improvement was virtually identical (within one letter difference on an eye chart) for either drug when given monthly. In addition, no difference was found in the percentage of patients who had an important gain or loss in visual function. Also, when each drug was given on an as needed schedule, there also was no difference (within one letter) between drugs. As needed dosing required four to five fewer injections per year than monthly treatment. Visual gains were about two letters less with as needed than with monthly treatment but overall visual results were still excellent.

In the monthly treatment arms, Avastin was equivalent to Lucentis, with 8.0 and 8.5 visual acuity letters gained, respectively, and in the as-needed arms, Avastin was equivalent to Lucentis with 5.9 and 6.8 letters gained.

Lucentis as needed was equivalent to monthly Lucentis treatments, although the comparison between Avastin as needed and monthly treatments was inconclusive.  The mean decrease in central retinal thickness was greater in the Lucentis-monthly group (196 μm) than in the other groups (152 to 168 μm, P=0.03 by analysis of variance).

Rates of death, myocardial infarction, and stroke were similar for patients receiving either Lucentis or Avastin (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with Avastin than with Luentis (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern.

It should be noted that the median age of patients in the CATT Study was over 80 years, and a high rate of hospitalizations might be anticipated as a result of chronic or acute medical conditions more common to older populations.

In conclusion, the CATT Research Group reported that at 1 year, Avastin and Lucentis had equivalent effects on visual acuity when administered according to the same schedule. Lucentis  given as needed with monthly evaluation had effects on vision that were equivalent to those of Lucentis administered monthly. Differences in rates of serious adverse events require further study.

Or to put it another way, Avastin and Lucentis are equivalent in treating wet AMD, as needed dosing is nearly as effective as monthly injections and, there are no major safety differences between the two drugs.

I have chosen two graphics to illustrate the study results.

Graph 1 shows the changes in visual acuity over the course of the study and illustrates the equivalency of the four arms of the study.

Graph 1

The part of Table 2 that I have chosen, again shows how close the results were for the four arms of the study, and in addition, shows the number of treatments for each arm, as well as the average annual cost to the patients, with Lucentis costing as much as 40 times the cost of Avastin. This will have an important impact on national health care costs when extrapolated to the more than 250,000 patients who are treated for neovascular AMD annually in the United States.

Table 2

(By clicking on the table, an enlarged version will become visible.)

Another important observation was made concerning adverse effects. The CATT Research Group noted that "Clinical trials of intravenous Avastin in patients with cancer have identified associations with arteriothrombotic events, venous thrombotic events, gastrointestinal perforation and hemorrhage, wound-healing complications, and hypertension. With a limited statistical power to detect important adverse events, we found no significant differences between the two drugs in rates of death, arteriothrombotic events, or venous thrombotic events, findings that are consistent with the results of a study of Medicare claims involving more than 145,000 treated patients.However, in our study, the rate of serious systemic adverse events, primarily hospitalizations, was higher among Avastin-treated patients than among Lucentis-treated patients (24.1% vs. 19.0%, P=0.04). The excess numbers of these events were distributed over many different types of conditions, most of which were not identified in cancer trials involving patients who were receiving intravenous doses of Avastin that were 500 times those used in intravitreal injections. We also did not observe increased rates of adverse events with increased exposure to the study drugs; rates were higher for the two drugs when given as needed than when given monthly. The difference in rates may be attributable to chance, imbalances in baseline health status that were not included in the medical history or multivariate models, or a true difference in risk. Resolving this issue will require many more patients than were available for this study. Results from the second year of this study and from other comparative trials will provide more information regarding the relative risks of serious adverse events."


Dr. Philip Rosenfeld (the father of Avastin) provided an editorial to accompany the CATT Study results in the NEJM. Here is the full text of his editorial:

Editorial

Bevacizumab versus Ranibizumab - The Verdict

Philip J. Rosenfeld, M.D., Ph.D.

April 28, 2011 (10.1056/NEJMe1103334)

For 5 years, patients and clinicians have wrestled with the choice between two drugs for the treatment of neovascular age-related macular degeneration (AMD), a common cause of irreversible blindness among the elderly worldwide. Vision loss results from the abnormal growth and leakage of blood vessels in the macula, a specialized portion of the retina responsible for the best visual acuity. Without this macular vision, patients become legally blind. Vascular endothelial growth factor (VEGF), the cytokine primarily responsible for blood-vessel growth, is inhibited when anti-VEGF drugs are injected repeatedly into the eye, and blindness is prevented in most patients. The majority of treated patients go on to have some improvement in vision.

The two anti-VEGF drugs most commonly used are bevacizumab (Avastin) and ranibizumab (Lucentis), both developed by Genentech. Bevacizumab, a full-length humanized monoclonal antibody, has been approved by the Food and Drug Administration (FDA) for the systemic treatment of certain cancers. Ranibizumab, an antigen-binding fragment, is a smaller molecule that was specifically developed and approved to treat eye diseases and is derived from the same anti-VEGF mouse monoclonal antibody as bevacizumab. Both ranibizumab and bevacizumab bind VEGF at the same position; however, they differ in size, affinity for VEGF, speed of clearance from the eye, and cost. Ranibizumab, the FDA-approved treatment for neovascular AMD, costs approximately $2,000 per dose, whereas bevacizumab, the off-label treatment, costs approximately $50. This cost difference, along with the perceived clinical similarities between these two drugs, has led to the widespread use of bevacizumab in the absence of level I evidence.

Editors Note: According to various sources, approximately 65% of ophthalmologists in the U.S. currently use Avastin over Lucentis as their primary treatment for neovascular AMD.

In this issue of the Journal, Martin and colleagues provide such evidence in their findings from the first year of the Comparison of AMD Treatment Trials (CATT), a large, prospective, multicenter, randomized clinical trial comparing bevacizumab and ranibizumab. Despite formidable obstacles, the investigators successfully compared the two drugs and two different dosing regimens: a monthly regimen versus an as-needed regimen (i.e., drug administration only when signs of exudation are present). A monthly regimen is considered the standard for treatment. An as-needed regimen is used less frequently and relies on clinical judgment and imaging techniques to determine when to reinject the drug. The most common imaging method that is used is optical coherence tomography (OCT), a noninvasive technique that identifies fluid leakage from blood vessels. This VEGF-mediated exudate resolves after the injection of ranibizumab or bevacizumab. An OCT-guided as-needed regimen has been shown to result in improved visual acuity, but CATT is the first prospective approach to directly compare a monthly regimen with an as-needed regimen.

Martin et al. found that the monthly use of either bevacizumab or ranibizumab results in the same visual acuity outcome. This finding holds true for the mean visual acuity and the proportion of patients who gain 15 letters (which represents a doubling of the visual acuity), lose 15 letters, or remain stable. Critics will argue that the OCT outcomes suggest differences between these two drugs. Although the OCT retinal thickness measurements favor ranibizumab, this difference is not reflected in any of the visual-acuity or angiographic outcomes. Whether this difference is associated with changes in vision should become clear during the second year of follow-up.

In addition, Martin et al. observed equivalent visual-acuity outcomes with both the monthly and the as-needed regimens of ranibizumab. This result is particularly good news for patients. The success of the as-needed regimen in a multicenter clinical trial cannot be overstated, given the intrinsic difficulties associated with the training of investigators to agree on OCT interpretation and retreatment guidelines. Given deficiencies that were reported by the reading center, it is likely that visual acuity and anatomic outcomes would have been even better with improved investigator compliance. Other strategies to improve overall treatment outcomes might include the use of newer OCT techniques with improved image resolution to help with retreatment decisions and the use of three mandated monthly injections at the start of the study.

Although the as-needed regimen with bevacizumab appeared similar to the as-needed regimen with ranibizumab, the as-needed bevacizumab regimen compared less favorably with monthly regimens for either bevacizumab or ranibizumab. One possibility may be that bevacizumab has a less durable treatment effect in a subgroup of patients and thus more frequent administration may be required. If the frequency of administration were increased, then the outcomes in such patients should approach the outcomes observed with monthly treatments.

Although CATT addresses the question of efficacy, the study was insufficiently powered to identify differences in drug-related adverse events. Although bevacizumab persists longer than ranibizumab in the systemic circulation after an intravitreal injection, Martin et al. observed none of the expected adverse events associated with systemic anti-VEGF therapy. Although more patients receiving bevacizumab had multiple systemic serious adverse events and hospitalizations than those receiving ranibizumab, these events were not associated with organ systems typically identified with systemic anti-VEGF therapy. The results from the second year of CATT and from five other large, ongoing, multicenter comparative clinical trials in Europe should help to clarify whether these adverse events are related to intravitreal anti-VEGF therapy.

The CATT results, together with the totality of global experience, support the use of either bevacizumab or ranibizumab for the treatment of neovascular AMD. An as-needed regimen is an acceptable alternative to a monthly regimen, but strict compliance on the part of both the clinician and the patient is required. Health care providers and payers worldwide will now have to justify the cost of using ranibizumab. Regulators in certain countries will be forced to reconsider their policies that make it illegal to use drugs off-label, particularly when so many of their citizens cannot afford ranibizumab. The CATT data support the continued global use of intravitreal bevacizumab as an effective, low-cost alternative to ranibizumab.

Gene Therapy in Ophthalmology Update 21 New Gene Therapy Company Spark Therapeutics Launches

Children’s Hospital of Philadelphia (CHOP) announced that it had spun off its work in gene therapy to a new, fully integrated company, Spark Therapeutics, that will assume control over two current gene therapy clinical trials: a Phase III study for Leber’s Congenital Amaurosis, an inherited disease that results in blindness caused by mutations of the RPE65 gene, and a Phase I/II study for hemophilia B. The new company is also advancing toward the clinic with gene therapy programs to address neurodegenerative diseases and additional hematologic disorders and other forms of inherited blindness. One such program, in the latter category, already in pre-clinical development at CHOP, could be its study for the treatment of Choroideremia, a rare inherited disorder that causes progressive loss of vision due to degeneration of the choroid and retina.

Editors Note: It should be noted that one clinical trial using gene therapy to treat Choroideremia is already underway at Imperial College London and Oxford University, in conjunction with Moorfields Hospital in London.

The new company has been launched with a $50 million capital commitment from Children’s Hospital to advance and commercialize multiple ongoing programs with clinical proof of concept.

As noted by Susan Young, writing about the launch in Technology Review, “Spark has a chance to be the first gene-therapy company to obtain FDA approval. Results for a late-stage trial of a gene therapy for Leber's Congenital Amaurosis ... are expected by mid-2015. That treatment is one of several gene therapies in or nearing late-stage testing contending to be the first gene therapy approved by the FDA for sale in the U.S.”

The Phase III trial was initiated late last year, and CHOP has made significant progress in enrolling patients. Spark will be sharing additional details on its progress and encouraging results in the very near future.

And, as shown in my table of Ongoing Clinical Trials in Ophthalmology, it is the only gene therapy trial (in ophthalmology) that has advanced to Phase III.

Editors Note: For clarity, is should be noted that there are five other clinical trials underway to treat Leber’s, as shown in my table, but all are currently Phase I or Phase I/II studies. The Spark Therapeutics trial is the farthest advanced.

“The creation of Spark is the culmination of a decade-long commitment by CHOP and our founding team to drive the field of gene therapy forward during a time when many in the industry had moved away,” said Jeffrey D. Marrazzo, co-founder, president and chief executive officer of Spark Therapeutics. “Their vision and long-term dedication have enabled us to effectively address many of the key challenges facing the field and to emerge with one of the industry’s most robust clinical-stage gene therapy pipelines; as well as exclusive rights to commercialize a proprietary manufacturing platform, supply from a world-class manufacturing facility and a founding team with a proven track record of executing safe and effective gene therapy trials for nearly two decades. We are working with great urgency and care to deliver gene therapy products with the potential to transform the lives of those affected by severe genetic diseases.”

Spark builds on the work of CHOP’s Center for Cellular and Molecular Therapeutics (CCMT), established in 2004 as a world-class center for gene therapy translational research and manufacturing. Many of the CCMT’s leaders will assume management roles within Spark or engage with the company as scientific advisors, including Katherine A. High, M.D, a gene therapy pioneer who has served as the director of the CCMT since its inception.

“Gene-based medicines are among the most complex therapeutics ever developed,” said Dr. High. “We at CCMT have persevered through more than a decade of scientific and clinical development and are now closer than ever to realizing the ambitious vision of one-time, potentially curative therapies to address serious genetic conditions. The team at Spark has incredible goals for the treatment of diseases including hemophilia B and inherited blindness, and we look forward to working with them to deliver groundbreaking new treatments to patients in need.”

Spark has entered into agreements with multiple academic institutions to assemble the technology, programs and capabilities needed to deliver its pioneering gene therapy products. Notably, Spark has exclusive rights to commercialize CHOP’s proprietary manufacturing technology and will use clinical-grade gene therapy vectors produced by the CCMT’s state of the art good manufacturing practices (cGMP) clinical facility.

Pioneers in AAV delivery

Over the past two decades, the Spark leadership team has developed unrivaled expertise in the design, manufacturing and delivery of gene therapies using adeno-associated virus (AAV) vectors. AAV has been demonstrated in clinical studies to be a safe and effective vehicle for the delivery of genetic material into targeted cells and provides unique advantages over alternative delivery approaches. The Spark team was among the first to demonstrate human clinical proof of concept in two distinct organ systems — the eye and the liver — establishing a strong foundation for the company’s current programs, and has clinical experience in 15 studies across diverse genetic and non-genetic diseases and five distinct routes of administration.

Spark’s most advanced clinical program is a Phase III study to address blindness caused by mutations in the RPE65 gene. There is currently no pharmacologic treatment for this form of inherited retinal degeneration, which ultimately causes irreversible blindness.

The open-label, randomized, controlled study builds on an earlier clinical study in which 12 patients with RPE65-related blindness demonstrated notable improvement in visual function, moving in some cases from being profoundly blind to being able to recognize faces and ambulate independently. All school-age patients enrolled in the trial were able to transfer from Braille classrooms to sighted classrooms.

One such patient was Corey Haas, whose story is related in the book “The Forever Fix: Gene Therapy and the Boy Who Saved It”.

Corey Haas, his parents, and the CHOP team that treated his Leber’s and gave him back his vision.

 

Read Corey’s story in Ricki Lewis’ book, The Forever Fix: Gene Therapy and the Boy Who Saved It.

The team's experience in the clinical study of gene therapy – from designing and manufacturing vectors to conducting studies that have shown strong potential for safety and efficacy – is unparalleled in the field. Clinical-grade vectors prepared by the team have been used to safely treat more than 100 human subjects in 12 clinical trials in the U.S. and EU, across five parenteral routes of administration in genetic and non-genetic diseases. No other group can claim this breadth of expertise and experience in human gene therapy.

The adeno-associated virus (AAV) vectors used in the clinical programs have been demonstrated to be safe and effective vehicles for delivering genetic material into targeted cells, providing unique advantages over alternative therapeutic approaches. The team has established human proof of concept in two organ systems – the eye and the liver – and are advancing a Phase III program in blindness caused by mutations of the RPE65 gene; a Phase I/II program in hemophilia B; and preclinical programs in neurodegenerative diseases and other hematologic disorders and forms of inherited blindness.

Avastin Lucentis Update 22 Recent Avastin Study Compared to Use of Lucentis in PrONTO

Dr. James Folk, writing in his Medical Rounds Blog, commented on a recent study done by Bashshur and colleagues and published in the American Journal of Ophthalmology. In the Bashshur study, the doctor and his colleagues treated 60 patients with Avastin only, but at a higher than normal dosage – 2.5 mg vs 1.25 mg. They gave one injection and then observed the results one month later using OCT.

If the OCT was dry, the authors didn’t give an injection but asked the patient to return one month later for a re-examination. The treatment paradigm was similar to the PrONTO study except in PrONTO, Lucentis at 0.5mg was used instead of Avastin and the patient first received three monthly injections followed by additional injections as needed.

The other difference was that Bashshur and colleagues would not reinject if the eye showed persistent subretinal or intraretinal fluid after three injections. They believe that these eyes often remain stable. Therefore they would follow them and only reinject if they worsened. In the PrONTO study, any fluid on OCT was an indication for another injection.

As Dr. Folk noted, the Bashshur study was small, only 60 patients (with 9 lost to followup), but the Comparison of AMD Treatment Trials (CATT) is starting and will be the definitive study comparing Avastin to Lucentis for the treatment of wet AMD. The results of Bashshur and colleagues however predict that at most, we’ll probably only find a modest difference between the two drugs.

AMD Update 13 Retinal Procedures on the Rise

A new study, just published in the October issue of Archives of Ophthalmology and reported by Ophthalmology Web, MedPage Today, and Medscape Medical News,  shows that among those in the Medicare population (age 65 plus), treatments for retinal conditions nearly doubled between 1997 and 2007 – and this trend is expected to continue with the aging of the population and seniors living longer.

Since more than 50% of all permanent blindness in older Americans is the result of two different retinal diseases: age-related macular degeneration and diabetic retinopathy. Advancing age raises the risk for both conditions. As the number of US residents older than 65 years continues to grow -- the figure is predicted to double by 2040 -- the incidence of both diseases will likely escalate. To prepare for that prospect, the researchers analyzed Medicare fee-for-service claims filed during the 10-year period 1997 - 2007.

The new report, "Use of retinal procedures in Medicare beneficiaries from 1997 to 2007", by Pradeep Y. Ramulu, M.D., M.H.S., Ph.D., of the Wilmer Eye Institute, Johns Hopkins University, Baltimore, and colleagues, states:  "Retinal disease is highly prevalent among older individuals, and both age-related macular degeneration (AMD) and diabetic retinopathy account for more than half the irreversible blindness in older Americans. The prevalence of both macular degeneration and diabetic retinopathy increases with age, and the number of Americans affected by these conditions is expected to increase substantially as the number of Americans older than 65 years doubles from 2010 to 2040." The authors continued, as background information to the article, "The last decade has seen substantial changes in the treatment options available for many retinal diseases, particularly in the treatment of neovascular AMD," a form of the disease involving abnormal blood vessel growth in the eye.

Procedure volumes changed most markedly for treatments directed toward neovascular AMD. New treatments for this condition include intravitreal therapy-injections of drugs administered directly into the eye-of antibodies that block the formation of new blood vessels. (Both Avastin and Lucentis.) Between 1997 and 2001, fewer than 5,000 such injections were performed each year. However, rates more than doubled each year through 2006, increasing between 2001 (when 4,215 of these procedures were performed) and 2007 (when injections totaled 812,413). “These treatments now represent a major component of the treatment of retinal disease”, the researchers observed.

Aside from the VEGF inhibitors, other pharmacologic agents used for intraocular injections have included steroids for macular edema and pegaptanib (Macugen) for macular degeneration.

Prior to the introduction of pharmacologic agents, including Avastin in 2005  and Lucentis in 2006, the sole treatment option to have demonstrated benefit for choroidal neovascularization was thermal laser treatment. Thermal laser treatments also fell by 83% between 1997 and 2007, from a high of 56,966 to 13,821. Then in 2000, photodynamic therapy became available.

Photodynamic therapy peaked in 2004 with 133,565 procedures and then decreased 83 percent to 22,675 procedures in 2007. Laser treatment of choroidal lesions (potentially cancerous eye tumors) and neovascular AMD also decreased 83 percent, from a peak of 82,089 in 1999 to 13,821 in 2007.

Vitrectomy-surgical removal of the gel inside the eye, used to treat retinal detachments – increased 72 percent, from 11,212 in 1997 to 19,923 in 2007. Scleral buckling, a treatment for the same condition involving placing a silicon buckle around the eye, can be performed with or without vitrectomy. Scleral buckling alone became less common during the study period (a 69 percent decrease, from 8,691 to 2,660).

The increasing use of retinal procedures means that greater attention should be paid to the financial implications, the authors observed. The annual price tag for ranibizumab (Lucentis) is about $24,000 for a single patient, and investigations are needed to determine if lower-cost options (Avastin) could provide equivalent improvements in vision and quality of life. For instance, a study currently underway – the CATT Study,  is comparing the less costly Avastin with Lucentis in a double-blinded four-arm study. (Initial results of this study are expected to be released early next year.)

"Observing use patterns adds value, because it demonstrates how disease is treated and can be used to identify possible discrepancies between the best evidence-based treatments for a condition (as defined by clinical trials and meta-analyses from the literature) and current practice patterns," the authors concluded. "In this report, we observed that intravitreal injections of pharmacologic agents have gained widespread acceptance for the treatment of neovascular AMD and that vitrectomy is being increasingly applied to a wide range of retinal conditions."

The researchers stated several limitations to their study: the focus on only Medicare claims prohibited the discovery of trends in those younger than 65 years and prevents generalization of findings to those with private insurance, and in addition, possible systematic errors in coding may have biased results.

The National Institutes of Health supported the study.

References:

Arch Ophthalmol. 2010;128:1335-1340

Ophthalmology Web

MedPage Today

Medscape Medical News