Eyeworld

EW CORNEA 58 August 2018 by Maxine Lipner EyeWorld Senior Contributing Writer impact, making an agent such as miltefosine easier to obtain. Dr. Tu recalled how difficult this was to ac- quire initially. "For the first several patients, I had to go through not only IRB approval at my institution but also had to import it through the FDA," he said. "Now you can send a prescription to your pharma- cy and get it." Considering the regimen Currently, practitioners are uncer- tain for which Acanthamoeba kerati- tis patients miltefosine may be best suited. Dr. Tu pointed out that while patients generally tolerate it well, this is a systemic medication, which does have some side effects. "It's a teratogen, meaning that it can affect developing babies," Dr. Tu said, add- ing that women of child-bearing age should be cautioned about this. Dr. Tu's patients with Acan- thamoeba keratitis have found themselves in desperate circum- stances. "In those situations, we know generally that these patients are not going to do well and that a good percentage will either lose vi- sion or lose their eye," he said. "But miltefosine does offer some hope for them." However, he added, if it was more widely available, practitioners might be able to treat the disease at earlier stages. "Whether it would be more or less beneficial at that time, we don't know," he said. Likewise, the cases in which Dr. Iovieno has used miltefosine have been the chronic resistant ones involving patients who have been on Acanthamoeba treatment for at least 4–6 months. "They tried different combinations of drugs and increased potency of drops," Dr. Iovieno said, adding that they had failed on other oral treatments such as voriconazole before trying milte- fosine. Some had also undergone a therapeutic keratoplasty for either a perforation or a non-responding infection, but this was ineffective. His approach is different when treating the early patient. Dr. Io- vieno's first line of treatment for a superficial Acanthamoeba keratitis case is monotherapy with poly- hexamethylene biguanide (PHMB). Often when the diagnosis is made early, this treatment is sufficient exceedingly hard to obtain since this has not been given orphan drug status there as of yet. "It needs to be imported from other countries, and we get it by special approval from Health Canada," he said. "A week's treatment is about $5,000 Canadian, which tends to be quite expensive considering that in cases in which we've treated patients with miltefos- ine, they need to be on it for more than a month." In Europe it's a different story. "It has been approved by the European Medicines Agency as an orphan drug," Dr. Iovieno said. "This means that depending upon the country in Europe, you may get some funding from the national government." Orphan drug status in the Unit- ed States is reserved for those agents that are applicable to a small num- ber of patients per year where there is no other good therapy available, Dr. Tu explained. With Acanthamoe- ba keratitis, the incidence generally quoted is 1–2 cases per million con- tact lens wearers per year. "That's somewhere between 300 and 600 cases," Dr. Tu said. Although in certain regions where there has been an outbreak, this has increased to about 10 per million contact lens wearers per year. While limited in scope, the orphan drug status can have a great Acanthamoeba when studying its po- tential to save those with this infec- tion in the brain. While this study 1 indicated that both agents worked somewhat, it was the miltefosine that had the most activity. Dr. Tu first became aware of miltefosine about 10 years ago when he found himself faced with an Acanthamoeba keratitis patient who had failed other treatments, includ- ing use of voriconazole. "She was going to lose her eye," he said. "I went through the process of getting IRB [Institutional Review Board] approval for emergency use through the FDA to import this drug from Germany." The drug saved her sight. "She does not have perfect vision, but it's pretty good," he said, adding this was after having failed all of the other medications plus two corneal transplants. The drug was difficult to obtain as well as very expensive, at around $2,500–$3,000 per month at the time. He has since had several other patients in similar need and has found that half responded to milte- fosine. "That's a reasonable success rate," he said. "I think it has more effect than any other oral medica- tion that we've used previously." Orphan drug impact In Canada, where Dr. Iovieno practices, miltefosine remains How practitioners are putting this orphan drug to use W hen faced with Acan- thamoeba keratitis, practitioners in the United States today have access to the parasitic agent miltefosine (Impavi- do, Profounda, Orlando, Florida), which in the past required hercule- an efforts to obtain. Miltefosine was approved by the FDA as an orphan drug for the treatment of Acan- thamoeba keratitis and encephalitis in early 2017, according to Alfonso Iovieno, MD, PhD, associate profes- sor, University of British Columbia, Vancouver. Miltefosine is an ammonium compound. "It's a drug that was initially developed for the treatment of leishmaniasis, which is largely a disease of dogs," Dr. Iovieno said, adding that this parasitic infection can also affect humans. This agent was found to have good potential against Acanthamoeba, although the mechanism of action has not been fully elucidated, Dr. Iovieno noted. "It does inhibit mitochondrial ac- tivity as well as destroy the plasma membrane and induce apoptosis in the amoeba cells," he said. Recognizing miltefosine's activity Elmer Tu, MD, professor of clin- ical ophthalmology, University of Illinois, Chicago, noted that in humans, leishmaniasis tends to be more of a skin disorder, but it can also affect internal organs as well as the brain. "It's usually found in jungle environments, places like Colombia and other subtropical ar- eas," he said. But its penetration and mechanism of action appear to also be well suited to other parasites. Dr. Tu credited Govinda Vis- vesvara, PhD, who he described as the "godfather of Acanthamoeba research at the CDC," with rec- ognizing miltefosine's potential here. "He tested two compounds, voriconazole, an antifungal medi- cation, which we've used before for Acanthamoeba, and miltefosine," Dr. Tu said, adding that he found miltefosine had activity against Adopting miltefosine for Acanthamoeba keratitis Pharmaceutical focus continued on page 60 Acanthamoeba keratitis Source: Alfonso Iovieno, MD

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