August 2018

CORNEA

Pharmaceutical focus
Adopting miltefosine for Acanthamoeba keratitis


by Maxine Lipner EyeWorld Senior Contributing Writer


Acanthamoeba keratitis
Source: Alfonso Iovieno, MD

“Don’t skip the other drugs to
get to this one. But if things don’t seem to be going well, this may be
a treatment in the near future, and its role may expand later.”
—Elmer Tu, MD

How practitioners are putting this orphan drug to use

When faced with Acanthamoeba keratitis, practitioners in the United States today have access to the parasitic agent miltefosine (Impavido, Profounda, Orlando, Florida), which in the past required herculean efforts to obtain. Miltefosine was approved by the FDA as an orphan drug for the treatment of Acanthamoeba keratitis and encephalitis in early 2017, according to Alfonso Iovieno, MD, PhD, associate professor, 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 activity 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 clinical 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 areas,” he said. But its penetration and mechanism of action appear to also be well suited to other parasites.
Dr. Tu credited Govinda Visvesvara, PhD, who he described as the “godfather of Acanthamoeba research at the CDC,” with recognizing miltefosine’s potential here. “He tested two compounds, voriconazole, an antifungal medication, which we’ve used before for Acanthamoeba, and miltefosine,” Dr. Tu said, adding that he found miltefosine had activity against Acanthamoeba when studying its potential to save those with this infection in the brain. While this study1 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, including 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 miltefosine. “That’s a reasonable success rate,” he said. “I think it has more effect than any other oral medication that we’ve used previously.”

Orphan drug impact

In Canada, where Dr. Iovieno practices, miltefosine remains 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 miltefosine, 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 United States is reserved for those agents that are applicable to a small number of patients per year where there is no other good therapy available, Dr. Tu explained. With Acanthamoeba keratitis, the incidence generally quoted is 1–2 cases per million contact 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 impact, making an agent such as miltefosine easier to obtain. Dr. Tu recalled how difficult this was to acquire 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 pharmacy and get it.”

Considering the regimen

Currently, practitioners are uncertain for which Acanthamoeba keratitis 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, adding that women of child-bearing age should be cautioned about this.
Dr. Tu’s patients with Acanthamoeba keratitis have found themselves in desperate circumstances. “In those situations, we know generally that these patients are not going to do well and that a good percentage will either lose vision 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 miltefosine. 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. Iovieno’s first line of treatment for a superficial Acanthamoeba keratitis case is monotherapy with polyhexamethylene biguanide (PHMB). Often when the diagnosis is made early, this treatment is sufficient to resolve the disease within 2 or 3 weeks. “Unfortunately, that’s not the case for many patients with Acanthamoeba because they come late to the tertiary center,” Dr. Iovieno said. “They’ve been seen by other ophthalmologists and might have other initial diagnosis.” By the time Dr. Iovieno treats them, they often have deeper stromal disease. For these patients, he combines use of PHMB with hexamidine, another standard agent for Acanthamoeba keratitis treatment.
“In the resistant cases, where we don’t see a resolution of the disease within the initial 3–4 months of treatment, then we have to employ other strategies,” Dr. Iovieno said, adding that use of voriconazole is usually the next step. However, this can be inconsistent. “In vitro data for voriconazole is all over the place,” he said. “It seems to be active in a different way in different settings.” Miltefosine becomes an option in resistant cases when practitioners want to add to the standard treatment. Until this point, the big problem with miltefosine has been availability, whereas voriconazole is commercially available in pharmacies all over the world, Dr. Iovieno pointed out.
Another possible treatment option that some practitioners consider is crosslinking. However, Dr. Iovieno himself does not favor this approach. “It doesn’t seem to work well,” he said. “It may seem to work for other kinds of infections but not for Acanthamoeba.” Still, with such new treatments, the jury is still out.
The main side effect to be wary of with miltefosine treatment is gastrointestinal upset, Dr. Iovieno noted, adding that he has seen this in many of his patients. “However, there wasn’t enough to prompt discontinuation of treatment,” he said.
Visual results with miltefosine vary depending on how severe the eye is at presentation. “For someone with superficial disease, there is no reason the patient shouldn’t regain vision fully,” Dr. Iovieno said. “Unfortunately, in the vast majority of the cases they end up with some degree of corneal scarring, to the point where a transplant for optical purposes later on in patients with Acanthamoeba is common, occurring in about one-third of patients.”
In addition to expanded miltefosine use for the treatment of Acanthamoeba, more research is being conducted on PHMB with a new multicenter trial underway in Europe expected to lead to the approval of this agent at a concentration that is three times higher than standard, Dr. Iovieno noted. “I think the results of this trial will be available by the end of this year or the beginning of next,” he said.
Overall, Dr. Tu advised practitioners considering miltefosine to remember that this is still in its nascence. “Generally, the results have been positive but they are early reports,” he said, adding that the traditional medications can work well and should be tried first. “Don’t skip the other drugs to get to this one,” Dr. Tu said. “But if things don’t seem to be going well, this may be a treatment in the near future, and its role may expand later.”

Reference

1. Schuster FL, et al. In-vitro activity of miltefosine and voriconazole on clinical isolates of free-living amebas: Balamuthia mandrillaris, Acanthamoeba spp., and Naegleria fowleri. J Eukaryot Microbiol. 2006;53:121–6.

Editors’ note: Dr. Iovieno and Dr. Tu have no financial interests related to their comments.

Contact information

Iovieno
: alfonsoiovieno@hotmail.com
Tu: etu@uic.edu

Adopting miltefosine for Acanthamoeba keratitis Adopting miltefosine for Acanthamoeba keratitis
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