U.S. clinicians get their first peek at Rescula

The new prostaglandin derivative could appear in the United States this year.

Rescula (unoprostone isopropyl; CIBA Vision) remains unapproved in the United States. but research brought forward at scientific symposia late last year offers clinicians a chance to evaluate this new class of glaucoma therapy. CIBA Vision will file a new drug application in the first quarter of 2000.

Unoprostone received approval for Japanese distribution in 1994, and most Central American and South American countries have granted approval, as well. More than 250,000 patients have used the drug, with no major systemic side effects reported in clinical trials or post-marketing reports.

According to Peter A. Netland, MD, PhD, the hope is that unoprostone will become available in the United States sometime this year.

Dr. Netland is director of the glaucoma service and associate professor of ophthalmology at the University of Tennessee, Memphis, which sponsored a CME-accredited symposium on Rescula in Orlando during the annual meeting of the American Academy of Ophthalmology. The symposium was supported by a grant from CIBA Vision.

According to CIBA Vision, unoprostone was developed from a prostaglandin metabolite. It is a docosanoid — a class of compounds based on a 22-carbon-atom backbone, which makes for properties very different from the 20-atom eicosanoids (that is, prostaglandins). Unoprostone was found to be inactive in prostaglandin-sensitive tissues.

Its permeability through the corneal epithelium is comparable to timolol and better than pilocarpine and epinephrine, according to several studies. It shows no affinity for pigmented ocular tissues and has not caused the iris color changes seen in latanoprost (Xalatan; Pharmacia & Upjohn).

Unlike prostaglandins, unoprostone does not induce smooth muscle contraction or act on the normal circulatory system. It has no known systemic effects, nor does it induce tachyphylaxis.

Unoprostone promotes aqueous outflow and has no effect on aqueous production and uveoscleral outflow. It is believed to increase outflow through the trabecular meshwork, although not enough experimental evidence exists to confirm the hypothesis.

A different drug

CIBA published a product monograph in 1999 to review clinical trials, as well as product safety and efficacy.

In the monograph, Japanese re-searchers reported side effects in less than 7% of patients. Most side effects included superficial punctate keratitis, conjunctival hyperemia and transient stinging and burning.

Corneal signs predominate among local side effects, including corneal epithelial defects and keratitis. These defects disappear after stopping treatment, or their incidence falls after long-term application.

Researchers did not find a cause for the appearance of epithelial keratitis, although they studied cytotoxicity to corneal epithelial cells, decreased corneal epithelial barrier function and the reduction of tear secretion, according to the monograph.

The drop did not show the side effects of increased IOP, bitter taste, bradycardia, tissue inflammation, miosis, changes in visual acuity or accommodation, damage to the blood- aqueous barrier or decreased blood pressure. Iris color change, hypertrichosis and eyelid pigmentation were reported in less than 0.01% of patients treated with unoprostone for 5 years. This finding correlates with data from 12 month clinical trials in Japan, where Rescula did not change iris color, while latanoprost caused pigment changes in 8.4% of the patients.

Iris color change attributed to latanoprost is typically seen in blue-yellow eyes, which are rarely encountered in the Japanese population.

One published report of iris color change attributed to unoprostone exists in the literature. A 64-year-old Japanese man with normal tension glaucoma (NTG) showed an iris color change in an unoprostone-treated eye. The iris color before treatment was uniformly brown but, 20 months after treatment, the iris had darkened, slightly roughened and appeared somewhat atrophic compared with the fellow eye.

UENO Fine Chemicals performed three large post-marketing surveys in the 4 years since the product’s launch. To date, 4,447 patients have been followed for safety and efficacy.

The overall incidence of all ocular side effects among the evaluated patients was 12.95%. The most common adverse reactions were transient eye irritation (4.38%), corneal erosion (2.63%), keratitis (2.43%) and conjunctival hyperemia (2.07%). The main systemic adverse reaction was headache (0.31%).

Vital P. Costa, MD, PhD, director of the glaucoma service at the University of Campinas, Sao Paulo, Brazil, reported on a study of 10 monkeys followed for 1 year. The study showed that unoprostone induced no iris color change. Those same monkeys using latanoprost showed hyperpigmentation 3 months after the beginning of the treatment.

“In humans, though, we do see some cases of iris hyperpigmentation,” he said. “Most recently, about four cases have been described, but they happen long after the beginning of the therapy — around 20 months after the beginning of the therapy.”

No controlled study has compared iris color change in unoprostone and latanoprost.

“But it is my feeling that here we may be facing a different drug with fewer side effects, in terms of anterior uveitis, lid pigmentation and iris pigmentation,” Dr. Costa said. “Still, we need long-term comparative control studies comparing both drugs.”

Comparing regimens

One Argentinean physician presented his research at a CIBA-sponsored symposium conducted in Stockholm, Sweden. His study attempted to compare the efficacy and safety on tolerability, as well as corneal and conjunctival effects. Daniel Grigera, MD, compared unoprostone added to timolol (Ofal), as opposed to dorzolamide hydrochloride (Trusopt; Merck) added to timolol.

The study was a single center, open, non-parallel, prospective study of 57 eyes of 30 patients. Of the patients, 19 were female, 11 were male and all were Caucasian. Of this group, 11 had ocular hypertension and 18 had primary open-angle glaucoma (POAG).

Patients had IOP controlled between 15 mm Hg and 21 mm Hg for at least 3 months before the study. They were treated with a regimen of timolol and dorzo lamide for 2 weeks and then switched to timolol and unoprostone for 8 weeks.

IOP at baseline in patients treated with timolol alone was 17.86 ± 2.3 mm Hg. IOP fell to 16.19 ± 2.3 mm Hg when dorzolamide was added. When dorzolamide was replaced by unoprostone IOP fell further to 14.57 ± 2.03 mm Hg.

At the end of the study, no patients receiving timolol and unoprostone reported bitter taste. There were no differences in corneal status.

Dr. Costa, who also is an associate professor at the University of Campinas, reviewed this study at the Orlando symposium.

When treatment with dorzolamide ended, some patients complained of a stinging sensation, yet no patients complained of a stinging sensation by the end of week 8, when they received timolol and unoprostone.

“A few patients felt uncomfortable when the dorzolamide was used, and those patients felt better when unoprostone was started between week 2 and week 8,” Dr. Costa said.

Maintaining visual field

Since the drug has been approved in Japan the longest, a survey of the Japanese literature uncovers the most data.

In one study, unoprostone maintained visual fields in 92% of 135 NTG patients, researchers reported in the Japanese journal Atarashii Ganka in 1997. Researchers administered unoprostone 0.12% in NTG patients for 12 to 24 months, with an average of 20.8 months.

They compared the initial and final mean deviation of the Humphrey (Dublin, Calif.) 30-2 test. More than 4 dB of improvement was seen in four eyes (1.5%) in the early stage of the disease (–10 dB). Mean deviation worsening of at least 4 dB was seen in 16 eyes (5.9%), 33% of them in the advanced stage (–20 dB). The remaining 92% of the treated eyes maintained their visual fields without change during the study period of 12 months to 24 months.

The study also concluded that unoprostone 0.12% reduced IOP an average of 1.6 mm Hg (12.3 mm Hg after treatment from a baseline of 13.9 mm Hg).

In another study, Fujimori et al reported on 13 NTG patients treated for 24 weeks. Mean baseline IOP values of 15.6 mm Hg were reduced by 1.8 mm Hg. Four patients achieved more than 2.5 mm Hg and one patient achieved more than 3 mm Hg reduction.

Azuma et al reported study results at the Stockholm symposium. Dr. Azuma reported data from 142 patients treated for 4 years with unoprostone. Of the group, 74 had POAG, 48 had NTG and 20 had ocular hypertension.

Clinically significant IOP reduction was achieved in 79% of the POAG and ocular hypertension patients and in 73.5% in the NTG patients. Visual fields improved in the POAG group by 25%, was unchanged in 60% and worsened in 15%. Visual field in NTG patients improved in 27%, were unchanged in 65% and worsened in 8%.

Adverse drug reactions included seven patients (4.9%) who reported ocular irritation and four patients (2.8%) with superficial keratitis.

Based on Japanese nationwide post-marketing surveillance, adverse reactions were suspected in 13.8% of patients who showed transient eye irritation, corneal lesions and conjunctival hyperemia.

Dr. Azuma wrote in the symposia proceedings that, “Since the introduction of unoprostone isopropyl eye drops in Japan, its market share has steadily increased to approach that of timolol, because many ophthalmologists have recognized the stable usefulness of this docosanoid-related drug.”

A fourth study reported a mean IOP reduction of 2.1 mm Hg 1 month after switching patients from dipivefrin to unoprostone. Unoprostone maintained the IOP level when patients switched from beta blockers or pilocarpine. In another study, the same authors reported an IOP reduction after 1 month of 4.5 mm Hg when unoprostone was the first choice of treatment in previously untreated patients. IOP fell 3.7 mm Hg when patients received unoprostone as an additional drug and 1.5 mm Hg when used as a replacement medication.

Diurnal effect

According to Dr. Netland, diurnal variations of IOP have been associated with glaucoma damage. Aqueous production drops at night, when patients sleep, and increases when they awaken. So researchers also compared the effects of unoprostone and timolol on the diurnal variations in IOP.

Araie et al studied 12 patients, six treated with unoprostone and six with timolol, for 4 weeks. Differences between baseline and last day IOP values were higher in the unoprostone treated group (P < .001) compared with the timolol group (P < .05).

The IOP values in the unoprostone group during the evening hours (17 through 21) on the last day of administration were significantly lower than the corresponding figures on the day before treatment. IOP values during the evening hours reached statistical significance (P < .05) in the timolol group at the 21st hour.

Another study comparing the circadian variation of the IOP-lowering effects of timolol and unoprostone reported that timolol significantly reduced IOP during the day but not at night. However, IOP reduction with unoprostone was significant during the day and at night.

Another study investigated diurnal IOP levels with twice-daily treatment of unoprostone or timolol for 2 weeks. It also investigated the effect of unoprostone three times daily compared with timolol twice daily for another 2 weeks.

Both regimens showed comparable efficacy between the two compounds.

According to Dr. Netland, unoprostone does lower the IOP consistently during the day. Head-to-head comparisons showed that unoprostone offers more IOP reduction than timolol at different points throughout the day, and that difference is statistically significant.

“Timolol, on the other hand, does have reduced effect on this at night. This has been shown in multiple studies,” Dr. Netland said.

Another trial conducted by Azuma et al involved a double-masked study of 286 eyes of 158 patients with ocular hypertension and POAG. The 12-week study reported comparable efficacy of unoprostone to timolol.

Overall, 91.4% of patients treated with unoprostone and 88.3% treated with timolol improved with IOP reduction more than 20%, with no significant differences between the two groups.

Blood flow

  Rescula studied

Alon Harris, PhD, reviewed animal studies to evaluate unoprostone’s effect on blood flow. These were not his own studies.

The studies are mostly animal models reported in Japanese peer review journals. In one report, Sugiyama et al used hydrogen gas clearance flowmetry to show unoprostone’s effect on blood. Hydrogen gas clearance flowmetry measures the concentration of hydrogen gas in the optic nerve with electrodes inserted into the tissue. They suggested that intravitreal injection of unoprostone increased optic nerve head blood flow 14%, Dr. Harris said.

But most importantly, he added, researchers pretreated the animal with intravitreal injection of unoprostone followed by intravitreal injection of endothelian 1 (ET-1), a potent vasoconstrictor. They found unoprostone inhibited the reduction of optic nerve head blood flow resulting from ET-1.

In another study, Sugiyama applied unoprostone topically to rabbits and used a hydrogen gas clearance technique.

Intravitreally injected ET-1 decreased the capillary blood flow in the optic nerve head by 47% in the rabbits that had placebo pretreatment. The topical unoprostone pretreated group inhibited the decrease of ET-1 in a dose-responsive manner, Dr. Harris said.

“What this says is that topical unoprostone effectively blocks the vasoconstrictive effects of intravitreally injected ET-1 and that also suggests indirectly that the drug appears at the back of the eye in the retina and choroid in sufficient concentrations to block the ET-1 effect,” he said.

“If these effects of Rescula are proven true, then Rescula could combat the disease in an additional way than just lowering IOP,” he said.

Human applications

Dr. Harris said that a different study by Kojima in 1996 looked at five normal human subjects who received unoprostone versus vehicle before and after single instillation using laser speckle flowgraphy. In their reports, there was an increase in optic nerve head blood flow 3 and 4.5 hours after treatment. The increase is in the optic nerve head and in the choroid.

Finally, a study by Emi in 1996 reported on 18 normal human eyes be-fore and 2 hours after instillation of the drug. By using color Doppler imaging, researchers increased blood flow velocity in the central retinal artery and the posterior ciliary artery.

“From all the studies that I reported about what is relevant to humans, that is the strongest data to suggest that it might have an effect on ocular blood flow in humans,” Dr. Harris said. “However, when peak systolic velocity and endostolic velocity increase in parallel fashion, as it did in their study, it can be a sign of increased blood flow and increased blood velocity.”

For Your Information:

• Peter A. Netland, MD, PhD, is director of glaucoma services at the University of Tennessee, Memphis, Department of Ophthalmology. He can be reached at 956 Court Ave., Memphis, TN 38163; (901) 448-5884; fax: (901) 448-1299. Dr. Netland has no direct financial interest in any of the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
• Vital P. Costa, MD, PhD, is director of the glaucoma service at the University of Campinas, Brazil. He can be reached at Av Pacaembu 1782, Sao Paulo, 01234-000, Brazil; (55) 11-386-544-967; fax: (55) 11-386-59630; e-mail: vpcosta@originet.com.br. Dr. Costa has no direct financial interest in any of the products mentioned in this article nor is he a paid consultant for any companies mentioned.
• Alon Harris, PhD, professor of ophthalmology and of physiology and biophysics, is director of the glaucoma research and diagnostic center at the Indiana University Department of Ophthalmology. He can be reached at 702 Rotary Circle, Indianapolis, IN 46202-5175; (317) 278-2566; fax: (317) 278-1007. Dr. Harris has no direct financial interest in any of the products mentioned in this article, nor is he a paid consultant for any companies mentioned.

• CIBA Vision can be reached at 11460 Johns Creek Parkway, Duluth, GA 30097-1556; (678) 415-3014; fax: (678) 415-3592.
• Pharmacia & Upjohn Co. can be reached at 95 Corporate Drive, Bridgewater, NJ 08807; (908) 306-4400; fax: (908) 306-8713.

Reference:

• Yamamoto T, Kitazaza Y. Iris-colour change developed after topical isopropyl unoprostone treatment. J Glaucoma. 1997;6:430-432.
• Fujimori C, et al. The clinical evaluation of UF-021, a new prostaglandin related compound, in low tension glaucoma patients. J Jpn Ophthalmol Soc (Nippon Ganka Gakkai Zasshi). 1993;97:1231-1235.
• Ogawa I, Imai K. Long-term clinical effect of isopropyl uno prostone in normal-tension glaucoma. J Eye (Atarashii Ganka). 1997;14(2):251-253.
• Azuma, et al. Double-masked comparative study of UF-021 and timolol ophthalmic solutions in patients with primary-open angle glaucoma and ocular hypertension. Jpn J Ophthalmol. 1993;37(4):514-525.
• Takashi I, et al. Effect of unoprostone ophthalmic solution as replacement therapy for primary open-angle glaucoma. Rinsho Ganka. 1997;51(4):643-646.
• Takashi I. Clinical studies on the efficacy of isopropyl unoprostone. A newly developed antiglaucoma agent in primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 1997;38(4):S282.
• Araie M, et al. Effect of UF-021 and timolol on diurnal fluctuation of intraocular pressure in patients with primary open-angle glaucoma or ocular hypertension. J Eye (Atarashii Ganka). 1993;10(12):2117-2121.
• Oda Y, Takashi G, Kitahara K. Reduction of intraocular pressure by additional isopropyl unoprostone. Ganka Rinsho Iho. 1997;91(3):411-413.
• Motegi Y, Araie M, Suzuki Y, et al. Clinical Study of UF-201 ophthalmic solution in refractory glaucoma. Folia Ophthalmol Jpn. 1993;44(1):12-18.
• Azuma I, Masuda K, Kitazawa Y, et al. Long-term study of UF-201 (Rescula) ophthalmic solution in patients with primary open-angle glaucoma and ocular hypertension. J Eye (Atarashii Ganka). 1994;11(9):1435-1444.
• Inami H, Saito A, Yamasita K, Suzuki A. The intraocular pressure lowering effect of isopropyl unoprostone ophthalmic solution. Shizuoka Saiseikai Sogo Byoin Igaku Zassi. 1995;12(1):55-61.