Catching Up With 5 Sustained-Release Drugs

Patients are least likely to adhere to drop regimens after eye surgery, so any product that reduces the need for drops is bound to be a welcome addition.

Recently FDA-approved, Dextenza (dexamethasone ophthalmic insert) 0.4mg is a tiny plug that’s inserted into the punctum and canaliculus — “a very straightforward and efficient way of applying the steroid after surgery,” says ophthalmologist I. Paul Singh, MD the Eye Centers of Racine and Kenosha (Wisc.). “What’s unique about having a punctal plug is that it’s not inside the eye. That makes it easier and more efficient for doctors who don’t feel comfortable inserting some other devices intraoperatively. It can be done post-op, pre-op or intra-op, because it’s external to the eye.”

The plug typically stays in for 30 days, delivering a tapered dose of dexamethasone to treat ocular pain after surgery, and alleviating compliance concerns.

“The idea that patients consistently take their steroids 4 times a day for a month is just false,” says John A. Hovanesian, MD, an assistant professor at the UCLA Jules Stein Eye Institute who practices at Harvard Eye Associates in Laguna Hills, Calif. “There’s overwhelming evidence that most patients fail to take drops as directed. Taking the delivery of medicine out of the hands of the patient is really a step in the right direction.”

And if an unlikely complication occurs? “You have the freedom also of being able to take it out if, say, someone has a pressure spike for some strange reason,” says Dr. Singh. “The control you have to modulate, to change it postoperatively, is very important.”

But, as Dr. Hovanesian points out, such a complication may actually be less likely with an implant. “We think pressure spikes with steroids happen because of high intermittent dosing, and there is some evidence to support that,” he says. “With drugs that release a low but steady level of steroid, we don’t really see pressure spikes.”

Dextenza is currently approved for the treatment of surgical pain, but the company is also looking to have it approved for ocular inflammation.

“It’s talked about in terms of cataract surgery,” says Dr. Singh, “but it’s really meant for any post-operative pain.” Ocular Therapeutix has also submitted an application for transitional pass-through payment status and an application for a J-code.

As noted, patients can be overwhelmed by the regimens they’re instructed to follow after cataract and other eye surgeries. And among the various types of drops patients are told to administer, steroids tend to be the most challenging, because they’re administered more often and for longer periods than antibiotics and NSAIDs. Plus, they need to be tapered over time.

Recently FDA-approved, and commercially available for the first time this spring, Dexycu (dexamethasone intraocular suspension) 9% is another type of implant that eliminates the need for steroid drops.

After all, the list of things that can go wrong with drops is daunting, says Cynthia Matossian, MD, FASC, of Matossian Eye Associates in Pennsylvania and New Jersey: “Patients get confused about how many to put in. They may have a hard time squeezing the bottle, because they have arthritis in their hands. They may have tremors from Parkinson’s. They may have arthritis that makes it difficult to bend their necks back.”

And if they miss, and the drops end up on their cheeks or foreheads, they may run out before they complete the recommended course. “Which means they’ll call us for a refill,” says Dr. Matossian, “which adds to our phone calls, and adds to the patient’s cost, which of course upsets them. All of that is eliminated by putting the product into the eye [during surgery].”

The steroid medication — a liquid that when injected immediately forms a tiny spherule — is put in place via a cannula under the iris at the end of the surgical procedure. Using an injectable sustained release and biodegradable intraocular drug delivery system called “Verisome,” Dexycu bio-erodes in a way that mimics the tapering process that patients find so challenging.

“Drops are dramatically reduced by eliminating the need for the steroid, and we’re taking compliance out of the patient’s hand,” says Dr. Matossian. “We know for sure it’s in the eye because we’re putting it in there. Now they’re down to 2 drops instead of 3, and it’s a much simpler regimen, especially because the non-steroidal drop is just once a day.”

Moreover, says Dr. Matossian, Dexycu doesn’t irritate the ocular surface the way the chemicals in drops can.

Dexycu has a permanent J-code (J1095) and a 3-year pass-through status, “so it doesn’t cost the patient any money, doesn’t cost the doctor any money and doesn’t cost the insurance carrier any money,” says Dr. Matossian.

If you don’t like seeing patients suffer, don’t do shoulder surgeries. That, says Shariff Bishai, DO, MS, FAOAO, was his attitude when he was finishing his residency, a little more than a decade ago. “After seeing those patients in so much pain and agony, I remember saying to myself, I never want to be a shoulder surgeon.”

Guess what Dr. Bishai, of the Associated Orthopedists of Detroit (Mich.), is doing these days.

“Ironically, that’s what I have become,” he says. But with a lot less pain and agony than there used to be, he’s quick to add, thanks to arthroscopic advances, nerve blocks and, above all, liposomal bupivacaine, the not-so-secret sauce that’s winning converts to Exparel.

“What we’ve seen with Exparel is something completely different,” he says. “Patients come in post-op Day 1 and say they have no pain. They ask whether I actually did anything.”

Patients, that is, who had surgery at the Premier Surgical Center of Michigan, where Dr. Bishai is able to use Exparel.

“I would love to use it at the hospital, too,” he says, “but certain hospitals have taken it off formulary. I’m fighting with them, because I think we should be worried about what’s making patients better, not about costs.”

Exparel typically adds about $300 per case, but that shouldn’t be the point, Dr. Bishai insists. “I have to scratch my head and say that when we start worrying about cost superseding patient care, that’s the epidemic,” he says.

Dr. Bishai says his staff can easily identify his Exparel patients. “A traditional interscalene block is going to use something like Marcaine (bupivacaine hydrochloride), which usually lasts about 18 hours, at most,” he says. But Exparel’s liposomes dissolve at different rates over time, so the relief can last for days

“The short-acting agent is working right out of the gate, and by the time the Marcaine starts to wear off, the bupivacaine that’s in the liposomes is starting to release, thereby taking the patient 3 or 4 days out. That’s usually where you’d have the worst pain.”

Just make sure it’s administered correctly. “When you put those tiny liposomal (fat) globules in, they don’t move that well,” says Dr. Bishai. “If you don’t move the needle around when you’re putting it in, you’re not going to get the whole area. It’s one series of injections, but it’s a bunch of little pokes.

“It’s given me the opportunity to be a shoulder surgeon — to do big surgeries through scopes and have patients not be in a lot of pain afterward,” he says. “And patients who aren’t in a lot of pain are able to do more when it comes time for therapy. They’re able to wear their slings in the appropriate positions, so they don’t hurt. That means what I do during surgery stays in place for them, and they end up doing well.”

For glaucoma patients, compliance is a challenge that never ends. They may be expected to self-administer drops every day for decades.

That could change with the iDose implant, which can continuously provide medication without drops for years at a time. “The question everybody has is how long is it going to last,” says Russell Swan, MD, of Vance Thompson Vision in Bozeman, Mont. “Are we going to get 24 months or 36 months?”

Phase III trials are next for iDose, with a projected FDA-approval date of 2021 or 2022.

A 3-arm Phase II study included both “slow-eluting” and “fast-eluting” arms, in addition to a placebo, and “both showed between 32% and 33% sustained IOP reduction from baseline over a 12-month period,” says Dr. Swan.

The iDose uses an anchoring mechanism that holds it in place in the trabecular meshwork, where it elutes the common glaucoma medication Travatan (travoprost). “It sits in the anterior chamber angle and releases medicine over a period of 1 to 3 years,” says Dr. Swan. “So, patients don’t have to put drops in their eyes every day or multiple times a day.”

The implanting procedure is straightforward and takes about 5 minutes, says Dr. Swan. “You make a small incision, place some viscoelastic or gel inside the eye, use a little prism to be able to visualize the angle, place the implant, and clear out the gel.”

Eliminating the need for compliance, while important, isn’t the only benefit, he says. “We’re learning more and more that the topical drops we place on the eye, which we generally think of as benign, actually cause a lot of ocular surface disease, as well as issues with dryness, redness and irritation. And when you’re talking about a chronic disease, where you might use drops for 20, 30 or even 40 years, it can accumulate over time and cause significant issues. We don’t expect to see that ocular surface disease with an intracameral delivery device.”

Another recently approved implant is for the less common — but often more costly — posterior segment non-infectious uveitis.

“[Uveitis] is a condition that often occurs in young, working-age people, and it can become a real impediment to their most productive years,” says David Eichenbaum, MD, the director of clinical research and a partner at Retina-Vitreous Associates of Florida.

The Yutiq (fluocinolone acetonide intravitreal implant) 0.18 mg implant is a non-bio-erodible intravitreal micro-insert that releases small doses of fluocinolone acetonide over the course of 36 months.

A long-acting treatment that’s safe and effective is a far preferable alternative to the frequent ocular and peri-ocular injections and systemic steroids or immunosuppressants that surgeons have traditionally used to treat the condition, says Dr. Eichenbaum.

“Most of the immunosuppressants are effective drugs, but none of them are benign,” says Dr. Eichenbaum. “If we can achieve local control with ocular drugs, and if we can do it without frequent dosing, that’s better. That’s why there’s a lot of excitement about Yutiq.”

It’s implanted using a relatively straightforward vitreoretinal surgical procedure that can be done in a physician’s office, he adds.

The only drawback: the price. “I’m having a hard time getting it for my patients because it’s so new and extraordinarily expensive,” says Dr. Eichenbaum. “But we’re working with patients’ insurances and with EyePoint Pharmaceuticals, to try to limit out-of-pocket expenses. That’s always tough with a new drug.”