Aerie's Netarsudil's Safety Questions May Determine Fate At Advisory Committee
Executive Summary
Proposed treatment for elevated intraocular pressure would be first in new rho-associated protein kinase inhibitor class.
Aerie Pharmaceuticals Inc. may have to overcome safety concerns in trying to gain approval for the first in a new class of drugs to treatment of elevated intraocular pressure.
The company has proposed once-daily netarsudil, proposed trade name Rhopressa, for reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. The rho-associated protein kinase inhibitor is a new class of medication that lowers IOP by increasing trabecular outflow.
Netarsudil appeared to reach its non-inferiority margin for efficacy in at least one of its Phase III trials, but when the US FDA's Dermatologic and Ophthalmologic Drugs Advisory Committee considers the product Oct. 13, it may be more concerned with the safety issues that emerged during the trials, which compared it to twice-daily timolol, a now generic beta adrenergic antagonist.
Aerie scrapped a twice-daily dose of netarsudil after the trials showed it was not well-tolerated. In its CS302 study, 40% of patients discontinued within the first three months of the 12-month study, FDA said in its briefing documents for the meeting.
The once-daily dose fared better – 18% of patients discontinued prior to month three in study CS302 – but 42% of patients discontinued prior to the end of the trial, compared to 19% of those in the timolol arm.
Adverse events were by far the most common reason given for discontinuation in the netarsudil once-daily dosing group (28%) in the CS302 trial.
In the CS301 study, 15% of netarsudil patients discontinued, compared to 6% in the timolol arm.
Among the most common treatment emergent adverse events in the studies were conjunctival hyperemia (eye redness) and corneal deposits.
Aerie wrote in its briefing document that conjunctival hyperemia was an expected pharmacological effect for ROCK inhibitors, since they are known to cause vasodilation. The company also said that incidence and severity increased with dosing frequency, but overall the majority receiving a once-daily dose did not note a change in eye redness during the studies.
Corneal deposits were the subject of a special safety study Aerie conducted. FDA indicated in its briefing document that by completion, all instances had resolved except in three patients. In those cases, the deposits had stabilized.
Aerie also argued that netarsudil offers a potential safety advantage over timolol.
"Netarsudil provides similar ocular hypotensive efficacy as the beta-adrenoceptor antagonist class of ocular hypotensive medication without the systemic beta-blockade safety risk," the company said in its briefing document.
Advisory committee members will vote on whether netarsudil's efficacy outweighs the safety concerns raised in the studies, and could suggest post-marketing or additional studies. The draft questions ask those who vote no what additional trials they would recommend.
FDA and Aerie Disagree On Non-Inferiority
FDA agreed with Aerie that netarsudil showed efficacy in reducing IOP in some patients, but the agency also noted that netarsudil once daily is less efficacious than timolol twice daily in patients with a maximum baseline IOP of 25 mmHg or more.
In study CS301, netarsudil and timolol had similar average IOP reductions in patients with an average IOP baseline of less than 25 mmHg. In patients with an average IOP of 25 mmHg or greater, timolol performed better, the agency said.
The agency also noted that that in the study CS301 per protocol population, the once-daily netarsudil dose did not meet the pre-specified criteria for non-inferiority against timolol given twice daily. The upper 95% confidence limit for the differences in mean IOP was within 1.5 mmHg at six of the nine time points and within 1.0 mmHg at four of the nine time points, FDA wrote. The intent-to-treat population performed similarity in the study, the agency said.
But in study CS302 patients with a maximum IOP less than 25 mmHg, there were no clinically significant differences in IOP reduction between netarsudil once daily and timolol. The upper 95% confidence limit for the difference in mean IOP was within 1.5 mmHg at the nine time points and within 1.0 mmHg at six of the nine time points.
Aerie wrote in its briefing that a pooled efficacy analysis of all trials showed non-inferiority of netarsudil once daily compared to timolol.
Advisory committee members will vote on whether the clinical trials supported netarsudil's efficacy for reducing intraocular pressure. If not, they also were asked to suggest what additional trials should be required.
FDA Wants To Discuss Its Labeling Edits
A committee discussion question focuses on labeling suggestions. FDA included a red-lined version of Aerie's proposed labeling submitted Aug. 30 in its briefing document.
Some of the agency's suggested changes included removing a statement that the majority of conjunctival hyperemia cases were mild in nature. Aerie tried to include the "mild" phrasing in the summary section as well as the Adverse Reactions section.
The company also described corneal deposits in the adverse reactions section as "mild in 95% and moderate in 5% of patients," which FDA nixed.
In addition, the agency told Aerie to remove a statement that the "IOP lowering effect increased gradually after the first daily dose" from the pharmacodynamics section.
Will Manufacturing Problems Be Resolved In Time?
FDA's goal date for a decision on netarsudil is Feb. 28, 2018, but manufacturing problems could affect the decision. Aerie disclosed recently that another drug manufacturer received a complete response letter because of a Good Manufacturing Practice problem at a Tampa facility that also made netarsudil. At the time, Aerie said it believed any open issues would be resolved before the netarsudil review goal.
Aerie also had to withdraw its initial application for netarsudil because its contract manufacturer was not prepared for the pre-approval inspection. (Also see "Keeping Track Of CRLs: US FDA Again Faults Bausch + Lomb Manufacturing" - Pink Sheet, 11 Aug, 2017.)
Aerie appears to have a lot riding on the drug's approval. It has indicated it will seek approval in the first half of 2018 for its glaucoma candidate Roclatan, which combines netarsudil with Pfizer Inc.'s now generic Xalatan (latanoprost). (Also see "Aerie's M&A Potential Rises As Roclatan Passes Second Phase III Glaucoma Test" - Scrip, 26 May, 2017.)