The success of Kala Pharmaceuticals’ Eysuvis in its third pivotal dry eye disease study is a tribute to persistence, smart trial design, and learning quickly from a previous failure to pre-empt a regulatory request.
Eysuvis therefore now looks highly approvable, but that, as they say, is the easy part. More tricky will be meeting the sellside expectations underpinning the product; within four years of launch Eysuvis will be the second-best selling dry eye medication, EvaluatePharma calculates, eclipsed only by Novartis’s Xiidra.
Perhaps no other recent product illustrates the difficulty of this space better than Xiidra. This had been filed by Shire in 2015 after yielding mixed clinical results, and it took the FDA over a year to approve it after a request for more data.
Takeda then bought Shire, and swiftly offloaded Xiidra to Novartis (Novartis sees hidden value in Xiidra, May 9, 2019). Last year sales totalled a modest $192m, and a major obstacle to meeting forecasts is the recent availability of generic versions of Allergan’s Restasis – notwithstanding its approved use being only for dry eye signs, versus Xiidra’s signs and symptoms label.
Still, the Xiidra deal showed that Novartis was still interested in prescription ophthalmology drugs after its Alcon spinout. Some Kala investors will now be hoping for a buyout of their company, and on an analyst call yesterday the group somewhat unsubtly pointed out that “Novartis acquired Xiidra for $3.4bn”.
The good news for Kala is that, after yesterday’s success in the Stride 3 trial, Eysuvis is virtually assured of being approved for dry eye signs as well as symptoms.
Previous data had put this in some doubt: in Stride 1 Eysuvis met co-primary endpoints of dry eye disease sign (conjunctival hyperaemia) and symptom (ocular discomfort severity), while Stride 2 was a hit only for the former; this led to a US complete response letter requesting data from Stride 3.
But Kala had made the smart strategic decision to file on the mixed data while at the same time hedging its bets by starting Stride 3. That study kept the four-times daily, two-week dosing used in Stride 1 and 2, also in 900 subjects, but increased powering by focusing its primary endpoint only on ocular discomfort.
This, Kala said, was met in all-comers with a high level of statistical significance, as well as in a predefined subgroup of subjects with severe baseline discomfort. The main adverse effect to watch seems to be intraocular pressure increase; across the three Stride trials two subjects had a >10mmHg increase, versus none in placebo cohorts.
|Kala's pivotal trials of Eysuvis|
|Results of primary endpoints, baseline to day 15, ITT population|
|Study||Sign endpoint (conjunctival hyperaemia)||Symptom endpoint (ocular discomfort severity)|
|Stride 1||Met, p<0.0001||Met, p<0.0001|
|Stride 2||Met, p<0.0001||Missed, p=0.1298|
|Stride 3||NA*||Met, p=0.0002|
|*p<0.0001, but not tested as a primary endpoint. Source: company statements.|
Kala says Eysuvis could be positioned to treat dry eye disease flares, targeting patients who have breakthrough flares while on Restasis or Xiidra, as well as the 90% or so of patients who are not taking either drug. It plans an imminent filing resubmission and US launch by the end of 2020, and wants to have 100 to 125 reps in place to sell the product.
However, whether the latest data set Kala up as a takeover candidate is a highly relevant question. Many Kala investors will now hope that their company never has to find out the complexity of the dry eye market first hand.