Gene therapy’s duration is less than Krystal clear

At 90 days data from Krystal Biotech’s epidermolysis bullosa trial looked good. At 120 days there has been some backsliding.

In June data on three subjects in a phase II trial of Krystal Biotech’s epidermolysis bullosa gene therapy sent the group's share price up 41%. Today a final update from the trial, including results from two new patients, left investors unmoved. 

This might have something to do with the updated data showing that two lesions that had been successfully treated with Krystal’s therapy at 90 days had reopened a month later, raising questions about whether the treatment works in the long term.

The two new patients with severe recessive dystrophic epidermolysis bullosa (RDEB) had been added to the trial in June 2019, after the initial data release (Krystal plays down dropout to claim a mid-stage win, June 25, 2019). Bercolagene telserpavec or B-Vec for short, formerly called KB103, was administered to one wound on each patient every other day for two weeks, or until the wound closed completely. The other wound was treated with a placebo gel. 

This differs slightly from the earlier phase II patients, who had B-Vec administered to two wounds each and placebo to a third. In its press release Krystal trumpeted that, of all 10 wounds treated in the phase I and phase II trials, nine had healed at 90 days. 

90-day phase I and II data on B-Vec
  Phase I Phase II (cohort 1)* Phase II (cohort 2) Total Success rate (%)
No of wounds treated w B-Vec 2 6 2 10  
No of wounds treated w B-Vec healed at 90 days 2 5 2 9 90%
No of wounds treated w placebo 2 3 2 7  
No of wounds treated w placebo healed at 90 days 1 0 0 1 14%
*Excludes one patient who dropped out. Source: company website & Vantage coverage.

The unhealed 90-day lesion was a chronic wound, reported to have been open for over four years, in one of the patients in the first phase II cohort. It was still only 42% closed at 90 days following the initial administration of B-Vec. The wound was re-dosed with B-Vec approximately three and a half months later, and healed within a week of this second dose. 


But the company glossed over the fact that, at four months, two of the healed B-Vec-treated wounds in cohort 1 had reopened: at 120 days a lesion on one patient’s back had returned to only 77% closure, and another patient had a lesion on their left upper arm return to 85% closure. 

Moreover, one of the placebo-treated wounds that had not healed at 90 days did heal at 120. At the four-month point, across both phase II cohorts, the success rates are 63% for B-Vec versus 20% for placebo – not quite emphatic as the earlier 90% versus 14%. 

120-day phase II data on B-Vec
  Phase II (cohort 1)* Phase II (cohort 2) Total Success rate (%)
No of wounds treated w B-Vec 6 2 8  
No of wounds treated w B-Vec healed at 120 days 3 2 5 63%
No of wounds treated w placebo 3 2 5  
No of wounds treated w placebo healed at 120 days 1 0 1 20%
*Excludes one patient who dropped out. Source: company website.

One question is which time point is the more important? On the primary endpoint cutoff is listed as wound healing at 24 weeks – a completely different point, and one that has not yet been reached, despite Krystal’s statement that this would be the final update from the phase II trial. 

EB is a cyclical disease. Wounds open, close and reopen in the natural course of the condition even without treatment, so it can be tricky to show a drug’s effect. Krystal intends to move B-Vec into phase III, and investors might want to take careful note of the time point regulators pick for the primary endpoint.

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