Krystal gets a flying start in epidermolysis bullosa gene therapy

Krystal Biotech shares have surged 53% so far this week on gene therapy data in two patients, but rivals are waiting in the wings.

Patients with the very challenging skin condition epidermolysis bullosa might soon be treated with a topical gene therapy. This is the bet investors made this week when they piled into Krystal Biotech after the company released data from just two patients in a phase I/II trial of KB103.

The serious nature of the disorder and unmet need mean that a potentially curative therapy would be welcomed with open arms. But Krystal still has a long way to go, and several other gene therapy developers are at a similar stage. The company will need to reproduce its results in more patients if it is to come out on top in this rare disease.

The most advanced EB candidate is Amryt’s AP101; the company is awaiting the final interim analysis of its an ongoing phase III trial, due later this year (Amryt awaits crucial readout as it prepares rare disease push, August 14, 2018). This is not a gene therapy but a topical gel formulation of the plant extract botulin. AP101 is already approved to treat partial thickness wounds in Europe, but producing a benefit in EB will be a much tougher task.

EB sufferers have extremely fragile skin that is prone to extensive blistering. Gene and other advanced therapy projects target the dystrophic form of EB and aim to treat its underlying cause by targeting the COL7A1 gene encoding collagen VII; this gene is mutated in dystrophic EB.

All the gene therapy candidates are delivered directly to the skin. Abeona Therapeutics looks to be slightly ahead of Krystal, having reported data from seven patients in an investigator-sponsored candidate of its project, EB-101, at the American Society for Gene and Cell Therapy in Chicago, in May. 

At the time Abeona said it planned to start a pivotal study of EB-101 this year.

Upcoming readouts in epidermolysis bullosa 
Project Company Description Trial  Note
Phase III
AP101/Episalvan   Amryt Pharma Betulin formulated as topical gel   Ease, NCT03068780 Interim analysis due Q4 2018
Phase II
EB-101 Abeona Therapeutics   Autologous, ex-vivo COL7A1 gene therapy NCT01263379 Data on 7 pts reported at ASGCT in May 2018
KB103 Krystal Biotech  HSV vectored COL7A1 gene therapy  NCT03536143 Data on 2 pts reported
QRX-313 Proqr Therapeutics RNA-based oligonucleotide – skips exon 73 of COL7A1 gene Wings, NCT03605069 Interim data due late 2018
FCX-007 Fibrocell Science Lentiviral vector COL7A1 gene therapy NCT02810951 Interim data due Q1 2019
RGN-137 Lenus Therapeutics (Regenerx, G-treeBNT JV) Tβ4-based dermal gel formulation NCT03578029 Phase III targeted to start in 2019
Diacerein Castle Creek Pharmaceuticals Diacerein formulated as topical gel  Delivers, NCT03154333 Primary completion Nov 2018
Phase I
BPM 31510 Topical Berg Topical formulation of ubiquinone (co-enzyme Q10) NCT02793960 Primary completion Jan 2019
Source: EvaluatePharma.

Meanwhile, Proqr Therapeutics started an eight-patient phase I/II trial of its candidate, QRX-313, in the second quarter. Interim data are expected in late 2018, with full results following next year. QRX-313 is not a gene therapy but rather an RNA-based oligonucleotide designed to skip exon 73 of the COL7A1 gene, formulated as a gel applied directly to EB wounds.

And Fibrocell will report interim results from a phase I/II trial of its gene therapy contender, FCX-007, early next year. It is enrolling into the six-patient phase II portion of the study.

Closing wounds

All of the four advanced therapy trials, which target the dystrophic form of EB, have slightly different endpoints. This will make them difficult to compare, on top of the usual caveats about cross-trial analyses, but any data on wound healing or closure, and signs that wounds are remaining closed, will be eagerly awaited.

In its presentation this week, Krystal focused on the durability of patients' response. Two patients had two wounds treated, one with KB103 and one with placebo, and in both patients the KB103-treated wounds closed in two weeks. In the first patient, the placebo-treated wound closed in 10 weeks, while in the second the wound did not close completely. The company said the first patient has had 4.5 months of complete wound closure and the second 3.5 months, and they continue to be tracked. 

Krystal expects the study to complete this study the first half of next year, and hopes to move into phase III later in 2019. 

Other, less innovative EB candidates, including topical projects from Lenus Therapeutics, Castle Creek Pharmaceuticals and Berg, are also awaiting readouts soon.

With EB thought to affect only 1,100-2,500 patients in the US, there will probably not be room for all the advanced therapies. The next readouts will be vital for Krystal, Abeona, Proqr and Fibrocell.

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