information: Interim results
Announcement: interim results
Company: Krystal Biotech (USA - PA)
Product: KB103 (replication defective herpes simplex type 1 virus (HSV-1) vector expressing human COL7 protein)
- gene therapy. KB103 is a replication-defective, non-integrating herpes simplex virus (HSV-1) based gene therapy engineered to deliver a human collagen protein. The viral vector has been engineered employing Krystal’s STAR-D platform to deliver functional human COL7A1 genes directly to the patients’ dividing and non-dividing skin cells.
- Krystal’s Skin TARgeted Delivery platform, or STAR-D platform, is a proprietary gene therapy platform consisting of an engineered viral vector and skin-optimized gene transfer technology that Krystal is employing to develop off-the-shelf treatments for dermatological diseases for which there are no known effective treatments.
- Dystrophic epidermolysis bullosa (DEB) is a chronic, progressive and incredibly painful skin disease caused by mutations in the gene coding for type VII collagen, or COL7. As a result of mutated COL7, DEB patients' skin is incredibly fragile, resulting in blistering or skin loss at the slightest friction.
Disease: dystrophic epidermolysis bullosa
area: Rare diseases - Genetic diseases - Dermatological diseases
- The Phase 1/2 trial at Stanford University is a single-center, open-label, placebo-controlled Phase 1/2 study conducting an intra-subject comparison of randomized treatment and control wounds. It is designed to evaluate the safety and tolerability of KB103 in subjects with the recessive form of dystrophic epidermolysis bullosa. Efficacy is also evaluated through wound imaging and analysis of collagen VII expression and anchoring fibril formation in the basement membrane zone.
- Six subjects are planned for this study: 3 adults and 3 subjects age 5 and older. Adults are enrolled first and data from the adults is evaluated for KB103 safety and bioactivity prior to administration to children. Subjects are enrolled upon obtaining consent and meeting entry criteria. One wound is selected for treatment during this study. This wound will receive topical KB103 at Days 0, 2, 28, and 30. Another similar wound will be administered a placebo gel. Intact skin will be administered small injections of KB103 for the purpose of mechanism of action evaluations. Throughout the study wounds will imaged and intact skin and wounds will be biopsied for safety and efficacy analyses. Subjects will be on-trial for approximately 4 months, at which point they will be asked to participate in a 5-year long-term follow-up study. (NCT03536143)
- • On October 15, 2018, Krystal Biotech announced interim results from its ongoing placebo-controlled Phase 1/2 clinical trial of KB103. Two adult Recessive Dystrophic Epidermolysis Bullosa (“RDEB”), NC1[+] patients aged 35 and 28 years old have completed treatment with topical KB103 to date. The patients were re-dosed during the study. In each patient, two wounds with an approximate surface area of 10 cm2 were randomized to receive either topical KB103 or placebo (for a total of 4 wounds evaluated). KB103 was also injected intradermally in both patients to intact skin to evaluate the mechanism of action of KB103 and validate molecular correction. Both KB103-treated wounds and intradermally injected intact skin were biopsied to assess functional COL7 expression and anchoring fibril formation. KB103-treated wounds were also evaluated for clinically relevant healing compared to placebo-treated wounds and to baseline. They were also monitored for general and recombinant viral infection and autoimmune response at each evaluation.
- Interim Data Update: Results on 2 patients met all primary efficacy (presence of functional COL7 expression, observation of NC1 and NC2 reactive anchoring fibrils and continued expression following repeat administration) and safety endpoints (no adverse events, inflammation or irritation) in topically administered KB103 wounds.
- 1. Analysis of KB103-treated wounds demonstrates clearly detectable robust functional COL7 expression by immunofluorescence (IF) in the biopsy samples from the two treated patients as early as Day 2 of treatment. Functional COL7 was determined by staining the tissue samples with NP185 and LH24 antibodies that bind to NC1 and NC2 domains of the COL7 protein respectively. Both of the patients were NC1 positive at baseline. The tissues from the skin biopsies show the presence of both the NC1 and NC2 domains demonstrating production of functional COL7 that has linearly deposited along the Basement Membrane Zone (BMZ).
- 2. NC1 and NC2 reactive anchoring fibrils were observed by immunoelectron microscopy (IEM) as early as Day 14 and up to the last biopsy for both patients.
- 3. Safety data from both patients show that KB103 was well tolerated. No serious adverse events, and no product-related adverse events were reported. No inflammation or irritation was observed at KB103-treated wounds. In addition, no antibody response was noted for type VII collagen (COL7).
- 4. Repeat administration of KB103 in both patients demonstrated continued expression of COL7 expression with no immune or safety concerns.
- With respect to secondary endpoints – topically administered KB103 wounds closed in 2 weeks and continue to stay closed to date. Topically administered placebo wounds took 10 weeks to close in patient 1 and did not completely close throughout the study in patient 2.
- 5. In Patient 1, the wounds administered with KB103 closed in 2 weeks while wounds administered with placebo closed in 10 weeks. In Patient 2, the wounds administered with KB103 closed in 2 weeks also - demonstrating a faster rate of wound closure on KB103- administered wounds to date compared to placebo. Patient 2’s placebo-administered wound did not fully close throughout the study
- .6. To date, both of the patient’s KB103-treated wounds remain closed, representing 4.5 months of total closure for Patient 1 and 3.5 months of total closure for Patient 2. Patient 1 has chosen to discontinue bandaging on the KB103-treated wound that previously required regular bandaging.
- KB103 when administered intradermally to intact skin on both patients shows presence functional COL7 expression and anchoring fibrils.
- 7. Analysis of KB103-treated intact skin revealed clearly detectable functional COL7 expression by immunofluorescence in biopsy samples collected from the intradermal injection sites.
- 8. Clinical data from two patients were submitted to the FDA. FDA acknowledges molecular correction as evidenced by expression of COL7 and anchoring fibrils. Consequently, the protocol has been amended to remove the intradermal arm for patients in the Phase 1/2 trial going forward.
- 9. Per discussion with the FDA, the amended protocol will now enroll pediatric patients and will focus on evaluating durability of wound closure in preparation for selecting endpoints for Phase 3 clinical trial. With safety and molecular correction established, the revised Phase 1/2 protocol allows for increased dosing and KB103 administration to larger wound areas.
- • On May 10, 2018, Krystal Biotech announced that the first patient has been dosed in the Phase 1/2, first in-human trial of KB103 for the treatment of dystrophic epidermolysis bullosa Bullosa
- • On April 26, 2018, Krystal Biotech announced the clearance of an Investigational New Drug (IND) application by the FDA for KB103. The planned Phase 1/2 clinical study of KB103 is a single site study at Stanford University expected to start in May 2018. Initial data from the study are expected to be released by the end of 2018.
- • On March 27, 2018, Krystal Biotech announced the submission of an Investigational New Drug (IND) application with the FDA to initiate a Phase 1/2, first in-human trial of KB103, an HSV-1 based gene therapy engineered to deliver a human collagen-producing gene to patients with Dystrophic Epidermolysis Bullosa.