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Kytogenics Pharmaceuticals, Inc.

Kytogenics_Medical Devices

MACC Platform

Adhesion formation is a characteristic but unwanted result of surgical intervention; it occurs with almost every surgery and appears as fibrous tissue joining normally separated surfaces.  This complication can lead to obstruction of the intestine following abdominal surgery; infertility following pelvic surgery; cardiac adhesions after heart surgery; immobility after orthopedic surgery; pain and sometimes mortality.  The formation of adhesions is essentially an inflammatory reaction with factors released from inflammatory cells increasing the permeability of blood vessels that release a protein-rich fluid.  Fibrin, the filamentous clotting protein in the fluid, forms a thin coating on local organs that becomes organized into permanent fibrous adhesions consisting mainly of tissue proteins.

Currently in a Phase III clinical trial for the reduction of post-surgical gynecological adhesions, Adhes-XTM has demonstrated safety and efficacy in a number of pre-clinical studies and early clinical trials.  Adhes-XTM is a gel-like substance that forms a barrier over injured tissue to reduce the development of unwanted adhesions.  Interim data on 69 patients from the ongoing Phase III study has shown that Adhes-XTM is safe and initial efficacy results demonstrated that 23% of Adhes-XTM treated patients achieved a 50% or greater reduction in MCASM adhesion score (sum of extent and severity) compared to only 9% for the control group (ringer’s lactate).  Kytogenics believes it has already satisfied the requirements of CE Mark approval and intends to file for CE Mark in the second half of 2006 with commercial sales in Europe beginning in Q4 2007.

When Kytogenics resumes the Phase III clinical trial, it is anticipated that a total of 150 additional evaluable patients will be enrolled at 14 investigational sites.  The clinical study will continue to evaluate the effectiveness of the Adhes-X anti-adhesion device in laparoscopic surgery for gynecological indications. The Phase III trial was undertaken to further evaluate clinical safety and efficacy in an expanded patient population at geographically dispersed study sites, in order to determine the overall risk-benefit ratio of the compound, and to provide an adequate basis for product labeling.  Each trial is conducted in accordance with certain standards under protocols that detail the objectives of the study, the parameters to be used to monitor safety and the efficacy criteria to be evaluated.  All details regarding the design of the Phase III gynecological clinical trial protocol have been agreed to with the FDA.  After 69 patients were enrolled, the data from these patients were analyzed by Kytogenics and submitted to the FDA for review. FDA approval was granted and Kytogenics will continue enrollment into the trial until 220 patients have been enrolled.

Kytogenics has previously completed a Phase I/II clinical trial designed to demonstrate the safety and preliminary efficacy of the Adhes-X resorbable adhesion device in 34 women undergoing gynecological surgery.  The Phase I/II clinical trial was designed as a randomized, evaluator-blinded, controlled, parallel group, multi-center trial in adult women undergoing laparoscopic surgery for a gynecological condition.  The laparoscopic surgeries involved 34 patients, and the study was conducted as follows:

  • Patients undergoing myomectomy, ovarian cystectomies, oophorectomy or salpingectomy, tuboplasty, ovarian biopsy, or treatment of mild endometriosis were enrolled.  During the surgery pre-existing adhesions were to have been lysed if possible, and patients were randomized to receive Adhes-X or lactated ringers solution at completion of the initial surgery.  Second-look laparoscopy was performed between 2 and 8 weeks after the initial surgery.

  • Safety was assessed by comparing pre- and post-operative data for patient complaints and/or symptoms, adverse events, physical examination findings, clinical laboratory test results and vital signs.  Efficacy parameters included the number of sites with adhesions in the Adhes-X versus control group and the extent and severity of the adhesions. Blinded evaluators examined efficacy using videotape recordings of the procedures.

  • The results of the trial established the initial safety of Adhes-X in humans based on no difference in incidence or severity of adverse events in Adhes-X treated patients as compared to controls.  The trial also demonstrated a reduction in adhesion extent and severity as well as a reduction in adhesion reoccurrence with 61% of control subjects experiencing adhesion reoccurrence compared to 38% of patients treated with Adhes-XTM.   

The rationale behind initiating human clinical trials was based on 5 years of pre-clinical work involving numerous toxicological tests and more than 8 different surgical models involving over 400 animals.  The animal studies utilized standard models of cardiac abrasion, uterine horn abrasion, bowel transection, abdominal sidewall incision plus abrasion, as well as several innovative and “challenging” models (e.g. adhesiolysis in small bowel rodent model).  In all cases, there was no evidence of an inflammatory response to the implanted Adhes-X materials and the incidence of adhesions was reduced by 60-90% compared to the controls.  Furthermore, the severity of the adhesions that did form was also reduced by 60-80%.

Other Medical Devices

Orthopedic Devices
Kytogenics has conducted research in two orthopedic applications using MACC- based pastes.  In the first formulation, MACC was combined with hydroxylapatite (HAp) to form a bone graft substitute.  In vivo studies demonstrated that the MACC/HAp paste was osteoconductive (supported bone growth) and when combined with bone marrow, the MACC-based paste became osteoinductive (inducing bone growth).  In a second formulation, MACC was combined with demineralized bone (DMB) which contains all of the osteogenic factors required to induce the formation of new bone.  In all cases where MACC was used as the carrier of DMB, there was active bone formation with no inflammation and minimal fibrous connective tissue around the implant. These results confirmed that MACC was suitable for use in orthopedic devices since it was biocompatible, supported the growth of new bone and was an effective carrier or delivery device for osteoinductive materials.

The viscoelastic and bioadhesive properties of MACC also suggest that it is an ideal candidate for a device to supplement synovial fluids and, simultaneously, to deliver therapeutic agents directly to osteoarthritic joints.  A combination of MACC solution and gel will provide lubrication and the sustained delivery of anti-inflammatories, enzyme inhibitors or growth factors for cartilage repair.  In addition, the degradation products of MACC include glucosamine, which is presently found in a number of OTC oral preparations that are taken to alleviate the discomfort of osteoarthritis.

Ophthalmology Devices
High viscosity MACC solutions have also been evaluated as viscoelastic aids for ophthalmic surgery.  The effect of different MACC formulations on corneal thickness, intraocular pressure, recruitment of inflammatory cells, corneal cloudiness and conjunctival swelling were compared to the commercial product, Healon (Pharmacia), following injection into either the anterior chamber or into the vitreous.  Statistically significant differences were not observed between the 2 treatment groups confirming that MACC was suitable for use in viscosurgery.  With similar efficacy, the use of MACC in ophthalmic surgery offers an additional competitive advantage over Healon or other viscoelastic materials.  During glaucoma filtering surgery, for example, the surgeon forms an opening or “flap” in the iris to provide for the drainage of aqueous humor (fluid of inner eye) and the consequent reduction of intraocular pressure.  Fibroblasts are implicated in closing the flap and cytotoxic drugs (e.g. 5-fluorouracil) have been used to prevent the closure.  Because MACC inhibits the attachment of fibroblasts and prevents adhesions from forming, it represents a more benign method of maintaining the flap opening and therefore, it could represent a new generation of ophthalmic surgical aids.

1Fertility and Sterility, Vol. 80, No.3 Sept 2003