The Company is initially focused on the prevention of adhesions after flexor tendon repair in the hand, but foresees potential to also develop products based on PXL01 for other medical applications such as prevention of adhesions after total knee arthroplasty and dermal scarring after surgery.
Adhesion formation is recognized as a particular problem for injuries in zones I and II of the hand, where the tendon excursion relative to the tendon sheath is the largest, and therefore, peritendinous adhesions have the highest impact on finger mobility. The product is administered as a single treatment in connection to the operation around the repaired tendon before the closure of the surgery wound.
The product candidate is intended for application as a single administration in conjunction with tendon repair surgery. PXL01 is formulated in a hyaluronic acid-containing gel that is presented in a pre-package syringe. During the surgical procedure, the gel is locally administered around the
Mechanism of Action
The underlying mechanism of action for scarring is similar various clinical contexts, such as scarring on the skin, post-surgical adhesions, peripheral nerve damages and burn injuries (1). It is well established that inflammation and fibrin formation after surgery are two pivotal mechanisms that strongly contribute to scar formation (2).
PXL01 is a synthetic peptide derived from the human lactoferricin peptide, which is part of the milk protein lactoferrin. PXL01 has several mechanisms of action; including immunomodulation and enhancement of fibrinolytic activity. PXL01 produces its immunomodulatory action by inhibiting the release of pro-inflammatory cytokines, such as IL-1β, IL-6 and Il-8 as well as TNF- α (tumor necrosis factor alpha). PXL01 also inhibits the local production of PAI-1 that is an important mediator of fibrinolysis. The anti-inflammatory properties combined with the modulation of fibrinolysis are assumed to account for the ability of the product candidate to prevent post-surgical adhesions and scar formation.
Clinical Study Results
Promore Pharma completed a Phase I clinical trial on PXL01 in 2009. The trial included 15 healthy volunteers at one site in Sweden. The objective was to assess the safety and local tolerability of the drug candidate as well as exploring the pharmacokinetic properties of the drug. The treatment was well tolerated and no serious adverse events were observed after administration. The systemic exposure of PXL01 was very low at all doses investigated, which indicate that only a very small amount of the drug reaches the systemic circulation.
The efficacy of PXL01 has been investigated in a randomized, double-blinded Phase IIb trial including 138 patients with accidental flexor tendon transection in the hand (3). In the study, a single dose of PXL01 was administered in a highly viscous solution containing hyaluronic acid in conjunction with the tendon repair surgery. The patients were assessed for various efficacy parameter up to 12 months after the surgery.
At all time points investigated after the surgery (four, six, twelve weeks, and six and 12 months) the mobility in the DIPAM joint was improved in patients receiving PXL01 versus placebo. The largest magnitude in difference was observed after six months. Additionally, the total active motion (TAM) in the injured finger was also assessed along with estimates of the tip-to-crease distance, the requirement for secondary surgery (tenolysis) and sensory loss/recovery in patients with adjacent nerve injury.
Measurement of mobility in the PIP (Proximal Interfalangeal) joint and the most distal joint, DIPAM (Distal Interfalangeal)
Furthermore, the Phase II trial did not indicate any differences in strength of the repaired tendon between patients receiving PXL01 and patients treated with placebo; the frequency of post-surgical ruptures was comparable in the two groups.
Phase III Trials in Europe and India
The Company is preparing a Phase III clinical trial of PXL01 in Sweden, Germany, Poland and India, of which Promore Pharma shall be the official sponsor, although the work is conducted as strategic alliance with the clinical research organization Technomark.
The Phase III trial is planned as a randomized, double-blinded study including 500-600 patients with flexor tendon injuries in the hand where a single administration event of PXL01 at two different doses will be compared with placebo.
The primary endpoint shall be assessed after six months (where all major efficacy variables explored in the prior clinical trial reached statistical significance) and this shall form the basis for a market authorization application.
An additional Phase III Trial is being planned in the US for Market Approval in North America
For market approval in the US, two clinical trials are required. Promore Pharma has started a dialogue with the US Food and Drug Administration (FDA) together with its strategic partner in the US, Cellastra Inc. The intention is to start a Phase III trial in the US that mimics the clinical trial protocol applied in Europe and India.
(1) Nilsson E, Björn C, Sjöstrand V, Lindgren K, Münnich M, Mattsby-Baltzer I, Ivarsson M-L, Olmarker K, Mahlapuu M. (2009). A novel polypeptide derived from human lactoferrin in sodium hyaluronate prevents post-surgical adhesion formation in the rat. Ann Surg, 250(6):1021-8.
(2) Shaw TJ, Martin P. (2009) Wound repair at a glance. J Cell Sci., 122(18): 3209–3213.
(3) Wiig M, Dahlin LB, Fridén J, Hagber L, Larsen SE, Mahlapuu M. (2014). PXL01 in sodium hyaluronate for improvement of hand recovery after flexor tendon repair surgery: randomized controlled trial. PLOS ONE, 9(10):e110735.