Ensereptide – Prevention of Post-Surgical Adhesions and Scars

The company is initially focused on the prevention of adhesions after flexor tendon repair surgery in the hand, but foresees potential to also develop products based on ensereptide for other medical applications such as prevention of adhesions after spinal surgery used in the treatment of degenerative disc disorder and dermal scarring after surgery or trauma.

The rationale for selecting prevention of adhesions after tendon repair surgery as a first indication for ensereptide was (i) tendon repair in the hand represents an area of high medical need due to high incidence of adhesions; (ii)

the same surgical method is used in flexor tendon repair worldwide and the methods used for clinical evaluation of hand function are standardized and quantifiable and are the same throughout the world; (iii) the injury is common among young healthy patients, which means that the risk of comorbidity is low and the socioeconomic need is large; (iv) hand surgery is a distinct specialty among surgeons, which facilitates recruitment in clinical studies, but also the marketing and sale of an approved future product.

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 candidate is intended for application as a single administration in conjunction with tendon repair surgery. Ensereptide is delivered a pre-packaged syringe and is mixed with a hyaluronic acid containing gel . During the surgical procedure, the gel is locally administered around the repaired tendon between the tendon and the tendon sheath, via a specialized applicator before the surgical site is closed.

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).

Ensereptide is a synthetic peptide derived from the human lactoferricin peptide, which is part of the milk protein lactoferrin. Ensereptide has several mechanisms of action. The peptide has, among other things, 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). Ensereptide also increases the fibrinolytic activity by inhibiting the local production of PAI-1. Both these properties  are assumed to account for the peptide’s ability to prevent post-surgical adhesions and scar formation.

Clinical Study Results

Promore Pharma has completed a Phase I clinical trial on ensereptide. 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 ensereptide 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 ensereptide has also 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 ensereptide 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 ensereptide 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)

In the clinical Phase II study, it was shown that ensereptide achieve a significant prevention of adhesions without having a negative effect on the strength of the healed tendon. There were no 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 ensereptide in Sweden, Germany, Poland, Italy and India. Promore Pharma shall be the official sponsor for the trial, although the work is conducted as strategic alliance with the clinical research organization Technomark/Kentron.

The Phase III trial is planned as a randomized, double-blinded study including approximately 600 patients with flexor tendon injuries in the hand where a single administration event of ensereptide 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.

It is the ambition of the company to conduct a similar  Phase III Trial in the US for Market Approval in North America. For market approval in the US, two clinical trials are required, where the clinical Phase III study that is being conducted in Europe and India can be one of the required studies..

(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.

Prevention of Dermal Scarring

The company is preparing to conduct a small, well-controlled clinical trial to explore the feasibility of utilizing ensereptide for prevention of dermal scarring after surgery or trauma.

The company is evaluating the possibility of conducting a Phase I/II clinical trial of ensereptide, a study that can be performed in Sweden with Promore Pharma as the official sponsor

(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.