INTRADISCAL INJECTION OF A WELL DOCUMENTED MOLECULE

STA363 is based on an endogenous and well documented small molecule together with a contrast agent assuring safe and accurate injection. Administration will be a single intradiscal injection. The effect of one single injection of STA363 is presumed to last the patient’s entire life and require minimal if any rehabilitation. STA363 transforms the disc into connective tissue and has therefore the potential to permanently achieve a significant reduction of the patient’s pain. STA363 will enter phase 2b studies in H1 2020.

HEALTHY DISC

A disc consists of two main parts: Nucleus pulposus (disc centre) and anulus fibrosus (disc wall). Nucleus pulposus consists largely of a highly hydrated gel together with nucleus pulposus cells and fibroblasts.

DEGENERATED DISC

As the disc degenerates throughout ageing, tears in the anulus fibrosus appear and nucleus pulposus loses its gel-like structure resulting in a mechanically unstable disc 1. Inflammatory changes occur and the tears allow leakage of pro-inflammatory substances from the nucleus pulposus irritating and sensitising nerves both within and outside the disc2.

DISC INJECTED WITH STA363

One single injection of STA363 transforms the disc into dense connective tissue. The transformation restricts synthesis and leakage of pro-inflammatory agents and re-stabilises the intervertebral segment. By achieving these two effects, Stayble believes that STA363 has the potential to significantly reduce discogenic low back pain.

REFERENCES

WHY STAYBLE’S TREATMENT is expected to reduce pain

The transformation of the disc into connective tissue induces the following changes which are anticipated to act synergistically to reduce the patient’s pain durably.

Re-stabilisation of the disc

One single injection of STA363 will stabilise the segment by transforming the nucleus pulposus into connective tissue and by rigidifying the anulus fibrosus. The rapid transformation will break the vicious cycle of degeneration and prevent further destabilisation.

Limitation of leakage

Annular tears allowing leakage of pain-producing agents is a proposed cause of discogenic back pain2,8,9. Pro-inflammatory substances are known to produce pain when applied to the nerve roots10,11. By transforming the disc into connective tissue, STA363 reduces both production of pain-generating molecules and their spread to nerves.

Simulates the discs spontaneous transformation

An experience shared by many orthopedic surgeons is that patients suffering from discogenic back pain often recover with age due to sclerosation (transformation into connective tissue) of the disc3,4,5. This is however a slow process that may take decades. Another mechanism for spontaneous healing is the reduced prevalence of annular tears with the ageing6,7. STA363 will, by transforming the disc into connective tissue, simulate the natural sclerosation but considerably quicker.

PRECLINICAL STUDIES VERIFY THE EFFICACY OF STA363

Stayble has performed several preclinical studies, both in vitro and in vivo. The in vitro studies showed that STA363 concentration-dependently increased collagen secretion from disc cells. In vivo studies in a pig model have focused on disc transformation, dose dependency and local toxicity, both intra- and extradiscally.

STA363 stimulates collagen secretion in vitro

In vitro studies have been performed on nucleus pulposus cells to understand the concentration dependency after exposure to STA363.

The studies demonstrate that STA363 induces collagen production in a concentration-dependent fashion up to a ceiling level.

STA-363 stabilizes the motion segment

A pig model was used to verify that sclerosis produced by STA363 increases the stiffness of the motion segment. The L3/4 disc was injected with either STA363 or placebo and a flexibility test was performed four weeks later. A drastic decrease in flexural movement (i.e. increased stiffness) of the motion segment was demonstrated comparing treated discs to both placebo and untreated discs.

STA363 transforms the nucleus pulposus to fibrotic tissue

The discs evaluated for stiffness (see above) were also subjected to macroscopic analysis with regard to the amount of newly formed connective tissue. Sclerosation was measured as the maximal height from the anterior to the posterior margin of the nucleus pulposus.

A major replacement of nucleus pulposus by connective tissue was seen in all STA363 treated discs compared to both naïve and placebo injected discs. This study demonstrated that a single injection of STA363 transforms most of the nucleus pulposus to fibrotic (connective) tissue.

Histological evidence for sclerosation of the nucleus pulposus after treatment with STA363

Islets of notochordal cells (asterisk in left picture) are embedded in gel (double asterisks) in the untreated pig disc. One month after injection of lactic acid, the nucleus pulposus has been replaced by dense fibrotic tissue (right picture).

SUCCESSFUL COMPLETION OF PHASE IB STUDY IN PATIENTS WITH DISCOGENIC PAIN

The first-in-human-study on STA363 has been finalised. It included 15 patients and was performed at Stockholm Spine Center in Sweden.

The study was a double-blinded trial that included 3 doses of STA363 and was placebo-controlled.

The primary objective, to establish safety and tolerability of the treatment, was achieved. No serious adverse events were noted and adverse events were restricted to transient increase in low back pain after injection. This is an expected side-effect and was observed at similar frequency in all treatment arms, including placebo.

Preliminary Magnetic Resonance Imaging data suggest that STA363 dose-dependently transforms the disc into connective tissue.

REFERENCES

  1. Boos N, Weissbach S, Rohrbach H, Weiler C, Spratt KF, Nerlich AG. Classification of age-related changes in lumbar intervertebral discs: 2002 Volvo Award in basic science. Spine (Phila Pa 1976). 2002;27(23):2631-2644.
  2. Byröd G, Rydevik B, Nordborg C, Olmarker K. Early effects of nucleus pulposus application on spinal nerve root morphology and function. Eur Spine J. 1998;7(6):445-449.
  3. Rhyne III AL, Smith SE, Wood KE, Darden II B V, Deyo RA. Outcome of unoperated discogram-positive low back pain. Spine (Phila Pa 1976). 1995;20(18):1997-2001.
  4. DePalma MJ, Ketchum JM, Saullo T. What is the source of chronic low back pain and does age play a role? Pain Med. 2011;12:224-233.
  5. Laplante BL, Ketchum JM, Saullo TR, DePalma MJ. Multivariable analysis of the relationship between pain referral patterns and the source of chronic low back pain. Pain Physician. 2012;15(2):171-178.
  6. Sehgal N, Fortin JD. Review Article Internal Disc Disruption and Low Back Pain. 2000;3(2):143-157.
  7. Schwarzer  a C, Aprill CN, Derby R, Fortin J, Kine G, Bogduk N. The prevalence and clinical features of internal disc disruption in patients with chronic low back pain. Spine (Phila Pa 1976). 1995;20(17):1878-1883.
  8. Satoru K, Konno S, Olmarker K, Shoji Y, Kikuchi S. Incision of the annulus fibrosus induces nerve root morphologic, vascular, and functional changes.pdf. Spine (Phila Pa 1976). 1996;21(22):2539-2543.
  9. Derby R, Kim BJ, Chen Y, Seo KS, Lee SH. The relation between annular disruption on computed tomography scan and pressure-controlled diskography. Arch Phys Med Rehabil. 2005;86(8):1534-1538.
  10. Murata Y, Onda A, Rydevik B, Takahashi I, Takahashi K, Olmarker K. Changes in pain behavior and histologic changes caused by application of tumor necrosis factor-alpha to the dorsal root ganglion in rats. Spine (Phila Pa 1976). 2006;31(5):530-535.
  11. Olmarker K, Blomquist J, Strömberg J, Nannmark U, Thomsen P, Rydevik B. Inflammatogenic properties of nucleus pulposus. Spine (Phila Pa 1976). 1995;20(6):665-669.

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