kringle-pharmaCo., Ltd.

DEVELOPMENT

Research and Development

Acute Spinal Cord Injury

The spinal cord comprises nerves that connect the brain to the rest of the body and is protected by bones called the spinal column. Spinal cord injury occurs following damage to the spinal cord tissue owing to trauma from an external force, such as accidents and falls. Such injuries can result in loss or impairment of motor or sensory functions to develop motility disorder or sensation disturbance. Reportedly, there are about 17,000 new cases of spinal cord injury per year in the U.S. However, to date, there is no effective treatment for spinal cord damage, and only symptomatic treatment is available, including surgery for a fracture or dislocation of the spinal column that encloses the spinal cord, and rehabilitation for utilizing the remaining nerve functions and conducting activities of daily living.

Mechanism of spinal cord injury and therapeutic effect by HGF

Mechanism of spinal cord injury and therapeutic effect by HGF

As HGF protects neurons and promotes the extension of axons, it can be developed as a potential treatment for spinal cord injury. In the acute phase of spinal cord injury, extensive damage to the surrounding tissue, referred to as secondary damage, is sustained following primary damage to the tissue by an external force. It is considered that the purpose of treatment in the acute phase of spinal cord injury is to minimize secondary damage.

In collaboration with the Department of Orthopedic Surgery of the Keio University School of Medicine, we conducted preclinical studies to identify the pharmacological effects of recombinant human HGF using animal models of spinal cord injury. We confirmed the therapeutic efficacy of HGF treatment for such injury in the motor function assessment. In addition, we conducted preclinical toxicity and pharmacokinetic studies necessary for drug development and progressed to the double-blind, placebo-controlled Phase I/II clinical trial. The results of Phase I/II clinical trial in patients with acute spinal cord injury are summarized in the table below:

Summary of Phase I/II study for acute spinal cord injury subjects
Study design

Multicenter, randomized, double-blind, parallel-group, placebo-controlled comparative study

Patient population

Patients who have suffered a cervical spinal cord injury within the past 78 hours whose modified Frankel classification was A/B1/B2 at 66 to78 hours after injury
Patient’s age is ≥ 18 years and ≤ 75 years

Dosage and administration

0.6㎎/body, repeating weekly 5 times, intrathecally
(KP-100IT group:28 subjects、placebo group:17 subjects)

Primary endpoints
  • Evaluation criteria

    Evaluation of adverse events including evaluation of whether anti-KP-100 antibody was produced Changes from baseline in American Spinal Injury Association (ASIA) motor score at 24 weeks

  • Results

    Regarding safety, there were no serious adverse events of antibody production due to KP-100IT KP-100IT did not obtain a significant difference from placebo in the primary endpoint.

Secondary endpoints
  • Evaluation criteria

    Changes of neurological endpoints

  • Results

    Changes in ASIA motor score, a significant difference was found at Day 140.

As for the primary endpoints in the Phase I/II, the safety and tolerability of HGF administration to acute spinal cord injury patients were confirmed. Although there was no significant difference in the change in ASIA motor score from baseline at week 24, which was used as the primary endpoint of efficacy, the HGF-treated group showed a consistent trend of functional recovery throughout 6-month observation period, compared with the placebo group. Moreover, the two groups significantly differed with regard to the change in the ASIA motor score from baseline at week 20, which was included as the secondary endpoint of efficacy. Thus, we considered that the proof of concept (POC) for HGF treatment in acute spinal cord injury was established.

Based on the results of this trial, HGF was designated as an orphan drug for acute spinal cord injury by the Japanese Ministry of Health, Labour and Welfare in September 2019. In addition, the study results have been published in an international medical journal, the Journal of Neurotrauma (Nagoshi et al., 2020). We planned a nonrandomized, confirmatory Phase III clinical trial to verify the POC established in the Phase I/II and commenced it in July 2020 as indicated in the summary table below:

After successful completion of the Phase III trial, we are aiming to obtain regulatory approval in Japan for marketing of drug indicated for the treatment of acute spinal cord injury. Supply chain collaboration for the approved drug have been already formed in Japan, as illustrated in the figure. We believe that a smoother, more reliable supply chain has been established for the marketing and promoting products by our partnership with these companies.

Summary of Phase III study for acute spinal cord injury subjects
Study design

Non-randomization, single group, multicenter study

Patient population

Patients who have suffered a cervical spinal cord injury within the past 78 hours whose modified Frankel classification was A at 66 to78 hours after injury
Patient’s age is ≥ 18 years and ≤ 89 years Estimated enrollment: 25 subjects

Dosage and administration

0.6㎎/body, repeating weekly 5 times, intrathecally

Primary endpoints

Evaluation criteria

Parcentage of subjects with an improvement of at least two AIS(American Spinel Injury Association) grade, A to C/D at 24 weeks after administration.

Secondary endpoints

Evaluation criteria

Time course of neurological endpoints
Evaluation of adverse events

References

Kitamura K, Iwanami A, Nakamura M, et al. Hepatocyte growth factor promotes endogenous repair and functional recovery after spinal cord injury. J Neurosci Res 2007; 85:2332-2342.

Kitamura K, Fujiyoshi K, Yamane J, Toyota F, Hikishima K, Nomura T, Funakoshi H, Nakamura T, Aoki M, Toyama Y, Okano H, Nakamura M. Human hepatocyte growth factor promotes functional recovery in primates after spinal cord injury. PLoS One. 2011; 6: e27706.

Kitamura K, Nagoshi N, Tsuji O, Matsumoto M, Okano H, Nakamura M. Application of Hepatocyte Growth Factor for Acute Spinal Cord Injury: The Road from Basic Studies to Human Treatment. Int J Mol Sci. 2019 Feb 28;20(5):1054.

Nagoshi N, Tsuji O, Kitamura K, Suda K, Maeda T, Yato Y, Abe T, Hayata D, Matsumoto M, Okano H, Nakamura M. A phase I/II study for intrathecal administration of recombinant human hepatocyte growth factor in patients with acute spinal cord injury: a double-blind, randomized clinical trial of safety and efficacy.. J Neurotrauma. 2020 Apr 23. doi: 10.1089/neu.2019.6854