kringle-pharmaCo., Ltd.

DEVELOPMENT

Research and Development

Amyotrophic lateral sclerosis(ALS)

ALS is a fatal intractable neurological disease, which progressively results in impairment in the ability to move because of motor neuron degeneration. Currently, approximately 20,000 patients have been diagnosed with ALS in the U.S. Various factors are involved in the development of ALS, including genetic causes, glutamate toxicity or unknown causes. However, commonality among the patients is that loss of motor neurons due to damage leads to muscle atrophy; thus, protecting motor neurons may produce therapeutic effects. Therefore, as in the case of spinal cord injury, neuron protection and the extension of axons via the action of HGF are expected to become treatment for ALS.​

Onset mechanism of ALS and therapeutic effect by HGF

Onset mechanism of ALS and therapeutic effect by HGF

In a collaborative study with the Department of Neurology of the Tohoku University Graduate School of Medicine, we conducted tests to identify the pharmacologic effects of recombinant human HGF using an animal model of ALS. The administration of HGF was confirmed to be effective in several parameters including in restoring motor function, delaying ALS onset, and increasing survival. Additionally, we conducted preclinical toxicity and pharmacokinetic studies necessary for drug development and progressed to the open-label, dose-escalation Phase I trial. The results of Phase I clinical trial in patients with ALS are summarized in the table below:

Summary of Phase I study for ALS patients (completed)
Study design

Open labeled, dose escalation, single site study Single dose: 3 groups Repeated dose: 2 groups (3 subjects each groups)

Patient population

ALS patients within 3 years of onset
Patients with ALS severity grade* 1 or 2 Patient’s age was ≥20 years and ≤65 years

Dosage and administration

Intrathecal administration through a catheter and subcutaneous port Single dose: 0.2, 0.6, 2.0 mg/person Repeated dose: 0.6, 2.0 mg/person, once a week, 5 times

Primary endpoints
  • Evaluation criteria

    Safety and tolerability

  • Results

    Good safety and tolerability

Secondary endpoints
  • Evaluation criteria

    • Pharmacokinetic profile
    • Presence/absence of anti-KP-100 antibody production
  • Results

    • The mean half-life of KP-100 was 1.2-1.4 days The trough KP-100 concentrations remained constant
    • Anti-KP-100 antibody was not detected

Regarding the safety and tolerability as primary endpoints of this study, no serious adverse events were occurred, and the HGF treatment was shown to be safe and well tolerated. Furthermore, as a secondary endpoint, drug pharmacokinetics were analyzed to determine the appropriate dose. The results provided information about the dosing regimen required to examine the efficacy. These results have been published in an international medical journal, the Journal of Clinical Pharmacology (Warita et al., 2019).
Based on the findings noted above, we are currently conducting double-blind, placebo-controlled Phase II clinical trial for verifying the POC. An overview of the Phase II clinical trial in patients with ALS is shown in the table below:

Summary of Phase II study (on going)
Study design

Placebo controlled, double blind, parallel-group, comparative study Containing non-blinded continuous administration period (if subjects desire) Investigator initiated study

Patient population

ALS patients with changes in ALSFRS-R score in the range of -1 to -3 during the 12 weeks pre-observation period Patient’s age is ≥20 years and ≤70 years Estimated enrollment: 48 subjects (KP-100IT: 32 subjects, placebo: 16 subjects)

Dosage and administration

Intrathecal administration through a catheter and subcutaneous port 2.0 mg/person, every 2 weeks for 24 weeks (double blinded period) +24 weeks (open period, if subjects desire)

Primary endpoints

Evaluation criteria

Changes of ALSFRS-R score between two groups at 24 weeks (double blinded period only)

Secondary endpoints

Evaluation criteria

Efficacy and safety for long period administration of KP-100IT

In this investigator-initiated clinical trial, Kringle Pharma is the investigational drug provider, holding exclusive rights to commercialize the product after completing the trial.

References

Sun W, Funakoshi H, Nakamura T. Overexpression of retards disease progression and prolongs life span in a transgenic mouse model of ALS. J Neurosci. 2002;22:6537-6548

Ishigaki A, Aoki M, Nagai M, Warita H, Kato S, Kato M, Nakamura T, Funakoshi H, Itoyama Y. Intrathecal delivery of hepatocyte growth factor from amyotrophic lateral sclerosis onset suppresses disease progression in rat amyotrophic lateral sclerosis model. J Neuropathol Exp Neurol. 2007;66(11):1037-1044

Warita H, Kato M, Asada R, Yamashita A, Hayata D, Adachi K, Aoki M. Safety, Tolerability, and Pharmacodynamics of Intrathecal Injection of Recombinant Human HGF (KP-100) in Subjects With Amyotrophic Lateral Sclerosis: A Phase I Trial. J Clin Pharmacol. 2019 59(5):677-687.