kringle-pharmaCo., Ltd.

DEVELOPMENT

Research and Development

Others

Vocal fold scar

Vocal fold scarring is associated with changes in the vocal fold (fibrosis and scarring), resulting in slow movement and voice disorders such as dysphonia. Although its pathogenesis is not clear, it often occurs after vocal cord trauma, inflammation, or surgery. Based on the results of a small-scale epidemiological study, it has been estimated that there are 3,000 to 12,000 patients with vocal fold scarring in Japan. To date, there is no effective treatment for this condition. Symptomatic treatment, which is main existing treatment, involves rehabilitation with vocal training and surgery to move the position of the vocal cord.

Description of vocal cord scar

Mechanism of suppression of fibrosis by HGF

Mechanism of suppression of fibrosis by HGF

In addition to other biological activities, HGF mediates the antifibrotic effect that can be used to treat vocal fold scarring. In collaborative work with the Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, and the Foundation for Biomedical Research and Innovation at Kobe, we injected recombinant human HGF into the vocal cords of an animal model of vocal fold scarring and confirmed improvement in vocal cord function. We then conducted additional preclinical studies involving vocal cord injection and progressed to the clinical trial stage. The results of the open-label, dose-escalation Phase I/II clinical trial in patients with vocal fold scarring are summarized in the table below:

Summary of Phase I/II study for vocal fold scar
Study design

Open labelled, dose escalation study Investigator initiated study

Patient population

Patients with vocal fold scar Patient’s age was ≥20 years and ≤65 years

Dosage and administration

1, 3, 10 µg, unilaterally injected into the vocal fold, once a week, 4 times (same dosage was injected into both side vocal folds)

Primary endpoints
  • Evaluation criteria

    Evaluation of safety

  • Results

    Hyperemia of the vocal folds were observed, then all cases recovered. No other serious adverse event was observed

Secondary endpoints
  • Evaluation criteria

    Phonatory outcomes evaluated by examining the improvement in each phonatory parameter

  • Results

    3 of the 5 phonatory outcomes indicated tendency of the improvement

Regarding safety, the primary endpoint of no serious adverse reactions was met; moreover, the HGF drug was well tolerated. In addition, we could obtain clinical data on endpoints that showed improvement and the evaluation timing of these endpoints. The study results have been published in an international medical journal, the Journal of Tissue Engineering and Regenerative Medicine (Hirano et al., 2018).

Based on the results described above, we designed the next phase of clinical trials. Specifically, considering a placebo-controlled, double-blind comparative study to establish the POC, we selected several trial sites, primary endpoints, and secondary endpoints to develop the outline of the protocol through consultation with the Kyoto Prefectural University of Medicine. Using this protocol, we have begun discussions for the next phase of clinical trials with the Japanese Pharmaceuticals and Medical Devices Agency in a preliminary consultation.

If the POC of HGF is verified for vocal fold scarring, the drug discovery concept based on the antifibrotic effect of HGF will be confirmed. It may then have a wider application to other chronic diseases caused by fibrosis (e.g., chronic kidney disease, liver cirrhosis, and pulmonary fibrosis) in addition to vocal fold scarring.

References

Mizuta M, Hirano S, Ohno S, Kanemaru S, Nakamura T, Ito J. Restoration of scarred vocal folds using 5 amino acid-deleted type hepatocyte growth factor. Laryngoscope. 2014; 124: E81-86.

Hirano S, Kawamoto A, Tateya I, Mizuta M, Kishimoto Y, Hiwatashi N, Kawai Y, Tsuji T, Suzuki R, Kaneko M, Naito Y, Kagimura T, Nakamura T, Kanemaru SI. A phase I/II exploratory clinical trial for intracordal injection of recombinant hepatocyte growth factor for vocal fold scar and sulcus. J Tissue Eng Regen Med. 2018 12:1031-1038.

Acute Kidney Injury

Acute kidney injury is characterized by a rapid decline in renal function over a short period of time (hours to days) due to conditions such as kidney damage, inadequate blood supply to the kidneys, and urinary tract obstruction, resulting in the inability of the kidney to excrete fluids and waste products in the urine and maintain the balance of fluids and salts in the body. Reportedly, acute kidney injury can occur in 5% to 7% of inpatients and 20% to 25% of patients in intensive care units. There are about 80,000 new cases of acute kidney injuries in Japan every year. Emergency care is required for serious cases and is associated with high mortality. The cause of acute kidney injury is often unidentified, as a number of factors are involved in its development, and no effective treatment has been established yet.

Onset of Acute Kidney Injury and Mechanism of Action of HGF

Onset of Acute Kidney Injury and Mechanism of Action of HGF

As HGF protects kidney cells and promotes cell growth, it can be developed as a potential drug for treating acute kidney injury. We conducted early clinical trials in the U.S. with the supports of a nephrology clinic (Rogosin Institute). As the objective of the Phase Ia and Ib studies was to confirm the safety and pharmacokinetics of the intravenous administration of recombinant human HGF, we considered it inappropriate to enroll acute kidney injury patients with unstable condition. Thus, chronic kidney disease patients with relatively stable condition were included in the studies. We received fast track designation from the U.S. Food and Drug Administration to conduct this study, which is a program to expedite the review of new drugs with immediate medical needs. The results of the clinical trials are summarized in the table below:

Summary of Phase I studies for chronic kidney disease
Study design

Phase Ia: open labelled, dose escalation study (9 subjects)
Phase Ib: placebo controlled, double-blind study (15 subjects)

Patient population

Patients with chronic kidney disease Patient’s age was ≥18 years and ≤85 years

Dosage and administration

Phase Ia: single intravenous administration for 3 dosage groups
Phase Ib: repeated intravenous administration, once a day, 5 times, 2 dosage groups

Primary endpoints
  • Evaluation criteria

    Safety and tolerability

  • Results

    There was no serious adverse event

Secondary endpoints
  • Evaluation criteria

    Pharmacokinetic profile

  • Results

    Pharmacokinetic profile

Based on the findings of this study, the next phase of clinical trials in patients with acute kidney injury is being designed. At the same time, we are also developing an additional Phase I study to be conducted in Japan (a small-scale study to determine the maximum tolerated dose in Japanese patients). Specifically, to develop a protocol for patients with acute kidney injury, we are continuing to interview medical experts, review other companies’ clinical trials, and examine biomarkers. Currently, the next phase of clinical trial is expected to be a relatively large, placebo-controlled, double-blind comparative study. To implement this clinical trial, we are first looking to secure funds by partnering with pharmaceutical companies.

As the highest level of systemic absorption of the test drug can be achieved by intravenous injection, safety issues are likely to occur using this route of administration. We have procured important information for the development of other routes of administration as the safety of the drug was confirmed in these studies. Intravenous injection can easily be expanded for applications in various diseases. We will continue development on this front while identifying diseases other than acute kidney injury for which the safety and efficacy of the drug can be ensured.

References

Matsumoto K, Nakamura T. Hepatocyte growth factor: renotropic role and potential therapeutics for renal diseases. Kidney Int. 2001;59(6):2023-2038

Kawaida K, Matsumoto K, Shimazu H, Nakamura T. Hepatocyte growth factor revents acute renal failure and accelerates renal regeneration in mice. Proc Natl Acad Sci USA. 1994;91:4357-4361.

Research

Our company is conducting basic research in collaboration with universities and other companies in Japan and overseas and strengthening new pipeline drugs. If promising preclinical data was obtained on drug substances provided by our company, we would efficiently move on to the next stage of clinical testing by utilizing our proprietary preclinical and clinical data.

Indication Site Research Non-clinical Clinical
Ophthalmology USA (API supply from Kringle Pharma) completed Ongoing planning
Neurology JAPAN Ongoing
Others(Feasibility stage) Two universities in Japan Ongoing