Delving into the Latest Updates on SPK-241 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [1]

Target-

Mechanism

Apoptosis inducers

Therapeutic Areas

Nervous System Diseases

Active Indication

Peripheral Nervous System Diseases

Inactive Indication

Multiple MyelomaNeoplasmsNeuralgia

Originator Organization

Kirin Holdings Co., Ltd.

Active Organization

Kirin Holdings Co., Ltd.

Inactive Organization

DARA Therapeutics, Inc.

Fortovia Therapeutics, Inc.Startup

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC28H43N7O7

InChIKeyLQIPDFIUPOYMPR-BKYURJJWSA-N

CAS Registry151276-95-8

CONTEXTNeuropathic pain in patients with cancer can be difficult to treat effectively.OBJECTIVESThe purpose of the study was to determine safety and efficacy of KRN5500, a novel, spicamycin-derived, nonopioid analgesic agent, in patients with advanced cancer and neuropathic pain of any etiology.METHODSThe study was a Phase 2a, multicenter, double-blind, placebo-controlled, dose escalation clinical trial. Patients with refractory neuropathic pain and advanced cancer were randomly assigned 2:1 to receive a maximum of eight single escalating doses of KRN5500 or placebo, ranging from 0.6 to 2.2 mg/m(2). The primary objective was safety and tolerability. The secondary objective was efficacy, measured by change in average pain intensity on a 0-10 numeric rating scale administered one week after the patient's final dose.RESULTSNineteen patients received treatment (KRN5500 n=12; placebo n=7). The most frequently reported adverse events were gastrointestinal symptoms, which were more frequent and severe with KRN5500 than placebo; two (17%) KRN5500 patients discontinued the study because of nausea and vomiting. At study endpoint, KRN5500 exhibited a significant median decrease in pain intensity from baseline of 24% compared with 0% for placebo (P=0.03). The median for largest weekly reduction in target pain intensity was 29.5% for KRN5500 and 0% for placebo patients (P=0.02).CONCLUSIONThis proof-of-concept study for KRN5500 in patients with advanced cancer and any type of neuropathic pain found gastrointestinal adverse events to be the predominant safety concern. The results also provided the first indication of clinical and statistical efficacy in reducing pain intensity.

01 Nov 2011·British Journal of HaematologyQ2 · MEDICINE

KRN5500, a spicamycin derivative, exerts anti‐myeloma effects through impairing both myeloma cells and osteoclasts

Q2 · MEDICINE

Article

Author: Watanabe, Keiichiro ; Yata, Ken‐ichiro ; Sakai, Akira ; Nakano, Ayako ; Oda, Asuka ; Kagawa, Kumiko ; Takeuchi, Kyoko ; Ikegame, Akishige ; Cui, Qu ; Nakamura, Shingen ; Miki, Hirokazu ; Amou, Hiroe ; Ozaki, Shuji ; Hiasa, Masahiro ; Harada, Takeshi ; Fujii, Shiro ; Matsumoto, Toshio ; Abe, Masahiro

SummaryThe spicamycin analogue KRN5500 alters glycoprotein processing and induces damage in the endoplasmic reticulum (ER)‐Golgi apparatus in cancer cells. In the present study, we explored the cytotoxic effects of KRN5500 on multiple myeloma (MM) cells and the bone marrow microenvironment with special reference to ER stress. Cell proliferation assay showed that KRN5500 induced G1 arrest and apoptosis in MM cells in a time‐ and dose‐dependent manner. KRN5500 enhanced ER stress independently of caspase activation in MM cells. This cell death was observed even in the presence of bone marrow stroma cells or osteoclasts. Notably, KRN5500 induced cell death also in osteoclasts. In vivo effects of KRN5500 were evaluated using two xenograft models established in severe combined immunodeficient (SCID) mice by either subcutaneous injection of RPMI 8226 cells or intra‐bone injection of INA‐6 cells to subcutaneously implanted rabbit bones (SCID‐rab model). KRN5500 significantly inhibited tumour growth in both animal models, and decreased the number of osteoclasts, which resulted in prevention of bone destruction in the SCID‐rab model. These results suggest that KRN5500 exerts anti‐MM effects through impairing both MM cells and osteoclasts. Therefore, this unique mechanism of KRN5500 might be a useful therapeutic option in patients with MM.

01 Feb 2006·Nihon rinsho. Japanese journal of clinical medicine

[Spicamycin derivative].

Review

Author: Mizumura, Yasuo

Spicamycin, induced differentiation of human myeloid leukemia cells (HL-60), is found to show a potent antitumor activity by inhibiting protein synthesis. Among the various semisynthetic derivatives of spicamycin, KRN5500 showed a marked efficacy in human tumor xenograft model. KRN5500 itself has, however, only minor inhibitory effects on protein synthesis in cell free system. A metabolite, SAN-Gly, which is thought to be generated through metabolism of KRN5500 by a cytosomal enzyme, exhibited a marked inhibitory effect. KRN5500 is expected to be useful even for treatment of refractory solid tumors because of its unique antitumor mechanism. A phase I clinical trials underwent at the National Cancer Center Hospital in Tokyo and at the National Cancer Institute in the USA. Unfortunately, the drug toxicities in addition to grade 4 pulmonary disorders were occurred, partly caused by the organic solvents and chemical essential for its dissolution. To overcome such a severe adverse effects, we conducted to examine whether incorporation of KRN5500 into polymeric micelles (KRN/m) could reduce a pulmonary disorder using a bleomycin (BLM)-induced lung injury rat model or exhibit antitumor activity similar to KRN5500. In conclusion, this study demonstrated that KRN/m is superior to KRN5500 because the pulmonary toxicity was reduced and the potent antitumor activity of KRN5500 was retained after the incorporation of KRN5500 into micelles. We think that these results justify a clinical phase I trial of KRN/m.

100 Deals associated with SPK-241

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15215

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Neuralgia	Phase 2	PR	DARA Therapeutics, Inc.	01 Jun 2006
Multiple Myeloma	Phase 2	US	Fortovia Therapeutics, Inc.Startup	-
Peripheral Nervous System Diseases	Phase 2	-	Kirin Holdings Co., Ltd.	-
Neoplasms	Discovery	PR	DARA Therapeutics, Inc.	01 Jun 2006
Neoplasms	Discovery	US	DARA Therapeutics, Inc.	01 Jun 2006
Neuralgia	Discovery	US	DARA Therapeutics, Inc.	01 Jun 2006