Drug Name World Status Pharma Status
M-40403 Phase II Clinical Trial Active
M-40404
M-40470
SOD mimetics, ActivBiotics
Latest Change
Updated On By Latest Change
16 Jan 2006 CR Merger of ActivBiotics with MetaPhore Pharmaceuticals reported
Company Status Data
Originator Country Development Stage
ActivBiotics USA Phase II Clinical Trial
Activity Data
Therapy Description Code Status
Analgesic, other N2Z Phase II Clinical Trial
Anticancer, other K6Z Phase II Clinical Trial
Antiarthritic, other M2Z Preclinical
Neuroprotective N7C Preclinical
Septic shock treatment B6A Preclinical
Symptomatic antidiabetic A10C Preclinical
Antiasthma R8A Preclinical
GI inflammatory/bowel disorders A16 Preclinical
Pharmacology Description Code
Superoxidase dismutase-2 stimulant SOD-2+
Therapy Code Pharmacology Code
N2Z
K6Z
M2Z
N7C
B6A
A10C
R8A
A16 SOD-2+
SOD-2+
SOD-2+
SOD-2+
SOD-2+
SOD-2+
SOD-2+
SOD-2+
Route of Administration Route of Administration Code
Parenteral, intravenous P-IV
Alimentary, po A-PO
Indication Status
Pain, post-operative Phase II Clinical Trial
Pain, cancer Phase II Clinical Trial
Cancer, renal Phase II Clinical Trial
Cancer, melanoma Phase II Clinical Trial
Pain, neuropathic Phase II Clinical Trial
Chemical Data
Origin of Material Code Description
CH-SY Chemical, synthetic
CAS Registry Number Molecular Weight Molecular Formula
479.36 C21H31Cl2MnN5
Chemical Name
Dichloro[(4aR,13aR,17aR,21aR)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-eicosahydro-1,7-nitrilo-7H-dibenzo[b,h] [1,4,7,10]tetraazacyclo-heptadecine-kappaN5,kappaN13,kappaN18,kappaN21,kappaN22]manganese
Structure
Patent Data
Country Number Priority Country Priority Date
US 6180620 US 9 April 1998
Country Data
Country Name Status Year Launched Licensing Op.
Argentina - Yes
Australia - Yes
Austria - Yes
Belgium - Yes
Brazil - Yes
Canada - Yes
Chile - Yes
China - Yes
Colombia - Yes
Denmark - Yes
Finland - Yes
France - Yes
Germany - Yes
Greece - Yes
Hong Kong - Yes
India - Yes
Ireland - Yes
Israel - Yes
Italy - Yes
Japan - Yes
Luxembourg - Yes
Malaysia - Yes
Mexico - Yes
Netherlands - Yes
New Zealand - Yes
Norway - Yes
Peru - Yes
Philippines - Yes
Portugal - Yes
Russian Federation - Yes
South Africa - Yes
South Korea - Yes
Spain - Yes
Sweden - Yes
Switzerland - Yes
Thailand - Yes
Turkey - Yes
UK - Yes
USA Phase II Clinical Trial Yes
Venezuela - Yes
Major Events
Event Date Act/Est Event Details
23 May 2005 Est New Indication Pain, neuropathic
29 Sep 2004 Est New Indication Pain, cancer
14 Jul 2003 Est Licensing Opportunities Worldwide
13 Jun 2003 Est Change in Status Phase II Clinical Trial
12 Jul 2002 Est New Therapeutic Activity Antiasthma (R8A) and Antipruritic/inflamm, allergic (D4A)
21 Jan 2002 Est New Therapeutic Activity Cardiovascular (C9Z)
28 Aug 2001 Act New Therapeutic Activity Symptomatic antidiabetic (A10C)
31 May 2001 Act Change in Status Phase I Clinical Trial
21 Feb 2001 Act New Patent Applications US6180620
6 Jul 2000 Act New Chemical Structure New
13 Dec 1999 Est Compounds Identified SOD mimetics, Metaphore
20 Oct 1999 Est New Product in Pharmaprojects
Ratings
Novelty Market Size Speed Total
Leading Compound (6) US$ 5001-10000 million (4) Slower than Average (2) 12
Detailed Information
M-40403 is an iv and po manganese-based stable superoxide dismutase (SOD) mimetic, under development by MetaPhore (ActivBiotics) for the treatment of inflammation, pain, rheumatoid arthritis (RA), cancer, stroke and diabetic neuropathy (Press release, MetaPhore, 18 Sep 2000; Company Web Page, MetaPhore, 14 Jan 2004). It may also reduce dose-limiting IL-2-induced hypotension. Other compounds in the series are in development for the treatment of pain, and for HIV and reperfusion injury (M-40419 and M-40401; both qv). Topical and PEGylated formulations of M-40403 (both qv) are also under development.
Marketing
An NDA filing was expected in the 4th qtr of 2005 (JP Morgan 22nd Ann Healthcare Conf (San Francisco), 2004). MetaPhore was awarded 4 SBIR grants by the NIH, to fund research into the use of SOD mimetics (Press releases, MetaPhore, 18 Sep 2000 & 19 Nov 2001).
Clinical
Phase II
It is in a randomized, double-blind, placebo-controlled Phase II trial in combination with opioids in moderate-to-severe cancer pain. The primary objective is to evaluate the analgesic effect of M-40403 in combination with prescribed pain medication (Press release, MetaPhore, 29 Sep 2004; BioVenture View Daily Online, 4 May 2005, B00880660). A randomized, double-blind, controlled, parallel-group, 350-patient Phase II trial at 2 US centres to assess the synergistic effects of M-40403 in combination with morphine for moderate-to-severe pain following dental surgery is complete. Patients received morphine 0.04, 0.08 or 0.12mg/kg iv alone or in combination with M-40403 0.25mg/kg or M-40403 0.25mg/kg alone. M-40403 improved the overall analgesic profile of morphine, and made the dose-response profile more predictable, with faster onset, longer duration, greater peak effect and greater overall effect. Median time to onset of analgesia in the M-40403 + morphine 0.08mg/kg group was 22.5min, cf >480min for patients on morphine 0.08mg/kg alone, and median time to rescue medication for the M-40403 + morphine 0.12mg/kg group was 2.76hr cf 1.53hr for morphine 0.12mg/kg alone. Adding M-40403 to a low dose of morphine gave pain relief similar to the highest dose of morphine administered alone but without a concomitant increase in morphine side-effects (Press release, MetaPhore, 27 Apr 2004). In a randomized, double-blind, placebo-controlled Phase II study in patients with moderate-to-severe pain following first metatarsal bunionectomy, at 2 US sites, 3 different doses of M-40403 iv x30min + fixed dose morphine iv x10min demonstrated a good safety profile. A randomized, double-blind, placebo-controlled Phase II trial has been initiated in approximately 240 post-bunionectomy pain patients at 2 US sites to compare 0.25 and 0.0625mg/kg M-40403 alone and in combination with morphine (Press release, MetaPhore, 27 Apr 2004; BioVenture View Daily Online, 4 May 2005, B00880660). In a single-dose, randomized, double-blind, parallel-group Phase IIa trial, 250 patients with mild-to-severe pain after dental extraction received M-40403 5, 10 or 20mg iv or ketorolac 30mg (qv). Significant pain relief with 20mg was observed and was superior cf placebo for up to 1hr following molar extraction, with no serious adverse events (Press release, MetaPhore, 12 Jun 2003). Phase II trials in advanced skin and end-stage kidney cancers in combination with IL-2 were conducted (Company Web Page, MetaPhore, 8 Dec 2003). Phase II trials of M-40403 po to stop or reverse RA progression are expected in 2005 (JP Morgan 22nd Ann Healthcare Conf (San Francisco), 2004).
Phase I
It is in Phase I trials as a monotherapy for the treatment of neuropathic pain (Bio Venture Forum East (Atlanta), 2005). A Phase I trial to test safety, efficacy and pharmacokinetics in healthy volunteers was completed (Company Web Page, MetaPhore, 11 Jun 2002).
Preclinical
In rats, it inhibited fibrosis when coated on implanted biomedical devices (as M-40470) (Company Web Page, MetaPhore, 8 Dec 2003). In preclinical studies, it prevented or reversed the development of tolerance to morphine, and lowered the amount of morphine required for analgesia (Scrip Daily Online, 14 Jul 2003, S00808496). In a rat model of RA, M-40403 daily reduced inflammation by up to 56%, joint erosion by at least 70% and TNF-\a and IL-1b levels to those of non-arthritic rats (Press release, MetaPhore, 6 Dec 2001). In diabetic rats, M-40403 improved blood flow to nerves and restored normal relaxation of vessels around the sciatic nerve and normal motor nerve conduction velocity (Press release, MetaPhore, 28 Aug 2001). In 2 separate animal models, in combination with IL-2, M-40403 prevented the onset of IL-2-induced hypotension and enhanced IL-2's ability to kill malignant cells (Press release, MetaPhore, 22 Mar 2001). In rats, M-40403 administered 30min before or after inducing inflammation inhibited oedema and cytokine release associated with the inflammatory response. M-40403 was more efficacious than native SOD. Low-dose M-40403 also increased survival in a rat model of severe shock induced by reperfusion damage to the gut and intestine. At 4hr post-injury, survival of animals treated with M-40403 was 90% cf 0% of untreated animals (Press release, MetaPhore, 7 Oct 1999). In oral albumin-sensitized guinea pigs, M-40403 and M-40419 1mg/kg ip or by aerosol before or during antigen challenge dose-dependently attenuated the increase in severity of dyspnoea, decrease in latency of appearance of bronchospasm, increase in respiratory failure, mast cell degranulation and neutrophil infiltration. In rats, M-40401 and M-40403 10mg/kg ip reduced the histological and enzyme changes seen during zymosan-induced multiple organ failure (14th World Cong Pharmacol (San Francisco), 2002, Abs 134.34 & 137.36). In an animal colitis model, M-40403 reduced the extent and severity of inflammation and tissue damage of intestinal wall. It also reduced diarrhoea and body weight loss and elevated pro-inflammatory cytokines (TNF-\a and interleukin-1\B) (Press release, MetaPhore, 12 Dec 2001).
Licensing
MetaPhore plans to partner M-40403 before Phase IIb (Scrip Daily Online, 14 Jul 2003, S00808496). Updated by KS on 23/5/2005.
