Document:

exv4w2

 

Exhibit 4.2

FORM 53-901F

SECURITIES ACT

MATERIAL CHANGE REPORT UNDER

SECTION 85(1) OF THE SECURITIES ACT (BRITISH COLUMBIA)

AND EQUIVALENT LEGISLATION OF OTHER JURISDICTIONS

	 	 	 
	Item 1.
	 	REPORTING ISSUER

	 	 	 

	 	 	Cardiome Pharma Corp.

	 	 	6190 Agronomy Road, 6th Floor

	 	 	Vancouver, BC V6T 1Z3

	 	 	 

	Item 2.
	 	DATE OF MATERIAL CHANGE

	 	 	 

	 	 	January 27, 2005

	 	 	 

	Item 3.
	 	PRESS RELEASE

	 	 	 

	 	 	January 27, 2005 — Vancouver, British Columbia

	 	 	 

	Item 4.
	 	SUMMARY OF MATERIAL CHANGE

	 	 	 

	 	 	Cardiome Pharma Corp announced the appointment of Dr. Charles Fisher to the
position of Chief Medical Officer and Executive Vice President, Clinical and
Regulatory Affairs.

	 	 	 

	Item 5.
	 	FULL DESCRIPTION OF MATERIAL CHANGE

	 	 	 

	 	 	See attached press release.

	 	 	 

	Item 6.
	 	RELIANCE ON SECTION 85(2) OF THE SECURITIES ACT (BRITISH COLUMBIA)

AND EQUIVALENT LEGISLATION OF OTHER JURISDICTIONS

	 	 	 

	 	 	Not Applicable.

	 	 	 

	Item 7.
	 	OMITTED INFORMATION

	 	 	 

	 	 	Not Applicable.

	 	 	 

	Item 8.
	 	SENIOR OFFICER

	 	 	 

	 	 	Name:             Christina Yip

	 	 	Title:               Vice President, Finance and Administration

	 	 	Phone No.:      604-677-6905

	 	 	 

	Item 9.
	 	STATEMENT OF SENIOR OFFICER

	 	 	 

	 	 	The foregoing accurately discloses the material change referred to herein.

	 	 	 

Dated at Vancouver, British Columbia, this 27th day of January, 2005.

 

	 	 	 	 	 
	 	CARDIOME PHARMA CORP.

 	 
	 	Per:	 	
 	 
	 	 	 	Christina Yip, 	 
	 	 	 	Vice President, Finance and Administration 	 
	 

IT IS AN OFFENCE FOR A PERSON TO MAKE A STATEMENT IN A DOCUMENT REQUIRED TO BE FILED OR FURNISHED
UNDER THE ACT OR THIS REGULATION THAT, AT THE TIME AND IN THE LIGHT OF THE CIRCUMSTANCES UNDER
WHICH IT IS MADE, IS A MISREPRESENTATION.

 

FOR IMMEDIATE RELEASE      NASDAQ: CRME      TSX: COM

CARDIOME APPOINTS DR. CHARLES FISHER AS CHIEF

MEDICAL OFFICER AND EXECUTIVE VICE PRESIDENT

Vancouver, Canada, January 27, 2005 Cardiome Pharma Corp (NASDAQ: CRME) (TSX: COM) today
announced the appointment of Dr. Charles Fisher to the position of Chief Medical Officer and
Executive Vice President, Clinical and Regulatory Affairs. Dr. Fisher will be responsible for
overseeing and implementing Cardiome’s clinical and regulatory programs and contributing to new
product development.

Dr. Fisher has over 20 years of experience in clinical research trials and Phase 1 to 4 drug
development. He was most recently Divisional Vice President of Global Pharmaceutical Development,
Abbott Laboratories, responsible for the global development of pharmaceuticals, biologics and drug
coated medical devices. While at Abbott Laboratories, he oversaw the development and FDA approval
of Humira for the treatment of rheumatoid arthritis. Prior to Abbott Laboratories, he was an
Executive Director and Clinical Research Fellow at Eli Lilly & Co. During his time with Eli Lilly,
he was responsible for developing business strategy for critical care, cardiovascular, inflammation
and bioproducts, therapeutics areas, identification of disease state targets, and business
development. Dr. Fisher led the Eli Lilly scientific team in the development and regulatory
approval of Xigris for the treatment of severe sepsis. He was a co-founder of the biopharmaceutical
company Incyte and assisted Ono Pharmaceuticals in achieving Japanese regulatory approval of
Elaspol for the treatment of acute lung injury.

Dr. Fisher is a Fellow of the American College of Physicians, American College of Chest Physicians,
American College of Critical Care Physicians, American College of Emergency Physicians, and the
American Academy of Emergency Medicine. He is also a member of numerous professional societies.

Prior to joining industry, Dr. Fisher had a distinguished career as Professor and Head, Critical
Care Medicine at the Cleveland Clinic Foundation. He is renowned as an international thought leader
in sepsis and is an invited speaker at international conferences. He has personally designed,
conducted and executed over 20 clinical trials as Principle Investigator. He scientifically
championed molecules, met with the US and European regulatory authorities, conducted investigator
meetings, sat on numerous scientific and advisory boards; and participated in various clinical
research groups. He has authored 88 peer-reviewed manuscripts and has been a reviewer for 14
journals. He has been issued four patents in the US, two in the EU, and has five patents pending.

Dr. Fisher obtained his MD in 1973 from Michigan State University. He completed his internship and
residency at the University of California, UC Davis Medical Center and fellowship training at the
University of Manitoba. From 1977-1997 Dr. Fisher held various Professorship and Directorship
positions at The University of Manitoba, the University of
California, Davis Medical Center, Case Western University and the Cleveland Clinic Foundation.

About Cardiome Pharma Corp.

Cardiome Pharma Corp. is a product-focused cardiovascular drug development company with three
clinical drug programs, two of which focus on atrial arrhythmia (intravenous and oral dosing) and
one directed at congestive heart failure.

Cardiome’s lead anti-arrhythmic product, RSD1235, is designed to be an acute-use, intravenous (IV)
administration treatment for termination of atrial fibrillation (AF) and a chronic-use oral drug
for the maintenance of normal heart rhythm following termination of AF. RSD1235 selectively blocks
ion channels in the heart that are known to be active during episodes of AF. Cardiome reported
Phase 3 results for IV RSD1235 in December 2004. Of the 237 patients with recent-onset atrial
fibrillation (AF), 52% of those receiving an IV dose of RSD1235 converted to normal heart rhythm,
as compared to 4% of placebo patients (p< .001). There were no cases of drug-related

 

“Torsades de Pointes”. Controlled-release oral formulations of RSD1235 are currently being evaluated in Phase
1 clinical trials.

Cardiome’s lead drug in the congestive heart failure (CHF) area is oxypurinol, a xanthine oxidase
inhibitor. CHF is the failure of the heart to pump blood at a rate sufficient to support the body’s
needs. Oxypurinol is currently in a Phase 2 clinical trial that will evaluate the safety and
effectiveness of oxypurinol in the treatment of patients with moderate to severe symptomatic CHF.

Cardiome is traded on the Toronto Stock Exchange (COM) and the NASDAQ National Market (CRME).
Further information about Cardiome can be found at www.cardiome.com.

For Further Information:

Don Graham

Director of Corporate Communication

(604) 676-6963 or Toll Free: 1-800-330-9928

Email: dgraham@cardiome.com

Forward-Looking Statement Disclaimer

Statements contained in this news release relating to future results, events and expectation are
forward-looking statements within the meaning of the United States Private Securities Litigation
Reform Act of 1995. These forward-looking statements involve known and unknown risks, uncertainties
and other factors which may cause the actual results, performance or achievement of the company, or
industry results, to be materially different from any future results, performance or achievements
expressed or implied by such statements. Such factors include, among others, those described in the
Company’s annual report on Form 40-F. The Toronto Stock Exchange has not reviewed and does not
accept responsibility for the adequacy or accuracy of this release.exv4w3

 

Exhibit 4.3

FORM 53-901F

SECURITIES ACT

MATERIAL CHANGE REPORT UNDER

SECTION 85(1) OF THE SECURITIES ACT (BRITISH COLUMBIA)

AND EQUIVALENT LEGISLATION OF OTHER JURISDICTIONS

	 	 	 
	Item 1.
	 	REPORTING ISSUER

	 
	 	 

	 	 	Cardiome Pharma Corp.

6190 Agronomy Road, 6th Floor

Vancouver, BC V6T 1Z3

	 
	 	 

	Item 2.
	 	DATE OF MATERIAL CHANGE

	 
	 	 

	 	 	February 4, 2005

	 
	 	 

	Item 3.
	 	PRESS RELEASE

	 
	 	 

	 	 	February 4, 2005 — Vancouver, British Columbia

	 
	 	 

	Item 4.
	 	SUMMARY OF MATERIAL CHANGE

	 
	 	 

	 	 	Cardiome Pharma Corp announced additional results from their recently completed 416-patial atrial
arrhythmia (“AF”) clinical study, called ACT 1.

	 
	 	 

	Item 5.
	 	FULL DESCRIPTION OF MATERIAL CHANGE

	 
	 	 

	 	 	See attached press release.

	 
	 	 

	Item 6.
	 	RELIANCE ON SECTION 85(2) OF THE SECURITIES ACT (BRITISH COLUMBIA) AND EQUIVALENT

LEGISLATION OF OTHER JURISDICTIONS

	 
	 	 

	 	 	Not Applicable.

	 
	 	 

	Item 7.
	 	OMITTED INFORMATION

	 
	 	 

	 	 	Not Applicable.

	 
	 	 

	Item 8.
	 	SENIOR OFFICER

	 
	 	 

	 	 	Name:              Christina Yip

	 	 	Title:                Vice President, Finance and Administration

	 	 	Phone No.:       604-677-6905

	 
	 	 

	Item 9.
	 	STATEMENT OF SENIOR OFFICER

	 
	 	 

	 	 	The foregoing accurately discloses the material change referred to herein.

 

 

Dated at Vancouver, British Columbia, this 4th day of February, 2005.

	 	 	 	 	 
	 	CARDIOME PHARMA CORP.

 	 
	 	Per:	 	
	 	 	 	Christina Yip,	 
	 	 	 	Vice President, Finance and Administration 	 
	 

IT IS AN OFFENCE FOR A PERSON TO MAKE A STATEMENT IN A DOCUMENT REQUIRED TO BE FILED OR FURNISHED
UNDER THE ACT OR THIS REGULATION THAT, AT THE TIME AND IN THE LIGHT OF THE CIRCUMSTANCES UNDER
WHICH IT IS MADE, IS A MISREPRESENTATION.

 

 

FOR IMMEDIATE RELEASE      NASDAQ: CRME      TSX: COM

CARDIOME REPORTS ADDITIONAL ACT 1 CLINICAL RESULTS

Vancouver, Canada, and Deerfield, IL, USA, February 4th, 2005 Cardiome Pharma Corp
(NASDAQ: CRME) (TSX: COM) and its co-development partner Fujisawa Healthcare, Inc. today announced
additional results from their recently completed 416-patient atrial arrhythmia (“AF”) clinical
study, called ACT 1. Top-line results for ACT 1 were announced on December 20, 2004, showing that
the drug converted 52% of recent-onset patients to normal heart rhythm, while causing no
side-effect arrhythmias. Data released today covered three aspects of the clinical data that were
not available at the time of the announcement in December: the time to conversion, the rate of
relapse to AF, and the conversion rate in the atrial flutter sub-group.

In the recent-onset AF patients dosed with intravenous RSD1235 who converted to normal heart
rhythm, the median time to conversion was 11 minutes from the initiation of dosing. This study
result correlates very closely with the data from Cardiome’s CRAFT Phase 2 study where the mean
time to conversion was 11 minutes from the initiation of dosing.

Of those recent-onset AF patients dosed with RSD1235 who converted to normal heart rhythm within 90
minutes of the initiation of dosing, 1 of 75 patients relapsed to atrial arrhythmia within 24
hours. This relapse rate also compares well with the earlier data from the CRAFT Phase 2 study,
where 0 of 11 RSD1235-dosed patients who met the primary endpoint reverted back to atrial
fibrillation within 24 hours.

RSD1235 appears to be ineffective in converting atrial flutter patients to normal heart rhythm.
Only 1 of 39 patients dosed with RSD1235 converted to normal heart rhythm, while 0 of 15 placebo
patients converted to normal heart rhythm. In the 30 day interval following treatment
administration, serious adverse events occurred in 27% of placebo patients and 18% of drug group
patients. Potentially drug-related serious adverse events occurred in 0 placebo patients and in 2
patients receiving RSD1235. Patients with atrial flutter account for approximately 8% of the 2.4
million patients with atrial arrhythmia.1

In October 2003, Cardiome licensed North American rights to the intravenous formulation of
RSD1235 to Fujisawa Healthcare, Inc. Cardiome retains worldwide rights to oral RSD1235 for the
prevention of AF recurrence and all rights to the intravenous formulations outside of Canada, US
and Mexico. Intravenous RSD1235 is currently being evaluated in two further Phase 3 clinical
trials, entitled ACT 2 and ACT 3.

Cardiome has now begun clinical testing of an oral formulation of RSD1235, for potential
prophylactic treatment of AF patients who have been returned to normal heart rhythm. Cardiome owns
unencumbered world-wide rights to such an application of RSD1235.

AF is an arrhythmia (erratic heartbeat) of the upper storage chambers of the heart. The disease is
caused by irregular electrical impulses that regulate the heart’s rate and rhythm. AF
is often associated with other forms of heart disease and is a leading contributor to stroke,
congestive heart failure and sudden cardiac arrest. In 1999 there were 6.2 million cases of atrial
arrhythmia in the developed world. The worldwide market for drugs to treat atrial fibrillation, the
main category of atrial arrhythmia, was US$1.16 billion in 1999, with approximately $800 million of
this in the US alone. Currently available drugs to acutely treat AF lack sufficient efficacy and
have serious safety risks. These safety issues include risk of drug induced pro-arrhythmia and
other cardiac liabilities. Market growth will be driven by an aging population and safer
alternatives such as RSD1235.

	1	 	National Hospital Discharge Survey, 1999

 

 

Conference Call Notification

Cardiome will hold a teleconference and webcast today to discuss the results. The conference call
will be held at 1:00 p.m. EST (10:00 a.m. PST), please dial 1-877-461-2815 or 416-695-5261 to
access the call. There will be a separate dial-in line for analysts on which we will respond to
questions at the end of the presentation. The webcast can be accessed through the “What’s New”
section of Cardiome’s website at http://www.cardiome.com/new/index.php.

About Cardiome Pharma Corp.

Cardiome Pharma Corp. is a product-focused cardiovascular drug development company with three
clinical drug programs, two of which focus on atrial arrhythmia (intravenous and oral dosing) and
one directed at congestive heart failure.

Cardiome’s lead anti-arrhythmic product, RSD1235, is designed to be an acute-use, intravenous (IV)
administration treatment for termination of atrial fibrillation (AF) and a chronic-use oral drug
for the maintenance of normal heart rhythm following termination of AF. RSD1235 selectively blocks
ion channels in the heart that are known to be active during episodes of AF. Controlled-release
oral formulations of RSD1235 are currently being evaluated in clinical trials.

Cardiome’s lead drug in the congestive heart failure (CHF) area is oxypurinol, a xanthine oxidase
inhibitor. CHF is the failure of the heart to pump blood at a rate sufficient to support the body’s
needs. Oxypurinol is currently in a Phase 2 clinical trial that will evaluate the safety and
effectiveness of oxypurinol in the treatment of patients with moderate to severe symptomatic CHF.

Cardiome is traded on the Toronto Stock Exchange (COM) and the NASDAQ National Market (CRME).
Further information about Cardiome can be found at www.cardiome.com.

About Fujisawa Healthcare, Inc.

Fujisawa Healthcare, Inc., headquartered in Deerfield, Ill., develops, manufactures, and markets
proprietary pharmaceutical products in the United States and abroad. Fujisawa Healthcare, Inc. is a
subsidiary of Fujisawa Pharmaceutical Co., Ltd. based in Osaka, Japan. Fujisawa Pharmaceutical Co.,
Ltd., founded in 1894, is a leading pharmaceutical manufacturer with a major presence in the global
market. Additional information on Fujisawa Healthcare, Inc. and its products can be found on the
Internet at http://www.fujisawa.com. On April 1, 2005, Astellas Pharma Inc. will be created by the
merger of Fujisawa Pharmaceutical Co., Ltd. and Yamanouchi Pharmaceutical Co., Ltd. More
information regarding the formation of Astellas Pharma Inc. can be found at www.astellas.com.

For Further Information:

			
	Don Graham
	 	Maribeth Landwehr
	Cardiome Pharma Corp
	 	Fujisawa Healthcare, Inc.
	Director of Corporate Communication
	 	Manager, Corporate Communications
	(604) 676-6963 or Toll Free: 1-800-330-9928
	 	(847) 317-8988
	Email: dgraham@cardiome.com
	 	E-mail: mailto:maribeth_landwehr@fujisawa.com

Forward-Looking Statement Disclaimer

Statements contained in this news release relating to future results, events and expectation are
forward-looking statements within the meaning of the United States Private Securities Litigation
Reform Act of 1995. These forward-looking statements involve known and unknown risks, uncertainties
and other factors which may cause the actual results, performance or achievement of the company, or
industry results, to be materially different from any future results, performance or achievements
expressed or implied by such statements. Such factors include, among others, those described in the
Company’s annual report on Form 40-F. The Toronto Stock Exchange has not reviewed and does not
accept responsibility for the adequacy or accuracy of this release.

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