Document:

exv4w4

 

Exhibit 4.4

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 11, 2005

	 
	 	 

	Item 3.
	 	PRESS RELEASE

	 
	 	 

	 	 	February 11,
2005 – Vancouver, British Columbia

	 
	 	 

	Item 4.
	 	SUMMARY OF MATERIAL CHANGE

	 
	 	 

	 	 	Cardiome Pharma Corp announced results for the physician-sponsored “La Plata” clinical study for
oxypurinol in congestive heart failure (CHF) patients.

	 
	 	 

	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 11th 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 OXYPURINOL CLINICAL RESULTS

Vancouver, Canada, February 11, 2005 Cardiome Pharma Corp. (NASDAQ: CRME) (TSX: COM) today
announced results for the physician-sponsored “La Plata” clinical study for oxypurinol in
congestive heart failure (CHF) patients. The blinded, placebo-controlled 60-patient study showed a
statistically-significant improvement in an important measurement of cardiac function, the left
ventricle ejection fraction (LVEF).

The randomized, double-blind, placebo controlled trial involved 28 days of oral dosing of
oxypurinol in CHF patients with LVEF < 40% and class II-III CHF as rated by the New York Heart
Association classification system. The trial enrolled a total of 60 patients, of whom 47 met the
entry criteria. The remaining 13 patients enrolled had LVEF exceeding 40%, as measured by blinded
reading of echocardiograms upon completion of the study.

Following 28 days of oral daily dosing (600 mg/day), LVEF increased by 6.8% (p=0.017) relative to
placebo in the 47 patients who met the prospectively-defined entry criteria. The 6.8% average
absolute improvement over placebo represented an average relative increase in cardiac output of
22.6% for the patients receiving oxypurinol. Decreases in serum uric acid of 17.0 mg/L (p<
0.001) relative to placebo, were also demonstrated in patients who met the entry criteria (n=47).
Improvement in the 6 minute walk was seen in both treatment groups. However no statistically
significant difference between the two groups was observed. No safety concerns were noted.

“The large physiological effect of oxypurinol demonstrated in this study further confirms our
confidence in this program.” stated Dr. Charles Fisher, Cardiome’s Chief Medical Officer. “We are
especially encouraged that the observed improvement compares well with existing therapeutic
alternatives such as beta-blockers and cardiac resynchronization.”

Interim results for this study were presented at a satellite symposium to the Heart Failure Society
of America’s annual meeting in September 2004. Cardiome is also currently conducting a phase 2
study (called OPT-CHF) testing the benefit of six months of daily dosing of oxypurinol (600 mg/day)
on clinical outcomes of 400 heart failure patients. The last patient was enrolled in OPT-CHF in
December of 2004. Results of the OPT-CHF study are expected to be released in the third quarter of
2005.

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.exv4w5

 

Exhibit 4.5

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 23, 2005

	 
	 	 

	Item 3.
	 	PRESS RELEASE

	 
	 	 

	 	 	February 23, 2005 — Vancouver, British Columbia

	 
	 	 

	Item 4.
	 	SUMMARY OF MATERIAL CHANGE

	 
	 	 

	 	 	Cardiome Pharma Corp announced that it has received a US$6 million milestone payment from its
codevelopment partner, Fujisawa Healthcare Inc.

	 
	 	 

	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 23rd 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 RECEIVES US$6 MILLION MILESTONE PAYMENT

Vancouver, Canada, February 23, 2005 Cardiome Pharma Corp (NASDAQ: CRME) (TSX: COM) today
announced that it has received a US$6 million milestone payment from its co-development partner,
Fujisawa Healthcare Inc. The milestone payment was triggered by the successful completion of ACT 1,
the first of three Phase 3 clinical trials for Cardiome’s lead antiarrhythmic product, intravenous
RSD1235.

Cardiome licensed North American rights to the intravenous formulation of RSD1235 to Fujisawa
Healthcare Inc in October 2003. Cardiome retains worldwide rights to oral RSD1235 for the
prevention of AF and all rights to the intravenous formulations outside of Canada, US and Mexico.
Cardiome may receive an additional US$48 million in milestone payments from Fujisawa over the
course of the agreement, based upon the achievement of certain clinical and commercial milestones.

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.

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