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SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15 (d) of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): March 30, 2000
MATRIX PHARMACEUTICAL, INC.
(EXACT NAME OF REGISTRANT AS SPECIFIED IN ITS CHARTER)
Commission file number 0-19750
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DELAWARE 94-2957068
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(STATE OR OTHER JURISDICTION OF (I.R.S. EMPLOYER
INCORPORATION ORGANIZATION) (IDENTIFICATION NUMBER)
34700 CAMPUS DRIVE
FREMONT, CALIFORNIA 94555
(ADDRESS OF PRINCIPAL EXECUTIVE OFFICES)
(510) 742-9900
(REGISTRANT'S TELEPHONE NUMBER, INCLUDING AREA CODE)
Not applicable (Former name of former address, if changed since last report)
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Item 5. Other Events
A. ANNUAL MEETING OF STOCKHOLDERS
In May 2000, the annual meeting of the stockholders of the Company was held and
the following proposals were approved:
/ / Proposal No. 1- Election of the following persons as directors of
the Company: Michael D. Casey, J. Stephan Dolezalek, James R. Glynn,
Stephen B. Howell, Marvin E. Jaffe, Bradley G. Lorimier, and Julius L.
Pericola.
/ / Proposal No. 2 - Approval of an amendment to the Company's
Certificate of Incorporation to increase the number of shares of
Common Stock from 30 million shares to 60 million shares.
/ / Proposal No. 3 - Approval of an amendment to the Company's 1988
restricted Stock Plan ("the Plan") to increase the number of shares of
Common Stock authorized for issuance under the Plan by an additional
1,100,000 shares of Common Stock and extend the term of the Plan
through December 31, 2005.
/ / Proposal No. 4 - Approval of a series of amendments to the Company's
1991 Directors Stock Option Plan (the "Directors Plan") that effected
the following changes: (i) reduce the number of shares of Common Stock
subject to the automatic option grant made to an individual who first
joins the Company's Board of Directors as a non-employee director from
40,0000 to 20,000 shares; (ii) increase the number of shares subject
to the automatic option grant made to an individual upon re-election
to the Company's Board of Directors as a non-employee director from
3,000 to 10,000 shares; (iii) make both the initial and re-election
options immediately vested and exercisable for all the option shares
upon grant and (iv) extend the term of the Directors Plan through
December 31, 2005.
/ / Proposal No. 5 - Ratification of the Corporation's appointment of
Ernst & Young LLP as independent accountants of the Corporation for
the fiscal year ending December 31, 2000.
B. OTHER DEVELOPMENTS SINCE MARCH, 2000
RESULTS OF PIVOTAL PHASE III STUDIES OF INTRADOSE IN HEAD AND NECK CANCER
In May 2000, the Company presented results of two independent, corroborative,
placebo-controlled Phase III clinical studies in head and neck cancer at the
36th annual meeting of the American Society of Clinical Oncology ("ASCO").
Based on the positive results of these studies, the Company also announced
that it expects to submit a New Drug Application ("NDA") for
IntraDose-Registered Trademark- (cisplatin/epinephrine) Injectable Gel
("IntraDose") by the end of the year.
The objectives in both trials were to show that IntraDose therapy is effective
in reducing
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the size of tumors in late stage recurrent or refractory head and neck cancer
patients, and that the tumor response has a benefit to the patient. The results
of the studies show that these objectives were achieved.
The protocols for the two trials were identical except for geographic location,
allowing assessment on both a combined and individual basis. Objective tumor
response was evaluated for the primary target tumor identified by the clinical
investigator prior to treatment. Patient benefit was determined using treatment
goals selected before treatment by both the clinical investigator and the
patient. A total of 178 patients were evaluated.
COMBINED STUDY RESULTS
On an intent-to-treat basis, 29% of patients treated with IntraDose achieved an
objective tumor response versus 2% for placebo, a statistically significant
result (p < 0.001). Twice as many patients achieved complete responses (19%) as
partial responses (10%).
The pre-selected patient benefit goal was attained in 27% of the
IntraDose-treated patients versus 12% of the placebo-treated patients; the
difference was statistically significant (p=0.046). The association of
objective tumor response with attainment of the pre-selected patient goal was
statistically significant (p=0.006); 47% of patients with a tumor response
also achieved their predetermined benefit goal, compared to only 15% of
non-responders. These measurements of patient benefit are based only on the
pre-selected goal and do not reflect other benefits that patients may have
received from treatment.
Side effects of IntraDose therapy were generally limited to injection site
reactions, the most common of which was pain. The systemic side effects normally
associated with systemic cisplatin therapy were infrequent. During early stages
of the trials, four patients experienced cerebrovascular side effects; none
occurred after the protocols were modified to exclude patients with tumors
invading or in close proximity to the carotid artery.
INDIVIDUAL STUDY RESULTS
In the first study, conducted in North America with 86 patients, the objective
tumor response rate was 34% for IntraDose-treated patients versus 0% for
placebo; the difference was statistically significant (p=0.001). The
pre-selected patient benefit was attained in 34% of the IntraDose treated
patients versus 17% of the placebo-treated patients.
In the second study, conducted outside North America with 92 patients, the
objective tumor response rate was 25% for IntraDose-treated patients versus 3%
for placebo; the difference was statistically significant (p=0.007). The
pre-selected patient benefit was attained in 19% of the IntraDose-treated
patients versus 9% of the placebo-treated patients.
STUDY BACKGROUND
The studies included 178 evaluable patients in two Phase III, double-blind,
placebo-controlled Phase III studies (North America -86 patients, ex-North
America -92 patients). Eligible patients were adults (over 18 years) with
recurrent or refractory, histologically
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confirmed head and neck cancer and a primary target tumor volume up to 20 cm3,
who had undergone prior treatment but had not received therapy in the 28 days
prior to treatment in this study. Patients were randomized to receive IntraDose
or placebo (collagen gel) in a 2:1 ratio. Patients were allowed to switch to
unblinded therapy with IntraDose upon evidence of disease progression during the
blinded phase of treatment. For patients with more than one tumor, the primary
analysis of objective tumor response was based on the tumor that was
pre-selected by the clinical investigator as the primary target tumor. Patients
were given up to 6 intratumoral injections within an 8-week time period.
Complete responders experienced 100% tumor shrinkage while partial responders
experienced at least 50% but less than 100% tumor shrinkage. Responses had to be
sustained for 28 or more days.
Patient benefit was determined using treatment goals selected before treatment
by both the clinical investigator and the patient. Patients selected one goal
from eight palliative goals (pain control, obstructive symptoms, mobility,
physical appearance, wound care, ability to hear, ability to smell, or ability
to see) and investigators selected one goal from the eight palliative goals or
three preventative goals (prevention of tumor invasion, obstruction, or
subcutaneous tumors breaking through the skin).
The individual studies were designed to show an absolute difference of 20% to
30% in objective tumor response rate between IntraDose and placebo. The
individual studies were not designed to demonstrate statistical significance in
the patient benefit outcome.
RESULTS OF INTERIM PHASE II RESULTS OF INTRADOSE IN LIVER CANCER
In May 2000, the Company presented updated interim results of an ongoing Phase
II clinical study of patients with primary liver cancer -- or hepatocellular
carcinoma ("HCC") -- who are being treated with IntraDose. Results were
presented at the 36th annual meeting of ASCO in New Orleans and at the American
Association for the Study of Liver Disease ("AASLD") meeting at Digestive
Disease Week in San Diego.
The reported results expand on the presentation of interim results made in
November, 1999 at the 17th Annual Chemotherapy Foundation Symposium in New York
City and include 38 evaluable patients. The endpoints of this study are tumor
response and patient survival.
Overall, 55% (21 of 38) of patients experienced a response to therapy. Of the 21
responders, 9 experienced complete responses (100 percent reduction in viable
tumor volume) while the other 12 responders showed a reduction in viable tumor
of more than 50 percent. Median survival time from the date of study entry was
23 months for patients who responded to IntraDose and 13 months for
non-responders.
Of the 21 responding patients, 12 remain in remission. All of the 9 patients who
initially responded to therapy, but went on to have progressive disease,
experienced disease progression at a new, untreated site in the liver. None of
these patients exhibited disease progression at the treatment site. Of the 17
non-responders, 24% experienced disease progression at the treatment site and
41% progressed with new tumors at an untreated area of the liver.
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The study enrolled patients with biopsy proven and inoperable
hepatocellular carcinoma. Patients must have had three or fewer tumors, each not
exceeding 7 cm in diameter, and no more than 200 cm(3) in total tumor volume.
Patients must also have had adequate liver function. Patient responses are
assessed using imaging techniques to measure the extent of tumor necrosis. The
most frequently observed side effects in this trial to date are local pain,
fever, loss of appetite, nausea, vomiting, and weakness. Infrequently, the
treatment has resulted in bleeding from the tumor or worsening liver function.
The Company has concluded enrollment in the HCC trial and expects to report
final results in 2001 after patient follow-up is complete. Based on reviews with
experts and the FDA, the Company believes that a controlled, Phase III trial
will be required for approval in the U.S. The Company expects to develop a liver
cancer registration strategy after concluding a marketing partnership for
IntraDose.
NEW PATENT
In June 2000, the Company announced it had received a new U.S. patent covering
the composition of IntraDose. This new patent provides broad coverage on
cisplatin suspensions using nonionic surfactants as dispersants/stabilizers, an
integral part of the IntraDose formulation. Patent life extends to October 2015.
Issuance of this patent increases the Company's patent estate to eight issued
U.S. patents and six issued patents in Europe and Japan. In addition, Matrix has
three patents pending in the U.S. and seven in Europe and Japan.
NEW CLINICAL TRIALS INITIATED FOR FMDC
A Phase I/II trial with FMdC in combination with cisplatin has been initiated at
the University of Pennsylvania. After a Phase I dose escalation study to
establish optimum dosing, this combination therapy will be used to treat up to
15 non-small-cell lung cancer patients in the Phase II portion of the study.
FMdC is a new chemical entity in a class of compounds known as nucleoside
analogs that interfere with cell division. FMdC is believed to inhibit DNA
synthesis directly by incorporation into DNA strands and indirectly by blocking
the action of an enzyme, ribonucleotide reductase, which is essential for the
formation of the building blocks of DNA. In combination therapy, use of
DNA-damaging agents such as cisplatin may recruit quiescent cancer cells into
active DNA synthesis and repair, thereby making the cells much more susceptible
to the effects of FMdC.
ORPHAN DRUG STATUS
In April 2000, the U.S. Food and Drug Administration ("FDA") granted orphan drug
status to the Company's cisplatin/epinephrine product candidate for the
treatment of squamous cell carcinoma of the head and neck.
The Orphan Drug Act provides financial incentives to stimulate the development
of drugs for diseases that affect 200,000 people or less in the United States.
In addition to seven years of marketing exclusivity for the designated
indications, orphan drug designation also enables the Company to obtain research
funding, tax credits for certain research
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expenses, and a waiver of the application user fee.
INITIAL SECTIONS OF NDA SUBMITTED TO THE FDA
On March 30, 2000, the Company submitted the pharmacology and toxicology portion
of its IntraDose NDA. In June 2000, the second major portion, encompassing the
chemistry and microbiology sections, was submitted. These initial submissions
were made under provisions of the fast-track designation for IntraDose that
allow for early submission of complete NDA sections prior to submission of the
full NDA.
PRE-CLINICAL DATA ON FMDC
In April 2000, the results of three pre-clinical studies of FMdC, a novel
systemic chemotherapeutic in clinical development as an anti-cancer agent, were
presented at the 91st Annual Meeting of the American Association for Cancer
research ("AACR") held in San Francisco.
The combination of FMdC and cisplatin resulted in apparently synergistic
anti-tumor activity that was significantly greater than the sum of the two
agents used alone in human lung cancer models in vitro and in mice. In
colorectal cancer models, the combination was additive. The combination of FMdC
and 5-FU also showed additive activity in colorectal cell lines.
A third study evaluated resistance of FMdC to cytidine deaminase, an enzyme
found in many cancer cells. This enzyme tends to deactivate nucleoside analogues
and makes cells more resistant to the drugs. In several different cell lines, it
was demonstrated that FMdC is more resistant to cytidine deaminase deactivation
than gemcitabine or cytarabine. Further analysis also suggests, unexpectedly,
that tumor cell lines with higher levels of cytidine deaminase were more
susceptible to FMdC than were cell lines with low enzyme activity. If these
observations hold true in human clinical testing, it would provide important
differentiation of FMdC from other nucleoside analogues.
INTRADOSE MECHANISM OF ACTION PRE-CLINICAL STUDY
In April 2000, the Company presented results of a pre-clinical study indicating
that IntraDose may have a mechanism of anti-cancer action in addition to that of
traditional systemic cisplatin chemotherapy. The data was disclosed at the 91st
Annual Meeting of AACR.
The mode of cytotoxic action of traditional cisplatin chemotherapy given by
intravenous infusion is believed to lead to programmed cell death (apoptosis).
The results of the Matrix pre-clinical study show that the high cisplatin
concentrations achievable with IntraDose induce both apoptotic as well as a more
profound, non-apoptotic cancer cell death in a human hepatocellular carcinoma
cell line in vitro. As cells were exposed to increasing doses of cisplatin,
there was a shift in the mode of cell death from apoptosis to an apparently
different, non-apoptotic pathway. These findings indicate that IntraDose may
induce additional cytotoxic pathways to cell death. As part of this, the high
tumor concentrations of cisplatin achievable with IntraDose may also overcome
the acquired or natural resistance of cells to lower concentrations of the drug.
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C. CERTAIN RELATIONSHIPS AND RELATED TRANSACTIONS
In June 2000, Mr. James R. Glynn resigned from the Company's Board of Directors.
In June 1997, certain officers of the Company including Mr. Glynn, purchased
shares of the Company's Common Stock pursuant to the Shared Investment Program
under the 1988 restricted Stock Option Plan by delivering full-recourse
promissory notes in payment of the purchase price for those shares. Under the
Shared Investment Program, Mr. Glynn purchased 100,000 shares at $6.25 per
share. As of June 29, 2000 the outstanding balance on Mr. Glynn's note was
$761,965.17, including accrued interest. The note is secured by a pledge of the
purchased shares with the Company. The Company expects that the note will be
paid in full by the end of July 2000.
THIS FORM 8-K MAY CONTAIN, IN ADDITION TO HISTORICAL INFORMATION,
FORWARD-LOOKING STATEMENTS, INCLUDING WITHOUT LIMITATION, STATEMENTS REGARDING
THE TIMING AND OUTCOME OF REGULATORY REVIEWS AND CLINICAL TRIALS. ANY SUCH
FORWARD-LOOKING STATEMENTS ARE BASED ON MANAGEMENT'S CURRENT EXPECTATIONS AND
ARE SUBJECT TO A NUMBER OF RISKS AND UNCERTAINTIES SUCH AS NO ASSURANCE OF
REGULATORY APPROVALS; UNCERTAINTIES ASSOCIATED WITH CLINICAL TRIALS; HISTORY OF
LOSSES; FUTURE PROFITABILITY UNCERTAIN; ADDITIONAL FINANCING REQUIREMENTS AND
UNCERTAIN ACCESS TO CAPITAL MARKETS; LIMITED SALES AND MARKETING EXPERIENCE;
LIMITED MANUFACTURING EXPERIENCE; DEPENDENCE ON SOURCES OF SUPPLY; RAPID
TECHNOLOGICAL CHANGE; SUBSTANTIAL COMPETITION; UNCERTAINTY REGARDING PATENTS AND
PROPRIETARY RIGHTS; UNCERTAINTY OF PHARMACEUTICAL PRICING; AND NO ASSURANCE OF
ADEQUATE REIMBURSEMENT. PLEASE SEE THE "RISK FACTORS" SECTION INCLUDED IN FORM
10-K FOR THE YEAR ENDED DECEMBER 31, 1999. THE COMPANY DISCLAIMS, HOWEVER, ANY
INTENT OR OBLIGATION TO UPDATE THESE FORWARD-LOOKING STATEMENTS.
Item 7. FINANCIAL STATEMENTS AND EXHIBITS
(c) EXHIBITS
3(i).1 Amended and Restated Certificate of Incorporation
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SIGNATURE
Pursuant to the requirements of the Securities Exchange Act of 1934, the
registrant has duly caused this report to be signed on its behalf by the
undersigned thereunto duly authorized.
MATRIX PHARMACEUTICAL, INC.
Date: July 10, 2000 By: /s/ David G. Ludvigson
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David G. Ludvigson, Chief Operating
Officer, Chief Financial Officer &
Senior Vice President
Signing on behalf of the registrant
as principal financial officer
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Exhibit Index
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Exhibit Description
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3(i).1 Amended and Restated Certificate of Incorporation
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