0001125282-01-502091.txt : 20011009
0001125282-01-502091.hdr.sgml : 20011009
ACCESSION NUMBER: 0001125282-01-502091
CONFORMED SUBMISSION TYPE: 8-K
PUBLIC DOCUMENT COUNT: 3
CONFORMED PERIOD OF REPORT: 20011001
ITEM INFORMATION: Financial statements and exhibits
ITEM INFORMATION:
FILED AS OF DATE: 20011001
FILER:
COMPANY DATA:
COMPANY CONFORMED NAME: PROGENICS PHARMACEUTICALS INC
CENTRAL INDEX KEY: 0000835887
STANDARD INDUSTRIAL CLASSIFICATION: PHARMACEUTICAL PREPARATIONS [2834]
IRS NUMBER: 133379479
STATE OF INCORPORATION: DE
FISCAL YEAR END: 1231
FILING VALUES:
FORM TYPE: 8-K
SEC ACT: 1934 Act
SEC FILE NUMBER: 000-23143
FILM NUMBER: 1749175
BUSINESS ADDRESS:
STREET 1: 777 OLD SAW MILL RIVER ROAD
CITY: TARRYTOWN
STATE: NY
ZIP: 10591
BUSINESS PHONE: 9147892800
MAIL ADDRESS:
STREET 1: 777 OLD SAW MILL RIVER ROAD
CITY: TARRYTOWN
STATE: NY
ZIP: 10591
8-K
1
b313950_8k.txt
CURRENT REPORT
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) October 1, 2001
Progenics Pharmaceuticals, Inc.
-------------------------------
(Exact name of registrant as specified in its charter)
Delaware 000-23143 13-3379479
-------- --------- ----------
(State or other jurisdiction (Commission (IRS Employer
of incorporation) File Number) Identification No.)
777 Old Saw Mill River Road, Tarrytown, New York 10591
------------------------------------------------------
(Address of principal executive offices) (Zip Code)
Registrant's telephone number, including area code (914) 789-2800
--------------
--------------------------------------------------------------
(Former name or former address, if changed since last report.)
Item 7. Financial Statements and Exhibits.
(c) Exhibits
99.1 Press release dated October 1, 2001 (filed herewith).
99.2 Question and answer supplement relating to the
October 1, 2001 press release (filed herewith).
Item 9. Regulation FD Disclosure.
On October 1, 2001, Progenics Pharmaceuticals, Inc. issued a
press release announcing that it has entered into an agreement with UR Labs,
Inc. to obtain worldwide exclusive rights to methylnaltrexone. A copy of the
press release is attached as Exhibit 99.1. Attached as Exhibit 99.2 is a
question and answer supplement relating to the subject matter of the press
release.
The information furnished pursuant to Item 9 in this Form 8-K
shall not be deemed to be "filed" for the purposes of Section 18 of the
Securities Exchange Act of 1934 or otherwise subject to the liabilities of that
Section, unless we specifically incorporate it by reference in a document filed
under the Securities Act of 1933 or the Securities Exchange Act of 1934. We
undertake no duty or obligation to publicly update or revise the information
furnished pursuant to Item 9 in this Form 8-K.
SIGNATURES
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 hereunto duly authorized.
PROGENICS PHARMACEUTICALS, INC.
By /s/ PHILIP K. YACHMETZ
------------------------------
Philip K. Yachmetz
General Counsel and Secretary
Date October 1, 2001
---------------
EX-99.1
3
b313950_ex99-1.txt
PRESS RELEASE
[PROGENICS LETTERHEAD]
For Immediate release
Contact: Progenics Pharmaceuticals, Inc.
Richard W. Krawiec, Ph.D.
Vice President, Investor Relations and
Corporate Communications
(914) 789-2800
E-mail: rkrawiec@progenics.com
PROGENICS ACQUIRES DRUG IN LATE-STAGE CLINICAL DEVELOPMENT THAT BLOCKS
DEBILITATING SIDE EFFECTS OF OPIOID PAIN THERAPY
- Phase II trial of methylnaltrexone initiated in cancer patients with
opioid-induced bowel dysfunction -
Tarrytown, NY - October 1, 2001 - Progenics Pharmaceuticals, Inc.
(Nasdaq: PGNX) announced today that it has entered into an agreement with UR
Labs, Inc. to obtain worldwide exclusive rights to methylnaltrexone (MNTX), an
investigational drug in late-stage clinical development that has been shown to
reverse certain side effects of potent opioid pain medications such as morphine.
UR Labs licensed MNTX from the University of Chicago, where it was discovered.
To date, MNTX has been studied in 348 patients and volunteers in over a dozen
clinical trials. Published studies reported that the compound was well tolerated
and highly active in blocking opioid-associated side effects without interfering
with pain palliation. Financial details of the agreement were not disclosed.
Opioids are widely used for analgesia after surgery, traumatic injury,
or to lessen the suffering in terminal illness. To relieve pain, narcotic
medications such as morphine, codeine, and other opioid derivatives interact
with receptors that are located in the brain and spinal cord. Opioids also react
with receptors outside the central nervous system, and undesirable side effects
can result, including constipation, delayed gastric emptying, nausea and
vomiting, pruritis and urinary retention. MNTX is designed to block opioids from
activating the peripheral receptors in the body that cause these side effects.
As MNTX does not cross the blood-brain barrier, it does not interfere with
brain-centered pain relief.
Advanced Phase II studies beginning
Progenics also announced that the University of Chicago Medical Center
has initiated a double-blind, randomized Phase II study evaluating subcutaneous
doses of MNTX in cancer patients for the treatment of opioid-induced
constipation. Constipation is a debilitating complication of pain therapy that
is not adequately treated with laxatives and stool softeners. Progenics intends
to initiate Phase IIb clinical studies of MNTX in opioid-induced constipation
and post-operative bowel dysfunction, and anticipates that Phase III trials of
MNTX will begin in 2002.
"We are pleased to have in-licensed methylnaltrexone, a compound that
we believe will be an important new medicine for treating the serious side
effects of pain therapy," said Progenics' President, Ronald J. Prentki.
"Methylnaltrexone is a late-stage product candidate that
Progenics Acquires Methylnaltrexone Page 2
has demonstrated clinical proof of principle and addresses substantial unmet
medical needs. We believe that MNTX may be the first product candidate in our
pipeline to be approved for marketing, and therefore has the potential to create
significant near-term value for our shareholders."
MNTX: Major market opportunity for Progenics
"Many patients are forced to reduce or stop analgesic narcotics and
endure pain rather than experience the severe bowel dysfunction caused by
opioids," said Jonathan Moss, M.D., Ph.D., Professor, Department of Anesthesia
and Critical Care, and Vice Chairman for Research, the University of Chicago
Medical Center. "In our recent clinical study of methylnaltrexone in
opioid-induced constipation, we reported that methylnaltrexone exhibited rapid
onset of activity in reversing the peripheral effects of opioids in virtually
all patients tested. [Yuan, C.S., et al., 2000. JAMA 283: 367-372] We believe
that methylnaltrexone has the potential to make the treatment of pain more
manageable and to improve the quality of patients' lives."
"Experience to date has shown that methylnaltrexone is extremely active
in blocking a wide range of side effects of opioids when administered in either
oral form or by injection," said Robert J. Israel, M.D., Progenics' Vice
President of Medical Affairs. "We plan to develop multiple routes of
administration for methylnaltrexone in order to match the use of this unique
opioid antagonist with patient needs. We believe that methylnaltrexone may have
significant advantages over competing technologies under development because of
its dosing flexibility, rapid onset of action, and potential to antagonize
peripheral opioid receptors both within and outside the gastrointestinal tract."
Opioids are the mainstay of controlling severe pain, with approximately
170 million prescriptions written annually in the U.S. Reversing the peripheral
side effects of pain therapy, while maintaining analgesia, represents a major
treatment dilemma and a large, unmet medical need. Given the extent of MNTX
clinical testing completed to date, the Company is charting a development path
that is designed to achieve rapid initial approval of this compound.
o Among the first indications being pursued is relief of opioid-induced
bowel dysfunction in cancer patients, a group for whom MNTX therapy may
represent an important improvement in their quality of life. The
American Cancer Society estimates that 550,000 deaths occur each year
among cancer patients. Many terminal cancer patients are treated with
opioids for relief of severe pain. Opioid-induced side effects,
particularly severe constipation, are reported in 50% to 70% of cancer
patients taking these analgesics, according to previously published
reports.
o Progenics also plans to develop MNTX for treatment of post-operative
bowel dysfunction, a paralysis of the gastrointestinal tract that
frequently occurs after abdominal surgery and is accompanied by nausea,
vomiting and urinary retention. The Company estimates that annually in
the U.S. more than five million patients are at high risk for
developing post-operative ileus.
o Another opportunity the Company plans to pursue for MNTX is the
reversal of opioid-induced bowel dysfunction in ambulatory patients
with chronic pain, including those suffering from headaches, joint
pain, lower-back pain, sickle-cell disease, fibromyalgia, and other
disorders. Approximately four million patients take opioids for chronic
pain relief, according to a recent national survey conducted for the
American Pain Society and American Academy of Pain Medicine.
Progenics Acquires Methylnaltrexone Page 3
Progenics Pharmaceuticals, Inc., of Tarrytown, NY, is a
biopharmaceutical company focusing on the development and commercialization of
products for the treatment and prevention of viral, cancer, and other
life-threatening diseases. The Company applies its immunological expertise to
develop biopharmaceuticals to fight viral diseases, such as human
immunodeficiency virus (HIV) infections, and cancers, including malignant
melanoma and prostate cancer. The Company has initiated Phase II clinical trials
of its lead HIV product, PRO 542, a viral-entry inhibitor and is in preclinical
development with PRO 140 and other follow-on product candidates in HIV
infection. Progenics' most clinically advanced product, GMK, is a cancer vaccine
in Phase III clinical trials for the treatment of malignant melanoma. MGV, a
therapeutic vaccine for multiple cancers is also in clinical development. The
Company is developing cancer immunotherapies based on PSMA (prostate specific
membrane antigen) technology. Dehydroascorbic acid (DHA) a novel small-molecule
antioxidant is the subject of preclinical studies to treat stroke and other
disorders. The Company is preparing to initiate Phase IIb clinical studies of
methylnaltrexone (MNTX), a compound designed to block the debilitating side
effects of opioid-based analgesics without interfering with pain palliation.
This press release contains forward-looking statements. Any statements
contained herein that are not statements of historical fact may be
forward-looking statements. When the Company uses the words 'anticipates,'
'plans,' 'expects' and similar expressions they are identifying forward-looking
statements. Such forward-looking statements involve risks and uncertainties that
may cause the Company's actual results, performance or achievements to be
materially different from those expressed or implied by forward-looking
statements. Such factors include, among others, the uncertainties associated
with product development, the risk that clinical trials will not commence when
or proceed as planned, the risks and uncertainties associated with dependence
upon the actions of the Company's corporate, academic and other collaborators
and of government regulatory agencies, the risk that products that appear
promising in early clinical trials do not demonstrate efficacy in larger-scale
clinical trials, the uncertainty of future profitability and other factors set
forth more fully in the Company's Annual Report on Form 10-K for the fiscal year
ended December 31, 2000 and other periodic filings with the Securities and
Exchange Commission to which investors are referred for further information. In
particular, the Company cannot assure you that any of their programs will result
in a commercial product. The Company does not have a policy of updating or
revising forward-looking statements, and thus it should not be assumed that the
Company's silence over time means that actual events are bearing out as
expressed or implied in such forward-looking statements.
###
Editor's Note:
Additional information is available at http://www.progenics.com
EX-99.2
4
b313950_ex99-2.txt
Q&A SUPPLEMENT TO THE PRESS RELEASE
[PROGENICS LOGO]
Methylnaltrexone Q&A: Monday, October 1, 2001 1
What is methylnaltrexone?
[DIAGRAM OF METHYLNALTREXONE MOLECULE]
Methylnaltrexone
Mode of Action:
o Methylnaltrexone (MNTX) is a specific peripheral opioid antagonist. It
acts by binding to opioid receptors without activating them, thus
competing with the binding of opioid drugs. MNTX targets mu receptors,
the same receptors targeted by morphine.
o MNTX is a novel derivative of naltrexone, an established drug that
reverses the analgesic effects of morphine, codeine, heroin, and other
opioid analgesics.
o Researchers at the University of Chicago altered naltrexone by
attaching a methyl group to the compound. This modification created a
molecule that has a reduced ability to cross the blood-brain barrier.
The new molecule, methylnaltrexone, is designed to block opioid side
effects in the peripheral tissues of the body without interfering with
ability of opioids to relieve pain via the central nervous system.
Sites of Action:
o Clinical studies have demonstrated that MNTX does not interfere with
morphine's effect on pain, which is centered primarily in the brain,
nor does it cause acute opioid withdrawal symptoms, which also arise in
the brain.(3, 14)
o It is believed that MNTX gains access to opioid receptors located in
the gastrointestinal tract via both direct luminal access and through
the plasma.
o Clinical studies to date support the hypothesis that MNTX reverses
undesirable side effects of opioids by interacting with receptors in
areas of the body both within and outside of the gastrointestinal
tract. For example, activation of opioid receptors located in the
smooth muscle of the bladder is associated with opioid-induced urinary
retention.
[PROGENICS LOGO]
Methylnaltrexone Q&A: Monday, October 1, 2001 2
How does MNTX work?
MNTX has lower lipid solubility compared to naltrexone. This physical property
inhibits its ability to cross the blood-brain barrier and enter the central
nervous system. Lower lipid solubility is achieved by the formation of
quaternary nitrogen wherein an additional methyl group is attached to the
molecule. This confers a net positive charge on the molecule and limits its
ability to diffuse freely through the blood- brain barrier.
|
o The blood-brain | / Base of brain and
barrier (BBB) | Brain / gastrointestinal
separates the brain | Spinal Cord / tract
from other | o Pain Relief / o Nausea and
structures | o Respiratory / Vomiting
| depresssion /
o Morphine affects | / Lungs
receptors on both | / o Cough
sides of the BBB | / Suppression
| /
o Naltrexone blocks | / Gastrointestinal
morphine on both | / tract
sides of the BBB | / o Constipation
| /
o Methylnaltrexone | Blood-Brain Barrier Urinary tract
blocks morphine on | / o Urinary Retention
one side of the BBB | /
|
What side effects of opioid pain therapy does MNTX have the potential to treat?
o Constipation is the most common side effect of opioid use. Opioid-induced
constipation is not effectively treated with laxatives or stool softeners.
Therefore, MNTX has the potential to be an important drug in patients who
require chronic opioid therapy and find constipation to be a dose-limiting
side effect. Relief of constipation may be especially important in the
palliative care arena, where patients are on increasing doses of opioids
and have few analgesic alternatives. In clinical studies, single doses of
methylnaltrexone were able to produce a prompt bowel movement in all
subjects suffering opioid-induced constipation, while no subject had a
response to placebo.(3) Research conducted at the University of Chicago
also suggests that MNTX also may have activity in treating forms of
constipation not associated with opioid use.
o Gastrointestinal immobility: The inability to feed patients
post-operatively or in intensive care settings may be aggravated by
opioid-induced decreases in gastric and gut motility. This immobility may
delay recovery and hospital discharge or increase the likelihood of
bacterial transmigration of the gut and sepsis. MNTX may have utility in
the treatment of post-operative ileus, a form of bowel paralysis that
often occurs after major surgical procedures including those of the chest,
pelvis and abdomen. Endogenous opioids are thought to be released during
such surgery, resulting in activation of receptors in the gastrointestinal
tract and resultant gut paralysis. Post-operative bowel dysfunction is
further exacerbated if the patient receives opioids for pain relief.
Patients suffering post-surgical ileus are often delayed in their
discharge from the hospital until normal bowel function returns. In many
[PROGENICS LOGO]
Methylnaltrexone Q&A: Monday, October 1, 2001 3
patients, it take five days or more for gastrointestinal function to
return, during which period patients are severely limited in their ability
to eat, drink, or take oral medication.
o Nausea and vomiting are commonly experienced in patients treated with
opioids, and these side effects are exacerbated in the post-operative
setting. Methylnaltrexone has demonstrated efficacy in an animal model of
opioid-induced emesis.
o Urinary retention is a complication of opioid therapy that often requires
patients, particularly males, to be catheterized, especially
post-operatively. An effective peripheral opioid antagonist has the
potential to reduce or eliminate the need for catheterization and permit
patients to leave the hospital sooner, enhancing their quality of life and
lowering medical costs.
o Pruritis is an itching sensation experienced by many patients who receive
opioid therapy and is a debilitating and extremely troublesome side
effect. In a clinical study, MNTX reduced both the undesirable
psychological effects and pruritis associated with opioid use.(8)
o Because of its systemic distribution within the body, MNTX may also
provide relief for other side effects associated with opioid therapy,
including undesired cough suppression, myoclonus (twitching), and biliary
spasm.
What are the most important patient populations in which MNTX might have
clinical utility?
Opioids are the mainstay of controlling moderate and severe pain, with
approximately 170 million prescriptions written annually in the U.S. Side
effects of opioid therapy are a major dilemma and represent a large, unmet need
for treatment regimens that would reverse the peripheral side effects while
maintaining pain palliation. Progenics plans to conduct a broad development
program designed to demonstrate the clinical benefits offered by MNTX in several
patient populations which have been selected based on consideration of market
potential and medical need.
o Malignant pain: Among the first indications being pursued is relief of
opioid-induced bowel dysfunction in cancer patients, a group for whom MNTX
therapy may represent an important improvement in their quality of life.
The American Cancer Society estimates that 550,000 deaths occur each year
among cancer patients. Many terminal cancer patients are treated with
opioids for relief of severe pain. Opioid-induced side effects,
particularly severe constipation, are reported in 50% to 70% of cancer
patients taking these analgesics, according to previously published
reports.
o Post-operative bowel dysfunction: Progenics also plans to develop MNTX for
treatment of post-operative bowel dysfunction, a paralysis of the
gastrointestinal tract that frequently occurs after abdominal surgery and
is accompanied by nausea, vomiting and urinary retention. The Company
estimates that annually in the U.S. more than five million patients are at
high risk for developing post-operative ileus.
o Chronic pain, ambulatory patients: Another opportunity the Company plans
to pursue for MNTX is the reversal of opioid-induced bowel dysfunction in
ambulatory patients with chronic pain, including those suffering from
headaches, joint pain, lower-back pain, sickle-cell disease, fibromyalgia,
and other disorders. Approximately four million patients take opioids for
chronic pain relief, according to a recent national survey conducted for
the American Pain Society and American Academy of Pain Medicine.
[PROGENICS LOGO]
Methylnaltrexone Q&A: Monday, October 1, 2001 4
What potential advantages does MNTX have over existing and future medications?
o Today, there are no peripherally acting opioid antagonists approved for
marketing.
o Current treatment for opioid-induced constipation consists primarily of
over-the-counter laxatives and stool softeners, which are marginally
effective and may take days to act.
o In clinical studies, parenteral MNTX has exhibited a rapid onset of
action in reversing the peripheral side effects of opioids, often
within minutes of administration.
o To date MNTX has not caused any serious side effects at low doses that
are known to be associated with clinical activity.
o Unlike naltrexone, a drug sometimes used for the treatment of opioid
side effects, MNTX does not cross the blood-brain barrier, therefore it
does not reverse the analgesic effect of opioids in the central nervous
system. MNTX has not caused withdrawal in chronic opioid users,
whereas, naltrexone does cause withdrawal.
o MNTX has the potential to be formulated in a variety of dosing forms,
including oral, enteric coated, subcutaneous, and intravenous, each of
which may have specific patient benefits. Parenteral administration of
MNTX may be a preferred dosing form in patients:
o where rapid onset of action is desired
o in indications where oral administration is difficult, e.g.,
post-surgical patients, terminal cancer patients
o Adolor Corporation's compound ADL 8-2698, which is in Phase III
development, is only available as an oral opioid antagonist. Its
developer notes that the compound works only locally in the
gastrointestinal tract.
o MNTX is believed to target receptors both within and outside the
gastrointestinal tract. In addition to the potential of reversing the
gastrointestinal side effects of opioid therapy, MNTX may offer
benefits in treating other systemic opioid side effects, such as
urinary retention and pruritis.
What is the intellectual property position for MNTX?
The Company has acquired exclusive rights to issued US patents relating to MNTX
and its use to prevent or treat opioid-induced side effects. Additional patent
applications are pending in the U.S. and foreign countries.
How is MNTX manufactured and who will manufacture it for Progenics?
MNTX is made via a synthetic process by a well-established pharmaceutical drug
supplier who currently manufactures MNTX under current Good Manufacturing
Practices.
Will Progenics develop this internally or will the company seek a corporate
partner?
Progenics plans to complete the clinical development of MNTX itself; thereafter,
it may contemplate taking on a pharmaceutical or biotechnology partner to
provide financial support and marketing expertise, particularly outside the U.S.
market.
Since narcotics and MNTX affect the same receptors, is there any potential for
abuse of MNTX?
Narcotics agonize or activate opioid receptors within the central nervous system
(CNS), whereas MNTX antagonizes or blocks opioid receptors outside the CNS.
Importantly, MNTX has the potential to eliminate the debilitating side effects
of methadone, an opioid-based medication used to wean drug abusers from heroin,
and therefore may encourage addicts to remain on treatment programs by improving
their quality of life.
[PROGENICS LOGO]
Methylnaltrexone Q&A: Monday, October 1, 2001 5
Why did Progenics acquire MNTX?
Progenics believes that MNTX meets key criteria for development as a
pharmaceutical agent and potentially has important advantages over competing
technology in development.
o There is a large unmet need for a safe and effective product for the
treatment of opioid-induced side effects. The Company believes that
MNTX has a significant market potential.
o MNTX has demonstrated significant activity in a series of clinical
studies.(4)
o MNTX has exhibited an excellent safety profile to date, and matches the
Company's focus for developing therapies which potentially produce
little or no toxicity.
o Currently, there are no peripheral opioid antagonists approved for
marketing. The only other peripheral opioid antagonist in development
is available only as an oral formulation that does not affect receptors
outside the gastrointestinal tract.
o The Company believes that MNTX may have important advantages because of
its flexibility in mode of administration, rapid onset of action, and
potentially wide therapeutic window.
o Given the significant number of clinical trials already completed,
Progenics will enter MNTX directly into advanced Phase II trials. The
Company has created a development plan that provides a clear and timely
path to registration and marketing. Progenics believes that MNTX is an
important near-term product opportunity for the Company.
o Progenics has experience within the cancer and HIV communities via its
research and development programs. Terminally ill cancer and AIDS
patients are major users of opioids for pain palliation.
What are the milestones in the MNTX program that we can expect over the next 12
months?
The Company plans to aggressively develop MNTX and has announced plans to
initiate Phase IIb clinical studies in 2001. These trials are intended to
finalize MNTX dosing parameters in preparation for multiple Phase III trials
that are planned for 2002. The University of Chicago has also initiated
additional clinical studies of MNTX.
How will the MNTX development program affect the Company's burn rate?
Given the significant clinical and product development that has been completed
and manufacturing processes that are currently in place, we believe that Phase
III clinical development of MNTX has the potential to be completed in a timely
manner and at relatively modest cost.
How do you anticipate pricing MNTX, given that current laxatives, diuretics, and
anti-emetics are relatively inexpensive?
The debilitating side effects of opioids represent a serious problem for
patients in terms of their health and quality of life. Currently available
therapies including laxatives, stool softeners and anti-emetics are inadequate
to treat or prevent the side effects. The Company believes that MNTX can be
priced at a premium to existing medications for palliative care. Cost of therapy
may be comparable to that of anti-emetic therapies such as Kytril(R) and
Zofran(R).
What role will the University of Chicago play in the development of MNTX?
Given the extensive involvement of researchers at the University of Chicago in
the development and clinical testing of MNTX, the Company envisions working with
them as scientific advisors and consultants, and where appropriate, having them
continue to participate in the advanced clinical testing of MNTX. We have also
identified other leading experts in the areas of surgical, chronic, and
malignant pain to further assist and guide the Company in completing its
development programs.
[PROGENICS LOGO]
Methylnaltrexone Q&A: Monday, October 1, 2001 6
What percentage of cancer patients who use opioids experience side effects?
Various studies support the Company's belief that there is a large unmet medical
need for an effective opioid antagonist that can reverse the side effects of
opioid therapy while maintaining analgesia. Selected data regarding the use of
opioids in cancer care and their side effects are present in the table below.
Occurrence of opioid induced side effects
------------------------------------------------------------------------- ------------------------------------------
Occurrence side effects Reference
------------------------------------------------------------------------- ------------------------------------------
Cancer patients: Schug, S. et al. 1992, A Long-Term
o 51% required morphine Survey of Morphine in Cancer Pain
o 35 days average duration of morphine treatment Patients, J. Pain Symptom Management,
o 56% treated as outpatients 7(5): 259-266.
o 44% treated as inpatients
o 70% used laxatives on days with morphine
o 58% used anti-emetics on days with morphine
------------------------------------------------------------------------- ------------------------------------------
In patients receiving oral morphine for cancer pain, the following Cherney, N, 2001, Strategies to Manage
side effects were reported: the Adverse Effects of Oral Morphine: An
o Nausea and vomiting: 15% to 30% Event-Based Report, J. Clin. Oncology,
o Constipation: 40% to 70% 19 (9) 2542-25454.
o Myoclonus (twitching): 63%
o Pruritis (itching): 2% to 10%
------------------------------------------------------------------------- ------------------------------------------
o 69% of advanced cancer patients report pain Walsh, T.D., 1984, Oral Morphine in
o 36% nausea/vomiting Chronic Cancer Pain, Pain 18: 1-11.
o 45% have constipation, most common side effect of morphine
------------------------------------------------------------------------- ------------------------------------------
o 70% of advanced cancer patients report pain as a major symptom Beckwith, S.K. and Cole, B.E., 1998,
o 30% report pain as severe to excruciating Hospice, Cancer Pain Management, and
o Major complication of opioid analgesia therapy in cancer Symptom Control, CRC Press.
patients is constipation
o Constipation can lead to
o intractable nausea
o vomiting
o abdominal discomfort
o bowel perforation
o emotional distress
------------------------------------------------------------------------- ------------------------------------------
o Constipation is the most common problem in management of Cherny, N.I., 2000. The Management of
cancer pain. Cancer Pain, CA--A Journal for
o 10% to 40% nausea Clinicians, 50: (2) 70-116
o 15% to 40% vomiting
------------------------------------------------------------------------- ------------------------------------------
o 40% of patients at palliative care centers report constipation Glare, P. and J.N. Lickless 1992,
o 90% (70% severe) of patients treated with morphine report Unrecognized Constipation in Patients
constipation with Advanced Cancer: A recipe for
Therapeutic Disaster, J. Pain Symptom
Management, 7: (6) 369-371
------------------------------------------------------------------------- ------------------------------------------
o 37 to 51% of cancer patients are on opioids Cleeland, et al. 2000, Assessing Symptom
o 19% of cancer patients taking opioids had severe constipation Distress in Cancer Patients, Cancer 89:
o 32% of cancer patients have severe to moderate constipation 1634-1646.
------------------------------------------------------------------------- ------------------------------------------
[PROGENICS LOGO]
Methylnaltrexone Q&A: Monday, October 1, 2001 7
How large a market does MNTX therapy potentially address?
------------------------------------------------------- ----------------------------------------------------
Patient Type and Prevalence Reference
------------------------------------------------------- ----------------------------------------------------
Opioid use IMS data LTM 2Q01
170 million prescriptions are written annually in
the US for opioids.
------------------------------------------------------- ----------------------------------------------------
Chronic pain (ambulatory) "Chronic Pain in America: Roadblocks to Relief,"
o Moderate to severe pain that lasts six January 1999 report, survey conducted Roper Starch
months or more afflicts 25 million people, Worldwide, Inc. for the American Pain Society and
or about 9% of the US population (excluding American Academy of Pain Medicine
cancer pain)
o 16% or 4 million of these individuals are
taking opioid analgesics
------------------------------------------------------- ----------------------------------------------------
Malignant pain American Cancer Society Estimates, Jan/Feb 2001
Estimated 550,000 cancer patients will die in 2001
majority will experience moderate to severe pain
------------------------------------------------------- ----------------------------------------------------
Surgery National Center for Health Statistics, 1999
70 million surgeries International Classification of Diseases, 9th
40 million in-patient Revision
30 million out-patient
------------------------------------------------------- ----------------------------------------------------
High risk for post-surgical ileus Progenics estimate
> 5 million
------------------------------------------------------- ----------------------------------------------------
What has been the clinical experience with MNTX to date?
Safety:
o MNTX has been administered to at least 348 patients and volunteers in a
number of controlled clinical trials.
o No serious adverse effects have been reported with administration of
MNTX at clinically relevant doses. (4)
Maintenance of analgesia:
o MNTX had no measurable effect on morphine-induced analgesia. (3)
o The effect of MNTX on blocking opioid-induced decreases in oral-cecal
transit time in normal subjects has been demonstrated for both
intravenous and oral administration and is dose dependent. (2, 6, 7)
Constipation:
o Ten of 11 patients on a methadone maintenance program and suffering
from opioid-induced constipation experienced an "immediate" laxation
response following administration of MNTX. (3)
o All eleven responded to a second infusion of MNTX on day two.
o None of the 11 patients who received placebo responded.
o No opioid withdrawal was observed in any subject
[PROGENICS LOGO]
Methylnaltrexone Q&A: Monday, October 1, 2001 8
Selected bibliography: Human studies
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1. Yuan, C.S., J.F. Foss 2000 Oral methylnaltrexone for opioid-induced constipation, JAMA
284 (11): 1383-4.
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2. Yuan, C.S., J.F. Foss, M. 2000 Effects of enteric-coated methylnaltrexone in preventing
O'Connor, T. Karrison, J. opioid-induced delay in oral-cecal transit, Clinical
Osinski, M.F. Roizen, Pharmacology & Therapeutics 67(4):398-404.
J. Moss
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3. Yuan, C.S., J.F. Foss, M. 2000 Methylnaltrexone for reversal of constipation due to chronic
O'Connor, J. Osinski, T. methadone use: a randomized control, JAMA 28(3): 367-72.
Karrison, J. Moss, M.F. Roizen
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4. Yuan, C.S., J.F. Foss 2000 Methylnaltrexone: Investigation of Clinical Applications, Drug
Development Research 50: 133-141.
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5. Yuan, C.S. and J.F. Foss 2000 Oral methylnaltrexone for opioid-induced constipation, JAMA
284: 1383-1384.
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6. Yuan, C.S., Foss, J.F., 2000 Effects of enteric coated methylnaltrexone in preventing
O'Connor, M., Karrison, T., opioid-induced delay in oral-cecal transit time, Clinical
Osinski, J., Roizen, M.F. and Pharmacology & Therapeutics 67: 398-404.
Moss, J.
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7. Yuan, C.S., J.F. Foss, 1999 Effects of intravenous methylnaltrexone on opioid-induced gut
M. O'Connor, J. Osinski, M.F. motility and transit time changes in receiving chronic
Roizen, J. Moss methadone therapy: a pilot study, Pain 83(3):631-5.
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8. Yuan, C.S., J.F. Foss, M. 1998 Efficacy of orally administered methylnaltrexone in decreasing
O'Connor, J. Osinski, M.F. subjective effects after intravenous, Drug & Alcohol
Roizen, J. Moss Dependence 52(2):161-5.
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9. Foss, J.F., M.F. O'Connor, et 1997 Safety and tolerance of methylnaltrexone in healthy humans: A
al. randomized, placebo-controlled intravenous, ascending-dose,
pharmacokinetic study, Journal of Clinical Pharmacology 37(1):
25-30.
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10. Murphy, D.B., J.A. Sutton, et 1997 Opioid-induced delay in gastric emptying: a peripheral
al. mechanism in humans, Anesthesiology 87(4): 765-70.
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11. Roscow, C.E. 1997 Methylnaltrexone: reversing the gastrointestinal effects of
opioids [editorial comment], Anesthesiology 87(4): 736-7.
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12. Yuan C.S., J.F. Foss, J. 1997 The safety and efficacy of oral methylnaltrexone in preventing
Osinski, A. Toledano, M.F. morphine-induced delay in oral-cecal time. Clinical
Roizen, J. Moss Pharmacology & Therapeutics 61(4):467-75.
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13. Foss, J.F. M. O'Connor, C.S. 1997 Safety and tolerance of methylnaltrexone in healthy humans: a
Yuan, M. Murphy, J. Moss, M.F. randomized, placebo-controlled, ascending-dose, pharmacokinetic
Roizen study, Journal of Clinical Pharmacology 37(1):25-30.
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14. Yuan, C.S., Foss, J.F., 1996 Methylnaltrexone prevents morphine-induced delay in oral-cecal
O'Connor, M., Toledano, A., transit time without affecting analgesia: a double-blind
Roizen, M.F. and Moss, J. randomized placebo-controlled trial, Clinical Pharmacology &
Therapeutics 59(4): 469-75.
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