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 1934
Date of Report: July 15, 1997
INTERNEURON PHARMACEUTICALS, INC.
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(Exact name of registrant as specified in charter)
DELAWARE
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(State of other jurisdiction of incorporation)
0-18728 043047911
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(Commission File Number) (IRS Employer Identification No.)
One Ledgemont Center, 99 Hayden Avenue, Lexington, Massachusetts 02173
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(Address of principal executive offices) (Zip Code)
Registrant's telephone no. including area code: (617) 861-8444
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ITEM 5. OTHER EVENTS
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On July 15, 1997, Interneuron Pharmaceuticals, Inc. (the "Company")
reported preliminary results of the Company's recently completed Phase 3
clinical trial for citicoline in the treatment of ischemic stroke.
Reference is made to the Company's press release dated July 15, 1997
filed as Exhibit 99.1 hereto and incorporated by reference herein.
ITEM 7. FINANCIAL STATEMENTS, PRO FORMA FINANCIAL INFORMATION AND EXHIBITS
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(c) Exhibits
99.1 Press Release dated July 15, 1997
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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.
INTERNEURON PHARMACEUTICALS INC.
By: /s/ Glenn L. Cooper
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Glenn L. Cooper, M.D.
President and Chief Executive Officer
Dated: July 15, 1997
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CONTACT, AT (617) 402-3410:
GLENN L. COOPER, M.D. WILLIAM B. BONI
PRESIDENT AND CEO VP, CORP. COMMUNICATIONS
INTERNEURON PHASE 3 CITICOLINE
STROKE TRIAL SHOWS SIGNIFICANTLY IMPROVED NEUROLOGICAL
FUNCTION IN PATIENTS WITH MODERATE TO SEVERE STROKES
COMPANY PLANS TO SUBMIT NDA BEFORE END OF YEAR
LEXINGTON, MA, July 15, 1997 - Interneuron Pharmaceuticals, Inc. (NASDAQ: IPIC)
today announced that a preliminary analysis of the company's second Phase 3
trial for oral citicoline 500 milligrams in the treatment of ischemic stroke
showed significantly improved neurological function among patients with moderate
to severe strokes. In addition, the drug was well tolerated.
STUDY DESIGN
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Patients over 18 years old with no upper age limit who met entry criteria were
entered within 24 hours of their stroke in a 2 to 1 randomization to receive
citicoline 500 milligrams or placebo orally once daily for six weeks. Two
hundred sixty-seven patients received citicoline and 127 patients received
placebo. The primary outcome analysis of this double-blind, placebo-controlled
trial of 394 patients was improvement in the Barthel Index, a 100 point rating
scale of functional capabilities in neurological patients, at a time point three
months after an ischemic stroke. Other secondary outcome measures were assessed.
To account for baseline differences in stroke severity, the primary analysis
requires that 3-month Barthel scores be adjusted for stroke severity using the
NIH Stroke Scale.
The NIH stroke scale rates patients from 0 to 42 points for maximum severity.
Patients enrolled in the study were required to have an NIH Stroke Scale score
of 5 or greater. Patients were considered to have achieved complete or
near-complete functional recovery if they achieved a Barthel score of 95 or 100
at three months. Analysis of data was performed on an intent to treat basis with
assessments made using two methods: patients who completed the study and had a
three-month observation point (observed cases, or OC analysis) and patients
whose last recorded scores were carried forward to the 3 month point, regardless
of their study completion (last observation carried forward, or LOCF analysis).
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STUDY RESULTS
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In a responders analysis, 41 percent of citicoline-treated patients with an NIH
stroke scale on entry of greater than or equal to 8 (moderate to severe strokes)
achieved a Barthel Index of greater than or equal to 95 compared to 25 percent
of placebo-treated patients (OC analysis, p = 0.02). Thus, patients with
moderate to severe stroke treated with citicoline had a 64 percent greater
chance of complete or near-complete recovery relative to patients with moderate
to severe stroke treated with placebo. In the LOCF analysis, 33 percent of
moderate to severe citicoline patients and 21 percent of moderate to severe
placebo patients achieved a Barthel Index of greater than or equal to 95, a 57
percent increased chance of improvement in recovery (p = 0.05).
Overall, patients who had mild strokes on entry into the study (NIH Stroke Scale
5 through 7) had an excellent clinical outcome regardless of placebo or
citicoline treatment. For example, approximately 80 percent of patients with
mild strokes who received placebo and a similar percentage of citicoline-treated
patients with mild strokes achieved a Barthel score of greater than or equal to
95 at three months.
There was an unexpected highly significant baseline imbalance in the percentage
of placebo versus citicoline-treated patients who had mild strokes on study
entry (34 percent for placebo vs. 22 percent for citicoline (p = 0.006), due to
chance. The study was influenced by the significant preponderance of mild cases
in the placebo group. As a result of this imbalance and other statistical
factors, the primary analysis of the study, the distribution of Barthel Index
scores in citicoline vs. placebo-treated patients as a function of baseline NIH
Stroke Scale scores, did not achieve statistical significance. However, this
primary analysis was statistically invalid because the patient imbalance and
other statistical factors failed to satisfy the requirements for the correct
operation of the statistical model. Therefore, a protocol-defined responders
analysis, percentage of patients who achieve a Barthel Index greater than or
equal to 95, among patients with moderate to severe strokes, was employed (see
results above).
In another protocol-defined measure of functional clinical outcome, the 6-point
Rankin scale of physician-rated global assessment was utilized. A Rankin score
of 0 or 1 at study completion indicated complete or near-complete lack of
disability. Among patients with moderate to severe strokes, 24 percent of
citicoline-treated patients vs. 11 percent of placebo treated patients achieved
a Rankin score of 0 or 1, a 127 percent improvement in outcome (OC analysis, p =
0.02). In the LOCF analysis, 19 percent of moderate to severe citicoline
patients and 11 percent of moderate to severe placebo patients had a Rankin
scale of 0 or 1, a 73 percent improvement in outcome (p = 0.08).
Other secondary outcome measurements involving the Barthel Index, Rankin and NIH
stroke scales, duration of hospitalization, and neurocognitive ratings have not
yet been analyzed.
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Preliminary safety review indicated that citicoline was well tolerated. There
did not appear to be any medically serious adverse events that differed in
frequency from placebo-treated patients. Minor gastrointestinal complaints,
though relatively infrequent, appear to have occurred more frequently in
citicoline versus placebo treated patients. A previous study indicated an
increased incidence in dizziness and accidental injuries in citicoline-treated
patients. However, in the present trial there did not appear to be any
differences in dizziness or accidental injuries between drug and placebo-treated
patients. The mortality rates for drug-treated and placebo-treated patients were
identical (18 percent in each group).
"We are pleased that this Phase 3 trial of citicoline 500 milligrams has
confirmed the clinical importance of this novel oral medicine in the therapy of
patients with moderate to severe strokes," said Glenn L. Cooper, M.D. president
and CEO of Interneuron. "Stroke is a devastating illness with few treatment
options, causing disability in hundreds of Americans every day. An oral
medication that can be given within 24 hours after a stroke without fear of
serious side-effects could give physicians and patients a welcome new
therapeutic option.
"We believe that we have a strong, persuasive data package upon which to base a
New Drug Application (NDA) with the FDA and intend to file that application
before the end of the year," said Dr. Cooper. "We believe there is a compelling
consistency of positive clinical outcomes using multiple assessment scales in
multiple clinical trials.
"The NDA will include data from our two pivotal U.S. trials, supporting data
from a Japanese clinical trial conducted by Takeda Chemical Industries, Ltd. and
supportive clinical and post-marketing data from more than 20 countries where
citicoline has already been approved for the treatment of stroke," added Dr.
Cooper. "In addition, we continue to expand our clinical database with an
on-going U.S. multi-center pivotal trial exploring reduction in brain infarct
size and functional improvement in citicoline vs. placebo-treated stroke
patients using sophisticated brain imaging techniques. We also plan to initiate
further studies beginning this fall to explore areas such as post-stroke
learning and memory, combination with thrombolytic therapies and other clinical
paradigms such as treatment or prevention of peri-operative strokes and
treatment of head trauma."
Interneuron previously licensed U.S. and Canadian commercialization rights to
citicoline from Grupo Ferrer, a leading Spanish pharmaceutical company which has
marketed citicoline for several years. Ferrer, Takeda and others currently
market citicoline in more than 20 countries. Interneuron retains marketing
rights to citicoline in the U.S. and
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Canada. The use of citicoline to treat a variety of neurological conditions was
discovered by Dr. Richard J. Wurtman, scientific founder of Interneuron and
Cecil H. Green Distinguished Professor at the Massachusetts Institute of
Technology (MIT). The patent is held by MIT. Other use patents are pending.
Interneuron Pharmaceuticals is a diversified biopharmaceutical company engaged
in the development and commercialization of a portfolio of products and product
candidates primarily for neurological and behavioral disorders. Interneuron is
also developing products and technologies, generally outside the central nervous
system field, through four subsidiaries: Intercardia, Inc. focused on
cardiovascular disease; Progenitor, Inc. focused on developmental genomics;
Transcell Technologies, Inc. focused on carbohydrate-based drug discovery; and
InterNutria, Inc. focused on dietary supplement products.
Except for the descriptions of historical facts contained herein, this release
contains forward-looking statements that involve risks and uncertainties, as
detailed from time to time in Interneuron's SEC filings under the Securities Act
of 1933 and the Securities Exchange Act of 1934 under "Risk Factors" and
elsewhere. Actual results could differ materially from those currently
anticipated due to a number of factors including risks relating to the product
commercialization of Redux, such as regulatory, marketing, safety, patent,
product liability, supply and other risks; uncertainties relating to clinical
trials; risks relating to product launches and managing growth; government
regulation, dependence on third parties for clinical development, manufacturing
and marketing, competition and other risks.
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BACKGROUND INFORMATION
REVIEW OF FIRST PIVOTAL STUDY
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Interneuron's initial pivotal study of citicoline in stroke was previously
reported in 1996. Findings from that Phase 3 trial were presented on March 28,
1996 at the 48th Annual Meeting of the American Academy of Neurology and have
been accepted for publication by the journal Neurology.
In that trial, 259 patients with ischemic stroke were enrolled within 24 hours
following the onset of symptoms. The average time from onset of symptoms to
initiation of treatment was approximately 14 hours. Patients were randomly
assigned to receive placebo or one of three oral doses of citicoline (500
milligrams, 1000 milligrams or 2000 milligrams daily) for six weeks and were
monitored for an additional six weeks.
The primary efficacy outcome in the study was improvement in neurological
function, as assessed by the Barthel Index. Among all patients who received 500
milligrams daily of citicoline, 53% achieved a score of greater than or equal to
95 on the Barthel Index at 12 weeks, indicative of complete or near-complete
recovery from stroke, compared with 33% of placebo- treated patients, a 61
percent improvement in outcome (p less than or equal to 0.04). This
significantly greater improvement can also be expressed as the probability that
for every 100 stroke patients treated with 500 milligrams of citicoline within
24 hours of symptom onset, approximately 20 more would achieve complete or
near-complete recovery than if treated with placebo.
As previously reported, patients in both the 500 milligram and 2000 milligram
groups exhibited significantly greater (p less than or equal to 0.05)
improvement on the Barthel Index at week 12 than placebo-treated patients. In
addition, more patients in the 500 milligram and 2000 milligram groups exhibited
normal or near normal scores in mental function (p less than or equal to 0.04),
as measured by the Mini-Mental State Exam, which grades the cognitive state of
patients.
Also, patients who received 500 milligrams of citicoline daily were more than
twice as likely to manifest minimal or no disability at 12 weeks following
stroke as patients who received placebo, as measured by the NIH Stroke Scale.
The NIH Stroke Scale analysis showed that 34% of all citicoline-treated patients
versus 16% of placebo-treated patients achieved complete or near-complete
normalization of function, as indicated by scores 0 to 1, at 12 weeks following
stroke, a 125 percent improvement in outcome (p less than or equal to 0.04).
In addition, global neurologic status, assessed by the Rankin Scale mean scores,
was significantly improved (p less than or equal to 0.04) with citicoline
treatment compared to placebo.
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Efficacy outcome measures for the 1000 milligram daily group did not reach
statistical significance in this trial. Patients in the 1000 milligram group had
higher body weight on baseline entry into the study compared to the other
treatment groups and a significantly higher proportion of chronic pre-existing
cardiac and pulmonary disorders. These confounding variables may explain the
performance of the 1000 milligram group in the trial.
It was also reported that a small subgroup of patients were studied at the Beth
Israel Hospital in Boston with a specialized imaging technique to measure the
size of the infarct, or damage caused by the stroke. Analysis of this group of
patients suggests that citicoline treatment limited the size of infarct
following interrupted blood flow. A larger trial to confirm this finding is in
progress.
There was no significant difference in the incidence of death among the four
treatment groups in the trial. All doses of citicoline were well tolerated, as
indicated by analyses of adverse events and laboratory findings. The only
statistically significant differences among citicoline-treated patients versus
placebo-treated patients were an increase in dizziness and accidental injuries,
e.g., falling down. However, the 500 milligram dose citicoline group did not
significantly differ from the placebo group in these parameters.
Given the degree of effectiveness of the 500 milligram daily dose and the
absence of significant differences in adverse events between this dosage level
and placebo, 500 milligrams daily appears to be the optimal dose derived from
this study and was the dose chosen for the new study reported today.
NEUROCOGNITIVE FINDINGS
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Neuropsychological test findings among patients recovering from ischemic stroke
who participated in the first Phase 3 clinical trial also demonstrated a
significant improvement in the cognitive function of those patients who received
citicoline
The findings, previously presented at the 22nd International Joint Conference on
Stroke and Cerebral Circulation of the American Heart Association on February 8,
1997, demonstrated that patients who were given 500 milligrams of citicoline
within 24 hours following the onset of stroke symptoms and continuously for six
weeks thereafter scored statistically significantly higher on a battery of tests
measuring learning ability and memorization skills than did patients who
received placebo.
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The neurocognitive tests administered in this trial included the Folstein
Mini-Mental State Examination, the Hopkins Verbal Learning Test, Span Tests and
Trailmaking Tests. In all of these tests, patients receiving 500 milligrams of
citicoline daily achieved statistically significantly higher scores than did
placebo patients at time points ranging from three to twelve weeks following
stroke (p less than or equal to 0.05).
TAKEDA LONG-TERM MORTALITY DATA
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On April 7, 1997, Interneuron Pharmaceuticals, Inc. announced a data transfer
pact with Takeda Chemical Industries, Ltd. that provided Interneuron with
primary data from a previously unpublished long-term clinical trial
demonstrating improved functional recovery and reduced mortality among stroke
patients who received citicoline as compared to those who received placebo in a
double-blind fashion.
The Company believes the Takeda clinical trial data will be an important
supportive study to complement Interneuron's two U.S. pivotal trials of
citicoline in ischemic stroke. In the Takeda study, citicoline was given at a
dose of 1000 milligrams per day intravenously for two weeks.
Takeda, which markets citicoline in Japan and other countries, conducted the
study among 267 ischemic stroke patients to evaluate functional improvement up
to four months and mortality rates within one year after a stroke. The study
demonstrated significant functional improvement at 4 months after stroke as
measured by a physician-based global assessment ratings similar to the Rankin
scale used in the US studies (p less than or equal to 0.05) and a reduction in
mortality within one year of approximately 50 percent in the citicoline group (p
= 0.01).
"The Takeda study is a valuable addition to our internal database," said Dr.
Cooper, "While there are differences in the dosage, route of administration and
duration of therapy of citicoline in the Japanese study versus the U.S. studies,
we believe the clear efficacy and mortality benefit in the Takeda trial supports
the utility of citicoline in stroke."
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MECHANISM OF ACTION
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Citicoline is believed to have multiple mechanisms of action which may limit
stroke- induced brain damage:
- limiting the extent of the infarct, or tissue damage caused by
interrupted blood flow, by preventing the accumulation of toxic free
fatty acids;
- promoting recovery of brain function by providing two components,
cytidine and choline, required in the formation of nerve cell
membranes;
- promoting the synthesis of acetylcholine, a neurotransmitter
associated with cognitive function.
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