BETHESDA, Md., Aug. 11, 2014 /PRNewswire/ -- Northwest
Biotherapeutics (NASDAQ: NWBO) (NW Bio), a biotechnology company
developing DCVax® personalized immune therapies for solid tumor
cancers, announced today that, following a 9-month process of
regulatory submissions and reviews by regulators in the US, UK and
Germany, it has obtained
regulatory approvals to make certain enhancements to its ongoing
Phase III clinical trial of DCVax-L Glioblastoma multiforme (GBM)
brain cancer. The enhancements will allow the statistical
analysis of trial results to take account of a major new variable
which has been identified in GBM research since the Company's Phase
III trial began, and will lower the threshold for satisfying the
primary endpoint of the trial.
The Company has been blinded at all times, with no access to any
data in the Phase III trial, and will remain fully blinded until
the trial is completed. The changes relate to the statistical
analyses that will be done at the end of the trial, and do not
affect the treatment protocol, dosing, randomization of patients or
other such aspects. The changes were driven solely by
external factors -- particularly research reports about a newly
discovered variable which has been found to significantly affect
GBM patients' survival times, and which the Company recognized
could significantly skew the clinical trial results if the trial's
statistical analyses did not control for it. The Company's Phase
III trial design and statistical analyses already controlled for
key variables known at the time when the trial was designed, such
as a particular genetic factor (referred to as MGMT methylation),
the extent of tumor removal, and others.
The new variable involves the level of certain white blood cells
in GBM patients when they finish the 6 weeks of daily radiation to
the brain which is part of the current standard of care
treatment. Important recent research has found that as many
as 40% of GBM patients have such severely depressed white blood
cell counts following radiation that their level is comparable to
the level at which AIDs patients are put on continuous antibiotic
treatments, prophylactically. Further, this research has
found that these GBM patients' white blood cell counts do not
recover with the passage of time. See, for example:
Grossman et al., 2011: Clin Cancer
Res 17(16):5473-80; Ellsworth et al. 2014: Oncoimmunology
3(1):e27357. Epub 2014 Jan 3.
Most importantly, the recent research has identified a major
impact on these GBM patients' Overall Survival (OS): the
variable relating to severe depression of white blood cell counts
can make a difference of 6 months in OS. As a comparison, the
standard of care drug for GBM, Temodar, only makes a difference of
10 weeks in OS. If the statistical analysis of GBM trial
results does not take account of such a major variable, the overall
trial results could be significantly skewed.
Under the enhancements to NW Bio's Phase III trial, the
statistical analyses of the trial results will be modified to take
account of, and control for, this important new variable.
Also under the enhancements, the threshold for satisfying the
primary endpoint of the Phase III trial (which is Progression Free
Survival, or PFS) will be lowered from requiring a 6-month
difference to requiring only a 4-month difference between the PFS
of the patients treated with DCVax-L and the PFS of patients in the
control arm of the trial.
The bases for reducing the threshold from 6 months to 4 months
difference in PFS include increasing the total number of patients
in the trial from 312 to 348, and increasing the number of "events"
that will be counted in the statistical analyses at the end of the
trial. An "event" is a tumor recurrence or a patient
death.
The current trial plan involves counting 110 "events" from among
the 312 total patients in the trial to evaluate whether the primary
endpoint is met. Under the enhancements of the trial, 248
"events" will be counted from the 348 total patients in the trial
to evaluate whether the PFS primary endpoint is met.
By increasing the number of "events" counted, the statistical
basis of the trial, which is already quite strong, will be further
strengthened. As a result, it is anticipated that a 4-month
difference in PFS will be sufficient to reach the strong "p value"
planned in the trial (0.02), and it will not be necessary to show a
6-month difference in PFS. ("p value" is a measure of
statistical significance – the probability that trial results are
due to chance, rather than the effects of the treatment. So,
the smaller p value, the stronger the significance.
Regulatory authorities generally require that the p value of trial
results be 0.05 or lower for product approvals.)
The Company has obtained approval from the US FDA and the UK
Medicines and Healthcare Products Regulatory Agency (MHRA) and
conditional approval from the German regulatory authority (the Paul
Ehrlich Institute, or PEI). The Company is now working toward
the final approval from the PEI.
The trial enhancements will also have to go through
Institutional Review Board (IRB) review and approval at each of the
clinical trial sites. There are currently over 50 trial sites
in operation in the US and a number of sites in operation in the UK
and Germany. There will also be certain other requirements
for implementation of the changes, modified documentation and
procedures.
Taking into account the time required for these approvals and
implementation steps, and the 36-patient increase in the trial, as
well as the gradual ramp-up of the trial in Europe, the Company currently anticipates that
enrollment will be completed in approximately Q3 of next year, and
the primary endpoint of the trial will be reached about 3-5 months
after full enrollment or by around year-end next year.
"We are grateful to the regulatory agencies for allowing us to
take account of important new research findings in our ongoing
Phase III trial, to control for a variable that could have
significantly and artificially distorted the trial results, and we
are grateful to be able to maximize the number of "events" to be
counted from the patients in our trial," commented Linda Powers, CEO of NW Bio. "Although it
has been a long process to obtain approvals from three different
regulators for these enhancements of our trial, we believe that
achieving approval for these changes will be of great value to the
ultimate results of the trial and to the building of shareholder
value."
About Northwest Biotherapeutics
Northwest Biotherapeutics is a biotechnology company focused on
developing immunotherapy products to treat cancers more effectively
than current treatments, without toxicities of the kind associated
with chemotherapies, and on a cost-effective basis, in both
the United States and
Europe. The Company has a broad platform technology for
DCVax® dendritic cell-based vaccines. The Company's lead
program is a 348-patient Phase III trial in newly diagnosed
Glioblastoma multiforme (GBM). GBM is the most aggressive and
lethal form of brain cancer, and is an "orphan disease." The
Company is under way with a 60-patient Phase I/II trial with
DCVax-Direct for all inoperable solid tumor cancers, and has
completed enrollment in the Phase I portion of the trial. The
Company previously received clearance from the FDA for a
612-patient Phase III trial in prostate cancer. The Company
conducted a Phase I/II trial with DCVax for metastatic ovarian
cancer together with the University of
Pennsylvania. In Germany, the Company recently
received approval of a 5-year Hospital Exemption for treatment of
glioma (brain cancer) patients outside the clinical
trial.
Disclaimer
Statements made in this news release that are not historical
facts, including statements concerning future treatment of patients
using DCVax and future clinical trials, are forward-looking
statements within the meaning of the Private Securities Litigation
Reform Act of 1995. Words such as "expect," "believe,"
"intend," "design," "plan," "continue," "may," "will,"
"anticipate," and similar expressions are intended to identify
forward-looking statements. Actual results may differ
materially from those projected in any forward-looking
statement. Specifically, there are a number of important
factors that could cause actual results to differ materially from
those anticipated, such as risks related to regulatory review and
approvals of the Company's clinical trials, risks related to the
Company's ability to enroll patients in its clinical trials and
complete the trials on a timely basis, uncertainties about the
clinical trials process, uncertainties about the timely performance
of third parties, risks related to whether the Company's products
will demonstrate safety and efficacy, risks related to the
Company's ongoing ability to raise additional capital, risks
related to the Company's and Cognate's abilities to carry out the
intended manufacturing expansions, risks related to the Company's
ability to carry out the Hospital Exemption program and risks
related to possible reimbursement and pricing. Additional
information on these and other factors, including Risk Factors,
which could affect the Company's results, is included in its
Securities and Exchange Commission ("SEC") filings. Finally,
there may be other factors not mentioned above or included in the
Company's SEC filings that may cause actual results to differ
materially from those projected in any forward-looking
statement. You should not place undue reliance on any
forward-looking statements. The Company assumes no obligation
to update any forward-looking statements as a result of new
information, future events or developments, except as required by
securities laws.
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SOURCE Northwest Biotherapeutics, Inc.