CEL-SCI Corporation (NYSE American: CVM) today issued a
letter to its shareholders.
Dear CEL-SCI shareholders:
The purpose of this letter today is to address some confusion
regarding the Phase 3 study results we announced last week. In the
world’s largest Phase 3 study in newly diagnosed advanced primary
head and neck cancer, our Multikine® (Leukocyte Interleukin,
Injection)* immunotherapy produced a statistically significant
14.1% 5-year survival benefit in patients receiving surgery plus
radiotherapy, representing 40% of the study population and an
estimated 155,000 patients annually. The confusion appears to lie
in whether the data, which shows benefit in 1 of the 2 potential
treatment arms for our patients can be used for approval. As we
will explain here, the analysis for the successful treatment arm
was pre-specified in the protocol and conducted before unblinding.
This means the data from the successful treatment arm can be used
in seeking FDA approval. To be clear: we now have excellent 5-year
survival data with no safety issues and we know the use of this
data is permitted in seeking FDA approval.
Very Successful Pivotal Clinical Trial Results in Newly
Diagnosed Advanced Primary Head and Neck Cancer Patients
On June 28, 2021 we announced results from our Phase 3 cancer
study that proved that Multikine met all of the protocol required
benefits stated in the study protocol in patients in the treatment
arm receiving surgery and radiation as their standard therapies.
Based on this we will be filing for and seeking FDA approval for
the use of Multikine in the treatment of advanced primary head and
neck cancer in this patient population.
Our Phase 3 results showed a long-term 5-year overall survival
(OS) benefit in this treatment arm that was robust and durable,
with no safety issues, something not commonly seen with cancer
drugs. In fact, the survival benefit increased over time and at
5-years the overall survival benefit reached an absolute 14.1%
advantage for the Multikine treated arm over control (n=380, total
study patients treated with surgery plus radiation), which is about
a 29% improvement, control arm 48.6%, Multikine arm 62.7%
That means an additional 21,000 patients would be alive at
5-years if all 155,000 eligible patients received Multikine plus
surgery and radiation compared to the current standard of care
(SOC). This is extremely significant because the survival benefit
is large and the last approval for this indication was many decades
ago. This is a serious disease with an unmet medical need,
something very important when you apply for FDA approval.
The Study Design is Based on National Comprehensive Cancer
Network (NCCN) Treatment Guidelines with 2 Different Treatment
Arms, One of which was Very Successful
Let me give you some details about the study design so that you
can understand what happened. The NCCN Treatment Guidelines
recommend to all physicians that the treatment for advanced primary
head and neck cancer cases should be surgery first. Following the
surgery there are two different treatment arms. The first treatment
arm for the SOC is surgery plus radiation (about 40% of the
patients) and the second treatment arm is surgery and concurrent
radiochemotherapy (chemotherapy and radiation at the same time,
about 60% of the patients). The toxicities in that
radiochemotherapy arm can be very harsh, debilitating, and even
fatal. In our protocol, the study endpoint was a 10% absolute
improvement in OS when comparing the Multikine treatment regimen
plus SOC vs SOC alone.
Patients receiving Multikine followed by surgery and radiation
showed excellent 5-year survival benefit and met and exceeded all
the designated parameters set for the protocol for the study to be
deemed successful. Per the protocol, these determinations could
only be done after at least 298 events (patient deaths) had been
reached in the combined comparator arms of the study. If you look
at the study protocol you will see that we thought that it might
take us about 3 years of follow-up to achieve 298 events, but the
significantly slower accumulation of events extended that time
frame allowing us to see over 5 years of survival data, which is
even better. The 5-year OS benefit was 14.1% in absolute terms
exceeding the protocol required 10% or better. The study result’s
p-value was 0.0236 exceeding the protocol required p-value of
<0.05. The study result’s Hazard Ratio was 0.68 exceeding the
protocol required 0.721.
The Analysis of the 2 Different Treatments Arms is Permitted
since it was Pre-Specified in the Protocol and Done Before
The analysis for the successful treatment arm was pre-specified
in the study protocol and also the study Statistical Analysis Plan
(SAP). These documents specified that we would analyze and present
to the FDA not only the combined results of the two treatment arms
but also each individual treatment arm, such as Multikine followed
by surgery and radiation (the successful group in the study) and
also Multikine followed by surgery and radiochemotherapy. What we
saw in the study is that patients who had been treated with
Multikine followed by surgery and radiation had a robust and
durable survival benefit that exceeded the parameters set for the
study endpoints, but we also saw that when chemotherapy was added
to radiation in the other treatment group, the survival benefit
from Multikine was negated.
We have determined that it is possible to select the population
that would receive the Multikine benefit at their time of
diagnosis. We have vetted this with a number of expert physicians
in the field and they agreed with the feasibility of the proposed
False Assertions Addressed
Some false assertions and misrepresentations have been made and
published by parties who either did not understand the protocol and
statistical analysis or had ulterior motives pertaining to our
stock price. The key false assertion was that CEL-SCI is not
permitted to rely on the surgery plus radiation treatment arm on
its own to file for FDA approval. I say it clearly: this is
absolutely false and incorrect. The surgery plus radiation arm of
the study was pre-specified and is in fact one of the 2 potential
treatment arms per the NCCN Treatment Guidelines for this disease.
Analysis of any of the treatment arms on their own was always a
part of the SAP, and it was pre-specified before database lock and
before anyone began analyzing the data. To summarize again, all
analyses were pre-specified in the protocol and SAP and were
performed only following database lock and prior to unblinding to
the study data. Therefore, we are permitted to use the Multikine
plus surgery and radiation data for FDA approval submission.
We intend to seek FDA approval for patients who receive
Multikine followed by surgery and radiation. Why should a lack of
survival benefit for the treatment arm also receiving chemotherapy
have negative ramifications on the approval for the patients who
only receive Multikine followed by surgery and radiation?
We are talking about a clear long term statistically significant
survival benefit in one of the two treatment arms which had 380
patients. This was about 40% of the total study patient population,
not some small subgroup of patients who could potentially benefit.
Two different and pre-specified treatment arms were given to the
patients following surgery and both follow the NCCN Standard of
Care Guidelines, one worked really well, while the other one did
Other false assertions made were that CEL-SCI had the data in
our possession for over a year and that we had been “data mining”
to find a benefit and “p-value hacking”. CEL-SCI did not receive
the data until just before we made the announcement and up until
that time, we were blinded to it. The p-value of the study was in
fact very strong.
Support From the Independent Statistician
We are confident that the decision to pursue a claim for a
pre-defined treatment arm (Multikine followed by surgery and
radiation) is sound and based on significant data and solid
results. Here, we are being very transparent and sharing the
following from our independent statistician:
(Note: When the statistician says ‘low risk’ treatment group the
statistician is referring to the surgery plus radiation treatment
CEL-SCI developed Multikine to treat locally advanced SCCHN
(Squamous cell carcinoma of the head and neck). It has been >30
years since any new therapy has been approved to treat the Stage
3-4 SCCHN. The CEL-SCI protocol and SAP were designed with a
primary efficacy endpoint (overall survival) to be studied in three
pre-defined populations with two clinically relevant starting
points (randomization, surgery). The protocol pre-defined subgroup
analyses are consistent with the literature and the SEER database;
these include tumor stage, tumor location, surgical margin, risk
group, and disease-directed therapy. This is the largest Phase 3
study ever conducted in locally advanced SCCHN. The study
randomized patients at 78 sites on 3 continents.
The decision to pursue a claim for a pre-defined subgroup is
supported by the following considerations:
- The primary efficacy endpoint remains overall survival
- Efficacy target was met: The 0.68 hazard ratio for the
low-risk subgroup was consistent with the previously targeted 0.721
hazard ratio to the entire population.
- Analysis methods are robust: Statistical significance was
reached for the pre-specified log rank test (primary analysis) in
the key intent to treat (ITT) population and supported by other
populations in the study
- Survival outcomes are robust: Statistical significance was
supported whether measuring from the time of randomization or
- Model results are robust:
- Statistical significance was supported for the treatment
low-risk interaction using the Cox proportional hazard model
containing pre-specified covariates
- Statistical significance was supported for the low-risk
subgroup using the Cox proportional hazard model containing
- The study did not encounter any overall safety issues.
- Every one of the above analyses were prospectively defined
in the SAP.
P-value hacking occurs when the original protocol and/or
statistical analysis plan (SAP) are modified after the fact in the
attempt to reach statistical significance:
- Collecting additional data.
- Dropping aberrant data.
- Focusing on alternative measures.
- Changing the analyses method.
- We collected the data pre-specified in the protocol and
- We did not drop any data; we used the NCCN low risk
definition and we used the ITT population.
- We focused on the protocol-specified primary efficacy
endpoint (overall survival [OS]).
We followed the pre-planned analyses to compute [Overall
Survival] OS hazard ratios and p-values.
Based on all of the foregoing, NO “data mining” took place to
support the (information in the CEL-SCI) press release.”
We believe this very detailed statistical data will serve to
inform those who are well versed in statistics as they apply to
clinical trial data.
Do Short Sellers Value Their Profits More Than the Tens of
Thousands of Lives That Can Be Extended?
I believe that there are people with a large incentive to drive
the stock down since CEL-SCI had a 25% short position. Before we
announced our Phase 3 data, it was understandable that some people
would bet against our company and our drug since the outcome was
uncertain. But now, the data clearly shows that Multikine extends
life in 40% of newly diagnosed advanced primary head and neck
cancer patients. In fact, after we file for FDA approval, should
Multikine receive marketing clearance, tens of thousands of people
may live longer five years after treatment. What kind of person
continues to sell short and attack a company that can make this
kind of difference in the lives of cancer patients?
Uncertainty from the fact that the chemotherapy treatment arm
did not work allowed attacks on the stock. It looks as if the
shorting volume on our stock on the day of the announcement was 56%
of the daily volume and around 40% for the next few days
(www.shortstockvolume.com/Chart/CVM/). That should not be possible
since there are not enough shares to borrow and brokerage firms are
supposed to check if stock is available to borrow before selling
short. You draw your own conclusions.
We have followed all of the rules to achieve a very significant
never before seen long term survival benefit in advanced primary
head and neck cancer, for which no new therapy has come to market
in decades. In addition, no safety issues were identified,
something not seen in other cancer drugs. The disease indication
represents an unmet medical need and in fact, Multikine has
received an Orphan Drug designation from the FDA for the
“neoadjuvant therapy in patients with squamous cell carcinoma of
the head and neck (SCCHN)”.
In closing, our very successful data for the Multikine treatment
regimen in patients who received surgery plus radiation treatment
eliminates the data risk. Since the analyses were pre-specified in
the protocol and the SAP and analyses were done after database lock
and before unblinding to the study data, we are allowed to use the
data showing robust and durable 5-year overall survival benefit in
our FDA submission. No safety issues were identified. We have $47M
in the bank. We are now preparing to meet with the FDA for a
pre-Biologics License Application (BLA) meeting and seek and file
for FDA approval.
In talking to experts in the field we hear only positive
reactions to our study results. FDA and/or the medical community
will look at the clinical impact: improved survival over SOC alone;
benefit/risk of the drug; the safety profile (excellent); the
statistical calculations (excellent); and also analyze and assess
all the results with the knowledge that this is an unmet medical
need for which no new treatments have come to market in decades. As
one physician wrote: “Head and neck cancer is possibly the most
horrific of all cancers. Not only does it take your life, but it
takes your beauty, your voice and your dignity.”
Thank you for your support and interest as we seek to help these
patients. More data will be presented in peer reviewed
Geert Kersten Chief Executive Officer
This press release contains forward-looking statements within
the meaning of Section 27A of the Securities Act of 1933, as
amended, and Section 21E of the Securities Exchange Act of 1934, as
amended. When used in this press release, the words "intends,"
"believes," "anticipated," "plans" and "expects," and similar
expressions, are intended to identify forward-looking statements.
Such statements are subject to risks and uncertainties that could
cause actual results to differ materially from those projected.
Such statements include, but are not limited to, statements about
the terms, expected proceeds, use of proceeds and closing of the
offering. Factors that could cause or contribute to such
differences include, an inability to duplicate the clinical results
demonstrated in clinical studies, timely development of any
potential products that can be shown to be safe and effective,
receiving necessary regulatory approvals, difficulties in
manufacturing any of the Company's potential products, inability to
raise the necessary capital and the risk factors set forth from
time to time in CEL-SCI's filings with the Securities and Exchange
Commission, including but not limited to its report on Form 10-K
for the year ended September 30, 2020. The Company undertakes no
obligation to publicly release the result of any revision to these
forward-looking statements which may be made to reflect the events
or circumstances after the date hereof or to reflect the occurrence
of unanticipated events.
* Multikine (Leukocyte Interleukin, Injection) is the trademark
that CEL-SCI has registered for this investigational therapy, and
this proprietary name is subject to FDA review in connection with
the Company's future anticipated regulatory submission for
approval. Multikine has not been licensed or approved for sale,
barter or exchange by the FDA or any other regulatory agency.
Similarly, its safety or efficacy has not been established for any
version on businesswire.com: https://www.businesswire.com/news/home/20210707005476/en/
COMPANY CONTACT: Gavin de Windt CEL-SCI Corporation (703)
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