Dear CEL SCI investors:
The aim of the letter we sent today is to clear up some confusion about the Phase 3 study findings we released this week. In the largest Phase 3 study in newly diagnosed primary neck and head cancer Our Multikine(r) (Leukocyte Interleukin, Injection)* immunotherapy resulted in an statistically significant 14.1 percent 5-year survival improvement for patients who received surgery and radiotherapy. This is 40 percent of the population in the study and 155,000 patients per year. The mystery lies in the question of whether the data that show benefit in one of two possible treatment options for our patients, is valid to determine if the treatment is approved. As we'll explain in this article the analysis performed for the treatment arm that was successful was specifically outlined in the protocol, and was conducted prior to blinding. This means that the results from the treatment arm that is successful could be used to seek FDA approval. To clarify: we have now excellent 5-year survival data that is free of security concerns and we are aware that how to use this information is permissible when trying to get FDA approval.
Very Successful Pivotal Clinical Trial Results in Newly Diagnosed Advanced Primary Head and Neck Cancer Patients
On the 28th of June, 2021 we released results from our Phase 3 study on cancer which proved that Multikine was able to provide all the protocols-required benefits listed in the study's protocol patients who were in the treatment arm who received radiation and surgery as their primary treatments. Based on this information, we will file for and requesting FDA approval to use Multikine to treat advanced neck and head cancers within this patient population.
Our Phase 3 results demonstrated long-term overall survival (OS) benefit for the treatment arms that were strong and long-lasting, without concerns about safety, which is not often seen in cancer treatments. The survival advantage grew over time, and by five years, the overall survival advantage reached an absolute 14.1 percent benefit in patients in the Multikine treated arm versus the control (n=380 of the total number of patients who received radiation and surgery) This is roughly 29% better than control in survival. Control arm 48.6 percent, Multikine arm 62.7% survival.
It means that more than 21,000 patients would have survived for five years when all eligible patients were treated with Multikine along with radiation and surgery in comparison with the standards of medical care (SOC). This is vital because the benefits of survival are substantial and the previous approval for this indication came several decades back. This is a very serious condition that has a medical need that is not met that is essential when applying to get FDA approval.
The Study's design is based On National Comprehensive Cancer Network (NCCN) Treatment Guidelines, which includes two different treatment Arms. One was very successful.
Let me provide details regarding the study's methodology to help you be aware of what transpired. In the NCCN Treatment Guidelines recommend to all doctors that treatment for advanced neck and head cancers must be surgical first. Following surgery, there are two treatment options. The first treatment option for patients with SOC is radiation and surgery (about 40% affected patients) and the second arm is surgery, and simultaneous radiochemotherapy (chemotherapy and radiation in the same session around 60% of patients). The toxicities of this radiochemotherapy regimen can be extremely painful, debilitating and sometimes fatal. In our research the study's endpoint was an improvement of 10% in OS in comparison to those who received the Multikine treatment regimen and SOC against SOC all by itself.
Patients treated with Multikine and with surgery and radiation demonstrated a significant 5-year survival improvement and exceeded the parameters specified in the study protocol to be considered to be successful. According to the protocol, these assessments were only possible when at least 298 deaths (patient deaths) were recorded within the combined comparator arm that were part of the study. If you review the study's protocol, you'll notice that we believed that it could take around 3 years to reach 298 events however, the much slow accumulation of events pushed this time-frame, and allowed us to view five years of survival information which is far superior. The five-year OS benefits were 14.1 percent in absolute terms, which was higher than the protocol's requirements of 10% or higher. The study's p-value is 0.0236 surpassing the protocol's value of <0.05. The study's Hazard Ratio (HR) was 0.68 over the protocol's requirement of 0.721.
The analysis of the two different Treatment Arms is allowed because it was explicitly stated by the Protocol and performed Before blinding.
The analysis of the treatment arm that performed well was set out by the research protocol, and as well in it was outlined in the Statistical Analysis Plan (SAP). The documents stated that we should review and report before the FDA not just the results from the two treatment arm but every treatment arm, for instance Multikine followed by radiation and surgery (the one that was successful of the research) as well as Multikine followed by radiochemotherapy and surgical procedures. What we observed in the study was that patients treated by Multikine with radiation and surgery had the highest and longest-lasting survival benefit that exceeded guidelines established for the study's goals, however, we discovered an increase in survival when chemotherapy is added in second treatment group, the benefit to survival of Multikine was canceled out.
We have concluded that it is feasible to choose the people who will receive benefits from the Multikine benefit at the moment of diagnosis. We've checked this out by consulting a range of expert medical professionals in the field and they were all in agreement with the viability of the pre-selection method we have proposed.
False Assertions Addressed
Certain false statements and false representations have been published by parties who did not comprehend the process and statistical analysis, or had ulterior motives regarding the price of our shares. The main false statement was that CEL-SCI cannot count on the surgery as well as the radiation treatment arm by itself to seek FDA approval. I will state it plainly: it is completely wrong and untrue. The radiation and surgery section that was studied was specified and was actually one of the two potential treatment options as per the NCCN treatment Guidelines for this type of disease. Analyzing any treatment arm by itself was included in the SAP as well as specified prior to locking the database and prior to anyone analyzing the data. In conclusion the analysis, each one was pre-specified in the SAP and protocol and only performed after locking of the database, and before blinding any of the data in study. Thus, we are able to utilize the Multikine along with radiation and surgery data to submit an FDA approval applications.
We plan to apply for FDA permission for the patients receiving Multikine followed by radiation and surgery. What is the reason why a lack of survival benefits for the treatment arm who also receive chemotherapy impact the approval of patients receiving Multikine which is then followed by radiation and surgery?
There was the clear and long-term, survival benefit that is statistically significant within one of two treatment arm that included more than 380 patients. It was around forty percent of sample of patients in the study and not just a tiny subset of patients that could be benefited. Two distinct and specific treatment arms were offered to patients after surgery. Both conform to guidelines of the NCCN Standard of Care Guidelines One performed very well, whereas the other one didn't.
Other false claims made were claims that CEL-SCI had the data for more than a year, and that we were "data mining" to find an advantage as well as "p-value hacking". CEL-SCI didn't receive the data until shortly before we announced the findings and, up to that point we were unaware of the fact that it was there. The p-value of this study was actually very high.
Support From the Independent Statistician
We are certain that our decision to file the claim of an established therapy arm (Multikine followed by radiation and surgery) is well-founded and is based on substantial data and solid findings. In this case, we're being open and transparent, and we are giving the following statement data from our independent statistician
(Note Note: When a statistician states "low risk" treatment group the statistician is referring the radiation therapy and surgery arm.)
CEL-SCI has developed Multikine to combat locally Advanced SCCHN (Squamous cell cancer of the neck and head). It's been more than 30 years since a new treatment was approved for treating the stage 3-4 SCCHN. The CEL SCI protocol and SAP were developed with a primary efficacy goal (overall life expectancy) to be evaluated in three pre-determined populations that have two relevant clinical starting point (randomization and surgery). The pre-defined subgroup analyses of the protocol conform to the published literature as well as the SEER database. They include the stage of tumor, location of tumor surgical margin the risk group, as well as treatment directed to the disease. This is the biggest Phase 3 study ever carried out in SCCHN with localized advanced disease. The study randomly assigned patients to three continents, 78 locations.
The choice to file a claim in a pre-defined subgroup is backed by the following factors:
- The most important endpoint for efficacy is general survival
- Efficacy targets were achieved The 0.68 hazard-to-risk ratio for the subgroup at low risk was comparable with the previously-targeted 0.721 percent of the whole population.
- Analytical methods are reliable The statistical significance was achieved with the log rank pre-specified test (primary analysis) within the main intention for treatment (ITT) population, and was backed by the other populations of this study
- Results of survival are robust. The statistical significance was confirmed by the data at the time of randomization or surgical procedure
- Results from the model are reliable:
- The statistical importance was demonstrated by the treatment-low-risk interaction with an Cox percent model that includes pre-defined covariates
- The statistical significance of the HTML0 was established in the low-risk subgroup by with the Cox proportional hazard model that includes covariates that were pre-specified.
- The study did not find any general safety issues.
- Every single one of the above analyses was future-orientedly defined by SAP. SAP.
Hacking of P-values occurs when the initial protocol and/or the the statistical analysis plans (SAP) are altered following the event in an effort to increase statistical significance.
- Data collection for additional information.
- Dropping of data that isn't legitimate.
- The focus is on other methods.
- Modifying the analysis methodology.
Specifically:
- We gathered data that is pre-specified in the protocol as well as in the eCRF.
- We didn't delete any data. We utilized an NCCN Low Risk definition, and we utilized the ITT population.
- We focused on the protocol-specific principal efficiency measure (overall survival [OSOS).
We used the previously planned analyses to calculate [Overall Survival[Overall Survival] OS hazards ratios, and p-values.
On the preceding no "data mining" took place to help support CEL-SCI's (information from the CEL SCI) statement."
We believe that this thorough statistical data will help to educate those knowledgeable about statistics in relation the clinical trial information.
Do Short Sellers Value Their Profits More Than the Tens of Thousands of Lives That Can Be Extended?
I believe there are those with an enormous incentive to bring the price lower because CEL-SCI was holding an unfunded short position of 25. When we first announced that we had released our Phase 3 data, it was understandable that some investors were hesitant to bet on our company and our product since the outcome was not certain. However, our data is clear that Multikine prolongs longevity in 40 percent of newly diagnosed advanced primary neck and head cancer patients. After we apply for FDA approval If Multikine be approved for marketing that tens of thousands of people could be able to live longer after treatment. Who is the kind of person who continues to promote a false story and denigrate a business that could create this kind of impact for cancer patients?
Uncertainty stemming from the fact that this treatment failed to perform allowed for an attack on our 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 . This shouldn't be the case as there aren't enough shares available for borrowing and brokerage firms are expected to verify if stocks are available for borrowing prior to selling short. Make your own decisions.
We've followed the regulations to get the most significant and never observed long-term survival benefit in the advanced stage of primary neck and head cancer. No new treatment has been introduced to the market for decades. Additionally no safety issues were discovered, which is not the case in other cancer medications. The indication for the disease is an unmet medical need , and in actual fact, Multikine has received an Orphan drug designation from the FDA to provide the " neoadjuvant therapy in patients with squamous cell carcinoma of the head and neck (SCCHN)".
Closing
In conclusion, our highly effective data for the Multikine treatment regimen for patients who underwent surgery and radiation therapy eliminates the risk. Since the analyses were specifically described in the protocol, and the SAP and analysis were conducted after the database was locked and prior to deblinding to study's data We are able to utilize the data that showed a robust and long-lasting 5-year overall survival benefits for the FDA submission. There were no safety concerns found. We have $47 million in the bank. We are currently in the process of in the process of preparing to meet with FDA to attend a pre-Biologics Licence application (BLA) meeting, and to request and file to get FDA approval.
When we speak to specialists in this field,, we get only positive feedback on the results of our study. FDA or the medical community will examine the clinical implications: better survival rate over SOC alone; the benefits and risks of the drug and its safety profiles (excellent) as well as analysis of statistical data (excellent) as well as examine and evaluate all of results with the knowledge that there is a gap in medical need, for which no new therapies have been introduced to the market in the past few decades. A physician has written: "Head and neck cancer could be the most devastating in all forms of cancer. It not only takes your life, it also will take your beauty, voice and dignity."
