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Introduction

On June 28, 2021, CEL SCI announced the results of its Phase 3 study on Multikine:

• Patients treated with the Multikine treatment regimen followed by surgery and radiation demonstrated statistically significant (p=0.0236, HR= 0.68) Overall Survival (“OS”) advantage vs. Standard of Care (SOC) alone. The 5-year survival advantage was 14.1% (62.7% vs 48.6%) for the pre-defined population receiving no chemotherapy. The OS benefit increased over time.

• Patients treated with the same Multikine treatment regimen prior to surgery and radiotherapy, but who also received chemotherapy, did not exhibit this survival advantage.

• No safety issues were found for Multikine in the treated population.

This is a very intriguing situation. The radiation arm exceeded the 10% objective for overall survival. As explained by the FDA in this guideline, overall survival is the gold-standard when it comes to assessing the effectiveness of a cancer treatment.

Survival is considered the most reliable cancer endpoint, and when studies can be conducted to adequately assess survival, it is usually the preferred endpoint.

14% is clearly a significant beat for the “radiation” population. However, the primary end point was not met for the entire population. Hence, questions were raised: Will the FDA approve Multikine based on a “subgroup” result? Is the sample size of the “radiation” population big enough? Will the pre-selection method present an obstacle to FDA approval?

In this article, we’ll focus on these above questions with respect to the FDA’s likely thought process on this matter as a result of its previous actions in several case studies.

Based on our analysis, we believe that CEL-SCI’s Multikine Phase 3 results have been both misinterpreted and misrepresented beyond the scientific community. Thus, in stock market circles, the drastic drop and current significantly lower share price. Yet CEL-SCI’s situation is not unique. As proof, we offer a case study in which a sponsor also reported “mixed” top-line results, yet the share price skyrocketed 10x upon receiving the FDA’s first signal of positive feedback.

For a broader discussion on why Multikine will likely be approved and why it is so absurdly undervalued, we recommend this article on SeekingAlpha.

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FDA Subgroup Approvals

In an article published on June 10, 2021, a group of authors from the FDA discussed the FDA’s thought process when it comes to subgroup analyses in oncology trials. The abstract said:

In general, if a subgroup is of interest, the subgroup analysis should be hypothesis-driven and have adequate sample size to demonstrate evidence of a treatment effect. In addition to statistical efficacy considerations, the decision on what subgroups to include in labeling relies on the pathophysiology of the disease, mechanistic justification, safety data, and external information available. The oncology drug review takes the totality of the data into consideration during the decision-making process to ensure the indication granted and product labeling appropriately reflect the scientific evidence to support patient population for whom the drug is safe and effective.

Clearly, the FDA will take a comprehensive look at the data to determine the patient population for which an investigational drug is safe and effective.

There are many examples of trials for which the FDA approved the investigational treatment for a subgroup with a strong benefit / risk ratio but not for subgroup(s) with poor benefit / risk ratios. Let’s examine three below:

Olaparib

On May 8, 2020, the FDA approved olaparib (LYNPARZA, AstraZeneca Pharmaceuticals, LP) in combination with bevacizumab for first-line maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (“HRD”) positive status defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability.

The approval was supported by the results of the pivotal trial PAOLA-1 (n = 806). The patient population includes 4 biomarker sub-groups, of which the 2 biggest ones are HRD-positive (n=389) and HRD-negative (n=274) subgroups. The study demonstrates a statistically significant improvement in the primary end of Progression-Free Survival (“PFS”) in the HRD-positive subgroup [HR 0.33 (95% CI: 0.25, 0.45)] while no treatment effect was observed for PFS and OS for the HRD-negative subgroup.

The FDA approved olaparib for the HRD-positive subgroup.

Atezolizumab

On March 8, 2019, the FDA granted accelerated approval to atezolizumab (TECENTRIQ, Genentech Inc.) in combination with paclitaxel protein-bound for adult patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1 as determined by an FDA-approved test.

Approval was based on pivotal trial IMpassion130 (n=902). There were 2 subgroups (1) patients with PD-L1 positive (n=369); and (2) patients with PD-L1 negative (n=533). In patients whose tumors express PD-L1, median PFS was 7.4 months (6.6, 9.2) for patients receiving atezolizumab with paclitaxel protein-bound and 4.8 months (3.8, 5.5) for those receiving placebo with paclitaxel protein-bound. The hazard ratio for PFS was 0.60 (95% CI: 0.48, 0.77; p<0.0001) in favor of the atezolizumab plus paclitaxel protein-bound arm. Objective response rate (“ORR”) in patients with confirmed responses was 53% compared to 33% for the atezolizumab and the placebo-containing arms, respectively.

For patients with PD-L1 negative, no treatment effect was seen.

The FDA granted accelerated approval to atezolizumab for the subgroup of patients with PD-L1 positive.

Eribulin

On January 28, 2016, the FDA approved eribulin (HALAVEN injection, Eisai Co., Ltd.) for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen.

The approval was based on a pivotal trial with 446 patients randomized into 2 arms, 225 to eribulin and 221 to dacarbazine.

There are 2 subgroups (1) patients with lipsarcoma (n=153); and (2) patients with leiomyosarcoma (n=297)

For the first subgroup, i.e. patients with lipsarcoma, the study demonstrates a statistically significant OS and PFS improvement of eribulin compared to dacarbazine. The median OS was 15.6 vs. 8.4 months [HR 0.51 (95% CI: 0.35, 0.75)] and the median PFS was 2.9 vs. 1.7 months [HR 0.52 (95% CI: 0.35, 0.78)] in patients treated with treated with eribulin compared to dacarbazine.

For patients with leiomyosarcoma, there was no evidence of efficacy for eribulin with median OS of 12.8 vs. 12.3 months [HR 0.90 (95% CI: 0.69, 1.18)] and median PFS of 2.2 vs. 2.6 months [HR 1.05 (95% CI: 0.81, 1.35)] in patients treated with treated with eribulin compared to dacarbazine, respectively.

As a result, the FDA approved eribulin for the subgroup of patients with lipsarcoma.

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Considerations for Multikine

Treatment Arms vs. Subgroups

In the previous examples, the FDA granted approvals based on subgroup results.

The word “subgroup” here means that all study patients administered the investigational product receive the same treatment. Then the analysis and the approval are based on the biological characteristics of each subgroup’s patients. The separation of subgroups relies on the biological characteristics of patients.

For Multikine, the situation is different. Patients receiving Multikine and surgery would subsequently receive either radiation or radio-chemotherapy. These two groups do not have the same treatment. The separation relies on the treatment that patients received and not directly on the biological characteristics of patients. It is as if CEL-SCI combined two clinical trials into a single one:

• Multikine + CIZ + Surgery + Radiation vs. Surgery + Radiation

• Multikine + CIZ + Surgery + Radio-chemotherapy vs. Surgery + Radio-chemotherapy

The distinction between treatment arms (based on different treatments) is even stronger than for subgroups (based on biological characteristics of patients). Therefore, the FDA will certainly examine the data of the radiation arm to assess the approval and there is no reason that the non-effectiveness of Multikine in the “chemo” arm would adversely influence the results of the “radiation” arm.

Sample size

Sample size is one of the key items that the FDA will take into consideration for the subgroup analyses. On July 1 call, Dr. Talor noted there were 380 patients in the “radiation” arm treatment. This number included a non-comparator arm which represents 1/7 of total randomized patients. Hence the number of patients in the 2 comparator radiation arms would be closer to 380*6/7=326 patients. This is a sizable number. As shown above, the FDA approved Eribulin with a subgroup of only 153 patients.

Pre-Selection Method

If Multikine is approved for the “radiation” patient population, then an interesting situation is encountered. Multikine is used before surgery, and the choice between radiation or radio-chemotherapy is usually made after surgery.

Hence there is a need to determine upon diagnosis whether a patient will receive only radiotherapy or radio-chemotherapy following surgery.

This question was asked during the July 1 call, and Geert replied:

That was the first thing our team thought of, and our team has determined a way, a clear way to ascertain which patients would end up receiving only radiotherapy following surgery. So we have that and so therefore you can easily prescribe for that patient indication.

In July 7 letter to shareholders, Geert wrote:

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 pre-selection methodology.

The exact method has not been disclosed yet. It could be based on a combination of contraindications of chemo drugs (e.g. cisplatin is contraindicated for patients with renal impairment) and some predictive biomarkers. But let’s be realistic here, the pre-selection method is a prediction method and by definition prediction cannot be 100% perfect. The method could predict a “radiation” patient who ends up receiving “chemo”; or a “chemo” patient who ends up receiving only “radiation”.

So, let’s try to view this conundrum from the perspective of the FDA whose role is to maximize the benefit while minimizing the risk for the greatest number of patients.

• If a “radiation-predicted” patient receives Multikine and then ends up having chemo, according to the study results, that person will receive no survival benefit. But there should be no additional risk either, since Multikine has been deemed safe. So from the FDA’s standpoint, this should not be viewed as a significant problem. In case there is an adverse reaction between Multikine and chemo, then it is likely that patients receiving Multikine will not be allowed to receive chemo afterward.

• What of the “chemo-predicted” patients who do not receive Multikine, and subsequently end up having only radiation administered? Such patients would unfortunately miss out on the benefit of Multikine. From the FDA’s perspective, this clearly is a less preferable situation compared to the initial one. However, it cannot be the reason not to approve Multikine because to do so would preclude many deserving patients from ever benefiting from Multikine.

Therefore, the benefit / risk assessment favors Multikine when it comes to assessing the pre-selection method. Even if that pre-selection method does not predict perfectly, the risk should be limited from the FDA’s point of view thanks to the safety profile of Multikine. Obviously, the better and more clear cut the pre-selection method, the easier and quicker will be the FDA’s assessment.

The pre-selection method will likely be discussed at the pre-BLA meeting and we should hear more about it in the coming 2-3 months.

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Misunderstood Story, Misunderstood Share Price

The story of CEL-SCI and its depressed share price is not unique. Among examples of companies reporting “mixed” results but whose share price subsequently rocketed upon receiving a clear first signal of positive FDA feedback, let’s look no further than at the recent case of NeuroMetrix.

The Story of NeuroMetrix

NeuroMetrix is a company focused on the development and commercialization of non-invasive medical devices for the diagnosis and treatment of pain and neurological disorders. The Company has three products:

• DPNCheck is a diagnostic device that provides rapid, point-of-care detection of peripheral neuropathies.

• ADVANCE is a diagnostic device that provides automated, in-office nerve conduction studies for the evaluation of focal neuropathies.

• Quell is an investigational device for the treatment of fibromyalgia.

On June 09, 2021, NeuroMetrix announced top-line results from a randomized controlled trial of Quell for treatment of fibromyalgia. In its press release, it said:

In the intention-to-treat (ITT) population, the treatment difference in the Patient Global Impression of Change (PGIC, primary endpoint) was not significant (sham 3.24 ± 0.26, active 3.58 ± 0.25, p=0.351). However, in a pre-specified subgroup analysis of subjects with elevated baseline pain sensitivity, the active treatment group exhibited a significant and clinically meaningful improvement compared to sham (sham 3.09±0.40, active 4.24 ± 0.37, p=0.032).

So this is a typical positive result in a subgroup based on patients’ characteristics that we illustrated above in the previous three case studies.

On July 20, 2021, NeuroMetrix announced that it received FDA Breakthrough Device Designation for the treatment of fibromyalgia with Quell. The press release said:

The data submitted by NeuroMetrix in support of the Breakthrough Designation included results from a double-blind, randomized, sham-controlled trial (NCT03714425). A total of 119 subjects with fibromyalgia were enrolled and randomized to a standard (active) or modified (sham) Quell device for 3-months of at-home use. In an intention-to-treat (ITT) analysis of all subjects, 56% of those on active treatment exhibited a clinically meaningful improvement in health-related quality-of-life (Fibromyalgia Impact Questionnaire, FIQR) compared to 35% that received sham treatment (p=0.029). There were additional positive outcomes in both the ITT population and in a pre-specified subgroup analysis of subjects with elevated pain sensitivity based on Quantitative Sensory Testing (QST).

The Breakthrough Device Designation does not guarantee approval but it demonstrated an initial positive signal from the FDA. Upon the news, the share price increased ~10x.

Conclusion

Even if Multikine’s Phase 3 study results are unique with a combination of Multikine being neoadjuvant and the bifurcation of SOC treatment between radiotherapy and radio-chemotherapy, we believe that the FDA’s subgroup analysis thought process will likely be favorably inclined to be impressed by Multikine’s extraordinarily positive results within the “radiation” arm.

Even if Multikine’s Phase 3 study results are unique with a combination of Multikine being neoadjuvant and the bifurcation of SOC treatment between radiotherapy and radio-chemotherapy, we believe that the FDA’s subgroup analysis thought process will likely be favorably inclined to be impressed by Multikine’s momentous results within the “radiation” arm.

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