European Medicines Agency Grants CEL-SCI a Waiver of Strict Pediatric Requirements, Clearing the Path Towards Marketing Authorization for Multikine®

CEL-SCI has cleared a significant hurdle that mandates cancer drugs in Europe comply with strict requirements for pediatric usage and clinical evidence

CEL-SCI Corporation (NYSE American: CVM) today announced that the European Medicines Agency (EMA) Paediatric Committee granted CEL-SCI a product-specific waiver of strict requirements for commercialization of cancer drugs in the European Union (EU). According to the opinion letter:

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Figure 1: The Phase 3 data showed that patients with pre-surgical responses from Multikine lived far longer than those without Multikine (Photo: Business Wire)

“The Paediatric Committee, having assessed the waiver application in accordance with Article 13 of Regulation (EC) No 1901/2006 as amended, recommends as set out in the appended summary report:

• to grant a product-specific waiver for all subsets of the paediatric population and the above mentioned condition(s) in accordance with Article 11(1)(c) of said Regulation….”

CEL-SCI’s investigational cancer immunotherapy Multikine (Leukocyte Interleukin, Injection)* is intended for newly diagnosed adult (>18 years old) patients with locally advanced resectable primary squamous cell carcinoma of the head and neck (SCCHN).

“The granting of a paediatric investigation plan waiver by the EMA’s Paediatric Committee is a big step forward for Multikine, because it is one less hurdle that we face on our path towards commercialization in Europe, which could have greatly delayed our plans in the EU had the waiver not been granted,” said Geert Kersten, CEO of CEL-SCI. “We are moving forward in multiple countries and regulatory jurisdictions at the same time, including not only the US and Europe but also the United Kingdom and Canada.”

The EU Paediatric Regulation which came into force in January 2007 dramatically changed the regulatory environment for pediatric medicines in Europe. Its objective is to bolster investigation and development of medicinal products for the paediatric population. The regulation’s main impact was the establishment of the Paediatric Committee (PDCO), which is responsible for coordinating the EMA’s work on medicines for children by determining the studies that companies must carry out as part of paediatric investigation plans (PIPs). A PIP is a development plan aimed at ensuring that the necessary data are obtained through studies in children, to support the authorization of a medicine for children.^{1, 2}

All applications for marketing authorization for new medicines in the EU must include the results of studies as described in an agreed PIP, unless the medicine is exempt because of a deferral or waiver.² The process of developing an agreed PIP and conducting research on children under a PIP is often lengthy and stringent. Much has been said publicly about these “onerous” requirements and how difficult they can be to navigate.³

A summary of the PIP process can be reviewed by clicking here.⁴

REFERENCES:

¹ European Medicines Agency. “Paediatric Regulation.” https://www.ema.europa.eu/en/human-regulatory-overview/paediatric-medicines-overview/paediatric-regulation

² European Medicines Agency. “Paediatric investigation plans.” https://www.ema.europa.eu/en/human-regulatory-overview/research-and-development/paediatric-medicines-research-and-development/paediatric-investigation-plans

³ Sharma, V. “‘Not What We Expected,’ R&D Industry Says Of ‘Onerous’ EU Paediatric Regulation”. Pink Sheet, 17 July 2017. https://pink.citeline.com/PS121086/Not-What-We-Expected-RampD-Industry-Says-Of-Onerous-EU-Paediatric-Regulation

⁴ BlueReg White Paper, Drug Development, 2022. “5 Must-Knows About Paediatric Investigation Plan in the EU.” https://blue-reg.com/wp-content/uploads/2022/12/White-Paper_5-Must-Knows-About-Paediatric-Investigation-Plan-in-the-EU_BlueReg.pdf

About Multikine

Multikine is designed to help the immune system “target” the tumor at a time when the immune system is still relatively intact and thereby thought to be better able to mount an attack on the tumor. A pivotal Phase 3 study in advanced primary squamous cell carcinoma of the head and neck (oral cavity and soft-palate) was started in early 2011 and was fully enrolled with 928 patients by September 2016, completed follow-up and database-lock occurred in December 2020. To test for an overall survival benefit, the study required CEL-SCI to wait until at least 298 (deaths) events had occurred among the two main comparator groups.

Multikine’s positive clinical outcomes come from the following pathway, which has been definitively proven in our Phase 3 trial:

• Multikine causes pre-surgical responses;
• Pre-surgical responses lead to longer life;
• Therefore, Multikine pre-surgery treatment is associated with achieving longer life.

A “pre-surgical response” is a significant change in disease before surgery, and there were two kinds of responses observed in our Phase 3 trial. First, there were “reductions” in the size of the tumor—a reduction of 30% or more qualified as a “pre-surgical reduction” or “PSR” for short. Second, there were disease “downstages,” e.g., the disease improved from Stage IV to Stage III. We call this a “pre-surgical downstaging” or “PSD” for short. Our 2022 European Society for Medical Oncology (ESMO) cancer conference presentation reported on PSR, and our 2023 ESMO presentation reported on PSD.

Across the whole Phase 3 trial, PSRs were seen in 8.5% of Multikine patients compared to zero in the control. PSDs were seen in 22% of Multikine patients vs 13% in the control. Because Multikine was the only therapy given to these patients before surgery, we believe the data show that Multikine was the cause of the higher rates of PSR and PSD. These results were seen in the entire Phase 3 study population, not from a subgroup.

The Phase 3 data also showed that patients with pre-surgical responses from Multikine lived far longer than those without Multikine. PSR patients were 72% likely to be alive after five years, whereas control patients were only about 49% likely to be alive after five years. Patients with PSD saw five-year chance of survival of about 68%. These results are also seen in the entire Phase 3 study population, not just in a subgroup. Moreover, they were shown with strong statistical significance with p-values < 0.005. (See Figure 1)

The Phase 3 study showed that Multikine worked best in patients who were deemed “low risk” after surgery, about 40% of the study population. These patients saw a significant 14.1% absolute 5‑year survival benefit vs control. It made sense biologically that these patients would benefit most from Multikine, because they tended to have immune systems that were not yet compromised by the disease. “High risk” patients, by contrast, typically had lymph nodes invaded by the tumor, and needed chemotherapy after surgery. Because their lymph nodes were compromised, this made it harder for their immune systems to work, and they needed surgery as soon as possible without waiting an extra three weeks to administer Multikine.

The Phase 3 study also showed that Multikine was more effective for patients with low PD-L1 tumor expression than for patients with high PD-L1 expression. PD-L1 is a protein receptor on the tumor surface that helps the tumor neutralize the immune system cells that attack the tumor. It makes sense that patients whose tumors express low PD-L1 would be more likely to respond to Multikine, because their tumors have lower defenses against the patient’s immune system. Low PD-L1 tumor expression represented about 70% of the study population.

Targeting low PD-L1 differentiates Multikine from other immunotherapies. For example, checkpoint inhibitors like Keytruda and Opdivo appear to best serve patients having high PD-L1, because these drugs work by blocking PD-1/PD-L1 receptor interaction. While none of these drugs are currently approved as a first-line treatment before surgery, even if such approvals came in the future, the large majority of patients in this group having low PD-L1 would still be expected to need Multikine.

In view of the above Phase 3 clinical evidence, the Multikine target population is directed to patients who present at diagnosis with N0 nodal involvement and also with low PD-L1 tumor expression (defined as tumor proportions score (TPS) < 10). These patients can be readily identified upon diagnosis with tests that physicians routinely use in cancer screening. For instance, a PET scan is used to determine the N0 nodal status and no extracapsular spread, and a screening biopsy is used to determine the low PD-L1 expression. Doctors already routinely screen head and neck cancer patients using PET scans and biopsy. (See Figure 2)

The Phase 3 data shows that Multikine cut the risk of death in half at five years versus the control in the target population. Survival increased from 45% in the control group to 73% in the Multikine group at five years. This means the risk of death fell to 27% in the Multikine group from 55% in the control. (See Figure 3)

Another way to see the survival benefit of Multikine in the target population is the Kaplan-Meier curve from our ESMO ’23 poster. (See Figure 4) These results had a low p-value of 0.0015, which is very significant as a statistical matter. These data show yield a low hazard ratio of 0.349, with 95% confidence intervals of 0.18 and 0.66.

Our regulatory strategy going forward is to seek immediate approval of Multikine wherever possible. What drives us forward is the compelling patient need for the pre-surgical responses from Multikine, which translates to much better survival. The patients’ need is paramount to all stakeholders, including regulators, physicians, CEL-SCI and CEL-SCI’s investors.

We believe the benefit-risk balance strongly favors immediate patient access to Multikine. (See Figure 5) An “unmet need” is a factor for approval considered by all major regulatory bodies worldwide. In the Multikine target population, there is also a tremendous unmet need for improved survival. The current standard of care provides only about a 50/50 chance of surviving five years, whereas Multikine could increase that survival rate to over 70% based on the Phase 3 data. Chemotherapy has improved outcomes for some head and neck patients, but chemotherapy is only indicated for high-risk patients, who are not likely to fall within the Multikine target population. Currently available immunotherapies are given after surgery or where surgery is not indicated. In contrast, Multikine is given before surgery to patients with resectable tumors. Available checkpoint inhibitors work best on tumors with high PD-L1 expression, whereas Multikine works best in tumors with low PD-L1 expression. Therefore, Multikine’s target population is underserved, and will continue to be underserved, by current therapies, but Multikine can meet the need for improved survival.

About CEL-SCI Corporation

CEL-SCI believes that boosting a patient’s immune system while it is still intact should provide the greatest possible impact on survival. Therefore, in the Phase 3 study, CEL-SCI studied patients who were newly diagnosed with locally advanced primary squamous cell carcinoma of the head and neck with the investigational product Multikine first, before they received surgery and radiotherapy or surgery plus concurrent radiotherapy and chemotherapy (the current standard of care for these patients). This approach is unique. Most other cancer immunotherapies are administered only after conventional therapies have been tried and/or failed. Multikine (Leukocyte Interleukin, Injection) received Orphan Drug designation from the FDA for neoadjuvant therapy in patients with squamous cell carcinoma (cancer) of the head and neck. CEL-SCI believes that this Phase 3 study is the largest Phase 3 study in the world for the treatment of locally advanced primary head and neck cancer.

The Company has operations in Vienna, Virginia, and near/in Baltimore, Maryland.

Forward-Looking Statements

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, 2023. 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. 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 use.

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