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.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20240131910101/en/
Gavin de Windt CEL-SCI Corporation (703) 506-9460
Cel Sci (AMEX:CVM)
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