Nearing the end of its long running Phase III trial for squamous cell carcinoma of the head and neck (SCCHN), CEL-SCI (CVM) has experienced several recent catalysts that have returned attention and interest to their novel immuno-oncology program. In June an arbitrator promulgated a final ruling in favor of CEL-SCI’s claims that their previous contract research organization (CRO) had breached the contract related to the timely enrollment of the Multikine Phase III trial. The arbitrator awarded ~$3 million to the company and settled counterclaims for a nominal amount. Combined with the lifting of an FDA clinical hold in August 2017, the arbitration resolution allowed management’s primary focus to return to the Phase III primary head and neck cancer study. Now that the clinical trial appears to be in its final stages, interest has returned to CEL-SCI and its innovative immunotherapy treatment.
View Exhibit I - CEL-SCI Logo
CEL-SCI was founded in the 1980s by Maximilian de Clara to advance the field of immuno-oncology decades before the specialty became well-known. Since then the company has refined its approach and developed a competency in cancer immunotherapy, developing Multikine, which has completed 11 clinical studies in a number of cancer areas. The company plans to target approval in indications for head and neck cancer and human papilloma virus (HPV) for patients with cervical dysplasia and other cancers. CEL-SCI’s second development platform is Ligand Epitope Antigen Presentation System (LEAPS) technology. LEAPS is advancing three investigational therapies for the treatment of rheumatoid arthritis, pandemic influenza and breast cancer.
View Exhibit II - CEL-SCI Development Pipeline
CEL-SCI Corp’s (CVM) primary goal is to develop its lead candidate Multikine, a biological product consisting of 14 natural cytokines, prepared from healthy donors’ peripheral blood mononuclear cells. The mixture of cytokines in Multikine includes many of the body’s natural defenses against cancer and consists of interleukins, interferons, chemokines and colony-stimulating factors. The product is mass produced, allogenic and allows the recipient’s immune system to acquire specificity against their tumor antigens when injected next to their tumor and draining lymph nodes.
CEL-SCI’s strategy with its lead candidate Multikine is to target head and neck cancer due to its severe and disfiguring nature, unmet medical need and benefit of orphan status. If successful in head and neck cancer, Multikine can serve as a platform for the development of neoadjuvant therapies for other solid tumors. The company is also developing its LEAPS technology which attempts to modulate T-cells by using heteroconjugates to guide the body to produce a specific and appropriate immune response against an offending antigen. Now in development for rheumatoid arthritis and supported by a grant from the NIH, the LEAPS platform technology has potential applications in bacterial, viral, parasitic, autoimmune, cancer and other diseases.
Multikine has a novel administration protocol as compared to other single and combination therapies and is given prior to any other treatment. Administration is begun after diagnosis and is completed prior to the standard of care for SCCHN, which consists of surgery, radiation and in many cases also chemotherapy. The goal of Multikine’s early administration is to enlist the body’s immune system to destroy the tumor and the micro-metastases that are associated with its recurrence. In the simplest terms, Multikine enables the body’s immune system to see the tumor and kill it when the immune system is strongest, prior to surgery, radiation and chemotherapy.
Multikine is injected both peritumorally and perilymphatically to place the medicine in the areas where it will have the greatest impact. The therapy is understood to help the immune system recognize and fight the tumor before the immune-weakening effects of surgery, chemotherapy and radiation occur, justifying its role as neoadjuvant therapy. The cytokines included in Multikine fall into three broad families: necrotic, to kill the tumor, lymphoproliferative, to help produce and proliferate an immune response specific to the existing tumor and chemotactic, to draw the immune system cells to the site of the tumor. These efforts combine in a concerted effort to mount an anti-tumor specific immune response to eradicate the tumor. Multikine consists of a broad variety of cytokines that can potentially recognize and bind to multiple receptors on both immune and cancer cells which are listed below.
View Exhibit III - Major Constituent Components of Multikine
The biologic’s proper name is Leukocyte Interleukin, Injection (LI) sourced from normal human donors’ derived preparations. The biologic has demonstrated the ability to induce CD3+ and CD25+ infiltration into tumor cells. It induces T-cell migration into tumor microenvironment and increases the ratio of CD4+ to CD8+ immune cells which infiltrates into the tumor. For the Phase I and II trials, LI was prepared from human peripheral blood mononuclear cells derived from source leukocyte preparations. The same product is now undergoing Phase III testing and, if approved, will be manufactured using a proprietary process in CEL-SCI’s manufacturing facility near Baltimore, Maryland.
Mechanism of Action
Multikine is a collection of cytokines sourced from normal human donor leukocytes. CEL-SCI hypothesizes that the unique cytokine mixture in Multikine may signal the immune system to produce an anti-tumor response. The biologic is also thought to upregulate the production of certain lymphocytes. Prior clinical studies suggest that Multikine could augment CD4+ immune cells’ ability to recognize and respond to tumor antigens present on the surface of tumor cells. The CD4+ action would augment CD8+ activity. CD8+ T cells may be less effective against tumors within the tumor microenvironment, as tumor cells are able to evade detection through various escape mechanisms including active checkpoints.
View Exhibit IV - Multikine Impact on Lymphocytes1
Additionally, Multikine may prevent cancer recurrence by stimulating the body’s immune system to recognize the cancer before it can proliferate. The drug is also thought to have a chemotactic effect and draw lymphocytes toward to offending cancer cells. In the Phase III clinical trial, the product is administered locally near the site of the tumor and adjacent to draining lymph nodes for three weeks prior to standard of care (SOC) treatment. The biologic’s understood mechanism of action may exhibit a potential positive effect on the clinical outcome as compared to the administration of SOC alone for patients with head and neck cancer. Multikine is injected in the area where metastases may develop, alerting the immune system to their presence and potentially preventing tumor recurrence.
Preliminary data suggests Multikine may:
‣ Act on multiple receptors on both immune and cancer cells
‣ Act on multiple components of the immune response and on tumor cells
‣ Activate immune pathways necessary for destroying the tumor
View Exhibit V - Multikine Mechanism of Action2
A Multikine pilot study was launched in 1994 for recurrent metastatic head and neck cancer and as of today, the candidate has completed 11 different clinical trials including pilot, Phase I and Phase II studies. 224 patients were treated in these trials, providing a useful data set for initial safety evaluation. The first study enrolled 16 patients and was conducted in the US and Canada and served as a stepping stone to a variety of other clinical work in several settings and tumor types. Other early stage clinical work included pre-surgery head and neck cancer, pre-surgery prostate cancer, a UK study for a variety of cancer tumors, HIV and cervical dysplasia in HPV induced cervical cancer. The last Phase II trial, which followed up with 19 subjects, has demonstrated favorable survival and other outcomes relative to SOC.
The last Phase II trial, which initially enrolled 21 patients, found a 33% higher overall survival compared to an identified control group as compiled from the scientific literature. Two subjects in this study were later found to be not evaluable for the trial as their original diagnosis for oral squamous cell carcinoma was reversed by a pathology review. The results demonstrated overall survival (OS) in 12 of 19 patients at 3 years 4 months from surgery, equivalent to a 63.2% rate of success. This compares to results compiled from a meta-analysis of 7,294 patients with the same disease indication, which documented a survival rate of 47.5% over a similar time period. Other observations from the Phase II reported a 50% decrease in tumor size during the three week Multikine treatment prior to SOC and a 10.5% complete response.
Safety outcomes for Multikine in the Phase II trials were favorable overall as reported by the clinical investigators. Adverse events included injection site pain, local minor bleeding, injection site edema, diarrhea, headache, nausea, and constipation were all minor in severity. No serious adverse events directly related to Multikine were reported by the investigators in any of the completed trials. In the human trials up to the latest complete Phase II, Multikine was tested in over 220 patients, providing a robust safety data set that along with preliminary efficacy results was sufficiently strong to support the launch of a Phase III trial.
The important takeaways from the Phase II trial are the greater than 10% (2/19) complete responses achieved and 50% reduction in cancer cells in only three weeks of Multikine treatment. The high level of safety with no reported serious side effects makes a strong case for an “intent to cure” therapy.
In 2011, CEL-SCI launched its Phase III trial for patients with advanced primary squamous cell carcinoma of the oral cavity and soft palate. The pivotal Phase III trial is being conducted in the US, Canada, UK, France and 20 other countries globally. The trial has completed enrollment of 928 newly diagnosed patients, with the final patient enrolled in September 2016. The trial seeks to demonstrate that the local/regional injection of mixed interleukins with a prescribed non-chemotherapeutic regimen of cyclophosphamide, indomethacin and zinc-multivitamins (CIZ) for only three weeks prior to SOC will overcome local immunosuppression, break tumor tolerance to tumor antigens and allow for a sustainable and effective anti-tumor immune response. The agent is injected around the tumor and near the lymph nodes prior to SOC therapy.
View Exhibit VI - Multikine Phase III Study Design
There are three arms examining squamous cell carcinoma of the oral cavity and of the soft palate; however, the CIZ-exclusion arm will be omitted for survival comparison:
1. Multikine plus CIZ followed by SOC
2. Multikine (CIZ-exclusion) followed by SOC
3. SOC therapy as the active comparator
The primary endpoint for the trial is overall survival (OS) requiring a 10% increase in overall survival for the Multikine plus CIZ and SOC compared to SOC only. The trial is event driven and requires 298 events in the combined comparison arms prior to completion. Secondary endpoints include Local Regional Control (LRC), which measures the spread of metastases and spread of the disease outside the head and neck area, Progression Free Survival (PFS) and Quality of Life (QoL), based on the European Organization for Research and Treatment of Cancer (EORTC) QoL questionnaire.
In August 2018, the Phase III study’s Independent Data Monitoring Committee (IDMC) conducted its periodic review of all 928 patients recommended that the study continue until all the necessary events have occurred. Based on current trends and historical survival rates, we anticipate that the trial will be completed in the first half of 2019.
Head and Neck Cancer
Head and neck cancer is found in the tongue, mouth, pharynx or other oral cavity. According to the American Cancer Society, this will represent approximately 52,000 new cases for the US in 2018. CEL-SCI has found similar prevalence with about 60,000 cases per annum in the US and 105,000 new cases per year in Europe. The World Health Organization estimates 550,000 cases developed worldwide in 2014. The majority of current therapy for this cancer is surgery in combination with radiotherapy or surgery followed by radiation with concurrent chemotherapy. The 3.5 year survival rate for head and neck cancer is 47.5% and five year rate, 42%3. Many times those that survive treatment suffer disfigurement and severe restrictions with eating and living a normal life. With fewer than 200,000 new cases per year in the US, head and neck cancer also qualifies for a US FDA orphan designation, which can provide a closer working relationship with the FDA, grants, tax credits, extended market exclusivity and potentially an accelerated review among other incentives.
Head and neck cancer presents itself as swelling in the oral cavity, nasal cavity, pharynx or larynx area and a sore that does not heal. Symptoms can also include voice changes, hoarseness, a neck mass, a sore throat that doesn’t respond to an antibiotic, coughing up blood, trouble swallowing or breathing, a red or white patch in the mouth, frequent nose bleeds or unusual discharge, ear pain or trouble hearing, headaches and frequent coughing.
Head and neck cancer is initially identified through a physical examination to find lumps or abnormalities, along with blood and urine tests. If the examination suggests cancer is present, then an endoscopy or imaging will be performed to confirm results. A biopsy is the best way to obtain a certain diagnosis which includes a cytologic examination. The examining physician will also seek to determine the stage of the disease and whether or not it has spread.
Standard of care for head and neck cancer is surgery, radiation therapy and chemotherapy. Surgery may include laser ablation, excision, or lymph node dissection followed by reconstructive surgery. Radiation therapy is most commonly external-beam radiation therapy which is precisely directed at the tumor cells, reducing damage to nearby tissue. Other treatments approved for patients unable to receive standard of care include epidermal growth factor receptor (EGFR) inhibitors such as cetuximab and immunotherapy such as pembrolizumab and nivolumab which were approved in 2016. These classes of drugs are only used when chances of survival are low and none are approved for use for patients that are destined for an “intent to cure” treatment.
There is no known direct competition for Multikine in the newly diagnosed but not yet treated advanced primary head and neck cancer patient population. This includes the immuno-oncology drugs such as checkpoint inhibitors and others currently on the market or in development. In these newly diagnosed “intent to cure” patients it is not acceptable to delay surgery since doing so may harm the patients. Therefore drugs given before surgery have a treatment duration limited to weeks. This is in contrast to the months of treatment required to show benefit for other immuno-oncology offerings. We highlight the rapid efficacy shown in the Phase II data in the three weeks prior to the start of SOC. While Multikine is differentiated from other therapies by its ability to show clinical impact in a three week period, it is at present the only therapy that can be used in the neoadjuvant setting for the ‘intent to cure’ (by SOC) cancer population.
CEL-SCI is in the final stages of its Phase III clinical trial and we provide recent milestones that have been achieved and are expected in the near future.
• Final Patient Enrolled in Phase III Trial – 3Q:16
• FDA Removes Clinical Hold on Phase III Trial – 3Q:17
• Company Wins Arbitration vs. CRO – June 2018
• Favorable Data Review by Independent Data Monitoring Committee – August 2018
• Achievement of 298 events - 2019
• Completion of data analysis & report topline – 2019
It has been a long and winding road for CEL-SCI over the last several years, but recent events, including completing enrollment for their Phase III trial, the reversal of the clinical hold on the Phase III trial and the successful resolution of the arbitration against their former CRO have placed the company in a strong position prior to the readout of their registrational study. The event driven trial is expected to reach 298 deaths in 2019 followed by an analysis and BLA submission to the FDA.
Multikine is a neoadjuvant therapy, used prior to standard of care, immediately following diagnosis. It contains a broad selection of pro-inflammatory cytokines that help the body fight cancer by enhancing the immune system’s ability to identify and locate tumor cells and proliferate CD4+ T helper cells and attract other immune cells to help kill the tumor. The lead indication in SCCHN is an underserved segment as there have been no new first line therapies approved since methotrexate in the 1950s. There are an estimated 550,000 cases world-wide with about 50 to 60,000 cases per year in the US, and the disease is particularly harsh on those who must undergo surgery and other SOC which can lead to permanent disfigurement and disability. The market is sufficiently large to support material sales even with modest penetration. CEL-SCI also has partners that will develop internationally, providing additional royalties. Multikine holds an attractive position as there is no other direct competition in SCCHN especially for the “intent to cure” population.
While we do not have data on the safety or efficacy of the blinded Phase III trial now underway, Phase II results were supportive on both axes with a 33% greater overall survival and no serious adverse side effects. With pivotal results expected in the short term, investors are close to realizing the potential of CEL-SCI.
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1 Based on: Talor et al., ASCO Annual Meeting Proceedings 22(14S): 189S, 2004
2 Source: Timar et al., Journal of Clinical Oncology 23(15) May 20, 2005
3 Data compiled by Seattle Cancer Care Alliance from National Cancer Data Base (NCDB) including all reported cases between 2003 and 2006 for Stage IV Head & Neck Cancer.