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CVM: A Focus on LEAPS

By John Vandermosten, CFA


NYSE:CVM


While CEL-SCI (NYSE:CVM) has experienced outstanding performance over the last several quarters due to the anticipated readout of Multikine in the IT-MATTERS clinical trial, the company also has a platform technology in development that has impressive potential in treating a number of human diseases. This platform is known as the Ligand Epitope Antigen Presentation System, or LEAPS. The technology has the potential to modulate the way the immune system reacts to disease-associated antigens and has shown promise in six different animal disease models. The approach may be effective in infectious diseases, cancers, autoimmune diseases and allergies among other disorders.


View Exhibit I - Corporate Logo1

The first LEAPS technology patent was issued in 1987. Since that time, development of the LEAPS platform has continued with the most recent patent issued this year centered on preferentially directing the immune response towards a cellular, humoral or mixed pathway. The LEAPS approach is appropriate for diseases where antigenic epitope sequences have been identified, such as infectious diseases, some cancers, some autoimmune diseases and allergies and it can modulate the autoimmune response. CEL-SCI is currently generating the data to enable it to submit an Investigational New Drug (IND) application. The IND will allow CEL-SCI to advance the LEAPS platform into the clinic where it will be evaluated as a therapeutic vaccine for rheumatoid arthritis (RA).

Two National Institute of Health (NIH) grants have been awarded to CEL-SCI to support the IND-enabling studies. These efforts will comprise a portion of the package needed to support the IND application required to initiate clinical trials for the company’s LEAPS candidate, CEL-4000 for RA.

The LEAPS technology has followed a long and winding path from when it was first conceived by Dr. Daniel Zimmerman in the late 1980s. Initial work using LEAPS conjugates was performed in herpes simplex type 1 (HSV-1) virus and was funded with grants and a collaboration with other companies using private funding. In 1995, CEL-SCI acquired the technology and work on HSV-1 continued. CEL-SCI’s efforts demonstrated potential efficacy in the murine autoimmune myocarditis model, supported by a Phase 1 SBIR grant from the National Heart and Lung Institute (NHLI), further validating the technology. Additional research in oncology, influenza (including H1N1 in collaboration with the NIAID) and arthritis models continued to show promise for LEAPS conjugates. Work on specific candidates, including CEL-2000 and CEL-4000 progressed through the 2009 economic downturn supported by economic development grants.

NIH Grant
In 2014, the NIH awarded a Phase 1 grant of $225,000 to CEL-SCI to support feasibility and proof of concept work for CEL-4000. The goal of the Phase 1 was to establish the technical merit, feasibility and commercial potential of the subject vaccine for the LEAPS Technology for RA. This was followed by a Phase 2 Small Business Innovation Research (SBIR) grant in late 2017 which has advanced the efforts achieved in the SBIR Phase 1. The commercialization track funding totals $1.725 million and will be received over a multi-year period which will continue until August 2020. The Phase 2 grant continues these efforts and specifically for CEL-SCI and LEAPS, helps press forward with requirements for an IND application, including funding good manufacturing process (GMP) manufacturing, IND enabling studies and additional mechanism of action studies.

The $1.725 million in awards were provided specifically from the National Institute of Arthritis Musculoskeletal and Skin Diseases, a center of the NIH that has recognized the commercial potential of the LEAPS technology as a possible treatment for RA. Pre-clinical work has been conducted at the Rush University Medical Center in Chicago in the laboratories of Tibor Glant, MD, Ph.D. Published work so far has demonstrated that administration of a proprietary peptide employing LEAPS has prevented the development and reduced the severity, including inflammation, of experimental proteoglycan induced arthritis in animal models.

How Does it Work?
LEAPS modulates the behavior of T cells by combining T cell binding ligands with small, disease associated peptide antigens. The technology creates a heteroconjugate in which an immune cell binding ligand (ICBL) is attached to a known antigenic peptide related to the disease under study. The ICBLs convert small peptides into immunogens which are directed towards a Th1 or Th2 response depending on type of ICBL-Antigen combination. LEAPS peptide conjugates can define the direction of the response towards a pro-inflammatory response (Th1 or TH17) or an anti-inflammatory/regulatory response (Th2 or Treg).

LEAPS peptides consist of an ICBL conjugated to a disease-related peptide (self or autoepitope) in the case of autoimmune conditions. In CEL-4000, the DerG ICBL from the human MHC class II β chain provides T helper cell 2 (Th2/Treg) polarizing activity, which may reduce Th1 or Th17 driven autoimmune responses present in RA. The mechanism of action is thought to modulate the underlying immune responses responsible for disease progression for proteoglycan induced arthritis (PGIA) and PG G1-domain induced arthritis in animal models of the disease.

LEAPS can prevent an undesired autoimmune response against a specific peptide where the peptide is conjugated to an immuno-modulating carrier, such as the CEL-4000 LEAPS peptide in RA indications. This is achieved by modulating the response of the various classes of T helper cells. LEAPS may represent an improvement over current RA therapies because it switches the immune response away from the pathological response rather than causing the removal of cytokines such as TNFα IL1β, or IL17. These cytokines are important participants in the normal immune system process to fight certain invaders such as microbial agents, parasites, oncological conditions allergies.

LEAPS can potentially improve upon the treatments provided by the biologics that are now considered the leading-edge treatment for RA. Rather than focus on a single epitope as the biologics do, LEAPS can target multiple epitopes and direct an immune response outcome from several directions.


View Exhibit II - LEAPS CEL-4000 Pathway in RA2

Rheumatoid Arthritis (RA)
RA is an autoimmune disease where the immune system recognizes self-antigens as foreign, thereby stimulating inflammation and resulting in an inflammatory response which leads to the breakdown of the normal functioning of the joints. It occurs when the immune system attacks the synovium, a connective tissue that lines the inner surface capsules of synovial joints and tendon sheath, causing inflammation. RA most commonly affects the joints of the hands, feet, wrists, elbows, ankles and the spine in spondylitis. A characteristic specific to RA as compared to other types of arthritis is its symmetry in the joints on each side of the body. While there are current treatments for RA, they do not consistently provide relief and can have toxic side effects and leave the patient at risk to infection and in some cases blood-born cancer.

Prevalence and Incidence
About 1.5 million people are affected with RA in the United States. The disease occurs in three of every 10,000 people globally and incidence increases with age. The incidence of the disease peaks between the ages of 30 and 60 and affects women at a higher rate than men.

Treatment
Treatment for RA includes the use of anti-inflammatories such as non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs). DMARDs can slow disease progression by modifying the immune system and include methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine among others. These medications are associated with unpleasant side effects including diarrhea, nausea and stomach pain among others. Anti-TNFs (tumor necrosis factor)3 biologics are the newest entry into the RA treatment space and may be used in conjunction with DMARDs. Side effects for anti-TNFs such as enteracept (Enbrel) and adalimumab (Humira) include serious infections, sepsis, risk of cancer and anaphylaxis.

CEL-4000
CEL-SCI’s lead LEAPS candidate is designated CEL-4000 and is under development for the potential treatment of RA. Final work leading to an IND application is being performed for submission to the FDA. Preclinical studies suggest that CEL-4000 could be effective against RA in cases where a Th1 signature cytokine (IFN-γ) is dominant. CEL-SCI believes that the candidate could provide a disease-specific therapy that is significantly less expensive and will act at an earlier step in the disease process than current therapies. It also may be useful in patients not responding to existing rheumatoid arthritis therapies.

Development Timeline
CEL-SCI is developing the components needed to compile and IND application for CEL-4000. Additional animal model studies need to be completed before the final IND-enabling data is available and we think the company could have an IND ready by next year. Contract research organization (CRO) selection, proper trial design and supportive data generation are all necessary before the IND can be finalized. Human Phase I trial design anticipates first enrolling healthy volunteers then transitioning to early stage RA patients in a Phase Ia trial. Results from this early safety and preliminary efficacy clinical work will determine the structure and design of later proof of concept studies.

Summary
CEL-SCI is on the cusp of the conclusion of its global pivotal Phase III trial for Multikine, a novel immuno-oncology treatment for head and neck cancer. While the majority of value and attention is focused on this important effort, the company has a deeper pipeline which includes a vaccine-based treatment designated LEAPS. The LEAPS platform can potentially modulate the response of the immune system to treat a broad span of disease including cancer, influenza, autoimmune disease and others. The lead candidate, designated CEL-4000 is the subject of an IND which may be submitted to the FDA next year. We see CEL-4000 and other potential conjugates from the LEAPS platform as a compelling follow up development effort upon the anticipated commercialization of Multikine.

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1. Source: CEL-SCI webpage. https://cel-sci.com/


2. Corporate Power Point presentation provided by CEL-SCI


3. Tumor necrosis factor (TNF)-α antagonists, such as infliximab (IFX), etanercept (ETN), adalimumab (ADA), golimumab (GOLI) and certolizumab pegol (CZP) are widely used for the treatment of RA.