The Market Need
CytoDel was founded to address the limitations of the only available countermeasure to weaponized BoT, a polyclonal antitoxin that can only inactivate toxin in the circulation, BAT (Heptavalent Botulism AntiToxin, Emergent BioSystems, MD). Antitoxins cannot reverse symptoms caused by the intraneuronal toxin. When used in patients with naturally occurring botulism, mechanical ventilation is required in the majority of patents to preserve life. A recent post-market study of the safety and effectiveness of BAT reported that the product was not effective when patients present more than 48 post-exposure (Yu et al, 2018. CytoDel has engineered rBoT derivatives that can be used as a “Trojan horse” to deliver therapeutic antibodies to the inside of BoT-intoxicated neurons, enabling development of the first BoT antidote that targets the toxin after it has been internalized into neurons.
Orphan Drug Indications:
Two additional orphan markets have been identified for Cyto-111: 1) Treating naturally occurring botulism when patients present at longer than 48 hours post-exposure). 2) As a treatment for iatrogenic adverse events that can arise after pharmaceutical BoT treatments, such as the dysphagia that can occur while treating cervical dystonia with BoT. Approximately 3000 adverse events that specifically use the word “overdose” are reported to FDA annually. These iatrogenic problems cause clinicians to dose on the side of caution, particularly when treating large muscle groups. The availability of a therapeutic that can reverse undesirable BoT-related side effects is expected to also increase therapeutic effectiveness by providing an additional margin of comfort with respect to dosing.
Cyto-111 Product Attributes:
CytoDel’s lead product, Cyto-111, is the first post-symptomatic antidote to BoT serotype A1 with an intraneuronal mechanism of action. The safety and effectiveness of Cyto-111 has been demonstrated in three species.
As a therapeutic for naturally occurring botulism, Cyto-111 is intended to extend the therapeutic window beyond the current 48-hour limit, during which BAT has proven to be effective.
Five US patents, with multiple foreign counterparts, have been granted (methods & composition) that protect CytoDel’s technology platform. Additional patents have been granted in the EU, and Japan, and are pending in the US.
Due to the severity of natural botulism and botulism caused by weaponized BoT, Cyto-111 is likely to be eligible for approval under the Animal Rule, which enables approval without Phase 3 efficacy studies in humans. Approval is based on a Phase 1 safety and dosing study, followed by two pivotal animal studies. For naturally occurring botulism, CytoDel intends to seek designation for Cyto-111 as an Orphan Drug.
The Market Need:
Class labeling for all FDA-approved BoT products includes a Black Box warning, noting that serious adverse events and death have been reported, particularly when using the large doses needed to treat large muscle group dystonia. The labeled maximum tolerated dose (MTD) for BoT products is correctly conservative, and intended to minimize the risk of off-target or systemic adverse events. However, this same MTD limitation is considered by many clinicians to also limit clinical outcomes in some indications. A cross-sectional survey of physicians who treat post-stroke spasticity estimated that a higher permitted label dose could improve therapy outcome in 75% of patients (Bensmail et al 2014). An international survey of spasticity patients reported that although BoT treatment improved stiffness in 81% of patients, only 43% had reduced pain, and only 31% had improvement in activities of daily living (Barnes et al, 2017).
Cyto-014 Product Attributes:
Cyto-014 is the first de novo designed rBoT molecule engineered to improve safety compared to currently available BoT products. Cyto-014 is produced using CytoDel’s proprietary platform for producing rBoT derivatives targeting specific clinical needs. It is specifically indicated for large muscle group dystonia and designed to improve both safety and effectiveness outcomes. The safety improvement is a consequence of Cyto-014’s reduced systemic toxicity and was confirmed in an established animal model for BoT modulation of muscle tonicity. The intended improvement in effectiveness outcomes is a consequence of the 4-fold improvement in MTD observed in these animal models.
The potential for Cyto-014 to improve clinical efficacy outcomes, over and above its safety advantages, is a defining characteristic expected to be important to both clinicians and patients. These findings have also been supported by discussions with key opinion leaders in the field. Safety advantages are expected to grow the market for multiple BoT indications over time, potentially growing the overall BoT market significantly.
CytoDel has been granted a US patent protecting the molecular design principle used to create “safer” BoT pharmaceuticals, and which includes a genus first claim (US 9,315,549 B2).
The pathway to FDA approval for BoT pharmaceuticals is clearly outlined by the published approval summaries for pharmaceutical BoT products currently on the US market. CytoDel intends to follow the well-traveled road of its predecessor products, helping to minimize the risk, time and cost to FDA approval.
CytoDel’s platform for intraneuronal antibody delivery has been demonstrated to be safe and effective in three animal species. This platform provides the first successful approach to specifically deliver functional antibodies to the cytoplasm of neurons without a viral vector.
The platform is modular by design and can be customized to diverse intra-neuronal targets by replacement of its single-chain antibody domain. Work-in-progress suggests a significant opportunity to treat diverse neurologic diseases by direct delivery to intraneuronal targets that were previously inaccessible to standard antibodies.