Cyto-014

The first BoNT molecule specifically engineered for improved safety

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Cyto-111

Intra-neuronal Delivery via Antibody Fusion Proteins (AFPs)

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Development Programs

Intra-neuronal Antibody Development Programs

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Cyto-014

The Market Need

Class labeling for all FDA-approved BoNT 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 BoNT 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 75.8% of patients, and that shorter treatment intervals could improve outcome in 66% of patients (Bensmail et al 2014). An international survey of patients reported that although BoNT 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 BoNT molecule engineered to improve safety compared to currently available BoNT products. Cyto-014 is manufactured using CytoDel’s proprietary platform for producing recombinant BoNT 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 BoNT 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 finding have also been supported by discussions with key opinion leaders in the field. Safety advantages are also expected to impact the market for other BoNT indications over time, and potentially grow the overall BoNT market.

Intellectual Property:

CytoDel has been granted a US patent protecting the molecular design principle used to create “safer” BoNT pharmaceuticals, and which includes a genus first claim (US 9,315,549 B2).

Regulatory Pathway:

The pathway to FDA approval for BoNT pharmaceuticals is clearly outlined by the published approval summaries for pharmaceutical BoNT products currently on the market. CytoDel intends to follow the well-traveled road of its predecessor products, helping to minimize the risk, time and cost to FDA approval.

Cyto-111

The Market Need

Biodefense:

Botulinum neurotoxin (BoNT) is considered a Tier 1 weapon of mass destruction. BoNT has no odor or taste, a single gram is sufficient to kill 1 million humans via inhalation, and currently there are no treatments to reverse symptoms. All currently available treatments for botulism are antibody products which can only neutralize toxins in the blood circulation. Once the toxin has entered the neurons controlling respiration, generally 24-72 hours after exposure depending on the dose, antibody-based products become ineffective. Standard antibodies cannot access toxins already inside neurons, and thus HBAT (Heptavalent Botulism AntiToxin, Emergent BioSystems, MD), the only FDA-approved antitoxin, is only effective while the toxin remains in the circulation.

Orphan Drug Indications:

An additional orphan market need has been identified for Cyto-111, treating naturally occurring botulism when patients present at longer than 48 hours post-exposure. A recent post-market study of the safety and effectiveness of HBAT reported that the product was not effective when patients present more than 48 post-exposure (Yu et al, 2018), leaving open an orphan indication for Cyto-111. Cyto-111 will also be developed as a treatment for iatrogenic problems that can arise after pharmaceutical BoNT treatments, such as the dysphagia that can occur while treating cervical dystonia with BoNTs. These iatrogenic problems cause clinicians to dose on the side of caution when treating large muscles. The availability of a therapeutic that can reverse undesirable BoNT-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:

Cyto-111 uses CytoDel’s Intraneuronal Delivery Platform to deliver an antibody to the inside of BoNT-intoxicated neurons, thereby allowing rescue after the toxin has entered neurons and is causing symptoms. This “Trojan horse” approach uses an inactivated BoNT derivative to carry the antibody inside BoNT-intoxicated neurons. Cyto-111 can uniquely reverse symptoms because it can deliver its antibody to toxin already inside the neuron. In biodefense scenarios, this significantly extends the post-exposure period during which treatment can reverse symptoms and save lives by minimizing the need for long-term artificial respiration. As a therapeutic for naturally occurring botulism, Cyto-111 is intended to extend the therapeutic window beyond the current 48-hour limit, during which HBAT has proven to be effective.

Cyto-111 is effective at times post-exposure when standard antitoxin is ineffective, especially when the toxin is already inside neurons and causing symptoms. Cyto-111 is the first drug to deliver an antibody that inactivates BoNT inside neurons. Efficacy has been demonstrated in three species including that have been used for prior NDA approval via the Animal Rule.

Intellectual Property:

Five US patents have been granted (methods & composition) that protect CytoDel’s technology platform. Product-specific patents have additionally been granted in the EU and are pending in the US.

Regulatory Pathway:

Due to the severity of the disease, Cyto-111 is likely to be eligible for approval under the Animal Rule, which enables approval without Phase 2 or 3 efficacy studies in humans. Approval is based on a Phase 1 safety study, followed by two pivotal animal studies. For naturally occurring botulism, CytoDel intends to seek designation for Cyto-111 as an Orphan Drug.

Development Programs

CytoDel’s platform for intra-neuronal 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 vehicle.

The platform is modular by design and can be customized to diverse intra-neuronal targets by modular replacement of its single-chain antibody domain. Work-in- progress suggests a significant opportunity to treat diverse neurologic diseases by direct delivery to intra-neuronal targets that were previously inaccessible to standard antibodies.