Fleximer Platform Overview

Chemical structure of Fleximer

Fleximer is a novel, biodegradable and bio-inert polymer that can be chemically linked to small molecules, biologics and nucleic acids to enhance their pharmacokinetics and safety. Attaching Fleximer to existing and experimental agents can transform the molecules into new, patentable drugs with potentially superior properties. The polymer is derived from clinically safe GMP dextran, a naturally occurring carbohydrate. Fleximer was invented at Massachusetts General Hospital, which licensed the technology exclusively to Mersana. Mersana's internal pipeline was generated with the Fleximer platform.

Fleximer has demonstrated the following important and differentiating qualities:

Can be conjugated to small molecules, biologics and nucleic acids (e.g. siRNA)
Improves the solubility of conjugated drugs, including small molecules
Provides longer drug exposure, resulting in increased tumor tissue uptake of the active drug
Provides enhanced biodistribution
Offers a tunable half-life and improved pharmacokinetics
Can be conjugated using a variety of linker technologies, each developed for specific applications and matched to a specific therapeutic program's goals
Can deliver more than one active agent in a single molecular entity, with controlled release of each drug, providing potential synergistic activity
Lacks immunogenicity
Is fully biodegradable, unlike several other drug delivery approaches
Has demonstrated safety in numerous studies - general toxicity and immunotoxicity
Has demonstrated manufacturing advantages - low COGS, scalable GMP process in place, excellent stability
Creates new intellectual property with each new product conjugate

The Fleximer platform has broad and versatile applications across therapeutic categories and for enhancing the delivery of all types of therapeutics:

> Small Molecules
> Biologics
> siRNA

Small Molecules

Conjugating small molecules to Fleximer provides important therapeutic advantages. Many anti-cancer small molecules are not readily soluble; however, solubility can be greatly improved through linking these agents to Fleximer. Fleximer can also improve the pharmacokinetics of small molecules with short half-lives, allowing the drug to circulate in the bloodstream for a longer period of time. Improving drug solubility and pharmacokinetics can potentially result in increased efficacy and decreased toxicity - longer drug exposure may decrease the dosage needed, resulting in decreased toxicity, and may also result in increased uptake of the drug into tumor tissues.

Additionally, linking Fleximer to small molecules offers the opportunity to incorporate targeting or synergistic molecules in the same molecular entity, potentially further enhancing therapeutic activity.

Biologics

Recombinant biologic-based drugs, such as proteins and peptides, often have a short half-life within the body. Other delivery approaches, such as pegylation, can extend half-life, but the agents are not fully biodegradable. Fleximer-conjugated biologics not only have increased half-lives, but are also fully biodegradable, which improves their safety profile, especially for high dose agents or those intended for chronic administration. Fleximer can dramatically extend the half-life of biologics, making these drugs potentially last much longer in the circulation. For example, Fleximer conjugation of Interferon α can extend the half-life from 11 minutes to >12.8 hours. This longer exposure may decrease the dosage needed, resulting in decreased toxicity.

Further, linking Fleximer to a biologic agent offers the opportunity to also link additional therapeutics to the same molecular entity, taking advantage of potentially synergistic and increased therapeutic activity.

Greater than 50x longer circulation time with Fleximer-IFNα

siRNA

Short-interfering RNA (siRNA)-based drugs hold significant promise for the treatment of an array of diseases; however, a major obstacle to turning this promising new class of drugs into viable therapies is solving the challenge of how best to deliver these nucleic acid-based molecules to tumors and other diseased tissues. Fleximer is being developed as a universal system for customized delivery of siRNA drugs across multiple tissue types. Fleximer-siRNA delivery conjugates have the potential to:

Target siRNA to the desired tissues,
Enable siRNA molecules to cross cell membranes and enter the cytosol,
Enable silencing of gene expression, and
Avoid undesired immunostimulatory effects.

Fleximer's ability to carry multiple payloads on a single molecule, its demonstrated lack of toxicity in humans, and its ease of manufacturing may address the targeted delivery and cell-uptake challenges experienced thus far with siRNA delivery.

Fleximer: A unique and promising approach for systemic siRNA delivery

Overview Publications and Published Abstracts		Share Overview Chemical structure of Fleximer Fleximer is a novel, biodegradable and bio-inert polymer that can be chemically linked to small molecules, biologics and nucleic acids to enhance their pharmacokinetics and safety. Attaching Fleximer to existing and experimental agents can transform the molecules into new, patentable drugs with potentially superior properties. The polymer is derived from clinically safe GMP dextran, a naturally occurring carbohydrate. Fleximer was invented at Massachusetts General Hospital, which licensed the technology exclusively to Mersana. Mersana's internal pipeline was generated with the Fleximer platform. Fleximer has demonstrated the following important and differentiating qualities: Can be conjugated to small molecules, biologics and nucleic acids (e.g. siRNA) Improves the solubility of conjugated drugs, including small molecules Provides longer drug exposure, resulting in increased tumor tissue uptake of the active drug Provides enhanced biodistribution Offers a tunable half-life and improved pharmacokinetics Can be conjugated using a variety of linker technologies, each developed for specific applications and matched to a specific therapeutic program's goals Can deliver more than one active agent in a single molecular entity, with controlled release of each drug, providing potential synergistic activity Lacks immunogenicity Is fully biodegradable, unlike several other drug delivery approaches Has demonstrated safety in numerous studies - general toxicity and immunotoxicity Has demonstrated manufacturing advantages - low COGS, scalable GMP process in place, excellent stability Creates new intellectual property with each new product conjugate The Fleximer platform has broad and versatile applications across therapeutic categories and for enhancing the delivery of all types of therapeutics: > Small Molecules > Biologics > siRNA Small Molecules Conjugating small molecules to Fleximer provides important therapeutic advantages. Many anti-cancer small molecules are not readily soluble; however, solubility can be greatly improved through linking these agents to Fleximer. Fleximer can also improve the pharmacokinetics of small molecules with short half-lives, allowing the drug to circulate in the bloodstream for a longer period of time. Improving drug solubility and pharmacokinetics can potentially result in increased efficacy and decreased toxicity - longer drug exposure may decrease the dosage needed, resulting in decreased toxicity, and may also result in increased uptake of the drug into tumor tissues. Additionally, linking Fleximer to small molecules offers the opportunity to incorporate targeting or synergistic molecules in the same molecular entity, potentially further enhancing therapeutic activity. Biologics Recombinant biologic-based drugs, such as proteins and peptides, often have a short half-life within the body. Other delivery approaches, such as pegylation, can extend half-life, but the agents are not fully biodegradable. Fleximer-conjugated biologics not only have increased half-lives, but are also fully biodegradable, which improves their safety profile, especially for high dose agents or those intended for chronic administration. Fleximer can dramatically extend the half-life of biologics, making these drugs potentially last much longer in the circulation. For example, Fleximer conjugation of Interferon α can extend the half-life from 11 minutes to >12.8 hours. This longer exposure may decrease the dosage needed, resulting in decreased toxicity. Further, linking Fleximer to a biologic agent offers the opportunity to also link additional therapeutics to the same molecular entity, taking advantage of potentially synergistic and increased therapeutic activity. Greater than 50x longer circulation time with Fleximer-IFNα siRNA Short-interfering RNA (siRNA)-based drugs hold significant promise for the treatment of an array of diseases; however, a major obstacle to turning this promising new class of drugs into viable therapies is solving the challenge of how best to deliver these nucleic acid-based molecules to tumors and other diseased tissues. Fleximer is being developed as a universal system for customized delivery of siRNA drugs across multiple tissue types. Fleximer-siRNA delivery conjugates have the potential to: Target siRNA to the desired tissues, Enable siRNA molecules to cross cell membranes and enter the cytosol, Enable silencing of gene expression, and Avoid undesired immunostimulatory effects. Fleximer's ability to carry multiple payloads on a single molecule, its demonstrated lack of toxicity in humans, and its ease of manufacturing may address the targeted delivery and cell-uptake challenges experienced thus far with siRNA delivery. Fleximer: A unique and promising approach for systemic siRNA delivery