May 15, 2009 (Vol. 29, No. 10)

Administering Novel Therapeutics and Improving Drug Safety Serve as the Driving Forces

Delivery methods to improve the safety and efficacy of existing drugs, extend their clinical applications, and enable delivery of novel products were the focus of Arrowhead Conferences’ “Drug Delivery Summit”, held earlier this month. Presenting companies discussed topics including the inherent challenges of RNAi delivery, delivery of ocular therapeutics to treat serious eye disease, and current issues in aerosol delivery development.

Aegis Therapeutics’ delivery platforms, based on its Intravail® transmucosal absorption agents, were developed at the University of Alabama Medical School. Edward Maggio, Ph.D., Aegis’ CEO, discussed progress with the Intravail platform and its applications for peptide-based drugs at the meeting.

Intravail technology comprises chemically synthesized transmucosal absorption enhancement agents that allow noninvasive systemic delivery of peptide, protein, nucleotide-related, and other small and large molecule drugs. These drugs may previously have been deliverable by injection only. 

According to Dr. Maggio, Aegis has established the feasibility of intranasal administration using Intravail technology for a variety of therapeutic molecules, including parathyroid hormone, beta interferon, calcitonin, and a new anti-obesity peptide.

Aegis is currently focused on peptide drug delivery, explained Dr. Maggio, who added that the therapeutic use of physiologically active peptides has been limited compared to small molecules and other chemically synthesized compounds.

“Peptides and proteins remain susceptible to destruction in the GI tract and, with few exceptions, require administration via injection in order to achieve therapeutic levels,” Dr. Maggio said. Aegis’ technology uses alkylsaccharides to reduce peptide and protein aggregation during manufacturing processes and in final formulations, thereby, enhancing stability and reducing undesirable immunogenicity, he added.

“When you can increase the bioavailability of a peptide drug, you can increase its applications,” Dr. Maggio noted. As an example, he cited his company’s work with intranasal calcitonin. “Calcitonin has only 3% on average bioavailability when delivered intranasally in current formulations used to treat osteoporosis. And while many important applications that require higher blood levels for efficacy have been described in the medical literature, the current calcitonin nasal spray is inadequate. 

“Our technology provides a 12-fold increase in calcitonin blood levels via intranasal delivery, therefore, enhancing the potential for other clinical uses for calcitonin, for example as an analgesic for opioid-resistant metastatic bone cancer pain.”

Aegis Therapeutics has established the feasibility of intranasal administration using its Intravail technology for a variety of therapeutic molecules.

Nanocochleate Technologies

Niraj Vasisht, Ph.D., vp, product development at BioDelivery Sciences (BDSI), described BDSI’s delivery platforms including its Bioral™ oral delivery system and its BioErodableMucoAdhesive (BEMA™) technology. 

The company’s first drug candidate using Bioral technology for oral delivery of the antifungal agent amphotericin B (Bioral Amphotericin B) entered Phase I trials last year. The company reported initial results in February that identified doses that were well tolerated with no meaningful changes in laboratory safety values. Plasma concentrations of amphotericin B were comparable to those seen in prior animal toxicology studies using the same formulation, according to Dr. Vasisht.

Bioral technology encapsulates a drug in a lipid crystal to allow its oral administration. Alternating layers of lipids spiral around a drug molecule, potentially protecting it from degradation by acid or digestive enzymes in the stomach. 

According to BDSI, unlike other technologies, Bioral protects the drug without chemically bonding to it, can be used for a wide variety of drugs, and facilitates oral delivery of drugs that currently require intravenous administration.

The company’s lead product, Onsolis™ (fentanyl buccal soluble film), consists of a small, dissolvable polymer film formulated with the opioid analgesic, fentanyl.

Applied to the buccal lining of the cheek, Dr. Vasisht said that BEMA technology delivers a dose of the drug quickly, and that Onsolis can manage breakthrough cancer pain in patients already receiving opioid treatment for underlying persistent cancer pain. Biodelivery Systems’ NDA for Onsolis is currently under late-stage review by the FDA.

A second product utilizing the BEMA drug delivery technology, BEMA Buprenorphine, is also under clinical development for various pain conditions.

Drug Encapsulation

Carigent Technologies is developing a delivery platform that allows high-density application of molecules to the surface of biodegradable, polymeric particles as well as high loading of RNAi material into FDA-approved polymers. The company’s technology, based on exclusive licenses from Yale and Cornell Universities, combines well-characterized, safe materials with a method of adhering ligands to particle surfaces at high density, thereb, allowing delivery of multiple therapeutic modalities.

“While our polymers have been used in humans for decades, people thought you couldn’t load them with potential drugs such as oligonucleotides because of charge incompatibilities and other factors,” Seth Feuerstein, M.D., J.D., president, noted. “It turns out you can; we achieve high loading and targeted delivery due to our symbiotic technologies.”

Carigent’s PLGA-based particles for drug loading and delivery range in size from tens of nanometers to hundreds of microns. Dr. Feuerstein said the company’s platform allows sustained release of therapeutic agents, tethering of surface ligands, targeting of therapy to a particular physiological site, and the ability to combine multiple agents into one vehicle made primarily from FDA-approved materials.

Using its proprietary process, Carigent can encapsulate the therapeutic of interest within the polymer matrix, while attaching choice ligands to the surface using amphiphilic functional groups at high densities, according to Dr. Feuerstein. The delivery vehicles are capable of targeted delivery, internalization by cells and tissues, and sustained release of the encapsulated therapeutic over a period of days to months. 

This combination of differentiating characteristics, he said, allows delivery of multiple therapeutic modalities such as RNAi, peptides, small molecules, and therapeutic vaccines as well as flexibility in targeting the drug delivery system for a variety of disease states and delivery routes and enhanced in vivo circulation times.

Dr. Feuerstein, in referring specifically to the significant challenge of siRNA therapeutics delivery, said lead delivery programs have, for the most part, revolved around lipid-derived and/or cationic delivery systems. “Carigent has designed its RNAi delivery systems for both direct delivery (injection into organs and topical applications) and IV delivery. Our system can protect the RNAi until it gets where it needs to go, and we also can design our particles for sustained RNAi release. This can’t be done with lipids.” Dr. Feuerstein believes that multiple delivery vehicles will be required for various oligos and their specific applications. “We can’t solve every delivery problem with our technology, but we can deliver a lot of oligos to a lot of relevant targets.”

Ophthalmic Therapeutic Peptides

Potentia Pharmaceuticals develops therapeutics to treat age-related macular degeneration (AMD) and other inflammatory ocular diseases. Potentia cofounder and COO Pascal Deschatelets, Ph.D., described the company’s approach to optical delivery of its drug candidate POT-4 for AMD treatment. 

Lack of delivery options for ocular therapeutics continues to complicate the development of new drugs for severe eye disease, according to Dr. Deschatelets. Most drugs targeted to the back of the eye require frequent intravitreal injections, an uncomfortable procedure for patients that is associated with potential serious complications. The need for frequent intravitreal injection poses particular concern since many AMD patients may require life-long treatment.

Rather than targeting angiogenesis as Genentech’s Lucentis does, POT-4 blocks activation of the complement system. POT-4, a synthetic 13-mer cyclic peptide, is structurally based on compstatin, a small molecule discovered at the University of Pennylvania.

POT-4 works by binding to and inactivating the enzyme that cleaves C3, a key protein component of the complement cascade, into its active form. While a normally protective biochemical cascade that occurs in response to the presence of bacteria or other foreign substances, inappropriate or untimely complement activation can trigger organ transplant rejection reactions and other disorders that may include macular degeneration. 

Over the past several years, genetic studies have identified polymorphisms in complement related genes that are associated with increased risk of AMD. Dr. Deschatelets explained that while “nobody really knows what causes AMD, genomic analysis has hinted that the complement pathway proteins are linked to all stages of macular degeneration and may constitute reasonable therapeutic targets.

“Given the identification of a variety of complement-related genes encoding multiple proteins that promote local inflammation, tissue damage, and upregulation of angiogenic factors such as vascular endothelial growth factor in the eye, we believe that POT-4 holds the potential to be effective against both dry and wet AMD.”

Aerosol Drug Development

James Fink, Ph.D., an aerosol researcher who is currently a scientific advisor to Aerogen, talked about the continuing need for aerosol delivery of protein, peptides, and other drugs despite the barriers created by the commercial failure of Pfizer’s Exubera, the first inhalable insulin.

According to Dr. Fink, Exubera, approved for use by the FDA in January 2006, was intended to bridge the transition from oral medications to injected insulin. Pfizer removed it from the market less than two years later, citing limited acceptance by physicians, patients, and third-party payers.

Further, during Exubera’s clinical trial program, some Exubera-treated patients developed lung cancer. While all of the Exubera patients who developed cancer were former cigarette smokers, and the incidence in the Exubera group was lower than the broader demographic of cancer in smokers, the reports nonetheless led development partner Nektar Therapeutics to terminate its inhaled insulin programs.

Citing challenges of developing aerosol drug formulations in the post-Exubera world, Dr. Fink said that “within weeks following the Exubera cancer scare, all but one of the pharma companies announced their withdrawal from developing inhaled insulin products.” Further, he noted that, “the Exubera story dampened enthusiasm for pulmonary drug delivery programs with other large molecule proteins and peptides.” 

Dr. Fink believes that Exubera’s, 17-year development saga provided some valuable lessons. Its dry powder formulation had an excellent shelf life, eliminating the cold-chain requirements associated with injectible insulin. Exubera, the first active dry powder inhaler, also provided high-efficiency lung delivery of drug independent of patient inspiratory flow. Most importantly, he said, Exubera proved that a large molecule protein could be inhaled multiple times each day with good therapeutic effect and minimal adverse events (in nonsmokers).

Dr. Fink described recent success with liquid aerosol immunization in the WHO/IVR-supported program for development of an aerosol measles vaccine. “Inhaled measles vaccine can provide five doses via inhalation versus one with the same volume of injected vaccine, with comparable immunogenicity,” he said.

“This program, now entering pivotal trials in India could ultimately support effective vaccination for up to 300 million children annually without risk of exposure to blood-borne pathogens.” Efforts are currently under way to develop dry powder options for inhaled vaccine delivery. 

Despite setbacks with Exubera, Dr. Fink predicted an exciting era ahead for pulmonary delivery in the post-Exubera world.

Patricia F. Dimond, Ph.D. ([email protected]), is the president of BioInsight Consulting.

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