Getting There

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By Deborah Komlos

Not only must a drug work — it must also get to where it is needed most.

Drug delivery is providing a challenging but exciting and practical application of research efforts in which technologies are building upon existing knowledge and biotech tools, much like the fields of proteomics and metabolomics have taken the ‘next steps’ after genomics. Firms focused on drug delivery are looking at how to optimize drug administration with a key goal in mind: to increase drug efficacy and ultimately improve the quality of life for patients with serious conditions, such as cancer, asthma and hyperactive immune systems.

Among Canadian firms developing core drug-delivery platforms, the use of liposomal technologies through drug infusion has become a common approach, providing the benefits of increased precision of drug delivery and reduced side-effects. However, oral administration routes via ingestion and inhalation are also among the novel technologies in the works. In addition to product site-specificity, providing controlled drug release over strategic time frames is a prominent focus of the various strategies.

The technologies of some of the Canadian drug-delivery firms that presented in May at Toronto, Ont.-held BioFinance 2003, a symposium on financing life science companies, are highlighted here.

Enabling Pills

Reformulating existing drugs to provide improved, oral sustained-release medications is the focus of Laval Que.-based Labopharm Inc. The firm has developed a cornstarch-based excipient called Contramid®, which permits controlled drug release over 24 hours. A once-daily version of the analgesic tramadol is Labopharm’s lead product, which is entering two Phase III clinical trials in the U.S.

Group leader of Platform Research at Labopharm, François Ravenelle, PhD says the technology plays on the natural, self-assembling properties of cornstarch.

“How Contramid works is that we mix the two powders, drug and Contramid, and we press this into a tablet. When water penetrates this tablet, the starch grains self-assemble or crystallize,” Ravenelle says. “So the tablet swells to a limit and then water inside is just dissolving the drug, which is just coming out slowly.

“The surface has a different morphology than the interior of the tablet to some extent, not a huge difference but there is a difference, and this surface membrane has a diffusion coefficient that is limited, so that is where the drug-controlled release is from,” he says.

Ravenelle says the system is advantageous as the tablet can be loaded with up to 70 per cent drug while maintaining its controlled- release characteristics.

Labopharm has also applied its Contramid technology to the creation of biodegradable implant tablets, which contain the antibiotic ciprofloxacin to treat or prevent bone infection. Similarly to the pill form, the implants swell in the physiological aqueous medium, Ravenelle says, and in this case, can release the drug over a month’s time.

Lipid-based Vehicles

Inex Pharmaceuticals Corp. (Burnaby, BC) has approached drug delivery via its two liposomal delivery platforms that are applied to already-approved anticancer drugs. Its lead product, Onco TCS, is an IV-administered proprietary drug based on the off-patent cancer drug vincristine, and uses the firm’s Transmembrane Carrier System (TCS) as the drug-delivery technology. Filing of a New Drug Application (NDA) to seek regulatory marketing approval for Onco TCS from the U.S. Food and Drug Administration for the treatment of relapsed non-Hodgkin’s lymphoma is expected late in the third quarter or early fourth quarter of 2003.

“For the Targeted Chemotherapy platform, what really makes our technology unique is that we have been able to develop compositions of liposomal carriers where we can control very precisely the release rate of the encapsulated drug, and previous liposomal formulations did not accomplish that,” says David J. Main, president and CEO of Inex Pharmaceuticals.

“Vincristine is an M-phase inhibitor, and it has been demonstrated that if you can prolong the exposure of vincristine to a tumour site to approximately 72 hours, you can get maximal efficacy,” Main explains. “So we have designed a carrier system that has an approximately 72-hour release profile for vincristine.”

Because the created carrier particles are so small and have prolonged bloodstream circulation, they tend to accumulate at tumour sites, Main says, which have leaky vasculature. After delivery, the lipid vehicles — made of naturally occurring lipids — are turned over through regular lipid metabolism in the body.

Current drugs have limited efficacy, he says, because upon injection into the bloodstream, only a small percentage ever arrives at the desired destination. The drug also ends up entering normal tissue, which causes toxicity.

Main says that the firm’s second platform, Targeted Immunotherapy, which is in early stage research, involves a way to co-deliver oligonucleotides (short DNA strands) along with a specific disease marker called an antigen to a diseased region. As a result, an immune response against a particular disease is elicited.

“With Targeted Immunotherapy, it’s a whole new class of drugs that we are enabling by use of the delivery system, enabling their activity to be able to harness the immune system to fight cancer,” Main says.

A spinoff from Inex Pharmaceuticals in 2001, Protiva Biotherapeutics Inc. (Burnaby, BC) also has IV-administered liposomal-based drug delivery at its heart. However, unlike the parent firm, Protiva Biotherapeutics uses a different type of lipid and its liposomes have an outer stabilizing polymeric layer called a PEG coating. (See p. 10) Its lead compound, Pro-1, targets metastatic melanoma and is entering a Phase I clinical trial this year.

The technology behind Pro-1 involves forming specialized liposomes called SPLP (stable plasmid lipid particles), which enclose a DNA plasmid that encodes a therapeutic protein of interest. As with Onco TCS, Pro-1’s lipid carriers are processed through the body’s normal lipid metabolism.

Mark J. Murray, PhD, president and CEO of Protiva Biotherapeutics, says current liposomal technologies have provided “potentially a very big breakthrough” in the field of in vivo drug encapsulation.

“There had been attempts to do that (deliver DNA within liposomes) in the field previously where people just made a mixture or a complex of liposomes and plasmid DNA and it was not successful. It performed poorly, basically aggregated and it was a mess,” Murray explains.

Progress came, he continues, with such technologies as Inex Pharmaceuticals’ method that allows liposome formation coincident with nucleic acid encapsulation. The technique was developed by Pieter R. Cullis, PhD, senior vice-president of Research and CSO, along with Ian MacLachlan, PhD, who was with Inex Pharmaceuticals but is currently CSO at Protiva Biotherapeutics.

Targeting diseased regions with such liposomes is effective, Murray explains, because cells in those areas are quite receptive to particle uptake.

“They’re weakened in the sense that there’s a pathological condition, but in terms of their cell biology, they’re actually pretty healthy,” he says. “There are a lot of active and growing cells in those sites, which unfortunately cause the pathological conditions to grow and enlarge. But the cells at the sites are very active and very able to take up the particles and express the proteins delivered.”

Loading Micelles

Montreal, Que.-based Supratek Pharma Inc. also has a platform involving minute drug carriers, in this case, micelles.

President and CEO of Supratek Pharma, Oleg Romar, says the firm’s technology, Biotransport™, is based on polymer chemistry, involving modification of the characteristics of block copolymers.

Romar explains that one of the phenomena in nature is that at a critically high concentration, polymer units (unimers) will spontaneously form micelles. “In our drug-delivery system, what you have is actually a complex that is made up of, if you allow me a simplification, micelles, unimers and drug that we are delivering, and these three components are in balance,” he says.

This combination, referred to by the firm as a “self-assembling supramolecular complex,” circulates in the blood, Romar says, with the micelles carrying the drug, the unimers behaving as the biological response modifiers and the drug as the active agent.

“Our scientists have identified certain categories of block copolymers that provide us with this ability to modify biological response,” Romar says. “What we’re able to do is give a drug molecule new characteristics, make it more ‘druggable,’ without changing its molecular structure.”

The carriers are not biodegradable, he says, but many of them are GRAS (generally recognized as safe), and are simply eliminated from the body.

The firm’s lead product, SP1049C, currently in Phase II clinical trials against adenocarcinoma of the esophagus and soft tissue sarcoma, is an injectable based on a novel formulation of the common anticancer drug doxorubicin in combination with the Biotransport carrier system. Doxorubicin has been in use for many years, but has reduced potency against drug-resistant and metastatic tumours, Romar says. (See p. 11)

“The reason why our carriers, our formulations work is because we have noted that resistant cells have high ATP cells,” Romar says. Such cells consume much energy to operate efflux pumps and defence mechanisms that prohibit drugs from entering their nuclei. Consequently, cell division cannot be stopped, making the cancer cells immortal. “What we have been able to do is find a formulation of this doxorubucin that inhibits ATP, depletes it, so the result is that it reduces the cancer cell defence mechanism,” he says.

A Breath Away

Apart from efforts to improve drug delivery via pill and infusion routes is Delex Therapeutics Inc. (Mississauga, ON), which has developed the proprietary ROSE-DS™ (Rapid Onset and Sustained Effect Delivery System) technology, involving systemic drug delivery via the lung. (See p. 11)

AeroLEF™ (aerosolized liposome encapsulated fentanyl) is the company’s lead product, which the firm hopes will enter Phase II clinical trials this fall for acute pain and breakthrough cancer pain, says its president and CEO, Diana Pliura, PhD.

Providing a simple, non-invasive administration route, the technology permits rapid onset, extended duration of action, and allows a patient to adjust dosing to match his or her analgesic need, Pliura says.

“If they take an oral medication, immediate release morphine for instance, it may be 30 minutes before they’ll start to feel full relief. Well, they’ve been in pain for half an hour,” Pliura says. “We’re trying to solve that problem; that’s the unmet challenge for appropriate pain management.”

With AeroLEF, a nebulizer the size of a medium-sized cell phone creates a soft mist containing the drug, which the patient simply inhales while breathing normally. The drug’s effect occurs within about 10 minutes and can last up to 12 hours, whereas other fast-acting narcotic pain-relief agents act for only two hours. Because the onset is so fast, Pliura says the patient can titrate the dosage by taking as many breaths as required to achieve the desired level of analgesia.

In taking fixed doses, such as pills, one may be too much or may not be enough. “So you kind of have to hope,” Pliura says.

The pulmonary route of drug delivery is advantageous, Pliura says, because the lungs are very permeable and allow the drug to rapidly enter the bloodstream, much like an intravenous injection. However, by going in fast, the drug would also just as quickly disappear. “So the challenge was to find a way of modifying the transport of the drug from the surface of the lung into the bloodstream, by slowing it down,” she says.

Pliura says using liposomes comprising the natural phospholipids that line the lungs provides a very gentle and biocompatible carrier that modifies the rate of drug release from the lung surface into the bloodstream.

Drug delivery via inhalation, but through a non-systemic route, is also the strategy being taken for Montreal, Que.-based Topigen Pharmaceuticals Inc.’s lead compound, ASM8, developed for asthma and currently in preclinical trials. The drug is based on antisense DNA technology, to locally target lung inflammatory and epithelial cells, and has potential to turn off the over-expression of specific genes involved in asthma.

“Antisense has had bad publicity sometimes over the years and a lot of it is due to the toxicity when you give it systemically. We’re circumventing that by giving it topically,” says Dr. Paolo Renzi, vice-president of Scientific Affairs at Topigen Pharmaceuticals. The firm’s name, Topigen, emphasizes the non-systemic nature of ASM8, which works with high site-specificity, topically within the lung. “The other advantage of this approach is it seems we don’t need much antisense to have efficacy within the lungs because it seems to get into the cells very easily when we deliver it there,” he says.

An investigator at the University of Montreal (Montreal, QC), Renzi says it was in the mid-1990s that he started researching delivery of antisense to the lungs.

“We got into the multiantisense approach thinking that for respiratory diseases, one target isn’t sufficient because most of them are heterogeneous diseases, and it turns out that for knocking out several targets you need much less antisense because there’s a synergistic effect,” Renzi says.

Topigen Pharmaceuticals’ product is designed to knock out or decrease the expression of CCR-3 (the receptor for chemokines) and one common sub-unit of three receptors (IL-3, IL-5 and GM-CSF) of cytokines. (See p. 11)

While other researchers are beginning to approach disease with this novel type of thinking, “It still is not the norm, especially not for pharmaceutical companies and regulation agencies where usually the approach is one molecule, one therapy, for one disease,” Renzi says. “But I do sense in the last three years that that way of thinking is starting to have a broader application.”

Building Barriers

Similar to the idea and purpose of Labopharm’s implants, drug-loaded barriers produced by ARC Pharmaceuticals Inc. (Vancouver, BC) aim to reduce pain.

The firm has developed expertise in loading anti-inflammatory drugs into biodegradable polymeric barriers used for the prevention and treatment of surgical adhesions, says president Chris Springate. (See p. 13)

Incorporating drugs that it has in-licensed from the University of British Columbia (Vancouver, BC), ARC Pharmaceuticals deals with three types of barriers for different surgical purposes, Springate explains. The first is a flexible film, the second a gel, and the third a viscous liquid formally called a hydroflotation barrier.

“The liquid barrier is a good device because sometimes when a physician is working in one area of the body, there will actually be adhesions that form distant to that,” Springate says. “So, the liquid or the gel can actually spread over a number of different organs, even organs that the physician hasn’t touched.”

Degrading over a week and releasing the drug in about five days, the barriers provide controlled drug release during a period when the majority of processes leading to adhesion development occur, he says. Current barriers on the market are just physical, Springate adds, and do nothing to prevent the inflammation that causes the adhesions.

Patients with surgical adhesions are in a fair amount of pain, he says, and dysfunction can result. “For example, with abdominal surgeries, they can end up with obstruction of the bowel because the adhesions end up forming between the bowel and other organs and then the bowel ends up getting twisted,” Springate says.

An early stage firm, ARC Pharmaceuticals has established safety and efficacy proof-of-principle for its barriers for surgical adhesions in both rat and rabbit models, Springate says. Over the next two years, he says a goal is to raise funds for continued research and to conduct formal preclinical studies.

In light of the advances made in drug delivery to date, Springate says he thinks the field is entering an evolution stage rather than a revolution stage.

“It’s important for people to keep in mind that it takes time to do the science and to do the clinical studies, and we’re now starting to see some of those benefits,” he says. “So I think over the next 10 or 15 years we’re going to see things come out onto the market that will make a major difference. It just takes time and money.”