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New Technologies Give Older Drugs a Makeover

By Peter Winter
BioWorld Insight Editor

The disappointing returns on biopharmaceutical research and development, despite the availability of advanced molecular technologies and the investment of billions of dollars, is forcing companies to a re-evaluate their business plans. One idea that appears to be coming back into vogue again is the strategy of giving older drugs a makeover. Reformulating and repurposing older drugs for new uses or improved versions is more attractive than developing a drug from scratch. Depending on the compound selected much will be known about its pharmacology, thus providing the developer with a "running start" in the product development cycle.

Growing Interest

This growing interest has many facets including finding new therapeutic roles for older drugs. A classic example of this is thalidomide. In the 1950s this drug was originally indicated for morning sickness in women, but was withdrawn following the side effects of serious birth defects. Many years later Celgene Corp. worked with the drug and found a new indication in multiple myeloma and today Thalomid continues to generate significant sales – $76 million in the second quarter of 2012, according to the company's most recent financial report. (See BioWorld Today, July 27, 2012.)

The National Institutes of Health (NIH) is also weighing into this area. Its newest center – the National Center for Advancing Translational Sciences (NCATS) – is hoping to accelerate the development of new drugs. One of the new initiatives that NCATS recently created is the Discovering New Therapeutic Uses for Existing Molecules collaborative pilot program, which aims to tackle problems that are beyond the scope of any one organization or sector. By giving access to compounds that have already moved several steps down the development process, including into clinical trials, the research community will have the opportunity to contribute their expertise to advancing these resources even further toward new disease indications. (See BioWorld Insight, Sept 4. 2012.)

In addition to these and many other options, a number of biotechnology companies are developing sophisticated technologies designed to ensure that drugs are efficiently delivered to their intended targeted tissues. The advantages in the drug repurposing arena is the fact that already discovered drugs can be modified to improve dosing parameters, reduce the risk of adverse reactions and help broaden their therapeutic applications. The added bonus is that many of the older compounds will have been "de-risked" to some extent with known safety concerns and mechanisms of action.

An Emerging Trend

One of the companies tapping into this emerging trend of further improving already proven, older drugs is Chimerix Inc., of Research Triangle Park, N.C. The company is using proprietary lipid conjugate technology with antiviral compounds.

Kenneth I. Moch, president and CEO, Chimerix, told BioWorld Insight that he is one of the first "reformulating drug guys" as a co-founder and vice president of The Liposome Company Inc., back in 1982. Chimerix, he said, is doing something similar but with some different twists.

The company's lead product, CMX001, a lipid mimic of cidofovir (Gilead Sciences Inc.), is in development for the treatment of double stranded DNA (dsDNA) cytomegaloviruses (CMV) in immune-compromised transplant recipients.

Chimerix reported Phase II data showing CMX001 produced a statistically significant benefit vs. placebo in preventing CMV viremia and/or CMV disease 13 weeks post-hematopoietic stem cell transplant. Patients receiving the broad-spectrum lipid-antiviral conjugate showed a reduction in CMV viremia (CMV > 200 copies/mL) or disease compared to patients in the placebo arm. (See BioWorld Today, Feb. 7, 2012.)

Moch said they are working to initiate a Phase III trial in the first half of 2013.

Chimerix also inked a deal with Merck & Co. Inc. giving it exclusive worldwide rights to CMX157, its lipid acyclic nucleoside that delivers high intracellular concentrations of the active antiviral agent tenofovir diphosphate (marketed in a prodrug form by Gilead as Viread) in development to treat HIV infection. Merck will take over development and commercialization of the oral nucleoside reverse transcriptase inhibitor in exchange for a $17.5 million up-front payment and up to $151 million in milestones, plus royalties on future sales. CMX157 has completed a Phase I study in healthy volunteers. (See BioWorld Today, July 25, 2012.)

"The deal validated our lipid-based technology that we believe dramatically increases the therapeutic index of these well-known antiviral compounds," noted Moch.

"Since we are developing new chemical entities through our proprietary chemical processes we still have to go through a long development cycle, even though we are working with proven drugs. However, there will be an advantage in the marketplace because the medical community is aware of the potential of these drugs."

Improving Older Drugs

South San Francisco-based Talon Therapeutics Inc. also is tapping into older drugs. It has produced an "improved" version of vincristine, a widely used chemotherapy that has been around for the past 50 years. Talon's Marqibo (vincristine sulfate liposome injection) recently received FDA accelerated approval for the treatment of adult patients with Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following two or more anti-leukemia therapies. (See BioWorld Today, Aug. 10, 2012.)

"We were able to lever the important properties of this well-known compound with our Optisome nanoparticle encapsulation technology, to provide prolonged circulation of vincristine in the blood," said Steven Deitcher, president and CEO of Talon.

Celator Pharmaceuticals Inc., of Princeton, N.J., is leveraging its liposomal technology to develop CPX-351, a fixed-dose combination of the established cancer drugs cytarabine and daunorubicin. The company recently reported positive survival analyses from two completed trials of CPX-351 in acute myeloid leukemia (AML). A subset analysis of data from a randomized Phase IIb study in first-relapse AML showed that patients with an unfavorable risk profile had significantly improved survival after treatment with CPX-351 compared to standard salvage therapies. (See BioWorld Today, June 6, 2012.)

iCo Therapeutics Inc., of Vancouver, British Columbia, which proudly calls itself a "reprofiling" company, is working with another 50-year old drug. Amphotericin B (Amp B), the gold standard for systemic antifungal drugs, is a highly efficacious drug but no oral formulations are currently commercially available. The company is testing an oral delivery method for Amp B for the treatment of systemic fungal infection.

The company recently was awarded a C$1.1 million non-repayable financial contribution from the National Research Council of Canada to support its oral Amp B delivery system as treatment for patients with HIV. The funding will support feasibility testing and preclinical toxicology studies, as well as human safety and efficacy trials designed to examine the role of the Amp B system in potentially treating patients with latent HIV reservoirs. (See BioWorld Today, June 1, 2012.)