Two London-based researchers have come up with a technique for modifying the structures of existing compounds that could herald a new breed of ‘ethical pharmaceuticals’.

Not only would these products circumvent existing patents, but they could be developed at a fraction of the cost of drugs emanating from big pharma, the researchers believe. Hence the ‘ethical’ tag: the idea is to generate affordable versions of existing drugs for diseases prevalent in developing countries.

The catalyst for the efforts of Sunil Shaunak, professor of infectious diseases at Imperial College, and Steve Brocchini, a research chemist at the London School of Pharmacy, was hepatitis C. The condition affects some 200 million people worldwide with relatively high prevalence in Africa, the Eastern Mediterranean, South-East Asia and the Western Pacific. The standard treatment is interferon-alpha, used in combination with the antiviral ribavirin. Without modification, however, interferon is rapidly metabolized and excreted, requiring injections three times a week to have any effect.

Pharmaceutical researchers got around this problem by attaching large sugar polymers (polyethelene glycol or PEG) to the protein so that it broke down less rapidly. But while pegylated versions of interferon-alpha, such as Roche’s Pegasys (peginterferon alfa-2a), have proved considerably more effective than the unmodified drug, they are also expensive. A single course of treatment costs the UK’s National Health Service around £7,000.

Cheapers means to peglyate interferon-alpha

This prompted Professors Shaunak and Brocchini to look for more cost-effective way of attaching PEG to interferon-alpha that would not trespass on existing patents and would keep the product stable in hot climates. Their technique, described last June in Nature Chemical Biology, involved modifying the protein’s disulfide bonds – previously regarded as out of bounds since they are crucial to a protein’s structure and function – by breaking these bonds and inserting in their place a three-carbon ‘bridge’ attached to the polythelene glycol.

The new form of PEG-interferon was found to have biological activity similar to that of the version in clinical use, while its half-life following subcutaneous administration in mice was 12 hours compared with one hour for unmodified interferon, the researchers reported.

The patents for the new pegylation method, now branded as TheraPEG PEGylation, have been lodged with PolyTherics, a spin-out company founded in 2001 by Shaunak, Brocchini and another researcher, Dr Anthony Godwin, to build on their innovations in polymer technology. As Shaunak explained, Imperial College will only support patents for 12-18 months. The opportunity to create an alternative patent vehicle arose when the UK government tendered £4 million to Imperial College and other medical institutions to create drug discovery spin-outs. Shaunak’s proposal scooped up £0.25 million and further investment came from the Wellcome Trust.

While PolyTherics now owns the patents on modified PEG-interferon and other discoveries filed by Shaunak and Brocchini, the two researchers decided six months ago to “cut the umbilical cord," Shaunak noted. While they still provide scientific input to Polytherics, they have resigned as directors to pursue a less commercial route focused on affordable treatments for infectious diseases.

One potential application of the TheraPEG technology is as a carrier for antibody fragments, a much more complex and costly proposition better geared to “first world” medicine, Shaunak pointed out. According to PolyTherics, the company has already entered into partnerships with a “major pharma company” for an unspecified protein and a “prominent biotechnology company” for an undisclosed project.

Despite these commercial imperatives, the major shareholders in PolyTherics are still charities and medical institutions (the Wellcome Trust is the largest), Shaunak observed. Moreover, the company serves not just as a harbour for academic patents but as a single point of contact for organisations interested in exploiting those patents. Such was the case with Shantha Biotechnics, the Indian company that last November licensed the TheraPEG technology for use with its own hepatitis C treatment, Shanferon (rDNA human interferon alpha 2b), in developing a new, improved pegylated interferon at an affordable price.

Indian firm takes on manufacturing responsibility

Shantha is the 10th largest biopharmaceutical company in India and has a strong relationship with the World Health Organization, Shaunak noted. It will be responsible for manufacturing the novel pegylated version of Shanferon as well as for animal toxicology testing and clinical trials. The Indian government is expected to provide financial support for clinical development, which should begin in around 12 months’ time.

Although pricing will ultimately be down to Shantha, the cost of the pegylated interferon should be less than a quarter what is spent on the existing version in UK hospitals, Shaunak says. Royalties have been set at a level geared to affordability, he stressed, describing PolyTherics’ commercial stake in the venture as “extremely modest”.

The Shaunak-Brocchini team is already pursuing another venture along these more altruistic lines. It has linked up with the Drugs for Neglected Diseases Initiative (DNDi), a non-profit, virtual organisation that initiates and co-ordinates R&D for drugs addressing unmet needs, to develop a new, non-toxic version of amphotericin B for the treatment of visceral leishmaniasis (kala-azar).

While US company Gilead’s patented Ambisome eliminates the toxicity of amphotericin B by using a liposomal drug delivery system, Professors Shaunak and Brocchini believe they can achieve the same end at a much lower cost by incorporating the drug in sugar- based polymers. In this, case DNDi and Médecins sans Frontières, one of its founders, are funding development right through to Phase III trials.

The mainstream pharmaceutical industry is treating Shaunak and Brocchini’s claims warily, conscious that a new generation of ‘ethical pharmaceuticals’ aimed at the Third World could come home to roost in the First. No doubt the patent status of these products will also come under close scrutiny. By Peter Mansell