Newsdesk
`
`Supercomputer-designed drug protects against chemotherapy
`toxicity
`BNP7787, a drug designed by Cray
`supercomputer technology to protect
`patients from the neurotoxic effects of
`chemotherapy, has just reached phase
`III clinical trials. “Preclinical work in
`rats has already demonstrated that
`BNP7787 can prevent toxicity induced
`by common chemotherapy treatments
`such as taxanes and cisplatin, while
`
`and the USA. LD50 data show that
`BNP7787 has
`toxicity
`similar
`to
`substances such as aspirin and table salt.
`“In addition, BNP7787 does not appear
`to affect the ability of Taxol or other
`chemotherapeutic agents
`to cause
`tumour apoptosis”, says Hausheer.
`Epie Boven and Herbert Pinedo
`(Vrije Universiteit Medical Centre,
`Amsterdam, Netherlands), who have
`carried out a dose-finding study with
`BNP7787, confirm that the compound
`is tolerated well and that it shows
`promising efficacy. “BNP7787 has the
`potential to act as a protective agent
`against dose-cumulative neurotoxicity
`from Taxol and cisplatin, without
`interfering with the chemotherapeutic
`activity”, says Boven. The use of
`supercomputer engineering to design of
`compounds by selecting favourable
`pharmacological characteristics that act
`against specific targets is, she adds,
`“extremely elegant”. Both Boven and
`Pinedo welcome the novel design
`approach being pioneered by Hausheer.
`“The use of supercomputer technology
`in drug development should lead to the
`discovery of many lead compounds in
`the near future”, predicts Boven.
`Kathryn Senior
`
`pretreatment infusion of BNP7787 at a
`dose of 18.4 g/m2; the other group will
`receive a control infusion. “We know
`from animal studies that the timing of
`the BNP7787 infusion is important,
`and so it will be given immediately
`after the hour-long Taxol treatment”,
`explains
`Kathy
`Hurtado
`of
`BioNumerik. Results are expected in
`summer 2001. BNP7787
`was
`given
`fast-track
`designation by the US
`Food and Drug Admin-
`istration in July, 1999; if
`the results of phase III
`trials
`are
`good,
`the
`product
`could
`receive
`approval only 6 months
`after study completion.
`BNP7787 is a water-
`(disodium-2,2⬘-
`soluble disulphide
`dithio-bis-ethane sulph-onate), which
`selectively
`inactivates
`the
`toxic
`monohydrated
`form
`of
`Taxol.
`“Approximately half of patients who are
`given weekly Taxol
`suffer nerve
`damage”,
`points
`out Hausheer;
`currently, there is no way to prevent or
`treat this damage. BNP7787 has shown
`an excellent safety profile in phase I
`studies at doses of 41 g/m2 in Europe
`
`Courtesy of BioNumerik
`
`Computer-generated 3-dimensional structure of
`BNP7787
`
`causing no side-effects,” says Frederick
`H Hausheer (BioNumerik Pharma-
`ceuticals, San Antonio, TX, USA).
`During the next
`few months,
`between 170 and 240 patients with
`metastatic breast cancer will be
`recruited. The trial will run for 24
`weeks and will monitor aggregate
`neurotoxicity in two groups of women
`receiving weekly doses of Taxol
`(paclitaxel); one group will be given a
`
`CCI-779: a new targeted anticancer agent
`
`A novel anticancer drug, CCI-779, has
`shown promise in a series of phase I
`studies, the results of which were
`presented at the European Society of
`Medical
`Oncology
`conference
`(Hamburg, Germany; Oct 13 – 17).
`The rationale for developing this
`anticancer agent came from studies
`into the mechanism of action of
`a well-known
`immunosuppressive
`agent, rapamycin. This drug was found
`to target a key component of a novel
`signalling pathway, called mTOR
`protein kinase. Preclinical research
`showed that CCI-779, a derivative of
`rapamycin, binds mTOR and inhibits
`the downstream pathway effects,
`leading to cell growth arrest in the G1
`phase of the cell cycle. The mTOR
`pathway can be hyperactivated by
`mutation or deletion of the PTEN
`tumour suppressor gene, which is
`found in many tumour types.
`
`198
`
`In a phase I dose-escalation study
`in France, 21 patients with advanced
`solid
`tumours were
`treated with
`7.5 – 220 mg/m2 CCI-779, given intra-
`venously once a week for 6 months.
`The maximum tolerated dose has not
`yet been reached, and toxic effects were
`mild. Eric Raymond (Institut Gustav-
`Roussy, Villejuif, France) reported
`that, of the 16 patients evaluable for
`response, three with renal-cell carc-
`inoma had a partial (one) or minor
`response (two), which was maintained
`for 7 months. There were two other
`partial
`responses
`(neuroendocrine
`tumour and breast cancer) and one
`stable disease (soft-tissue sarcoma).
`Manuel Hidalgo (University of
`Texas Health Science Center at San
`Antonio, TX, USA) reported the results
`of a US phase I study in 51 patients with
`advanced solid tumours. One partial
`response was observed in non-small-
`
`cell lung cancer, and minor responses
`or prolonged stable disease were seen in
`renal-cell carcinoma (three), cervical
`cancer (one), uterine cancer (one) and
`soft-tissue sarcoma (three).
`Two
`randomised multicentre
`phase II trials are underway, one in
`renal-cell carcinoma in the USA and
`the second, in breast cancer, is ongoing
`in Europe. “It also makes sense to
`investigate the use of CCI-779 in
`prostate cancer and in glioblastoma, as
`these tumours have high rates of PTEN
`mutations, and phase II trials in these
`tumours are being discussed”, says
`Raymond. “CCI-779 is a very specific,
`targeted agent. It is therefore crucial to
`analyse the data collected so far so that
`we can optimise the doses for tumour
`response, find out which tumours will
`benefit most, and use tumour profiles
`to identify the most suitable patients.”
`Ezzie Hutchinson
`
`THE LANCET Oncology Vol 1 December 2000
`
`West-Ward Exhibit 1081
`Hutchinson 2000
`Page 001
`
`