From today's results announcement:
Acquisition of KS Biomedix Holdings plc
On 14 August 2003 Xenova announced a recommended offer to acquire 100% of the share capital of KS Biomedix Holdings plc, a UK listed drug research and development group. This transaction became unconditional in all respects on 12 September 2003. The planned integration and rationalisation across the two businesses is well advanced. The Directors estimate that annualised cost- savings of approximately 10m pounds will be achieved across both businesses, based on reductions in headcount, facilities and R&D costs (including Xenova's restructuring activities commencing in May 2003). The one-off reorganisation and post acquisition integration cost of achieving these savings is expected to be approximately 3.3m pounds.
Like Xenova, KS Biomedix was focused on the development of products for the treatment of cancer, particularly clinical indications where survival prognosis is poor and there are few, if any, approved products. As a result of this acquisition, the enlarged Xenova Group now has a broader clinical pipeline with a total of 12 products in clinical stage development including eight products in oncology (three in Phase II or Phase III) and four in addiction and immunology. The table below summarises the Xenova's drug candidates and early development programmes. Programmes highlighted in bold text have been prioritised for development.
The Xenova Directors believe that greater shareholder value will be achieved by focusing on six key clinical development programmes. Of these six, four (TransMID(TM), tariquidar, TA-CD, XR11576/XR5944) benefit from external funding or support, substantially reducing the costs of clinical development to Xenova. Xenova has deprioritised the majority of its preclinical programmes except where externally funded, as is the case for the Genentech collaboration on OX-40.
Drug Therapeutic Stage of Partner
Candidates/Programmes area Development
Clinical programmes
TransMID(TM) (XR311) Glioma Phase III Sosei,
Nycomed,
Medison,
Ranbaxy
Tariquidar (XR9576) Cancer Phase II QLT (North
America only)
TA-HPV / TA-CIN Cervical cancer Phase II
TA-CD Cocaine Phase II NIDA*
addiction
XR303 Cancer Phase I
HumaRAD Cancer Phase I
XR11576/XR5944 Solid tumours Phase I Millennium
(North America
only)
DISC-PRO Genital and oro- Phase I
labial herpes
prophylaxis
TA-NIC Nicotine Phase I
addiction
DISC-GMCSF Cancer Phase I
DISC-VET Bovine Herpes Phase I Pfizer
Virus equivalent
Preclinical programmes
Triomics Solid tumours Preclinical Option to acquire
XR11612 Solid tumours Preclinical As XR11576
OX-40 Autoimmune Preclinical Celltech,
disorders Genentech
OX-40L Infectious Preclinical
diseases, anti-
cancer
PAI-1 Cardiovascular Preclinical Lilly
PAI-1 Cancer Preclinical Lilly (Option)**
MRP Cancer and Preclinical
asthma
VP22 (Phogen joint Intra-cellular Preclinical Genencor
venture) delivery system
HIF-1 alpha Cancer Preclinical
MEN-B Meningitis Preclinical
XR304 Ulcerative Preclinical
colitis
XR113 Cancer Preclinical
Ribosome display Cancer targets Preclinical Babraham
(Discerna)
* NIDA provides funding to independent investigators to conduct
certain trials of TA-CD, but has no rights for its commercialisation,
nor is funding required to be repaid by Xenova.
** Lilly has an option to acquire development and commercialization rights
relating to PAI-1 inhibitors in the cancer field.
Product Pipeline Year to Date Update
Clinical Trials
Cancer -- TransMID(TM) treatment for high-grade glioma Following the acquisition of KS Biomedix, TransMID(TM) is now the most advanced product in Xenova's pipeline, having already commenced Phase III development and shortly to enter Phase III clinical trials.
TransMID(TM) is a treatment for high-grade glioma (brain cancer) a disease for which no efficacious alternatives are currently available and which has a very poor prognosis. TransMID(TM) is a modified diphtheria toxin conjugated to transferrin. The diphtheria toxin gains entry to the tumour cell when the transferrin to which it is attached binds to transferrin receptors on the surface of the cells. Transferrin receptors are particularly prevalent on rapidly dividing cells, and the high level of transferrin receptor expression on glioma cells makes transferrin an ideal targeting mechanism for the diseased cells. Once inside a cell the diphtheria toxin interferes with protein synthesis and ultimately kills the cell.
TransMID(TM) is pumped directly into the brain tumour via two catheters using CED (Convection Enhanced Delivery -- licensed from the National Institute of Health, US). CED greatly enhances the distribution of drug through the tumour mass and produces high local concentrations of drug. Since TransMID(TM) is directly infused into the tumour, it circumvents the usual obstacles presented to drug delivery to the brain by the blood-brain barrier and reduces systemic side effects.
Plans to progress TransMID(TM) into Phase III trials in adults with recurrent and/or progressive non resectable glioblastoma have already been submitted by KS Biomedix and have been agreed with the FDA. However, following its acquisition of KS Biomedix Xenova intends to seek FDA approval to change the current Phase III programme design from one large Phase III trial to two smaller Phase III trials.
Cancer -- tariquidar multi-drug resistance (MDR) programme
In June 2002, tariquidar entered two pivotal Phase III clinical trials as an adjunctive treatment in combination with first-line chemotherapy for non- small cell lung cancer (NSCLC) patients. On 12 May 2003, QLT announced that the Phase III trials would be stopped following a recommendation from the independent Data and Safety Monitoring Committee (DSMC) which had just completed the unblinded interim review of the data for the two ongoing trials. A detailed review of the unblinded clinical data on the patients in the Phase III trials is continuing.
On 23 July 2003, QLT announced that enrolment in the Phase IIb trial for patients with chemo-refractory breast cancer, which is being carried out at the MD Anderson Centre, Texas, had been sufficiently completed at 17 patients. QLT will not be enrolling new patients in this trial.
Cancer -- Therapeutic Vaccines
On 14 April 2003, the Company announced the results of an open label, physician-sponsored Phase II 'prime-boost' study, targeting the treatment of human papillomavirus (HPV) associated ano-genital intraepithelial neoplasia (AGIN) using a combination of Xenova's TA-CIN and TA-HPV candidate therapeutic vaccines.
The results of this study indicated that a prime boost strategy, using a combination of Xenova's TA-CIN and TA-HPV candidate therapeutic vaccines, was both safe and well tolerated and demonstrated clear clinical responses, even in women with long-standing disease. Of the 26 patients meeting the entry requirements of the study, 15 (58%) showed evidence of symptomatic improvement, one (4%) had a complete response (confirmed by histological examination and viral clearance) and in addition, five (19%) showed a partial response (defined as a lesion area reduction of 50% or greater), for an overall response rate in this study of 23%. Five patients (19%) were HPV16 negative at the end of the study.
Cancer -- Novel DNA Targeting Agents
On 3 July 2003, Xenova announced the start of a Phase I clinical trial of XR5944, the second of three novel DNA targeting agents that are the subject of a licence agreement with Millennium Pharmaceuticals Inc. The first of these compounds XR11576, entered Phase I clinical trials in February 2002. The third, XR11612 is in preclinical development.
The XR5944 Phase I clinical trial is being conducted at three centres in the United Kingdom and will include approximately 40 patients. In preclinical studies, XR5944 has demonstrated a high level of anti-tumour activity against a number of human tumour models, causing both partial and complete regression of large established tumours. Recent data published in the Proceedings for the 2003 Annual Meeting of the American Association for Cancer Research, suggest that XR5944 acts through a novel mechanism of action distinct from other current cytotoxic agents. Further exploration into the mechanism of action of XR5944 is ongoing.
Vaccines of Addiction
On 15 January 2003, Xenova announced that it had reached an agreement with ImmuLogic Pharmaceutical Corporation Liquidating Trust ("ImmuLogic") to buy out all ImmuLogic's remaining rights to future milestone and royalty payments relating to two of Xenova's therapeutic vaccines; TA-CD for the treatment of cocaine addiction and TA-NIC for nicotine addiction.
TA-CD
The start of a Phase IIa cocaine administration trial was announced on 14 April 2003. The ten-patient open label trial is being conducted in the United States and is designed to evaluate the effect of TA-CD on behavioural changes associated with cocaine administration.
The results of a second Phase IIa dose escalation trial were reported on 17 June 2003. This study, which started in April 2002, was designed to evaluate the safety and immunogenicity of TA-CD using 4 or 5 dose vaccination schedules. The trial involved the enrolment of 13 subjects, all of whom were cocaine abusers seeking help with their addiction at the start of the trial. Patients were treated with up to five injections of the vaccine over a twelve week period using doses up to 360 5g each. Of the thirteen enrolled, twelve subjects completed the 12 month evaluation period to assess safety, immune response and cocaine usage.
As for the previous study, the results showed the vaccine to be safe and well tolerated with a dose-related immune response. Of those 16 patients in the two Phase IIa studies who used cocaine at any time following vaccination, 14 reported a reduction of the usual euphoric effect normally associated with cocaine use, providing further anecdotal evidence of the vaccine's proposed mode of action.
On 24 October 2003, Xenova announced the start of the first randomised, placebo controlled Phase IIb clinical trial for TA-CD. The primary objective of this new study is to determine the efficacy of TA-CD in addicts seeking treatment for cocaine abuse, and to determine appropriate end-points for a Phase III study.
Up to 132 subjects, all of whom are methadone-dependent cocaine addicts being treated for drug dependency are being recruited into this clinical study. Half the subjects will be treated with active TA-CD and half will be given a placebo. Subjects will be monitored three times a week to assess cocaine usage, including testing for cocaine metabolites in urine, for a period of 20 weeks. Patients will also undergo medical examinations and blood tests for anti-cocaine antibodies to assess the immunogenicity of the dosing schedule. The trial is expected to last up to two years (depending upon the rate of recruitment) and will allow an objective assessment of the efficacy of the TA-CD vaccine against placebo.
The TA-CD investigations are being supported by the National Institute on Drug Abuse (NIDA) which recognises cocaine abuse to be a major problem in the U.S. NIDA has also supported earlier clinical work as part of this programme.
TA-NIC
Xenova announced the start of a second clinical trial for TA-NIC on 8 October 2003. This second Phase I study builds upon the findings of a previous Phase I trial which were announced in June 2002. The results of this first study, which was the first evaluation of an anti-nicotine vaccine in man, showed that the vaccine generated a specific anti-nicotine response and that it was safe and well tolerated both systemically and locally.
In the new Phase I study approximately 60 smokers are being recruited into a double-blind, randomised, placebo-controlled trial which is being run at a European clinical centre experienced in testing smoking related therapies. The objective of the trial is to further establish safety and tolerability, and to determine the vaccination dose and schedule required to induce the optimal anti-nicotine antibody response. Three different doses of the vaccine will be evaluated. The impact of vaccination on nicotine-induced changes in heart rate and skin temperature will also be monitored.
Preclinical Programmes
OX-40
On 20 October 2003 novel findings relating to a research collaboration, involving Xenova's OX40 technology and its potential for the treatment of influenza, were published by Imperial College, London.
Pre-clinical studies conducted by Imperial College demonstrated that down-regulation of the immune response, through blocking the OX40-OX40 ligand interaction, could alleviate the symptoms of influenza, without affecting the ability to clear the virus. This new research suggests that the down- regulation of OX40 signaling may play an important role in the fight against the symptoms of influenza and perhaps other diseases similarly characterised by excessive immune response.
OX40 is a platform technology capable of producing multiple drug candidates targeting cancer, autoimmune and other diseases where the immune system is involved. Xenova's rights to the OX40 technology include rights relating to the up-regulation of the immune system which may be used for the development of novel treatments for cancer and infectious disease. Xenova's rights to down-regulate the immune system have been the subject of development and licence agreements entered into with Celltech and Genentech.
Contract Manufacture
On 5 June 2003, Xenova announced the signing of a two-year Manufacturing, Development and Clinical Supply Agreement with Pharmexa A/S (CSE: PHARMX - News) for the contract manufacture of clinical supplies of a vaccine targeting the human HER-2 protein. Manufacture will take place at Xenova's Clinical Trial Manufacturing Facility in Cambridge.
On 8 September 2003 Xenova received notification that its Clinical Trials Manufacturing Facility (CTMF) in Cambridge has been successfully inspected by the Medicines and Healthcare products Regulatory Agency (MHRA). The inspection took place under the Voluntary Scheme for Inspection of Manufacturers. Xenova has received a letter from the MHRA confirming that its operations are in compliance with EU Good Manufacturing Practices.
Xenova's CTMF has been manufacturing clinical trial supplies since 1995 and recently announced that it is offering the facility and its supporting Development organisation for contract manufacturing. Accreditation by the MHRA will enable Xenova to continue to provide contract manufacturing services in full compliance with the forthcoming Clinical Trials Directive into 2004 and beyond.
As well as its own CTMF facility in Cambridge, Xenova acquired additional manufacturing facilities in Edmonton, Canada though the acquisition of KS Avicenna a wholly-owned subsidiary of KS Biomedix. KS Avicenna manufactures KS Biomedix products for clinical trials.
Changes to the Xenova Board
On 13 August 2003, Research Director and Chief Scientific Officer Michael Moore, and Medical Director, John St Clair Roberts resigned from the Company and the Xenova Board. Further changes to the Xenova Board were announced, as planned, following the acquisition of KS Biomedix: on 12 October 2003 John Rennocks and Dr Michael Young, non executive directors of KS Biomedix, joined the Board of Xenova as non executive directors. Howard Wachtler and Gerard Fairtlough resigned their positions as non executive directors of Xenova on 17 October 2003.... |
