Mechanism of Action and Efficacy

HMPL-002 achieves its radiosensitising effect by reducing hypoxic conditions within the tumour cells, thus increasing the tumour's response to radiation. This biological effect is mediated by inhibition of multiple cellular metabolic pathways in tumour cells such as the regulation of oxygen homeostasis. In vitro findings were confirmed by in vivo animal results. Further efficacy studies comparing radiation only and radiation in combination with HMPL-002 oral administration confirmed that HMPL-002 improved radiation efficacy in mice.

Chinese clinical studies conducted in the 1990s confirmed the radiation-sensitizing effect of HMPL-002 in patients with solid tumours. Patients experienced a higher response and survival rate when HMPL-002 was added to the radiotherapy. Multiple clinical trials were conducted in China from 1993 to 1998 leading to its final China market approval. A representative proof of concept trial was a double blind, multi-centre placebo-controlled study involving 383 patients followed by a subsequent open label trial with 245 lung, oesophageal, or head and neck cancer patients. The data demonstrated a significant increase in complete response rate for the radiation plus HMPL-002 group in comparison to radiation alone. In addition, the radiation dose required to achieve a complete response in the head and neck patients was significantly lower for the HMPL-002 treated group than for the control group. A multi-centre, randomised, placebo-controlled Phase III study involving 1,880 stage III cancer patients and 923 cancer patients in the control group (radiation alone), resulted in a significantly increased complete response rate for all three types of cancers in the treatment group. 36 per cent of HMPL-002-treated lung cancer patients had complete tumour responses versus 10 per cent of patients on placebo (p<0.001), 50.8 per cent of HMPL-002-treated oesophageal cancer patients had complete responses versus 23.1 per cent of patients on placebo (p<0.001), and 56.3 per cent of head and neck cancer patients had complete responses versus 26.2 per cent of patients on placebo (p<0.001). More importantly, the 2, 3 and 5-year survival rates were significantly increased for the HMPL-002 treated group as compared to the placebo group.

Non-clinical safety studies carried out by Hutchison MediPharma have indicated that HMPL-002 is generally well tolerated in animals. HMPL-002 is neither mutagenic nor teratogenic. In all the sub-chronic toxicity studies in rats and dogs, the major clinical observations were gastrointestinal related, which is consistent with the clinical findings in Chinese patients. Importantly, no cytotoxicities have been reported in Chinese clinical studies.

The current US study is a Phase I/II trial for the treatment of head and neck cancer. The trials were designed by Hutchison MediPharma and its expert advisers and in collaboration with Pharmaceutical Product Development, Inc. ("PPD"), which is currently enrolling patients for the Phase I trial. The primary objective of the Phase I trial is to determine the maximum tolerated dose ("MTD"), to confirm the drug's safety profile in US patients, and to recommend an optimal dose for Phase II. The FDA has cleared HMPL-002 to enter directly into Phase II trials once the Phase I MTD trials are complete. The Phase II extension study will aim to enrol additional patients at multiple sites to examine overall tumour response and survival rates.

In China where HMPL-002 has been approved for use in combination with radiotherapy, a proof of concept study is on-going for the treatment of NSCLC in combination with chemotherapy and radiotherapy.

Opinion leaders in the therapeutic field in the US have endorsed both the US and Chinese trial protocols.

Sufficient quantities of clinical supplies have been manufactured for the planned Phase I and II trials in accordance with the appropriate FDA quality standards and GMP requirements.

• HMPL-002 is safe and effective for the treatment of cancer when used in combination with radiotherapy based on Chinese clinical trial data.
• HMPL-002 is an oral agent.
• HMPL-002 does not show cytotoxicity in vivo and in human studies and does not induce adverse events typically seen with chemotherapy treatment.

The following information relating to the market potential of HMPL-002 and the market for the treatment of head and neck cancer and NSCLC have been extracted or derived from statistical data and information published by various sources including a report commissioned and paid for by Chi-Med and produced by Cambridge Consultants Limited, an independent research organization, dated 24 February 2006. In collating that information, certain assumptions and qualifications have been made which may affect the interpretation of the information contained herein.

The incidence of all cancers in the US in 2005 was 1.37 million. Of these, approximately 3 per cent (40,000) and 11 per cent (150,000) were head and neck cancers and NSCLC respectively. Between 2000 and 2005, the number of new patients with these forms of cancer in the US rose from 183,000 to 189,000 with a CAGR of 0.6 per cent. Both head and neck cancers and NSCLC are commonly treated using radiotherapy, with approximately 80 per cent of head and neck cancer and NSCLC patients in the US treated with radiotherapy, representing approximately 151,000 patients in 2005.

In 2003, the US cancer market size was estimated at US$25.4 billion and projected to grow with a CAGR of 5.5 per cent to reach US$35 billion by 2009.

The potential radiosensitiser market in head and neck cancer and NSCLC may be estimated from the total number of patients who are currently undergoing radiotherapy treatment. According to the American Head and Neck Society, many patients with head and neck cancer receive radiotherapy, one of the primary treatment methods. For NSCLC, the National Cancer Institute ("NCI") guidelines suggest that radiotherapy should be used in patients at stages IIIA, IIIB, and IV, which accounts for around 80 per cent of total NSCLC patients.

There are currently no FDA or EMEA approved pharmaceuticals for use as radiosensitisers. There has however been some off-label use of certain cytotoxic agents as radiosensitisers in approximately 20 per cent of radiotherapy patients.

Of the above drugs in clinical trials for use as radiosensitisers, around 80 per cent are already approved for use as cancer treatments. The average estimated cost per course of treatment per NSCLC or head and neck cancer patient treated with radiosensitisers is US$7,200. Estimated costs range from Gemicitabine used to treat NSCLC at a cost of US$532 per patient to an NSCLC trial involving a Cisplatin/Paclitaxel combined treatment at a cost of US$14,500 per patient. The costs of radiosensitisers used in treating head and neck cancers also fall within this range.

At this point it is very difficult to estimate the size of the market for radiosensitisers as there are no approved drugs to benchmark against, but assuming that of the 80 per cent of patients treated with radiotherapy, 20 per cent would be treated in conjunction with a radiosensitiser, in 2005 there was a pool of around 30,000 NSCLC and head and neck cancer patients in the US who could have been treated with radiosensitisers. Proof of clinical efficacy from trials of radiosensitisers in these cancers may well increase the number of patients who could benefit from radiosensitiser treatment.