Interview – Chi-Med looks outside its comfort zone

After 17 years toiling at small-molecule drug development, most recently in cancer, Hutchison China Meditech is broadening its horizons. The trigger for this is the immuno-oncology revolution.

The China-based company has spent the past decade pursing more potent kinase inhibitors – work that should culminate in the first phase III readout in the coming weeks. But its chief executive, Christian Hogg, tells EP Vantage that R&D work is no longer limited to conventional molecules, and that the first novel compounds will hopefully enter the clinic in the next three or four years.

“The whole world is changing rapidly and you have to evolve,” he says. “And you have to develop drug candidates with that in mind.”

More detail will be revealed at an R&D day slated for the end of March. Describing the profile of the new agents as “unique”, Mr Hogg says “they are designed to work in combination with the earlier lines of innovation”.

The VEGF inhibitors fruquintinib and sulfatinib belong to the company’s first wave of innovation, as Mr Hogg describes it, drugs largely developed for the Chinese market. The second includes the c-Met inhibitor savolitinib, partnered in a global deal with Astrazeneca.

Playing a part

Although I-O is impossible to ignore, Mr Hogg contends that kinase inhibition will long remain crucial: “There is always going to be room for TKIs that hit very specific molecular pathways and switch off cancer cell proliferation."

Mr Hogg’s argument is that I-O has its place, and indeed a dose-finding study testing savolitinib in combination with Astra’s flagship checkpoint inhibitor, durvalumab, is under way in kidney cancer. Investigators are “not far away” from establishing the optimum combination dose, he says.

A phase III trial testing savolitinib monotherapy in renal cell carcinoma should start in the coming months, and will select patients for Met-driven disease. There are no targeted drugs approved for this tumour type, which accounts for 10-15% of kidney cancers, around half of which are driven by this mutation. A single-arm phase II study was presented at Asco-GU this weekend and confirmed that the agent is much more active in these patients; of the eight partial responses, all were Met-positive. 

Chi-Med contends that savolitinib is much less toxic that existing TKIs – Sutent and Votrient, for example – and in particular avoids their substantial renal toxicity. This claim remains to be confirmed in larger studies and will be closely watched as these commence, particularly in lung cancer, its biggest commercial opportunity.

In this indication results from the Tatton study, due in the second half, are eagerly awaited. A phase IIb extension arm combining savolitinib with Tagrisso, Astra’s EGFR inhibitor, in second-line disease is still recruiting.

Tagrisso has shown strong efficacy in second-line patients who have developed resistance to EGFR inhibitors like Tarceva and Iressa owing to the secondary mutation T790m – this accounts for about 45% of relapses. Combination with savolitinib could also help patients whose resistance is also driven by c-Met.

“If you do that, you are covering 65-70% of Iressa/Tarceva patients,” Mr Hogg says. “Our hope is at the end of the year we will make a decision on global phase III Tagrisso combos.”

A strong readout from the Tatton study will also likely see the partners apply for breakthrough designation. A further opportunity is third-line NSCLC, where it is thought that 18% of Tagrisso relapses are driven by c-Met.

On the market?

Chi-Med believes that savolitinib could become the first selective c-Met inhibitor to be approved globally – although Incyte’s Novartis-partnered capmatinib must be another strong contender here. Deutsche Bank estimates $1.1bn peak sales potential across kidney, lung and gastric cancers, and data due in the coming months will help determine whether huge sums like this are in its reach.

A much more tangible event is approaching, however, in the shape of pivotal data on fruquintinib. In early March a third-line colorectal cancer study will read out, and Mr Hogg maintains that this will show what the company is capable of: “My hope is that we will see a validation of what we’ve been saying all along - if you can have clean TKIs that patients can tolerate and stay on longer, you can really see a clinical benefit.”

The study, in 416 patients, will only secure approval in China, where the drug is partnered with Lilly. This perhaps tempers hopes for the project's commercial potential – analysts at Deutsche Bank see peak sales of $360m.

Still, pinning the validation of years of R&D on the outcome of a phase III trial is a bold statement. Mr Hogg is confident that, should this fail, it will not be the fault of the molecule – “we know fruquintinib hits VEGF as hard as any other small molecule, and the safety profile is as clean as we’ve seen” – but concedes that it would be a hit to confidence.

With the company apparently gearing up to move beyond its small-molecule comfort zone and closing in on a pivotal global development programme for savolitinib, achieving regulatory approval would be a huge milestone.

“All this 10-12 years of investment, it needs to play out into some approved drugs,” says Mr Hogg. “Once we’ve got that foundation established, then more investment in perhaps higher-risk innovation will be possible. But, until you’ve crossed the finish line with something, it’s all theoretical.”