SHANGHAI – Hutchison Medipharma Ltd. (HMP) is set to turn a corner announcing strong early results for not one, but three of its oncology drugs at ASCO 2014 this weekend in Chicago. Arguably the most exciting is the phase I data for Volitinib, a c-Met inhibitor that has shown strong results on patients with papillary renal cell carcinoma (PRCC), a rare form of cancer with no existing treatment.

HMP and partner Astrazeneca plc are hoping that Volitinib (HMPL-013/ AZD6094) will garner the much coveted breakthrough status.

"The only study done on PRCC had an objective response rate (ORR) of 13.5 percent, while we got 50 percent. It is a huge thing," said Christian Hogg, CEO of Hutchison Medipharma in an interview with BioWorld Asia. "With breakthrough therapy in the U.S., if you are able to show in a rare cancer type – one that does not have any approved treatment that you can deliver that kind of response rate then you are in a good situation."

But Hogg is cautious, aware that the challenge will be to replicate those results early on in the open-label, single arm, global multicenter phase II trial that just commenced. They are shooting for the same ORR of 50 percent that they saw in three of the six PRCC patients with partial tumor shrinkage of greater than 30 percent.

The other trial on PRCC was phase II study of Fortetinib conducted by Glaxosmithkline plc in 2012 – which showed a 13.5 percent ORR which they so far outmatch. "This is why we are optimistic on the prospects of the phase II PRCC study that we started last week with Astrazeneca," said Hogg.

The phase I conducted by HMP and Astrazeneca was a first-in-human dose escalation study to determine the maximum tolerated dose, dose limiting toxicities, pharmacokinetics profile and preliminary antitumor activity. Thirty-two patients were tested with the majority having PRCC while five patients had colorectal cancer.

Patients were treated at single daily doses of 100-1,000 mg or 300-400 mg twice a day. Volitinib was well tolerated at doses of up to 800 mg, once per day.

PK analysis showed rapid absorption with Tmax at two hours and half-life at five hours. Peak concentration and area under the curve showed a dose-proportional increase and no obvious accumulation. Common adverse events included constipation, diarrhea, fatigue, nausea, vomiting, dizziness and peripheral edema.

For patients with evidence of dysregulated MET signaling Volitnib holds promise for anti-tumor activity beyond the small numbers of patients with PRCC.

According to Hogg, most patients with PRCC have mutated c-Met or c-Met amplification, making a c-Met inhibitor a likely choice for approval in this indication. But c-Met is out of control in a number other cancer types, such as NSCLC and gastric cancer, and can be found in tumors of specific relevance to the Asian population such as lung, stomach, and esophageal cancers (with EGFR mutations).

While the potential market for Volitinib is great, the first step is to prove that Volitinib is worthy of a breakthrough designation.

The phase II study plans to enroll 100 patients but with no treatment for comparison it is not double blinded. According to Hogg, there is the potential to have the trial wrapped up quickly, within the year, with interim reporting to be done at the one-third, and two-third stages.

If granted, breakthrough designation can mean a drug is approved without having to undertake a phase III trial. Things can progress very quickly from there as evidenced by Pharmacyclics meteoric rise, a case study Hogg is hoping to emulate. (See BioWorld Today, Feb. 14, 2013.)

What truly excites the CEO is the potential for Volitinib to be combined with other therapies to treat many kinds of cancer.

"One of the Astrazeneca's strategies is to have a basket of targeted cancer therapies that can be combined, that can hit many cancers and many target types. And Volitinib is one in that basket basically," said Hogg.

But HMP is far from putting all its eggs in one basket, with three other promising drugs in its pipeline and two more with strong phase Ib and phase I results to be shared at ASCO, Fruquintinib (HMPL-013) and Sulfatinib (HMPL-012).

HMP started out as a company focused on botanicals and is known for its catalog of 50,000 medical substances derived from Chinese herbs and its China Healthcare Division, selling popular branded TCM products across the country at a healthy profit that helps to finance its R&D division.

After 12 years of steady and slow nurturing of the pipeline and $200 million invested in R&D, HMP has one botanical for ulcerative colitis partnered with Nestle expected to show phase III 8-week results in August, and a line-up of self-discovered small molecules that are showing results in the clinic.

MOVE OVER NEXAVAR, HERE COMES FRUQUINTINIB

Fruquintinib, a second-generation VEGFR inhibitor, has phase Ib data that "shows the efficacy of Fruquintinib in colorectal cancer is far superior to that of the existing therapies on the global market," said Hogg. According to Hogg it is the most targeted, selective VEGFR inhibitor, requiring only low doses leading to fewer side effects.

In the phase I trial, 40 patients with various heavily pre-treated solid tumors including colorectal cancer showed good tolerability and impressive antitumor activity.

Administered at 5 mg once daily in cycles of one-week rest after three weeks of dosing, Fruquintinib was well tolerated and given that it showed promising signs of early clinical efficacy, phase II commenced in early April.

For this asset HMP has partnered with Eli Lilly and Co., giving it the China-rights license and the option for global rights based on phase II proof of concept studies. Hogg is confident in the program and intends to kick-off phase III in China starting early next year.

There are two other tumor types, unannounced, that will kick off trials soon.

"Fruquintinib has showed such broad scale efficacy in multiple indications," said Hogg, "we felt partnering allowed us to go into many more indications. We have seen activity in gastric, lung, colorectal and breast. We could have done one (indication) on our own, but we partnered so we could do many."

PATIENCE PAYS OFF WITH SULFATINIB

Sulfatinib is a VEGFR/EGFR inhibitor that has been in phase I for three years. The reason for slowness, according to Hogg, was the time taken to fix PK absorption problems, remedied with a new formulation that has been showing results in slow growing and difficult to treat pancreatic neuroendocrine tumors (NET).

This drug was the first in oncology to be given the so-called expedited green channel for innovative drugs by the CFDA. So slowness is not the result of being stalled at the regulators. According to Hogg all of its candidates have benefited from the green channel because "we are the leading innovator in this field in China. Nobody else has programs like us."

While competitors such as Pfizer Inc.'s Sutent or Afinitor (everolimus) from Novartis AG do a good job of stopping tumor growth in about 10 percent of patients, Sulfatinib has a 30 percent response rate and "what we have seen in the clinic in China is Sulfatinib is doing a good a job of shrinking it (NET) that is why we are excited about it," said Hogg.

Hogg credits the partnerships with Lilly and Astrazeneca for really pushing the programs for Fruquintinib and Volitinib forward on a global stage, to not only inject the cash but also the "boots on the ground" to provide technical know-how. However, for the time being Sulfatinib is not partnered and HMP would like to continue to take it forward alone in China, with the possibility of partnering for future global opportunities.