Chi-Med transforming into fully integrated pharma

After 17 years of blistering growth in China, Hutchison China Meditech (Chi-Med) (AIM, NASDAQ:HCM) is taking center stage as a global drug innovator, with a fully integrated pipeline approaching regulatory approvals, a prolific discovery engine and an established commercial organization.

“We are endeavoring to become one of the first China-based biopharmaceutical companies to emerge on the global market, with therapies developed internally that can be competitive globally,” Christian Hogg, executive director and CEO, says in an interview with BioTuesdays.

Chi-Med’s innovation platform now comprises eight clinical drug candidates, primarily in oncology, in more than 30 clinical studies around the world and a scientific team of over 350 people based primarily in Shanghai.

“We were established with a deep strength in chemistry and now poses a prolific discovery engine that includes four Phase 3 drug candidates, four proof-of-concept assets and a third wave of exciting targeted therapies that are expected to move into the clinic during the next five years,” he adds.

“We are endeavoring to become one of the first China-based biopharmaceutical companies to emerge on the global market, with therapies developed internally that can be competitive globally”

All eight of Chi-Med’s clinical drug candidates were designed internally with a focus on kinase selectivity, he points out, giving them the potential for high potency and less off-target toxicity, and an ability to be combined with other kinase inhibitors, as well as immunotherapy and chemotherapy agents.

Mr. Hogg joined the company in 2000 as its first employee and has been CEO since 2006. He has led all aspects of the creation, implementation and management of the company’s strategy, including the establishment of both the innovation and commercial platforms. Chi-Med is a member of CK Hutchison Holdings.

Chi-Med’s commercial platform was assembled over the past 17 years through the acquisition and integration of various pharmaceutical assets and joint ventures. It now manufactures and markets more than 200 drugs through a team of over 3,300 marketing personnel, covering more than 300 cities and towns in China.

Chi-Med is guiding for 2017 revenue in a range of $225-million to $240-million, compared with $216-million for 2016, with consolidated commercial sales of almost $200-million for 2017 and sales of non-consolidated joint ventures approaching $500-million. The company also is forecasting a net loss of $13-million to $28-million for 2017 after R&D expenses of $85-million to $90-million.

“This is an example of the balanced financial approach we have tried to employ for the past 17 years,” he adds.

In its innovation arm, Chi-Med has six Phase 3 trials underway or being completed as well as 18 Phase 1b/2 proof-of-concept trials with eight drug candidates, four of which are expected to reach pivotal testing by mid-2018. Some 3,100 patients and subjects have been treated in the company’s studies to date, with more than 300 dosed during the first half of 2017.

Mr. Hogg points to three important potential milestones for Chi-Med in early 2018.

They include a decision with partner, AstraZeneca, on a strategy for a Phase 3 registration trial of savolitinib and potential for submission for FDA breakthrough therapy designation in non-small cell lung cancer (NSCLC) in combination with AstraZeneca’s Tagrisso; potential NDA approval of fruquintinib in China and a launch in the first half of 2018 in advanced colorectal cancer; and a potential presentation of preliminary efficacy data from Phase 1/1b dose escalation/expansion studies of HMPL-523 in hematological cancer.

“Potentially, we could be one of the first Chinese companies to receive breakthrough therapy designation from the FDA and consequently, possibly the first Chinese company to take a discovery all the way through to U.S. approval, which we are hoping to do with savolitinib,” Mr. Hogg suggests. “We are also looking forward to our first approval in China with fruquintinib, which we hope will lead to approvals in further indications during the next few years.”

Mr. Hogg explains that savolitinib has been designed to be the first selective inhibitor of the c-MET receptor to eliminate the renal toxicity exhibited by first generation selective c-MET inhibitors. Over activity of the c-MET receptor has been linked with certain types of cancer cell division and must be turned off to improve patient outcomes in these patients.

“Clinical efficacy has been observed in NSCLC, kidney, gastric and colorectal cancers,” he contends, adding that some 500 patients have been treated with savolitinib to date, with no material renal toxicity having been observed.

Savolitinib design eliminates renal toxicity first generation of selective c-MET inhibitors encountered.

However, the biggest opportunity for savolitinib is in NSCLC, Mr. Hogg points out, not only in the treatment of first-line naïve patients, but also those patients that have become resistant to first-line treatment with Iressa/Tarceva, and those that have become resistant to second-line treatment with Tagrisso.

“The further you go along the current treatment paradigm, the more c-MET emerges as a resistance pathway to existing therapies,” he suggests. For example, he points out that of patients who fail on Tagrisso, c-MET aberrance is present up to 30% of the time, which makes “savolitinib and Tagrisso a potentially powerful partnership.”

At the World Congress on Lung Cancer last October, Chi-Med and AstraZeneca presented encouraging clinical evidence from proof-of-concept studies that the addition of savolitinib to Tagrisso or Iressa demonstrated preliminary anti-tumor activity in patients with epidermal growth factor receptor (EGFR) mutation-positive NSCLC with MET-amplification, who had progressed following first-line treatment with an EGFR inhibitor.

Chi-Med also is developing savolitinib for patients with papillary renal cell carcinoma (PRCC), a rare kidney cancer where c-MET is very active. In a Phase 2 study, savolitinib demonstrated clear efficacy and a durable response in PRCC patients and “we’re looking into the potential for breakthrough therapy designation here as well,” Mr. Hogg suggests. Savolitinib also was safe and well tolerated in the study.

The company is exploring development of savolitinib in more than 13 studies, with a Phase 3 trial underway in kidney cancer and another in lung cancer about to start soon.

According to Mr. Hogg, Chi-Med’s fruquintinib is likely to be the most selective inhibitor of vascular endothelial growth factor receptors (VEGFR) in clinical trials globally, providing 24-hour full target coverage. VEGFR is associated with the proliferation of blood vessels that feed cancer cells so they can grow. By shutting off their blood supply, tumor cells starve and die.

At the ASCO meeting last June, Chi-Med presented full results of the FRESCO Phase 3 study in 416 patients with locally advanced or metastatic colorectal cancer. Primary endpoint median overall survival was 9.30 months for fruquintinib, compared with 6.57 months in the control group.

“If we are able to achieve approval in this late-stage setting, we have the potential to bring fruquintinib forward into earlier treatment, where the benefits could be greater and longer,” Mr. Hogg contends.

Fruquintinib, which is jointly developed in China with Eli Lilly, also appears to have side-stepped the hepatotoxicity exhibited by Bayer’s Stivarga, which is approved globally in third-line colorectal cancer.

In addition, fruquintinib is being studied in a Phase 3 pivotal trial in approximately 520 third-line NSCLC patients, known as the FALUCA study. Fruquintinib is concurrently being studied in a Phase 2 study in combination with Iressa in a first-line setting for patients with advanced or metastatic NSCLC.

Last October, Chi-Med initiated the FRUTIGA Phase 3 clinical trial with fruquintinib, in combination with Taxol, in more than 500 patients with advanced gastric or gastroesophageal junction adenocarcinoma.

In the U.S., Chi-Med recently initiated a Phase 1 bridging study to evaluate the safety, tolerability and pharmacokinetics of fruquintinib in U.S. patients with advanced solid tumors. The first drug dose was administered in December.

Sulfatinib’s unique angio-immuno kinase profile & Mechanism of Action (MoA) activates & enhances the body’s immune system, namely T-cells, via VEGFR/FGFR while inhibiting the production of macrophages (CSF-1R) which cloak cancer cells.

In addition to savolitinib and fruquintinib, Mr. Hogg says Chi-Med’s third novel tyrosine kinase inhibitor, sulfatinib, has a unique angio-immuno profile and mechanism of action that inhibits the production of macrophages, which cloak cancer cells, thereby allowing the body’s immune system, specifically T-cells, a clear shot at cancer cells.

Sulfatinib is being developed against various neuroendocrine tumors (NET), which is a type of hormone cancer that is slow growing, and difficult to diagnosis and recede. Sulfatinib is progressing in multiple Phase 3 NET studies around the world.

At the 14th Annual Conference of the European Neuroendocrine Tumor Society meeting last March, Chi-Med presented Phase 1b/2 data of sulfatinib that showed objective response rates of 15% to 20% and progression free survival of 13-to-19 months.

According to Mr. Hogg, the objective response rates of current first-line treatments for NET, Sutent and Afinitor, are in the 5% to 9% range, with progression free survival of about 11 months. “We are quite excited in sulfatinib’s potential.”

Chi-Med also has high hopes for its epitinib, an epidermal growth factor receptor-mutation inhibitor, which has been designed to penetrate the blood-barrier and benefit patients with brain metastases. Phase 1b data presented at the World Congress on Lung Cancer in 2016 showed 70% response rates in NSCLC patients with measurable brain metastases, which is “very encouraging,” Mr. Hogg suggests.

Approximately 7.4% of NSCLC patients will have brain metastases at initial diagnosis and 25% to 30% will develop brain metastases during the course of their disease. Life expectancy for these patients is poor, with a median survival of only 3.4 months. “The unmet medical need is obvious,” he adds.

Chi-Med is advancing epitinib into a Chinese registration trial with NSCLC patients with brain metastases, as well as a Phase 2 study in China in glioblastoma, or primary brain cancer, both in 2018.

Mr. Hogg says China is a large and complex commercial market, with Chi-Med’s national coverage of prescription drugs and consumer health products extending to 300 cities and towns, 18,700 hospitals and 87,000 doctors.

In 2015, Chi-Med took over exclusive Chinese commercial rights of AstraZeneca’s Seroquel, a second generation antipsychotic approved for the treatment of schizophrenia, bipolar disorder and as adjunct treatment of major depressive disorder, as well as Merck Serono’s Concor in certain markets, a beta-blocker approved for the treatment of hypertension.

Chi-Med also sells a portfolio of household prescription drugs and over-the-counter products, covering coronary artery disease, angina, anti-viral/flu, cerebrovascular disease, periodontitis and gallbladder stones, among others.

Chi-Med now has a CNS team of 120 reps to sell Seroquel, with sales of RMB253.1-million in 2016, up 29%, from 2015. Sales of Concor, which are conducted on a fee-for-service basis, reached RMB28.8-million, up 43%, from 2015.

“The next piece of our incremental growth will be approval and launch of fruquintinib in China this year,” Mr. Hogg predicts.