Chi-Med: SANET-ep data at ESMO

Our June 2019 Update note provided an overview of surufatinib, neuroendocrine tumours (NET), the clinical data to date, and Chi-Med’s development plans. Presentation of SANET-ep data at ESMO builds upon this and confirms that surufatinib is on track to become the first of Chi-Med’s unpartnered oncology drugs to reach the market in China.

Positive read out of the pivotal SANET-ep trial in advanced extra-pancreatic NET (epNET) supports a potential China NDA filing in Q419, which, if approval occurs in a similar timeframe to fruquintinib, could lead to surufatinib launch in late-2020 through Chi-Med’s own China Oncology commercial infrastructure.

The potential China opportunity in NET could be significant, as illustrated in Exhibit 1. Important features of this market include the:

• Limited treatment options: treatment protocols are standard despite the heterogeneity of the disease. NET is an umbrella term for tumours originating from the endocrine and nervous systems, commonly from the digestive and respiratory tracts;
• High prevalence vs incidence: NETs are typically slow growing, associated with a long duration of survival, and with patients treated for longer; and
• Diagnostic improvements: more treatment options coupled with improved diagnosis could increase recognition of NETs and raise current incidence.

Exhibit 1: The China NET opportunity

Source: Hutchison China MediTech Note: [1] current estimated prevalence to incidence ratio in China at 4.4, lower than US 7.4 ratio due to lower access to treatment options; [2] NRDL pricing references calculations assume FX rate of RMB 6.74/US$

NET is the first of many opportunities for surufatinib. The China and Global surufatinib development programme is focused on indications with high unmet need and with potential for a rapid path to market given the relative rarity of the cancer types targeted and limited treatment options.

Newsflow from the current development pipeline includes:

• Q419: Progression of the Shanghai Junshi global PD-1 collaboration, with completion of dose escalation of the surufatinib and Tuoyi combinaton, and initiation of the dose expansion stage in mutliple tumour types.
• Q419: Potential end-of-Phase II meeting with FDA.
• H120: Interim analysis of the China Phase III SANET-p registration trial in pancreatic NET (pNET).
• Mid-2020: Initiation of the surufatinib US/Europe registration study.
• Mid-2020: Interim analysis of the 300-pt China Phase IIb/III registration study in biliary tract cancer (BTC) based on the first 80 patients.

SANET-ep: surufatinib PFS benefit confirmed

The SANET-ep study (Exhibit 2) was stopped early for efficacy at a planned interim analysis following the IDMC (Independent Data Monitoring Committee) determination that the mPFS (median progression free survival) primary endpoint had been met. The study originally targeted the enrolment of 273 patients but included an interim analysis at 127 PFS events (c 70% of the planned PFS events for the final analysis), with early termination for superiority permitted if p<0.015.

Exhibit 2: SANET-ep Phase III study design

Source: Hutchison China MediTech, ESMO 2019

The SANET-ep primary analysis is illustrated in Exhibit 3, where surufatinib showed a statistically significant 5.4 months benefit to mPFS vs placebo. mPFS was 9.2 months on surufatinib vs 3.8 months for placebo (HR 0.334, p<0.0001). Subgroup analyses (Exhibit 4) indicated that all subgroups favoured surufatinib.

As a comparison, the single-arm Phase II China NET trial reported mPFS of 13.4 months for the epNET population (n=40), a result which reflects differences in patient baseline characteristics between the two trials (SANET-ep had a higher proportion of G2 patients with aggressive disease).

Exhibit 3: SANET-ep primary analysis (investigator assessed PFS)

Source: Hutchison China MediTech, ESMO 2019

Exhibit 4: Subgroup analysis of investigator assessed PFS

Source: Hutchison China MediTech, ESMO 2019 Note: Tumour origin A: jejunum, duodenum, thymus, cecum; B: lung, stomach, liver, appendix, colon, rectum; C: others or unknown origin. ULN: upper limit normal; SSA: somatostatin analogues; CgA: chromogranin A

PFS sensitivity analysis was carried out retrospectively in parallel by a blinded independent image review committee (BIIRC). There were some discrepancies in tumour image analysis between the investigators and BIIRC assessments (likely to be influenced by prior loco-regional therapies and/or liver lesion CT/MRI characteristics); however, the sensitivity analyses were supportive of the primary PFS analysis (Exhibit 5). Secondary endpoints were also consistent with a treatment benefit with surufatinib.

Exhibit 5: SANET-ep supportive analyses

Source: ESMO 2019 Note: ORR = overall response rate; DCR = disease control rate; BIIRC = blinded independent image review committee

From a safety perspective, surufatinib was generally well tolerated, with a safety profile consistent with prior data. Proteinuria and hypertension were the most frequent ≥Grade 3 adverse events but were manageable. The drug exposure safety analysis indicated that patients on surufatinib had median exposure of 217 days (c seven months) vs 146 days (c five months) for placebo patients, with a relative dose intensity of 86.42%.

Preliminary US Phase Ib/II surufatinib data

In addition to SANET-ep data, early findings from the US Phase Ib/II solid tumour study of surufatinib (Exhibit 6) were presented at ESMO, providing supportive evidence for the global applicability of the programme. The dose escalation phase of the study confirmed a maximum tolerated dose and recommended Phase II dose of 300mg QD surufatinib, which is consistent with the dosing of the China trials. Dose expansion is ongoing, although preliminary data from the pNET and BTC cohorts were presented. Data from 25 evaluable patients showed two confirmed partial responses (and two unconfirmed partial responses) in pNET patients.

Exhibit 6: Surufatinib US Phase Ib/II study design

Source: Hutchison China MediTech Note: * Soft tissue sarcoma (STS) cohort planned to open as a future cohort in Q419

A key takeaway from this study and the surufatinib data generated to date, is that it has shown anti-tumour activity in heavily pre-treated patients and across multiple tumour types. The US Phase Ib/II enrolled patients which had progressed on up to eight lines of prior therapy, and all of whom had progressed on everolimus (Afinitor, Novartis). Exhibit 7 illustrates the duration of treatment in the pNET cohort, highlighting both the number and diversity in the prior lines of therapy experienced.

Exhibit 7: US Phase Ib – pNET duration of treatment

Source: Hutchison China MediTech, ESMO 2019 Note: afib = aflibercept; atez = atezolizumab; bev = bevacizumab; cap = capecitabine; eve = everolimus; sun = sunitinib; tem = temozolomide

Everolimus is approved for the treatment of adults with non-functional NETs of gastrointestinal or lung origin, with unresectable, locally advanced, or metastatic disease, and currently has the broadest clinical evidence base across NETs by site of origin (Exhibit 7). Chi-Med, through its SANET-ep and SANET-p pivotal trials – and planned US/European registration trials – is seeking to rival this with surufatinib, to potentially offer a subsequent treatment option for NET patients who progress on everolimus.

Exhibit 8: Evidence landscape for advanced NETs by site

Source: James Yao, ESMO 2019 (Rinke et al. J ClinOncol. 2009. Caplin et al. NEJM 2014. Strosberg et al. NEJM 2017. Raymond et al. NEJM 2011. Yao et al. J ClinOncol. 2008. Yao et al. NEJM 2011. Yao et al. Lancet. 2016. Xu et al. ESMO2019)

Exhibit 9: Summary of financials

Source: Company, Trinity Delta  Note: Adjusted numbers exclude exceptionals. Historic and forecast EPS are adjusted for one-to-ten ordinary share split, with new ADS ratio of 1:5 shares. Our estimate of $250m proceeds from the proposed equity raise are shown as short-term debt in FY20e, until transaction size, structure, and terms are confirmed.