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Research: Healthcare
Data presented at the World Conference on Lung Cancer (WCLC) on combination approaches to treat resistant EGFR-driven non-small cell lung cancer (NSCLC) highlight a widening of the patient population that could be eligible to receive savolitinib in combination with either Tagrisso or Iressa. Partner AZN now has the data set to make a decision on global Phase III trials and evaluate breakthrough therapy designation (BTD) potential in both 2L and 3L EGFR-resistant NSCLC; in our view, data to date supports both. BTD could offer earlier entry into the US market. Furthermore, Phase II data presented on fruquintinib in combination with Iressa (first line EGFRm NSCLC) showed encouraging efficacy and acceptable safety. We place our forecasts and valuation under review as we revisit our peak sales assumptions.
Written by
Hutchison China MediTech |
WCLC highlights savolitinib combination potential |
WCLC update |
Pharma & biotech |
18 October 2017 |
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Hutchison China MediTech is a research client of Edison Investment Research Limited |
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Data presented at the World Conference on Lung Cancer (WCLC) on combination approaches to treat resistant EGFR-driven non-small cell lung cancer (NSCLC) highlight a widening of the patient population that could be eligible to receive savolitinib in combination with either Tagrisso or Iressa. Partner AZN now has the data set to make a decision on global Phase III trials and evaluate breakthrough therapy designation (BTD) potential in both 2L and 3L EGFR-resistant NSCLC; in our view, data to date supports both. BTD could offer earlier entry into the US market. Furthermore, Phase II data presented on fruquintinib in combination with Iressa (first line EGFRm NSCLC) showed encouraging efficacy and acceptable safety. We place our forecasts and valuation under review as we revisit our peak sales assumptions.
Year |
Revenue ($m) |
Net profit* |
EPS* |
DPS |
P/E |
Yield |
12/15 |
178.2 |
8.0 |
14.6 |
0.0 |
N/A |
N/A |
12/16 |
216.1 |
11.7 |
19.6 |
0.0 |
N/A |
N/A |
12/17e |
N/A |
N/A |
N/A |
N/A |
N/A |
N/A |
12/18e |
N/A |
N/A |
N/A |
N/A |
N/A |
N/A |
Note: *Net profit and EPS are normalised, excluding amortisation of acquired intangibles, exceptional items and share-based payments.
Savolitinib: Data in NSCLC demonstrates potential
Combinations of targeted therapies (TKI, monoclonal antibodies and immunotherapies) and chemotherapy is increasingly becoming the best approach to treating the complex and constantly mutating disease that is cancer. Savolitinib has the potential to be utilised across all lines of treatment in all MET-driven patients either as monotherapy or in combination. Data presented at the WCLC demonstrated positive efficacy for savolitinib in combination with Tagrisso or Iressa in EGFR-mutant, T790M +/-, MET-positive patients. Additionally, patients who had been previously treated with a third-generation T790M TKI (Tagrisso refractory) achieved a 33% PR (n=64). The importance of the data presented at WCLC is twofold; it underpins the scientific rationale at HCM in designing highly specific molecules that can be used both as monotherapy and in combinations to treat patients that are refractory to available EGFR therapies thereby opening up new treatment paradigms.
Fruquintinib: Impressive PR observed to date
Data were presented from an ongoing Phase II trial evaluating fruquintinib (VEGFR inhibitor) in combination with Iressa in EGFR-mutant NSCLC patients as first line therapy which supports this unique VEGFR inhibitor’s role in combination therapy. 13/17 patients (76.5%) had a partial response and four had stable disease (23.5%). No patients as of the data cut-off had progressive disease. Overall, an acceptable safety profile was observed.
Valuation: Under review
We place our forecasts and valuation under review.
Savolitinib demonstrates utility in NSCLC
At the recent 18th (2017) WCLC, preliminary data were presented on two separate Phase Ib/II proof-of-concept clinical trials assessing savolitinib in combination with AstraZeneca’s Tagrisso and Iressa for NSCLC patients. The data presented give an important insight into the potential utility of savolitinib in patients who have progressed following treatment with a first- (Iressa) or third- (Tagrisso) generation EGFR inhibitor. Patients treated were EGFR mutation-positive and presented with T790M and/or MET-driven disease, and, in our view, the data highlight savolitinib’s potential for use in second- and third-line MET-amplified, EGFR-mutant patients, irrespective of EGFR inhibitor utilised and T790M status. Secondary resistance mechanisms in cancer patients that have received mutation-targeted medicines are emerging and as such savolitinib’s place in addressing resistance in MET-driven lung cancers is becoming increasingly evident. The importance of the overall data is the potential widening of the NSCLC patient population that could be eligible to receive savolitinib as combination therapy. The safety profile across both the Iressa/savolitinib and Tagrisso/savolitinib combinations was consistent with the known safety profiles for each class of drugs.
Tagrisso and Savolitinib combination looks to US market
The Phase Ib/II TATTON trial is testing the combination of savolitinib and Tagrisso in patients with advanced EGFR-mutant MET-amplified NSCLC. Patients fell into three distinct groups: those who had prior third-generation T790M EGFR TKI treatment; those who had no prior third-generation T790M EGFR TKI treatment but were T790m-positive; and those who had also had no prior third-generation T790M EGFR TKI treatment but were T790m-negative. Sixty-four MET-positive patients were eligible for overall analysis of preliminary anti-tumour activity; of which 47 patients were confirmed centrally and 17 were confirmed locally (at the clinical site). Exhibit 1 highlights the preliminary anti-tumour activity in the savolitinib and Tagrisso group (based on all 64 C-MET positive patients). Patients with centrally confirmed MET-positive disease who had been previously treated with a third-generation T790M TKI had a 28% PR. This compared with 57% who had not been treated with a T790M TKI but were T790M-positive, and 53% who were T790M-negative. There were no complete responses in any of the patient groups, a result that is to be expected in this patient population with this class of drugs.
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Exhibit 1: Preliminary anti-tumour activity of the combination of savolitinib and Tagrisso in patients with centrally and locally confirmed MET-positive NSCLC |
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Source: Ahn M-J, et al. TATTON Phase Ib Expansion Cohort: Osimertinib Plus Savolitinib for Patients with EGFR-mutant MET-amplified NSCLC After Progression on Prior EGFR-TKI. Abstract #8985. Presented at the World Lung Cancer Congress 2017, Yokohama, Japan, 15-18 October 2017. |
While these data demonstrate the potential of savolitinib in second- and third-line settings, the expected move of Tagrisso to a first-line treatment following the positive FLAURA data could open up further opportunities for savolitinib as 2L treatment option in Tagrisso refractory patients. Data presented so far by HCM appear to indicate that around 30% of patients are MET-positive after Tagrisso treatment, compared with around 6% who are MET-positive and T790M-positive, and 10% who are MET-positive and T790M-negative after first-line, first-generation EGFR TKI (Iressa/Tarceva) treatment. While the percentage of patients who are MET-positive once Tagrisso is utilised as first-line treatment is unknown at this time, these data suggest that a larger patient population may be addressable by savolitinib once this shift in standard of care is made ie the use of savolitinib (2L and 3L) in Tagrisso resistance patient populations.
Opportunities in Asia in combination with first-generation EGFR inhibitors
We anticipate HCM to move forward with a strategy in Asia for NSCLC that focuses on combinations with first-generation TKI inhibitors such as AstraZeneca’s Iressa and Roche’s Tarceva, which are now off-patent in China. The Phase Ib/II expansion cohort tested a combination of savolitinib and Iressa in EGFR-mutant, MET-amplified NSCLC patients.
Preliminary anti-tumour activity was available in all 51 patients who were treated. 52% (n=12/23) who were T790M-negative, achieved a PR an expected result as Tagrisso (or another T790M targeting compound) was not utilised. As demonstrated in Exhibit 2, many of the responding patients in the T790M-negative arm are still receiving ongoing treatment and have ongoing partial responses.
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Exhibit 2: Duration of treatment in MET-amplified, EGFR mutation-positive patients who are treated with a combination of savolitinib and Iressa, N = 51 |
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Source: Hutchison China Meditech reports |
As expected response in T790M-positive patients was low, 9% (n=2/23) achieving a PR, we highlight that Iressa was not designed to address this patient subgroup (Tagrisso is now approved for this subgroup of patients). Stable disease at and beyond six weeks was similar in both groups, achieved in 30% (n=7/23) of T790M-negative patients and 39% (n=9/23) of T790M-positive patients. However, deaths occurred at a substantially increased rate in the T790M-positive arm (30% vs 13% in T790M-negative patients).
Fruquintinib
Fruquintinib is an oral small molecule that is a highly selective VEGFR1, VEGFR2 and VEGFR3 inhibitor, which in preclinical trials demonstrated fewer off-target toxicities, allowing higher drug exposure that translates to 24 hours a day VEGFR receptor inhibition. Fruquintinib's unique selectivity (lack of CYP450 inhibition/inducing) is favourable for potential in combination treatment regimens, given that many drugs are metabolised through the cytochrome p450 enzyme pathway.
Data were presented from an ongoing Phase II trial testing fruquintinib (VEGFR inhibitor) in combination with Iressa in EGFR-mutant NSCLC patients which supports this unique VEGFR inhibitor’s role in combination therapy. The trial tested fruquintinib at 4mg or 5mg once daily for three weeks on/one week off in combination with 250mg of Iressa once daily. Seventeen patients were eligible for efficacy evaluation, of which 13 (four PRs not confirmed as of data cut-off) patients (76.5%) had a partial response and four had stable disease (23.5%). No patients as of data cut-off had progressive disease and the median time to response was 56 days. 4mg dosing of Fruquintinib was determined to be the most suitable dose for further investigation as liver enzyme elevation was observed at 5mg. 8/26 (30.8%) patients reported a Grade 3-4 AEs, five of which were increases in alanine transaminase (ALT) as result of damage to the liver. Previously as a monotherapy, fruquintinib (plus best supportive care) in a Phase II trial in third-line NSCLC demonstrated median progression-free survival of 3.81 months vs 1.15 months for placebo (HR=0.275, p<0.001).
Exhibit 3: Financial summary
$000s |
2014 |
2015 |
2016 |
|
December |
US GAAP |
US GAAP |
US GAAP |
|
PROFIT & LOSS |
||||
Revenue |
|
87,329 |
178,203 |
216,080 |
Cost of Sales |
(58,849) |
(110,777) |
(156,328) |
|
Gross Profit |
28,480 |
67,426 |
59,752 |
|
Research and development |
(29,914) |
(47,368) |
(66,871) |
|
Other overheads |
(16,825) |
(29,829) |
(39,578) |
|
EBITDA |
|
(16,994) |
(7,756) |
(44,264) |
Operating Profit (before amort. and except.) |
|
(18,259) |
(9,771) |
(46,697) |
Intangible Amortisation |
0 |
0 |
0 |
|
Operating Profit |
(18,259) |
(9,771) |
(46,697) |
|
Net Interest |
(957) |
(953) |
(1,129) |
|
Exceptionals |
0 |
0 |
0 |
|
Profit Before Tax (norm) |
|
(19,957) |
(10,540) |
(47,356) |
Profit Before Tax (reported) |
|
(19,957) |
(10,540) |
(47,356) |
Tax |
(1,343) |
(1,605) |
(4,331) |
|
Equity investments, after tax |
15,180 |
22,572 |
66,244 |
|
Profit After Tax (norm) |
(6,120) |
10,427 |
14,557 |
|
Profit After Tax (reported) |
(6,120) |
10,427 |
14,557 |
|
Minority |
(3,220) |
(2,434) |
(2,859) |
|
Discontinued operations |
2,034 |
0 |
0 |
|
Net profit (norm) |
(9,340) |
7,993 |
11,698 |
|
Net profit (reported) |
(7,306) |
7,993 |
11,698 |
|
Average Number of Shares Outstanding (m) |
52.6 |
54.7 |
59.7 |
|
EPS - normalised (c) |
|
(17.8) |
14.6 |
19.6 |
EPS - normalised and fully diluted (c) |
|
(17.8) |
14.6 |
19.5 |
EPS - (reported) (c) |
|
(13.9) |
14.6 |
19.6 |
Average number of ADS outstanding (m) |
105.1 |
109.3 |
119.4 |
|
Earnings per ADS - normalised ($) |
|
(0.09) |
0.07 |
0.10 |
Earnings per ADS ($) |
|
(0.07) |
0.07 |
0.10 |
BALANCE SHEET |
||||
Fixed Assets |
|
120,992 |
140,087 |
175,057 |
Intangible Assets |
4,096 |
3,903 |
3,606 |
|
Tangible Assets |
7,482 |
8,507 |
9,954 |
|
Investments |
109,414 |
127,677 |
161,497 |
|
Current Assets |
|
89,842 |
89,675 |
167,380 |
Stocks |
4,405 |
9,555 |
12,822 |
|
Debtors |
27,924 |
38,628 |
49,349 |
|
Cash |
38,941 |
31,949 |
79,431 |
|
St investments |
12,179 |
0 |
24,270 |
|
Other |
6,393 |
9,543 |
1,508 |
|
Current Liabilities |
|
(75,299) |
(81,062) |
(95,119) |
Creditors |
(20,427) |
(24,086) |
(35,538) |
|
Short term borrowings |
(26,282) |
(23,077) |
(19,957) |
|
Other |
(28,590) |
(33,899) |
(39,624) |
|
Long Term Liabilities |
|
(37,584) |
(46,415) |
(43,258) |
Long term borrowings |
(26,923) |
(26,923) |
(26,830) |
|
Other long term liabilities |
(10,661) |
(19,492) |
(16,428) |
|
Net Assets |
|
97,951 |
102,285 |
204,060 |
Minority |
(17,764) |
(18,921) |
(19,790) |
|
Shareholder equity |
|
80,187 |
83,364 |
184,270 |
CASH FLOW |
||||
Operating Cash Flow |
|
8,359 |
(9,385) |
(9,569) |
Net Interest |
0 |
0 |
0 |
|
Tax |
0 |
0 |
0 |
|
Capex |
(3,729) |
(3,324) |
(4,327) |
|
Acquisitions/disposals |
689 |
0 |
0 |
|
Dividends |
(1,179) |
(590) |
(564) |
|
Equity financing and capital movements |
5,860 |
(1,676) |
97,076 |
|
Other |
(12,179) |
12,179 |
(29,270) |
|
Net Cash Flow |
(2,179) |
(2,796) |
53,346 |
|
Opening net debt/(cash and ST investments) |
|
4,645 |
2,085 |
18,051 |
Increase/(decrease) in ST investments |
12,179 |
(12,179) |
24,270 |
|
Other |
(7,440) |
(991) |
(2,651) |
|
Closing net debt/(cash and ST investments) |
|
2,085 |
18,051 |
(56,914) |
Source: Hutchison China MediTech reports, Edison Investment Research. Note: Equity investments after tax include the net profit contribution from JVs.
|
|
Research: TMT
Esker saw strong growth in revenues in Q317, with 17% reported growth and 14% growth on an organic, constant currency basis. The recent e-integration acquisition is performing in line with expectations and management has reconfirmed its FY17 outlook for double-digit organic revenue growth. We leave our forecasts unchanged.