KRAS之战：Sotorasib觉醒还是MRTX849的崛起

1、Amgen (AMGN) / Mirati (MRTX)KRAS Wars: Sotorasib Awakens Or The Rise Of MRTX849?North America Equity ResearchSeptember 2020Large Cap BiotechnologyUS SMid BiotechnologyCory W. Kasimov AC212-622-5266 HYPERLINK mailto:cory.w.kasimov cory.w.kasimovJ.P. Morgan Securities LLCGavin Scott212-622-0579 HYPERL

2、INK mailto:gavin.scott gavin.scottJ.P. Morgan Securities LLCMatthew T Holt, Ph.D.212-622-9602 HYPERLINK mailto:matthew.t.holt matthew.t.holtJ.P. Morgan Securities LLCTurner Kufe, MD212-622-4104 HYPERLINK mailto:turner.kufe turner.kufeJ.P. Morgan Securities LLCAnupam Rama AC212-622-0900 HYPERLINK mai

3、lto:anupam.rama anupam.ramaJ.P. Morgan Securities LLCMatthew Bannon212-622-0001 HYPERLINK mailto:matthew.bannon matthew.bannonJ.P. Morgan Securities LLCTessa T Romero212-622-4484 HYPERLINK mailto:tessa.t.romero tessa.t.romeroJ.P. Morgan Securities LLCSee the end pages of this presentation for analys

4、t certification and important disclosures, including non-US analyst disclosures.J.P. Morgan does and seeks to do business with companies covered in its research reports. As a result, investors should be aware that the firm may have a conflict of interest that could affect the objectivity of this rep

5、ort. Investors should consider this report as only a single factor in making their investment decision. Net takeaways: Amgen (AMGN)Amgen will present updated Phase 1 sotorasib (AMG510) data, focused on NSCLC, THIS WEEKEND at the ESMO Virtual Congress 2020 (9/19 9/21)Additional KRAS related catalysts

6、 to monitor in 4Q20 include updated MRTX849 data from the phase 1b NSCLC cohort at the Triple Meeting (10/24-10/25) and pivotal data for sotorasib in NSCLC sometime before YEAMGN (N; covered by Cory Kasimov)The updated Ph 1 data at ESMO will have a direct read-through to the potentially pivotal Ph 2

7、 data expected later this yearDuration in particular is a key outstanding question, and this weekends presentation should provide important visibility on this frontBased on our prevailing investor conversations (and our prior buy-side survey), we believe the rough bar for the pilot data in 2L/3L NSC

8、LC is an 30% ORR and 6 months PFS.We would expect a neutral to incremental positive reaction in AMGN shares on the heels of this base case scenario given marginal de-risking of a potential accelerated path to market for sotorasib. Underwhelming data could disappoint investors and set a lower bar for

9、 competitors (i.e. MRTX).The MRTX849 update at the Triple Meeting will better inform these competitive dynamics as investors scrutinize whether or not differentiation exists between the two drugs.This KRAS/sotorasib update kicks off an eventful sprint into year end for AMGNIn addition to the multipl

10、e KRAS data readouts, we also expect pivotal results in 4Q for tezepelumab in asthma and omecamtiv mecarbil in heart failurenot to mention a key competitive readout from BMYs TYK2 that has significant read- through to Otezla and multiple updates from Amgens BiTE platform (incl one at ESMO).However,

11、investor interest in sotorasib has largely dwarfed the other late-stage assets to date based on, among other things, 1) the market opportunity for a novel cancer therapeutic; 2) initial data updates; and 3) 100% ownership that more clearly enables a potential needle moving addition to the portfolio.

12、Overall AMGNs pipeline has garnered significant interest, and these late-stage readouts have the potential to drive multiple expansion as we discuss in our AMGN ExcavatorSource: J.P. Morgan Research2 Net takeaways: Mirati (MRTX)MRTX (OW; covered by Anupam Rama)For MRTX shares, as updated MRTX849 pha

13、se 1b NSCLC data are only a few weeks away, we expect that shares will most likely trade with the class for the sotorasib ESMO update (as they previously have) and any sizeable moves would most likely come following the Triple meetingThe sotorasib update at ESMO could be more incremental than game c

14、hanging for MRTX sharesWe would not expect major swings in either direction unless sotorasib meaningfully beats or misses expectationsThat said, given the run-up in MRTX shares, we acknowledge that on more mixed data from sotorasib at ESMO, there could be a more volatile response to the downside in

15、the near term on KRAS class concerns arising (still ultimately MRTX849 will be judged on the merits of it own data at the Triple Meeting)In our view, recent upside in MRTX shares has been driven by:Overall clinical execution despite COVID-19 pandemic (initiating MRTX849 combination studies, etc.)Mir

16、atis continued confidence in a differentiated profile for MRTX849Street perception of a more cautious tone from Amgen with regards to sotorasibDelays / setbacks from KRAS G12C competitorsEncouraging updated data for sitravatinib in May (an asset that we continue to believe is underappreciated)Intere

17、stingly, MRTX shares do appear to be more sentiment driven at this pointWe continue to believe that MRTX849 has the potential to show differentiation relative to sotorasibAt current valuation levels following the recent strength, we would note that differentiation may ultimately be necessary for the

18、 next leg up in MRTX sharesSource: J.P. Morgan Research3 As the next phase of the KRAS updates commencesthere is a clear focus on durability of response for the classAmgens sotorasib and Miratis MRTX849 are leading the race for KRAS G12C therapeuticsIn the key battleground indication of 2/3L NSCLC,

19、sotorasib and MRTX849 have entered potentially registrational studies as monotherapy in attempt to gain accelerated approval from the FDABoth candidates have demonstrated promising early signals of activity as measured by response rate in refractory NSCLC (albeit in a small number of patients)Sotora

20、sib (960mg QD) ORR: 54% (7/13)MRTX849 (600mg BID) ORR: 60% (3/5)Durability is the key outstanding question for the KRAS classBoth companies have been consistent in that a 30% ORR / 6 months DOR is likely the minimal bar needed for filing as a monotherapy in 2L/3L NSCLCThis bar has been validated in

21、our physician discussionsWhile some on the Street have noted a lower bar in the 25% ORR / 5 month DOR range (incrementally better than docetaxel which is the SOC), we would note this is inconsistent with company rhetoric and our physician feedbackand would likely (at least temporarily) decrease prev

22、ailing investor enthusiasm for the classImportantly, we believe the Street is largely aligned on this minimal threshold benchmarkSource: J.P. Morgan Research4Updated phase 1 sotorasib data will be presented at the virtual ESMO Congress on Sunday September 20th 8:25am ET (AMGN is hosting an investor

23、webcast on 9/20 2pm ET)The update will feature data from the expansion cohort of the sotorasib monotherapy arm for NSCLCRecall, the expansion cohort utilized 960mg QD as the go-forward doseGiven the abstract title and company guidance, the focus will be on durability (DOR / PFS)Abstract title: 1257O

24、 - Durability of clinical benefit and biomarkers in patients (pts) with advanced non-small cell lung cancer (NSCLC) treated with AMG 510 (sotorasib)Abstracts will be posted at 6pm ET on Fri 9/18; we anticipate a placeholder for sotorasibPotential Implications for AMGN & MRTX sharesFor AMGN shares, t

25、he updated Ph 1 sotorasib data will clearly inform expectations for the potentially pivotal Ph 2 readout later this year and thus the regulatory path forward in 2L/3L NSCLCFor MRTX shares, we see more incremental read-through from the sotorasib update at ESMO outside of a major upside or downside su

26、rprise on ORR / DOR / PFS at the conferenceIn our view, the more critical update for MRTX shares will be the Triple MeetingResultsKey metricsRead through toCommentsDuration of responseBest overall responseAmgenMiratiBetter than anticipated 6.5 months 40%PositiveNeutral / Incremental PositiveAmgen :

27、Share appreciation driven by incremental de- risking of potentially pivotal Ph2 studyMirati : Potentially viewed as class win; more material move for MRTX shares will be dependent on MRTX849 data at the Triple Meeting / 510 pivotal dataIn line with expectations5.5 - 6.5 months30-40%Neutral / Increme

28、ntal PositiveNeutralAmgen : We expect a relatively muted reaction to in- line results as attention shifts to the plethora of anticipated 4Q readouts, incl pivotal sotorasib data Mirati : MRTX shares will have more material movesaround the Triple Meeting / 510 pivotal dataWorse than anticipated 5.5 m

29、onths20 hoursMRTX849 may have better tissue distribution as measured by volume distribution at steady stateProjected Vd in humans is 10+ L/kg for MRTX849; however, we dont have the sotorasib comp in humans AMG510 (left) and MRTX849 (right) activity in NSCLC xenograft modelDose dependent anti-tumorac

30、tivity in NSCLC (H358) xenograft models was demonstrated for both drugsBoth show increases in activity at effective doses over time (see Figures to the right)Source: J.P. Morgan Research; Amgen IR Presentation (ESMO 2019); Mirati Corporate Presentation (Triple Meeting 2019); .16 Sotorasib and MRTX84

31、9 have demonstrated signals of clinical activity and a clean safety profile thus farWe are encouraged by the clinical efficacy presented for sotorasib and MRTX 849 thus far, particularly in NSCLC (albeit in small patients numbers across the board)Of note, there are no major safety concerns with eith

32、er product to dateCompanyAMGNMRTXDrugAMG 510MRTX849TrialPhase 1Phase 1SourceASCO 2019 (as of 4/4/19)IASLC 2019ESMO 2019AACR-EORTC-NCI 2019Cohort (dose)Overall (all)NSCLC(all)NSCLC (960mg)CRC (all)Other (all)NSCLC(all)NSCLC (960mg)CRC (all)CRC (960mg)Other (all)Overall (all)NSCLC(all)NSCLC (600mg BID

33、)CRC (all)CRC(600mg BID)Other (all)N (enrolled)351431923415291231265422EfficacyORR (out of evaluable)17% (N=5/29)*50% (N=5/10)*100% (N=3/3)0%0%48% (N=11/23)*54% (N=7/13)3% (N=1/29)8% (N=1/12)33% (N=1/3)33% (N=4/12)50% (N=3/6)60% (N=3/5)25% (N=1/4)50% (N=1/2)0% (N=0/2)PR rate17% (N=5/29)*50% (N=5/10)

34、*100% (N=3/3)0%0%48%(N=11/23)*54% (N=7/13)3% (N=1/29)8% (N=1/12)33% (N=1/3)33% (N=4/12)50% (N=3/6)60% (N=3/5)25% (N=1/4)50% (N=1/2)0% (N=0/2)SD rate62%(N=18/29)40%(N=4/10)0%72%(N=13/18)0%48%(N=11/23)46%(N=6/13)76%(N=22/29)83%(N=10/12)33%(N=1/3)58%(N=7/12)50%(N=3/6)40% (N=2/5)50%(N=2/4)50%(N=1/2)100%

35、(N=2/2)SafetyAEs71%(N=25/35)-76%(N=26/34)-SAEs17%(N=6/35)-24%(N=8/34)-Treatment-related AEsNotreported-35%(N=12/34)-Treatment-related SAEs0%-0%-Infections, Gr321% (N=9/42)21% (N=9/42)21% (N=9/42)21% (N=9/42)-* 1 pt with PR improved to CR post the week 18 cutoff; * 1 ptresponded post the intial cutof

36、fSource: J.P. Morgan Research; Amgen Reports; Mirati Reports17 Arguments for and against each program have been made but still more needs to be proven out in the clinicSource: J.P. Morgan Research18 Both sotorasib and MRTX849 are advancing through development in combination with other agentsGiven th

37、e shared mechanism, many of the combination approaches overlapClinical trials in combination with PD-1, EGFR, SHP2 are underway for both programsThese combination strategies could result in improved clinical results based on synergistic activityAmgen has not provided as much guidance granularity as

38、Mirati (see Table below), but the CodeBreak 101 trial (NCT04185883) has a number of sub-protocols for anticancer therapiesSo far for CodeBreak these include inhibitors for MEK, PD-1, SHP2, pan-ErbB tyrosine kinase, PD-L1, EGFR, and a chemotherapeutic regimenOf note, flexibility is built in for futur

39、e investigational treatments as neededMirati KRAS G12C Combination StrategyMRTX849 + KRAS + IndicationTrial initiationDataPembrolizumabPD-11L NSCLC1Q202021AfatinibPan-EGFR2L NSCLC3Q20-Cetuxi mabEGFR2L CRC1Q202021PalbociclibCDK4/62L NSCLC2H20-TNO155SHP22L NSCLC, 2L CRC2Q202021Notably, unlike Amgen, M

40、irati is not pursuing a MEK inhibitor combinationInterestingly, Mirati has highlighted that they do not expect this combination approach to be as promising from a risk/benefit standpoint (see Quotes From Management slide)While Amgen is 6 months ahead in single agent development, the combination tria

41、ls appear to be on similar timelinesSource: J.P. Morgan Research; .19 KOL calls we conducted largely support our view that KRAS G12C drugs are approvable, but outstanding questions remainOn expectations for updated data later this yearKOLs generally agreed that ORR is likely to hold up (with some dr

42、ift expected given higher patient numbers)One KOL mentioned that sotorasibs 54% ORR at the high dose (960mg) may not be representative of the true ORR, but believes that 40%-50% ORR is reasonable and that 10%-15% absolute variance is plausible nonetheless data are compelling to date and better than

43、his initial expectations of 30% (prior to the initial presentation)This expert had similar thoughts on MRTX849s updated ORR dataKOLs commented that duration in the range of 6-9 months would be clinically meaningful and within their expectationsOn differentiation between sotorasib and MRTX849One expe

44、rt commented that depth of response is often a surrogate for duration and that the deepest responses were 100% (CR) and 62% (PR) for sotorasib and MRTX849, respectivelyHe also noted that it was interesting that the CR reported by sotorasib was at the 360mg dose (second lowest) while the deepest resp

45、onse for MRTX849 was at the highest dose; quickly acknowledging that this was one patient and overall patient numbers are lowOn the flip side, another KOL cautioned on drawing a direct line with depth and duration of response, and that CRs often dont translate to longer PFSOverall, the experts think

46、 that the two drugs are more similar than different and generally agreed that a PFS delta of 2-4 months would be needed to underscore clinical differentiationOn potential commercial implicationsThe experts all agreed that the 2L NSCLC bar is low and that the KRAS drugs are approvable as a potential

47、treatment in this line, especially given the safety profileThey seemed to agree that first to market is a big advantage; one highlighted that 6+ months would be very significantPlease see our recent Lung Doc Rounds piece for notes from our KOL calls (link)Source: J.P. Morgan Research20 KRAS Commerci

48、al Opportunity21 The commercial opportunity for AMG 510 has become a key focus, thus we look at the commercial outlook on a comp and patient build basisWe view the EGFR class as one potential commercial comp to KRAS G12C in NSCLC (though we look at others as well)This is primarily based on prevalenc

49、e rates within NSCLC, where both EGFR and KRAS G12C are in the 10-15% rangeWe use pricing in these markets as a proxy for the potential pricing band for sotorasibWe acknowledge the inadequacy of comparing across markets (esp. given the clinical efficacy demonstrated by Tagrisso/EGFR); however, we fe

50、el that it is appropriate to use commercial data to begin to form somewhat of a benchmark (at least prior to adjuvant resectable/unresectable label expansion)Based on our comp analysis the KRAS G12C TAM is approximately $4.2B - $5.5B in lungWhere we could go wrong with this particular analysisMany n

51、uances exist between EGFR- and KRAS-driven cancers in NSCLC most notably, EGFR-driven NSCLC disproportionately impacts non-smokers (relative to KRAS), which may ultimately impact the duration of treatmentTagrisso (EGFR) has demonstrated 18.9 month mPFS and 38.6 month mOS, which may justify a higher

52、price pointTagrisso is also approved in the 1L setting and has demonstrated robust data in stage IB-IIIA NSCLC, and thus consensus numbers reflect this larger market opportunity (which we try to adjust for)For now, we assume KRAS G12C can penetrate a niche within the 1L market (likely in combo with

53、PD1)Duration remains an outstanding question for the KRAS G12C class, and we provide sensitivity analyses on the following slides to illustrate this dynamicSource: J.P. Morgan Research; Tagrisso label22 The commercial opportunity for sotorasib (AMG 510) and MRTX849 through the lens of targeted oncol

54、ogy compsWe believe the following commercial products provide some precedent for the potential KRAS NSCLC outlookThe table (& graph) below is not intended to be exhaustive, but rather illustrative of uptake and how 1L/2L approvals have impacted these commercial products, as well as how epi data corr

55、elate to the relative sizes of these opportunitiesBased on 2019A sales and projected 2025 sales (9 years post initial approval), Tagrisso (EGFR)* sales are 3-5x Alecensa (ALK) sales, largely in line with what the epidemiology data suggestCompanyMarketedUS ApprovalMutationIndicationLine of TxPrevalen

56、ceAnnual Cost ($)2019 Sales($M USD)2025E Cons.Sales ($M USD)RocheTarceva11/18/2004EGFRmEGFRm NSCLC2L+10-15% NSCLC$101,417$300$48(Erlotinib)4/18/20101L maint.5/17/20131L maint.6/1/2018EGFRm Panc.1L (gem combo)RocheAlecensa12/11/2015ALKALK + NSCLC2L+ (Xalkori failures)3-5% NSCLC$179,366$882$1,348(Alec

57、tinib)11/6/2017ALKALK + NSCLC1LPFEXalkori4/26/2011ALKNSCLC3L+3-5% NSCLC$202,303$530$343(Crizotinib)3/11/2016ROS-1NSCLC1% NSCLCAZNTagrisso11/13/2015 (AA)EGFRmNSCLC (T790M)2L (post EGFR)8%$178,923$3,189$7,667(Osimertinib)3/31/2017 (FA)2L (post EGFR)4/18/2018EGFRmNSCLC1L10-15%AZNIressa5/5/2003All comer

58、NSCLC2L$93,467$423$270(Gefitinib)7/13/2015EGFRmNSCLC1LBIGilotrif1/15/2013EGFRmNSCLC3L+$105,686N/AN/A(Afatinib)7/12/20131L4/15/2016sq-NSCLC2L1/16/2018EGFRmNSCLC1LBottom line, we use pricing, historical precedent, and consensus estimates as a comp to the KRAS G12C opportunity.$8,000$7,000Sales ($M USD

59、)$6,000$5,000$4,000$3,000$2,000$1,000$0Source: J.P. Morgan Research; Roche Presentations; bbg consensus; *we estimate the adjuvant opportunity is $2-2.5B, which is included in consensus estimates; FA = full approval; AA = accelerated approval.23Tarceva (EGFR)Iressa (EGFR)Tagrisso (EGFR) Alecensa (AL

60、K)Xalkori (ALK) Based on sales of commercial NSCLC drugs and epidemiology data, we assess the KRAS G12C TAMWe provide the table below to illustrate the KRAS G12C TAM compared with other targeted lung drugsOur mutation/prevalence rates are derived from medical publications and company reportsPeak sal