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With arguably the standout data from the 2019 American Society for Clinical Oncology (ASCO) annual meeting, Amgen has become the first company to show that KRAS, beyond its role as an oncogene, is also a viable drug target [1]. In presenting positive data from a Phase I dose-escalation study of AMG 510, an oral small molecule inhibitor of KRAS G12C, Amgen is on its way to creating a lucrative market for treating one of the most common underlying genetic causes of cancer. To briefly recap, AMG 510 achieved a 50% response rate among non-small cell lung cancer (NSCLC) patients expressing the KRAS G12C mutation, including 10% complete response, while showing a 72% disease control rate among the comparable colorectal cancer (CRC) population, with no responders to date.

 

The significance of the result was seen not only in Amgen’s share price – moving 4% despite being a $100bn+ business – but also for competitors such as Mirati Therapeutics, which was buoyed 32% by the proof-of-concept. Analysts at Leerink were quick to assign AMG 510 global sales of $2.3bn by 2028, risk-adjusted to approximately $750m considering the generally low likelihood of approvals for candidates at this early stage of development, using sources such as Biomedtracker. Considering the potential broad clinical utility of a KRAS inhibitor, it begs the question about how much upside such a forecast could have. We have therefore built our own model, and in deconstructing it for this article we aim to show the calculations and cogitations that underpin such uncertain assets.

 

Why all the KRAS fuss?

KRAS stands as one of the most common and deadliest oncogenes, found in around 16% of all human cancers [2]. The KRAS protein is implicated in the MAP kinase signaling pathway, and activating mutations lead to cell survival and proliferation mechanisms. Despite its discovery over three decades ago, it has remained elusive as a drug target, although several downstream mediators have been effectively drugged. KRAS itself is described as one of the master switches for cancer and is particularly associated as a driver for CRC, NSCLC, and pancreatic cancer.

 

Recent scientific advances have enabled the discovery and design of small molecule inhibitors against a specific KRAS mutation, G12C [3]. This particular oncogenic point mutation provides a cysteine residue on the protein surface, close to the guanosine triphosphate (GTP) binding pocket, KRAS’s natural substrate, that can be targeted to stabilize downstream signaling. With this unique binding, selective inhibitors against G12C have no affinity against wild-type KRAS, therefore providing a potentially wide therapeutic index.

 

KRAS G12C is one of many potential oncogenic mutations, so this approach is only amenable for a portion of KRAS-driven cancers. Nevertheless, it is still highly prevalent: G12C is present in approximately 40% of all KRAS-driven NSCLC cases and 10% for CRC [2]. The most common KRAS mutation, G12D, cannot be targeted in such a way, although there is separate discovery work involving a range of modalities, including small molecules, short interfering RNA, and T-cell receptors.

 

AMG 510 market potential

We are currently projecting AMG 510 to achieve sales of $2.8bn by 2029, so certainly within the same ballpark as other estimates. In breaking down the various steps to achieve this number, you can see the underlying inputs and assumptions, which we hope will invite some lively discussion.

Focusing first on the opportunity in NSCLC, Datamonitor Healthcare has modeled the incidence of Stage IV disease in the US, with over 100,000 new diagnoses each year [4]. To this, the proportion of patients that commonly receive drug treatment (70%) according to primary research with US prescribers is applied [4]. Among these treated patients, around 12% are assumed to possess the KRAS G12 mutation [2], of which 90% will be tested for KRAS mutations. This is assumed to be a high number owing to widespread testing for other mutations, and by the time AMG 510 launches the place of broad diagnostic tools such as FoundationOne CDx will be entrenched.

Based on current timelines, the earliest estimate for AMG 510’s first commercial availability would be Q2 2023. If Amgen is able to pursue a Xalkori (crizotinib; Pfizer/Merck KGaA)-like clinical development pathway, the total time spent in clinical development would be a mere 4.7 years. Biomedtracker first noted AMG 510 in clinical development in August 2018, which would mean US regulatory approval in April 2023, assuming that AMG 510 is able to collect incentives such as fast track and breakthrough therapy designations. Once on the market, a reasonable assumption is that AMG 510 will capture 70% of the addressable patient population by the time it reaches its peak. This represents the unmet need among these patients for a targeted therapy and longstanding demand for a specific drug against KRAS mutations. Uptake is expected to be rapid, noting that Tagrisso (osimertinib; AstraZeneca) was able to achieve a >60% adoption rate in first-line EGFR-mutant patients in the US, even with competitors, after its label expansion in April 2018 [5]. We reason that with potentially no competitors, AMG 510 will be able to achieve a similar uptake trajectory. This equates to around 6,000 NSCLC patients in the US receiving AMG 510 in the first-line setting each year.

 

AMG 510 patient potential in KRAS G12C NSCLC in the US, 2023–29

2023

2024

2025

2026

2027

2028

2029

US NSCLC Stage IV incident population

106,152

106,933

109,466

111,838

114,194

116,529

118,839

Drug treated (70%)

74,342

74,889

76,663

78,324

79,974

81,609

83,227

KRAS G12C+ (11.8%)

8,750

8,814

9,023

9,219

9,413

9,605

9,796

Genotyped (90%)

7,875

7,933

8,121

8,297

8,472

8,645

8,816

AMG 510 uptake

11%

25%

39%

53%

67%

70%

70%

AMG 510-treated population

827

1,944

3,127

4,356

5,634

6,051

6,171

Note: totals may not sum due to rounding.

Source: Datamonitor Healthcare, July 2019

 

Now that the patient potential of AMG 510 is established, the final step is to translate this into a revenue line for Amgen. There are plenty of tyrosine kinase inhibitors (TKIs) with established and accepted price points – we noted the $14,800 and $16,800 monthly costs of Tagrisso and Xalkori, respectively. With the novelty of AMG 510 being the first TKI for a KRAS+ population, the upper end of this precedent is appropriate. Taking a $17,000 monthly cost and conservatively applying 3% year-on-year inflation, AMG 510 would carry a price of around $19,100 by the time of launch in 2023.

 

An average 11-month treatment duration is arguably the least informed assumption within the model, as there is little clinical evidence to base this on. Benchmarking against other targeted therapies is precarious because of their different clinical profiles, but our best estimate is approaching one year on treatment. You could make the case for the monthly cost of treatment and the median length of treatment being intuitively linked, so if it turns out that patients can receive KRAS inhibitors for extended periods of time, then the overall cost would be counterbalanced. Factoring in a flat rebate of 15%, the cost per patient of AMG 510 is in the region of $200,000.

 

These all come together to produce a 2029 forecast of $1.3bn in the US within the NSCLC population. This number can be extrapolated to project sales outside of the US ($1.2bn) and market potential within CRC patients (~$300m), resulting in the final value of $2.8bn. To quickly model ex-US sales, we used geographical estimates for the ALK inhibitor Alecensa (alectinib; Roche), noting that the EGFR mutation is more common in Asian patients and that basing the ratio on drugs such as Tagrisso may overstate the global opportunity. Datamonitor Healthcare’s estimates of the incident Stage IV CRC patient population [6], combined with a 4% prevalence of the KRAS G12C mutation in this disease [2], place the sales potential within CRC as 11% of the NSCLC total.

 

AMG 510 sales potential in KRAS G12C tumors, 2023–29

2023

2024

2025

2026

2027

2028

2029

Monthly cost ($)

19,134

19,708

20,299

20,908

21,535

22,181

22,847

Cost per patient (11 months; $)

210,470

216,784

223,288

229,986

236,886

243,993

251,312

Rebate (15%; $)

178,900

184,267

189,795

195,488

201,353

207,394

213,616

AMG 510 US NSCLC sales ($m)

148

358

593

852

1,134

1,255

1,318

Ex-US (92%) NSCLC sales ($m)

136

330

547

785

1,045

1,156

1,215

NSCLC total sales ($m)

284

688

1,140

1,636

2,180

2,411

2,533

CRC (11%) total sales ($m)

32

78

129

185

247

273

287

AMG 510 total sales ($m)

316

766

1,269

1,822

2,427

2,685

2,820

Note: totals may not sum due to rounding.

Source: Datamonitor Healthcare, July 2019

 

 

 AMG_510_Sales_image_1

Source: Datamonitor Healthcare, July 2019

 

 

Upside and downside scenarios

Many of the assumptions detailed above can certainly be considered optimistic and/or best-case scenarios already. There are no guarantees that Amgen will be able to translate its proof-of-concept efficacy in NSCLC into an approved drug. Biomedtracker currently assigns a 9% likelihood of approval for AMG 510 (3% above average for Phase I oncology assets), although this will certainly rise as Amgen realistically has the data required to confidently progress to larger, even pivotal clinical trials. Furthermore, clinical trials for oncology assets that are guided by therapeutic biomarkers can have a two-to-three-fold higher chance of success [7].

 

Nevertheless, there are certainly scenarios in which Amgen may be able to accrue higher sales than currently estimated. NSCLC is certainly the most immediate application for AMG 510 considering the data so far, and Amgen is suggesting that its KRAS inhibitor is behaving more as a tumor-dependent, rather than tumor-agnostic targeted therapy [1]. However, as discussed previously, there is broader potential for KRAS G12C inhibition, not least within CRC where the data are maturing. With intra-patient dose escalation still ongoing and just one CRC participant receiving the recommended Phase II dose of 960mg, Biomedtracker suggests that responses may improve over time. CRC is currently included as a portion of the total forecast estimate, but KRAS G12C mutations have also been identified in other common solid tumors such as pancreatic and uterine cancer [2]. With limited prevalence information and no clinical data in these patients, it would be too speculative to assign any additional potential value, although these certainly present additional opportunities.

 

Amgen has stated that it intends to test AMG 510 in combination with a PD-1 inhibitor in NSCLC [1]. While this is appropriate considering that PD-1 inhibitors such as Keytruda (pembrolizumab; Merck & Co) are the current standard of care, there is the risk that AMG 510 does not achieve superiority or provide enough additional benefit when used in combination. Discerning the exact clinical profiles of AMG 510 monotherapy, Keytruda monotherapy, and the AMG 510 + Keytruda combination will be essential if Amgen is able to penetrate the newly diagnosed, first-line G12C+ patient population. Anything less than superiority for AMG 510 will greatly curb the assumed 70% uptake among these patients.

 

Also counting against AMG 510, other than the large risk of clinical failure, is the prospect of competition. There are several other companies following the science, not least Mirati Therapeutics, which is developing its own KRAS G12C inhibitors. Mirati currently possesses the only other clinical-stage KRAS G12C inhibitor, MRTX849, and was able to raise $234m via a follow-on public offering in order to fund its continued development [8]. While Mirati’s value has more than doubled over the course of 2019, it is likely to remain an attractive acquisition target for Big Pharma companies such as Pfizer, Novartis, and Roche, which are already marketing TKI portfolios. Other large companies with proprietary anti-KRAS assets include Johnson & Johnson and Merck, although public disclosure of preclinical programs is notoriously patchy.

 

Amgen certainly has a headstart over its potential rivals, and it is unlikely that a competitor would be able to catapult ahead of an expedited development program for AMG 510. Nevertheless, several of these drugs have the potential to gain a portion of Amgen’s predicted 70% uptake within the KRAS G12C population. There are examples in which having multiple products can help to grow the overall value of a drug class, so it is not necessarily completely negative for Amgen should it face rivals. Some of these potential competitors, in addition to approaches against other KRAS mutations that would expand the overall applicability of KRAS inhibition, are shown in the table below.

 

KRAS-targeting drug pipeline

Drug

Company

Target

Drug type

Highest phase

siG12D LODER

Silenseed

KRAS G12D

siRNA

Phase II

AMG 510

Amgen

KRAS G12C

Small molecule

Phase I

KRAS TCRs

Gilead

KRAS G12D, KRAS G12V

T-cell receptor

Phase I

MRTX849

Mirati Therapeutics

KRAS G12C

Small molecule

Phase I

JNJ74699157

Johnson & Johnson

KRAS G12C

Small molecule

IND

mRNA-5671

Merck, Moderna Therapeutics

Four common KRAS epitopes

mRNA personalized vaccine

IND

aKRAS

Oblique Therapeutics

KRAS unspecified

Antibody

Preclinical

ARS-1620

Johnson & Johnson

KRAS G12C

Small molecule

Preclinical

AU-BEI-8653

Aurigene

KRAS G12C

Small molecule

Preclinical

COTI-219

Cotinga Pharmaceuticals

KRAS unspecified

Small molecule

Preclinical

iExomes

Codiak Biosciences

KRAS G12D

siRNA

Preclinical

n/a

Mirati Therapeutics

KRAS G12D

Small molecule

Preclinical

RM-007

Revolution Medicines

KRAS G12C

Small molecule

Preclinical

IND = investigational new drug; siRNA = short interfering RNA

Source: Biomedtracker

 

 

References

[1] Scrip (2019) Amgen's KRAS Inhibitor AMG 510 Leans Toward Tumor-Dependent, Not Agnostic, Approach. Available from: https://scrip.pharmaintelligence.informa.com/SC125326/Amgens-KRAS-Inhibitor-AMG-510-Leans-Toward-TumorDependent-Not-Agnostic-Approach [Accessed July 5, 2019].

[2] My Cancer Genome (2019) KRAS G12C. Available from: https://www.mycancergenome.org/content/alteration/kras-g12c/ [Accessed July 5, 2019].

[3] Holderfield M (2018) Efforts to Develop KRAS Inhibitors. Cold Spring Harbor Perspectives in Medicine, 8(7). Available from: 10.1101/cshperspect.a031864 [Accessed July 5, 2019].

[4] Datamonitor Healthcare (2018) Epidemiology: Non-Small Cell Lung Cancer. Available from: https://service.datamonitorhealthcare.com/disease/oncology/lung-cancer/non-small-cell-lung-cancer/epidemiology/article132837.ece [Accessed July 5, 2019].

[5] AstraZeneca presentation (2019) Q1 2019 results. Available from:  https://www.astrazeneca.com/content/dam/az/PDF/2019/Q1-2019/Q1_2019_Results_presentation_.pdf [Accessed July 5, 2019].

[6] Datamonitor Healthcare (2018) Epidemiology: Colorectal Cancer. Available from: https://service.datamonitorhealthcare.com/disease/oncology/gastrointestinal-cancer/colorectal-cancer/epidemiology/article127522.ece [Accessed July 5, 2019].

[7] BIO (2016) Clinical Development Success Rates 2006-2015. Available from: https://www.bio.org/sites/default/files/Clinical%20Development%20Success%20Rates%202006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016.pdf [Accessed July 5, 2019].

[8] Scrip (2019) Finance Watch: Gene Therapy, Targeted Oncology Driving IPOs Despite Biopharma Stock Shakiness. Available from: https://scrip.pharmaintelligence.informa.com/SC125485/Finance-Watch-Gene-Therapy-Targeted-Oncology-Driving-IPOs-Despite-Biopharma-Stock-Shakiness [Ac

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