Blueprint Medicines: Unleashing A “New Era In The Management” Of ASM (EHA Preview)

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  • Blueprint Medicines plans to reveal updated data for advanced systemic mastocytosis (ASM)
  • When compared to current standard of care for ASM, Blueprint’s avapritinib appears to provide improved efficacy across many measures
  • EHA25 data is expected to provide more mature avapritinib data in ASM
  • Reasonable estimates have avapritinib achieving $800M in peak annual revenue in ASM, assuming it is able to achieve standard of care status
  • Although avapritinib’s profile appears more specific for ASM and is further along in development than competitor drug ripretinib (Deciphera Pharmaceuticals), other second-generation TKIs remain a significant threat to Blueprint’s potential in ASM

Blueprint Medicines (BPMC) intends to reveal “updated data” for their EXPLORER trial of avapritinib in advanced systemic mastocytosis (ASM) at the upcoming European Hematology Association 25th Annual Congress (June 11-14). The company intends to submit a NDA for the indication in the fourth quarter of 2020. The following article reviews the disease, current management, avapritinib data to date, what to look for at EHA, and avapritinib’s prospects in advanced SM moving forward.

Advanced systemic mastocytosis

Systemic mastocytosis results from a D816V KIT (exon 17) mutation that stimulates the proliferation of mast cells:

Systemic mastocytosis (SM) is a heterogeneous disease characterized by a clonal expansion and accumulation of neoplastic mast cells (MCs) in cutaneous and/or extracutaneous organs. The stem cell factor (SCF) receptor KIT is a transmembrane tyrosine kinase (TK) protein codified by the KIT oncogene that plays a key role in the function of MCs, via regulation of their differentiation, maturation, migration, survival, and cytokine production. Mutations involving the activating domain of KIT, mostly the D816V KIT mutation, are found in >90% of patients with SM when highly-sensitive diagnostic techniques are used.

Frontiers in Pharmacology

The proliferation of mast cells often presents itself on the skin in the form of lesions and pruritus. The inflammatory nature of the disease also makes sufferers more prone to allergic reactions and, potentially, deadly anaphylaxis. Other clinical manifestations include gastrointestinal upset, weight loss, osteoporosis, hematologic abnormalities (anemia, thrombocytopenia), and splenomegaly.

Mastocytosis symptoms

Image source: Novartis 

Because of the vast, unspecific variety of symptoms patients can present with, the disease is often either misdiagnosed (e.g. Crohn’s disease) or underdiagnosed.

Advanced systemic mastocytosis (ASM) is an aggressive form of systemic mastocytosis, characterized by multi-organ involvement and poor median survival (months to years).

ASM treatment algorithm

Treatment goals for ASM include the following: “control symptoms, mitigate organ damage, improve the quality of life (QOL), and extend survival” (UpToDate).

For ASM with KIT D816V mutation (the vast majority of cases), a KIT inhibitor is recommended for initial treatment. Midostaurin, FDA-approved for the treatment of ASM, is a “multi-kinase/KIT inhibitor that inhibits the protein product of KIT, including the kinase encoded by D816V-mutated KIT” (UpToDate).

Midostaurin has been studied, alone (versus no comparable drug or placebo), in nearly 150 patients with ASM. In two different trials, midostaurin procured overall response rates of 75% and 71%. In the formerly mentioned trial, midostaurin also

(…) decreased objective measures of MC burden (eg, bone marrow MC aggregates, serum tryptase levels), improved symptoms and quality of life, reverted organ damage, and decreased splenomegaly. Median duration of response (DOR) was 24 months, median overall survival (OS) was 29 months, and median progression-free survival (PFS) was 14 months.


Midostaurin is well-tolerated with the majority of events being lower grade and of gastrointestinal nature (e.g. nausea, diarrhea).

Cladribine is utilized in rapidly progressing ASM in patients who failed previous therapeutics.

Allogeneic hematopoietic cell transplantation is a curative option but is hardly utilized due to stringent selection criteria, cost, and lack of quality data, especially in light of potent TKIs.

Reports of allogeneic HCT for advanced SM are limited, with only small retrospective case series and comparisons to historical controls. No studies have randomly assigned patients to allogeneic HCT versus medical therapy alone. Furthermore, most studies describe outcomes from an era before the widespread use of potent KIT inhibitors, so their applicability to contemporary treatment of advanced SM is uncertain.


Avapritinib data in ASM

Blueprint’s avapritinib, a potent inhibitor of D816V KIT, has shown promise in ASM.

Compared to midostaurin, avapritinib is theorized to be a more effective therapy for ASM:

Given data from over a decade of experience with midostaurin, it is likely that its moderate efficacy and lack of on-target resistance mutations in SM result from the combination of poor pharmacokinetic properties, low potency and general lack of specificity for KIT in a disease with significant genetic complexity.

In contrast, avapritinib is a highly selective and potent KIT inhibitor. Though the genetic complexity of SM may pose a challenge for the success of all KIT-targeted therapies in SM, the early success of avapritinib in SM strongly suggests that avapritinib is exerting its effect through KIT inhibition, and that avapritinib may apply sufficient pressure on the disease to select for resistance-conferring KIT mutants.

Cancer Res

Let’s break down midostaurin versus avapritinib data, head-to-head, to date:

*Blueprint data includes patients with known midostaurin-resistance | Note: table’s data extracted from the following sources: UpToDate, Blueprint Medicines, Nature

It’s worth noting that midostaurin does appear to be a better tolerated drug, although avapritinib has yet to show any significant tolerability findings that would inhibit its opportunity for this indication. Obviously, there are limitations in comparing two different datasets for efficacy measures, but it does appear that avapritinib provides benefits over midostaurin in ASM.

Avapritinib EHA25 – what to look for
  • More patients may be evaluable for ORR. Investors would be well-pleased if this number were to rise into the 80’s. At the least, it would be good for the ORR to remain greater than or equal to 75%. So far, the ORR has only improved with great N, as it is up from 72% in 18 evaluable patients.
  • Blueprint data has yet to reach median OS and PFS, which is a good sign thus far. Investors will hope these numbers are not yet reached.
  • In the recent years, the FDA has stressed more quality of life measures in clinical trials. Investors will be on the look out for more QOL-related data.
  • Any significant safety issues could derail avapritinib for ASM.
Avapritinib ASM revenue estimate

Blueprint estimates there are 3,750 ASM patients in major markets, including 1,600 in the US. Novartis’ midostaurin (Rydapt) is estimated to cost nearly $400K per year. Assuming similar pricing to Rydapt ($400K/year), a 75% penetration rate, and a 50% ex-US price reduction, avapritinib nets nearly $800M in peak annual revenue for this indication.

Developmental competition in ASM

Because ASM is mostly a disease caused by D816V KIT mutations and following the advent of midostaurin in the treatment of ASM, KIT inhibitors (particularly second-generation ones) are expected to dominate the ASM market in the relevant future (until the end of current patent lives).

Deciphera Pharmaceuticals is also developing a KIT inhibitor, ripretinib. The company is currently recruiting ASM patients in a phase 1 basket trial. No human data in ASM is available to date. In the recent months, ripretinib has “dethroned” Blueprint from its former apparent lead in GIST, compiling more favorable efficacy data for the indication. Investors may be prone to extrapolate GIST data to ripretinib versus avapritinib expectations, but bear in mind that the two indications are different:

(…) comparison of WES in GIST with WES in SM shows GIST has a higher mutational burden than SM (35-60 mutations/sample in GIST vs 25 mutations/sample in SM). Given that GIST is at least as genetically complex as SM, and that resistance to KIT TKIs in GIST often involves on-target KIT mutations, it seems plausible that on-target mutations will confer avapritinib resistance in SM.

Cancer Res

Blueprint’s drug is described as being “specifically designed” for D816V KIT mutations and one can suspect it will procure superior data to Deciphera’s drug for ASM, but time and data will tell.

Final thoughts
  • TKIs for ASM are more-than-likely the standard way of treatment for many more years to come.
  • Second-generation TKI avapritinib, which is a highly specific inhibitor of the disease’s primary mutation, appears to provide benefits over standard of care (midostaurin) for ASM. More data is, however, needed to confirm benefit.
  • Assuming avapritinib achieves standard of care for ASM, reasonable estimates have the drug producing $800M in peak annual revenue.
  • Although Deciphera’s ripretinib is further behind in development and appears less specific for ASM than avapritinib, it will, nonetheless, serve as a major threat to avapritinib’s market potential until otherwise noted.
  • More/mature data is likely to continue to support the prospects and use of avapritinib for the treatment of ASM.

Disclaimer: The intention of this article is to provide insight, not investment advice. While the information provided in this article is intended to be factual, there is no guarantee and prospect investors are encouraged to do their own fact-checking and research before investing in a company. One must also consider one’s own financial standings, risk tolerance, portfolio diversification, etc. before making a decision to buy shares in a company. Many of my articles detail biotechnology companies with little or no revenue. These stocks are, therefore, speculative and volatile. Even when prospects seem promising, there is no predicting the future. Losses incurred may be significant.

Disclosure: I have no positions in any of the discussed stocks. I have no business relationships in any of the discussed companies. I received no compensation for this article and it expresses my own opinions.

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