Deciphera Plans Ripretinib NDA Filing For Q1 2020 On Phase III GIST Data
Executive Summary
CEO Steve Hoerter sees best-in-class potential for the drug based on both efficacy and safety in the fourth-line gastrointestinal stromal tumor setting, with the INVICTUS trial having positive readthrough to the ongoing Phase III INTRIGUE study in second-line GIST.
Deciphera Pharmaceuticals Inc.'s ripretinib met and potentially exceeded expectations in the placebo-controlled Phase III INVICTUS clinical trial testing the KIT and PDGFRa kinase switch control inhibitor in fourth-line treatment of gastrointestinal stromal tumors (GIST), justifying the filing of a new drug application (NDA) with the US Food and Drug Administration in the first quarter of 2020.
The company reported median progression-free survival (mPFS) in INVICTUS – the trial's primary endpoint – of 6.3 months (27.6 weeks) for ripretinib-treated patients versus one month (4.1 weeks) in the placebo group (HR=0.15; p<0.0001) on 13 August. CEO Steve Hoerter said during a same-day call with investors and analysts that the efficacy and the relative safety seen in the study could position the drug as a best-in-class agent and give it a competitive edge commercially.
Hoerter noted that while the ripretinib's fast track designation from the US FDA gives Deciphera the option of a rolling submission for its NDA, the company will not determine whether to file the application on a rolling basis until after it discusses the INVICTUS data with agency.
While the study's results still are being evaluated, with additional details to be presented at a medical conference later this year, Hoerter said the INVICTUS results and their consistency relative to Phase I data for ripretinib in GIST should provide positive readthrough to the ongoing Phase III INTRIGUE data in second-line GIST. He said Deciphera is pleased with the rate of patient enrollment in INTRIGUE, but the company did not give any guidance about the timeframe for that trial.
Analysts shared the CEO’s view that the INVICTUS results increase the likelihood of success for INTRIGUE.
"We believe this result, coupled with the relatively clean safety profile exhibited across ripretinib clinical trials, largely de-risk the company’s planned NDA submission to the FDA in 1Q20 in the setting of advanced GIST, and thereby increase our [possibility of success (POS) rating] in this setting from 90% to 95%," Deutsche Bank analyst Konstantinos Aprilakis said in a 13 August note.
"Further, we emphasize that we see positive readthrough to the ongoing pivotal Phase III study of ripretinib in 2L GIST (INTRIGUE), given that the active comparator in that trial, [Pfizer Inc.'s Sutent (sunitinib)], is associated with a mPFS of only 5.5 months; we increase our POS in this setting from 65% to 75%," Aprilakis continued.
Deciphera's stock closed up 80% at $35.90 per share on 13 August based on the highly-anticipated INVICTUS data. The company went public in September 2017 at $17 per share. (Also see "IPO Update: New Offerings Outperform As September Ends With Biopharma Trifecta" - Scrip, 29 Sep, 2017.)
Designed For Efficacy By Targeting Mutations Broadly
Ripretinib is designed to target the broad spectrum of KIT and PDGFRa mutations that drive GIST, which may account for the improved PFS observed among the heavily pre-treated patients enrolled in INVICTUS, Hoerter told the call.
SVB Leerink analyst Andrew Berens views the PFS data alone as enough to differentiate ripretinib in both the fourth-line and second-line GIST settings.
"The efficacy data appear strongly supportive of benefit in this later-line population, exceeding what the drug had previously shown in a similar setting in Phase I, and appear to at least partially de-risk the opportunity for ripretinib in the 2L setting versus Sutent, the larger and more commercially relevant opportunity in our view," Berens said in a 13 August note.
Deciphera estimates that the incidence of KIT-mutated GIST in the US is 2,600 patients in the second line and 2,100 in the fourth line. Jefferies analyst Maury Raycroft, in a 13 August note about the company's partner in China, said Zai Lab Ltd. estimates an incidence of 30,000 GIST patients in China. The companies' collaboration was announced in June. (Also see "Asia Deal Watch: BeiGene And Celgene Exit Their Anti-PD-1 Collaboration" - Scrip, 18 Jun, 2019.)
INVICTUS Closely Mirrors Updated Phase I Data
INVICTUS enrolled 129 GIST patients previously treated with all three drugs approved in the first, second and third-line settings – Novartis AG's Gleevec (imatinib), Sutent and Bayer AG's Stivarga (regorafenib), respectively; no drugs are approved in the fourth line.
Deciphera's top-line data review included both objective response rate (ORR) and overall survival (OS), which were among the secondary endpoints, but the company is saving other INVICTUS details for the conference presentation later this year.
The ORR for ripretinib was 9.4% compared with 0% for placebo (p=0.0504) and median OS was 15.1 months in the treatment arm and 6.6 months for placebo (HR=0.36, nominal p-value=0.0004).
Since ORR was not statistically significant, Deciphera noted that the hypothesis testing of OS was not formally performed, because the determination was to be based on a statistically significant ORR result, although the company described the OS data as "clinically meaningful." Results for the survival endpoint included placebo-treated patients who crossed over to ripretinib treatment after disease progression.
Given the trial's design linking OS significance to ORR significance, Hoerter said he could not comment on the likelihood that a survival benefit could be included in the ripretinib label, especially before talking with the US FDA about the INVICTUS data.
Nevertheless, SVB Leerink's Berens said the overall top-line efficacy data "appear to strongly support clinical benefit in this later-line patient population," especially given the Phase III study's results in comparison to the Phase I data.
Deciphera reported updated results from its Phase I study that enrolled patients who had received at least one prior treatment regimen. In the fourth line and beyond, the data were were similar to the Phase III INVICTUS results.
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Phase I Ripretinib Results In Second-Line Or Later GIST |
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|
Line Of Therapy |
ORR unconfirmed (confirmed) |
mPFS |
|
Second line (n=37) |
30% (22%) |
42 weeks |
|
Third line (n=31) |
23% (13%) |
40 weeks |
|
Fourth line (n=60) |
15% (8%) |
30 weeks |
|
Fourth line or later (n=110) |
11% (7%) |
24 weeks |
ORR/PFS Disconnect Not Dissimilar To Other Drugs
Hoerter attributed the statistically significant PFS benefit for ripretinib despite the lack of significance on ORR in INVICTUS to the specific binding of ripretinib to KIT and PDGFRa, which allows for broad activity against the targets' mutations. He also noted that Sutent and other approved therapies for first- through third-line GIST had similarly low response rates.
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Efficacy Comparison Across Approved GIST Patients |
|||
|
|
Gleevec (1L) |
Sutent (2L) |
Stivarga (3L) |
|
Median PFS |
23.2 months |
5.5 months |
4.8 months |
|
ORR |
53.9% |
6.8% |
4.5% |
Deutsche Bank's Aprilakis, who noted the potential for ripretinib to perform better than Sutent commercially given the Deciphera drug's 42-week (roughly 10-month) mPFS in second-line patients in the ongoing Phase I trial, adjusted his prediction for likely ripretinib pricing "from $27,500/month to $30,000/month to better reflect the value proposition we see for the asset."
Hoerter declined to compare ripretinib to Blueprint Medicines Corp.'s KIT and PDGFRa inhibitor avapritinib (BLU-285), which is pending at the US FDA with a 14 February action date for approval to treat fourth-line GIST patients and adult GIST patients with a PDGFRa exon 18 mutation regardless of prior therapy. The company reported positive results in people with this mutation in 2017 and won a breakthrough therapy designation from the FDA for treatment of those patients.
Hoerter noted the difficulty of cross trial comparisons, but said Deciphera believes it has a best-in-class drug.
Safety Also Could Be A Differentiating Factor
Hoerter said during the call that Deciphera also sees the safety of ripretinib relative to other GIST agents as a differentiating factor commercially. The company described the drug as generally well tolerated in INVICTUS, but didn't disclose treatment discontinuation rates.
However, Hoerter noted the tendency for patients to stay on drug even after disease progression in Deciphera's Phase I and Phase III studies and said that signals ripretinib is well tolerated.
Grade 3 and 4 treatment-emergent adverse events TEAEs were observed in 49% of ripretinib-treated patients (n=42) and 44% of placebo patients (n=19). Grade 3 and 4 TEAEs observed in at least 5% of ripretinib-treated patients were anemia (9%; n=8), abdominal pain (7%; n=6) and hypertension (7%; n=6), while 14% (n=6) in the placebo arm experienced Grade 3 or 4 anemia.
"We remain very comfortable with the competitive situation we have," Hoerter said, noting that Deciphera's commercial preparation are under way.
The commercial team is nearly fully built out, with exception of hiring sales representatives, and the medical affairs team is complete, he said, noting that "we intend on being prepared for a potential launch in 2020."