Welcome to your weekly digest of approaching regulatory and clinical readouts. Karyopharm is due to report results from its expanded phase IIb trial of selinexor by the end of April in penta-refractory multiple myeloma patients, looking to gain accelerated approval on the data; if this is successful it would be the company’s first ever green light.
Also, Aveo Oncology’s Fotivda will yield phase III results in third-line renal cell cancer in the second quarter. The company will hope that these will be enough to secure a US nod; the product gained a European approval on questionable data from its first-line trial, but the FDA was not so lenient, handing out a complete response letter five years ago.
Calm before the Storm
The phase IIb Storm trial tests oral selinexor plus dexamethasone in subjects with either quad or penta-refractory multiple myeloma; the latter group includes patients resistant to Johnson & Johnson/Genmab’s Darzalex. The primary endpoint of the single-arm study is overall response rate, and secondary endpoints include duration of response and clinical benefit rate.
In 2016 Karyopharm reported encouraging topline results from Storm in 78 evaluable patients. Among the 48 in the quad-refractory group the ORR was 21%, and in the penta-refractory group (30 subjects) it was 20%. Median overall survival was 9.3 months for all patients, and the median duration of response was 5 months. There were low rates of grade ≥3 non-haematologic toxicities, and no new safety signals were identified – increased sepsis rates had hit a previous trial in acute myeloid leukaemia.
The Storm trial was subsequently expanded to include a further 122 penta-refractory patients, and data from the expanded cohort will be reported at the end of April. With limited treatment options left for these advanced patients the company aims to file with the FDA for accelerated approval in the second half of this year.
Selinexor is a first-in-class XPO1 inhibitor whose 2022 revenues, according to EvaluatePharma sellside consensus, are forecast to reach $613m. Ono Pharmaceutical has licensed the asset in Japan and other Asian countries, and Karyopharm still hopes to find a partner to support European launch.
Selinexor has an NPV of $1.8bn, or 243% Karyopharm’s market cap. The company ended 2017 with $176m in cash, enough to fund it through at least the first quarter of next year, and will hope that the Storm results will be enough to spur interest from other potential partners.
|Ongoing studies of selinexor|
|Indication||Trial name||Data?||Trial ID|
|Multiple myeloma (penta-refractory)||Storm (phase IIb)||End of Apr||NCT02336815|
|Diffuse large B-cell lymphoma||Sadal (phase IIb)||2018||NCT02227251|
|Multiple myeloma (1-3 prior treatments)||Boston (phase III)||2019||NCT03110562|
|Liposarcoma||Seal (phase II/III)||2019||NCT02606461|
The latest study for Aveo is Tivo-3, testing Fotivda, whose active ingredient is tivozanib, versus Nexavar in refractory advanced renal cell carcinoma. The primary endpoint of the 322-patient trial is PFS, with OS, ORR and duration of response as secondary measures. The company has given a second quarter timeline to release PFS and OS data.
Aveo plans to use Tivo-3 alongside the results from its previous trial in first-line patients, Tivo-1, to file in the US. Tivo-1 was the basis for Fotivda’s approval in Europe last year, although this was controversial as despite meeting the primary PFS endpoint control-arm patients on Nexavar actually lived longer than those on active treatment.
The one-way crossover design of Tivo-1 might have confounded the data; Tivo-3 does not allow within-trial crossover. Sill, the FDA was not as convinced as the EMA by Tivo-1, and a negative adcom was followed by a complete response letter back in 2013 and a request for a further trial (Aveo reveals fallout of tivozanib failure, June 5, 2013).
Last year’s European approval of Fotivda helped improve sentiment, but Aveo's current valuation is a shadow of the levels seen in 2011. The company has just $33.5m in cash.
Eusa Pharma has European rights but Aveo is likely to need another partner – or more cash – to get Fotivda across the finish line in the US. Astellas handed back worldwide rights in 2014.