Welcome to your weekly digest of approaching regulatory and clinical readouts. Tobira (NASDAQ:TBRA) expects Phase IIb non-alcoholic steatohepatitis (NASH) data in the third quarter, and has maximized the chances of success with cenicriviroc by picking high-risk patients for the trial. Positive results could provide a much-needed cash injection.
And by the middle of the year, Karyopharm should get a readout from its Phase II Storm trial in refractory multiple myeloma. Its exportin 1 inhibitor selinexor will be tested in combination with low-dose dexamethasone in 80 patients, and if positive, the trial may be expanded to 150 patients, possibly allowing an approval filing. There are, however, safety concerns raised by prior studies in acute myeloid leukaemia.
The 289-patient Centaur trial of Tobira's cenicriviroc has enrolled NASH patients who are at increased risk of progression to cirrhosis relative to patients from trials conducted by Intercept and Genfit, the two leading groups in the NASH space (Therapy focus - NASH projects set for data in dog days of summer, May 03, 2016).
Leerink analysts note that thanks to this patient selection, cenicriviroc is well positioned to achieve Centaur's primary and secondary goals. The primary endpoint is improvement of non-alcoholic fatty liver disease (NAFLD) activity score at one year without worsening of fibrosis, while secondary outcomes include resolution of NASH, again without worsening of fibrosis.
12-week data from a Phase IIa study called Orion were released at the start of May. That trial, in prediabetic or diabetic patients with suspected NAFLD, showed improvements in insulin sensitivity with cenicriviroc. Insulin resistance is associated with the development of NAFLD and is the key driver for progression to its more severe form, NASH. 24-week Orion data are expected later this year.
Combination therapy could give Tobira an advantage over its rivals thanks to its recent cross-licensing arrangement with the South Korean firm Dong-A. A Phase I study of cenicriviroc and evogliptin, a DPP-IV inhibitor, will commence this year. In February, an agreement was reached with Novartis under which the Swiss group will provide Tobira with investigational materials for use in preclinical combination studies.
It is thought that the combination approach might address the underlying metabolic causation of NASH, alongside its inflammatory and fibrotic effects on the liver. Tobira plans to start a Phase III study of cenicriviroc in NASH next year. With $52.7m in the bank, it will be eager for a partnership or fund raising.
The open-label, single-arm Storm study is testing Karyopharm's selinexor in 80 patients with heavily pretreated multiple myeloma, who will receive 80mg selinexor plus low-dose dexamethasone, both twice weekly. Based on response rates in these patients, the company may expand the trial to more than 150 patients, potentially enabling it to seek accelerated approval.
Selinexor is the most advanced exportin 1 (XPO1) inhibitor. In fact, apart from a preclinical candidate from Stemline Therapeutics, Karyopharm appears to be the only company with such a project.
However, it has been dogged with safety issues. News that dosing in an AML trial called Sopra had to be lowered to 60mg owing to higher than expected rates of sepsis was buried in Karyopharm's second quarter report, and shares fell 39% (Karyopharm fails to contain sepsis signal, August 11, 2015).
An interim analysis from the Phase II Sopra study is expected in late 2016, with final top line overall survival data by the middle of next year. Karyopharm has stressed that sepsis has not been associated with treatment in other haematological malignancies or solid tumors.
Since the beginning of the year, the company's shares are off 38%. At the end of 2015, Karyopharm had $210m in cash, and expects to end 2016 with at least $120m, expected to fund R&D into 2018.
2022 worldwide sales consensus for selinexor sits at $439m, according to EvaluatePharma. With US sales pegged at $203m, the notion is that selinexor will be licensed out in the EU, with Karyopharm receiving royalties. Getting a partner will depend on whether the company can dispel further safety overhangs.