Targeting genetically defined patient subgroups has yielded a couple of success stories in acute myeloid leukaemia over the past few years, and Syros hopes to add its name to this list. The company accompanied an Ash presentation this weekend on SY-1425, a RARα agonist, with plans to push into pivotal development – and new funding to get the trials underway.
Syros claims that around 30% of AML patients, and a similar proportion of those with myelodysplastic syndromes, a precursor to full-blown leukaemia, have disease characterised by overexpression of the RARA gene. The company has developed a biomarker to identify these patients, and is now setting out to prove that SY-1425 can improve their prospects.
Data at Ash revealed some encouraging signals in newly diagnosed patients considered unfit for chemotherapy, which remains standard of care. The phase II trial tested SY-1425 on top of azacitidine. Sold as Vidaza but now off patent, this drug has known activity in AML so Syros needs to go on to prove what SY-1425 is contributing here.
Weaker signals were evident in relapsed patients, as could be expected.
|Phase II AML trial in RARA positive patients|
|Newly diagnosed, chemo unfit, + azacitidine||R/R AML + azacitidine|
|ORR||67% (12/18)||19% (4/21)|
|CR||50% (9/18)||5% (1/21)|
|CRi||11% (2/18)||10% (2/21)|
|mOS||18 months*||5.9 months|
|CRi = complete response with incomplete blood count recovery. *Among those who achieved CR or CRi. Source: company press release.|
Despite generating early evidence in AML, Syros has decided to first push into phase III in MDS patients, at high risk of progressing into AML. An azacitidine combination will be tested, and around 190 RARA positive patients recruited, with complete response rate as the primary endpoint. The trial will start early next year and the company is hoping to file in 2024.
Work in AML will proceed more cautiously with a phase II trial due to start later next year in newly diagnosed, RARA positive patients unfit for chemotherapy. This trial will test a triple combination of Venclexta, azacitidine and SY-1425.
RARA positive patients tend not to respond as well to the Venclexta and azacitidine combination, Syros says, but the company maintains there is a biological rationale for still using the two agents in this subgroup. Adding the drugs to SY-1425 might decrease the likelihood of a patient developing resistant populations of cancer cell downstream, as well improving the depth of responses and even durability, Syros’s chief science officer, Eric Olson, said on an investor call.
That all needs to be proven, and data from the AML triple trial should emerge in 2022. Notably, this is around the same time that Syros’s new funds will run out. Over the weekend the company also unveiled a $90m private placement, led by Bain Capital, that is estimated to fund operations into the second half of 2022.
Presumably the company is hoping that strong triplet data will provide the basis for the next funding round. However a third announcement over the weekend adds another storyline here – that of the acquisition of a novel oral formulation of arsenic trioxide (ATO), a drug that is already a proven treatment for another subset of AML.
Measures of success
Acute promyelocytic leukaemia, cases of which amount to around 10% of AML, is aggressive but curable: about 80% of patients diagnosed are cured with ATO. For now, however, this is only available as an infusion and the administration is very onerous, with patients needing up to 140 two to four-hour infusions over nearly a year.
An oral formulation could offer a substantial convenience advantage, Syros argues, and lower associated healthcare costs. The next step is a pharmacokinetics study to confirm that the oral project, now called SY-2101, can achieve suitable exposure levels. A phase III trial is pencilled in for 2022, with a filing in 2024.
Syros puts the market opportunity here at around $250m. But the asset was bought for only $12m upfront, and the company is liable for a further $16m in development and sales milestones.
A new formulation of arsenic is hardly high science, of course, and it is the progress of SY-1425 that will be followed more closely. Much needs to go right over the next few years for Syros but with two projects slated for filing in 2024, success will easily be measured.