Phase 1 data backs Cyclacel’s plans for CDK2/9 inhibitor

CYC065 stabiliized disease in a range of advanced cancer types. (PDPics/Pixabay)

Just over a year ago, Cyclacel was hit by a late-stage failure in leukemia that sent its shares into a tailspin and pushed an early-stage CDK inhibitor into the spotlight as its most promising candidate. Now, that CDK drug has shown it can stabilize disease in advanced cancers—and will be taken into a trial in combination with AbbVie’s would-be leukemia blockbuster Venclexta.

Cyclacel presented the phase 1 data on the CDK2/9 inhibitor CYC065 at the AACR meeting in Chicago yesterday, revealing that a disease stabilization was seen with the drug for up to a year in patients with tumors that are dependent on Mcl-1, MYC or CDK2/cyclin E for proliferation, survival and resistance to chemotherapy, including ovarian, parotid, uterine and ovarian cancers.

It’s welcome news for Cyclacel after last year’s negative read-out for acute myeloid leukemia (AML) candidate sapacitabine, which knocked back its chances of getting a drug to market anytime soon.

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CDKs are an enzyme family involved in regulation of the cell cycle, and have been linked to DNA repair pathways in cells and the spread of tumors. Research into the family has already yielded approved therapies targeting CDK4/6 for breast cancer—Pfizer’s Ibrance (palbociclib), Novartis’ Kisqali (ribociclib) and Eli Lilly’s Verzenio (abemaciclib)—but Cyclacel says CYC065 works via a different mechanism and could overcome resistance to those drugs.

The 26-patient study reported at AACR involved heavily pretreated patients who received various doses of CYC065 intravenously every three weeks. It showed that the drug was effective in suppressing the Mcl-1 in peripheral blood for at least 24 hours.

While stabilization of disease was the best outcome, Cyclacel CEO Spiro Rombotis pointed out that the first clinical trials of palbociclib reported mostly stable disease and almost no partial responses, only showing its true value when paired with the hormonal drug letrozole.

Cyclacel said it now plans to test a more intensive dosing regimen—giving the drug two days per week for two weeks of a three-week cycle—as well as move ahead with a long-anticipated combination study with AbbVie’s Bcl-2 inhibitor Venclexta (venetoclax) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL).

The company has said it thinks Mcl-1 modulates resistance to Bcl-2 inhibition, and as with palbociclib, it believes CDK2/9 drugs will show their true potential as part of combination therapy. And with Venclexta tipped to hit blockbuster status—albeit after a slower-than-expected start—Cyclacel’s drug could get a leg-up if further trials are positive.

The clinical data support biomarker-driven clinical development of CYC065 in selected patient populations,” said Rombotis. “The durable suppression of the Mcl-1 survival protein presents an exciting opportunity to combine CYC065 with other agents targeting the apoptosis pathway, such as venetoclax.”