FDA Grants Orphan Drug Designation to CFT7455 for Multiple Myeloma

The FDA has granted an orphan drug designation to CFT7455, a MonoDAC degrader targeting IKZF1/3, for use as a potential therapeutic option in patients with multiple myeloma, according to an announcement from C4 Therapeutics, Inc.¹

“We are pleased to receive FDA’s orphan drug designation for CFT7455 in multiple myeloma and believe this designation highlights the potential of CFT7455 to improve clinical outcomes for patients with multiple myeloma who face an incurable disease,” Adam Crystal, MD, PhD, chief medical officer of C4 Therapeutics, stated in a press release. “With far too many patients relapsing on numerous lines of therapy and succumbing to multiple myeloma, we are focused on advancing our phase 1/2 trial to bring this new treatment option to patients.”

In June 2021, a phase 1/2 trial (NCT04756726) was initiated to evaluate the safety, tolerability, and antitumor activity of the agent in patients with multiple myeloma. To be eligible for enrollment, patients need to be at least 18 years of age, have histologically or cytologically-confirmed non-Hodgkin lymphoma or multiple myeloma that is relapsed or refractory, and have measurable disease.²

Those with multiple myeloma had to have previously received at least 3 regimens, which included at least 2 consecutive cycles of lenalidomide (Revlimid), pomalidomide (Pomalyst), a proteasome inhibitor, a glucocorticoid, and a CD38 antibody.

Moreover, patients with peripheral T-cell lymphoma (PTCL), had to have received at least 1 line of therapy that contained alkylator-based chemotherapy; those with mantle cell lymphoma (MCL) or follicular lymphoma had to have received 2 or more prior lines of therapy, including a CD20 antibody and alkylator chemotherapy; those with diffuse large B-cell lymphoma (DLBCL) also had to have previously received 2 or more lines of therapy, including a CD20 antibody and autologous bone marrow transplant. Other patients with non-Hodgkin lymphoma had to have received all standard available therapies.

If patients had central nervous system (CNS) disease, active pneumonitis, peripheral neuropathy at was grade 2 or higher in severity, a known malignancy beyond the study indication that is progressing or required treatment within the past 3 years, or if they received live, attenuated vaccine within 4 weeks of the first dose, they were excluded.

Moreover, patients with non-secretory or oligosecretory multiple myeloma, plasma cell leukemia, systemic light chain amyloidosis, POEMS syndrome, lymphoblastic leukemia, mycosis fungoides, Sezary syndrome, primary cutaneous T-cell lymphomas, primary CNS lymphoma, and B-cell or T-cell prolymphocytic leukemia were also excluded.

In the phase 1 portion of the research, arm A enrolled patients with relapsed/refractory non-Hodgkin lymphoma or multiple myeloma who will receive once-daily CFT7455 for 21 days of a 28-day cycle. Arm B1 is comprised of patients with relapsed/refractory multiple myeloma who will receive once-daily CFT7455 until the maximum-tolerated dose (MTD) and the recommended phase 2 dose (RP2D) is identified. Arm B2 is composed of patients with relapsed/refractory multiple myeloma who are receiving CFT7455 plus a fixed dose of oral dexamethasone. In arm C, patients with relapsed/refractory non-Hodgkin lymphoma are receiving once-daily CFT7455 until the MTD/RP2D is determined.

The phase 2 portion of the research is comprised of 4 arms; the first arm includes patients with relapsed/refractory multiple myeloma who are receiving CFT7455, the second arm is comprised of patients with relapsed/refractory multiple myeloma who are receiving CFT7455 plus dexamethasone, the third is comprised of patients with MCL who are receiving CFT7455, and the fourth arm is composed of patients with PTCL who are receiving CFT7455.

The primary outcome measures in phase 1 of the trial include the safety and tolerability of CFT7455 and CFT7455 plus dexamethasone, as well as the MTD/RP2D for CFT7455 and CFT7455 plus dexamethasone. The primary measures in the phase 2 portion include examining the antitumor activity of CFT7455 and CFT7455 plus dexamethasone. Secondary and exploratory objectives will focus on characterizing the pharmacokinetic and pharmacodynamic profile of CFT7455.

Previously, results from in vitro studies showed that CFT7455 binds to cereblon with high affinity. Moreover, deep degradation of IKZF1 was demonstrated with the agent when used in preclinical models of non-Hodgkin lymphoma.³

Findings from cellular competition studies revealed a high potency of CFT7455 as a cereblon binder (IC50 = 0.4 nM). Moreover, when CFT7455 was given for 6 hours in a KiJK cell line of anaplastic large cell lymphoma (ALCL), it reduced IKZF1 protein levels by 89%. Additionally, CFT7455 was found to have strong antiproliferative activity across a panel of non-Hodgkin lymphoma cell lines with MYC, BCL2, and/or BCL6 translocations or rearrangements.

In xenograft models of non-Hodgkin lymphoma, the agent was found to improve in vivo potency and efficacy, which included durable tumor regressions in models of ALCL, DLBCL, and MCL, vs available immunomodulatory drugs (IMiDs).

In KiJK xenografts for which pomalidomide was found to be ineffective when given at a relevant daily dose of 3000 µg/kg, CFT7455, when given at a daily dose of 100 µg/kg, resulted in durable tumor regression, deep IKZF1 degradation, and IRF4 downregulation. In a TMD8 DLBCL xenograft model that was insensitive to IMiDs, CFT7455, at the same dose, encouraged tumor regression.

In a REC1 MCL xenograft model, when CFT7455 was given at a dose of 10 µg/kg or higher, it resulted in tumor regression. Pharmacodynamic studies revealed that the agent, when given at 30 µg/kg, resulted in IKZF1 degradation and downregulation of cyclin D1 and E2F1.

Lastly, in ALK (DL-40) and ALK-positive (KiJK) xenograft models, the agent was found to elicit dose-dependent efficacy. The agent was given at doses ranging from 3 µg/kg to 100 µg/kg and resulted in regressions at doses of 30 µg/kg or higher. Notably, the agent was noted to be greater than 30 to 100 times more potent than other IKZF1/3 degraders that are in clinical development, according to the clinical biopharmaceutical company.

References

1. C4 Therapeutics announces FDA orphan drug designation for CFT7455 for the treatment of multiple myeloma. News release. C4 Therapeutics, Inc. August 11, 2021. Accessed August 16, 2021. https://bit.ly/3CRuxHW
2. Study to assess the safety and tolerability of CFT7455 in relapsed/refractory non-Hodgkin’s lymphoma or multiple myeloma. ClinicalTrials.gov. Updated June 30, 2021. Accessed August 16, 2021. https://clinicaltrials.gov/ct2/show/NCT04756726
3. C4 Therapeutics presents pre-clinical data on CFT7455, a novel IKZF1/3 degrader for the treatment of hematologic malignancies, at the 16th Annual International Conference on Malignant Lymphoma. News release. C4 Therapeutics, Inc. June 21, 2021. Accessed August 16, 2021. https://bit.ly/3CUNb1y