Nuvation Bio is focused on treating patients with the most difficult-to-treat cancers, for which conventional therapies have failed. We are advancing up to six compounds that have resulted from our drug discovery and development programs, which include a cyclin-dependent kinase (CDK) inhibitor program, a BET inhibitor program, a WEE1 inhibitor program, an A2A adenosine receptor inhibitor program, and a drug-drug conjugate (DDC) platform that to date has yielded investigational compounds targeting hormone-driven cancers such as prostate, breast and ovarian cancers.
The U.S. Food and Drug Administration (FDA) accepted our first Investigational New Drug (IND) application for our lead investigational compound, NUV-422, a CDK2/4/6 inhibitor for the treatment of patients with high-grade gliomas, including glioblastoma multiforme (GBM). We initiated a Phase 1/2 study of NUV-422 in December 2020, with patient enrollment and dosing ongoing in adult patients with recurrent or refractory high-grade gliomas and solid tumors. We anticipate submitting up to five additional INDs by 2026 for therapies targeting some of the most difficult-to-treat solid tumors and hematologic cancers.
Conjugate (DDC) Platform
NUV-422, our lead product candidate, is a selective small molecule cyclin-dependent kinase (CDK) 2/4/6 inhibitor.
CDK4/6 inhibitors are known clinical entities with proven efficacy, but cancer cells can evade these treatments by increasing signaling through CDK2. Inhibition of CDK2 in addition to CDK4/6 cuts off the tumor’s natural escape route. NUV-422 is a potent inhibitor of CDK 2, 4 and 6. Preclinical studies have shown that NUV-422 has favorable blood-brain barrier penetration. NUV-422 is also designed to limit CDK1 inhibition, a potential cause of toxicity in other second-generation inhibitors.
The U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to NUV-422 for the treatment of patients with malignant gliomas. We are also advancing NUV-422 to treat patients with brain metastases, where FDA-approved CDK4/6 inhibitors have shown limited efficacy; hormone receptor-positive metastatic breast cancer (ER+ mBC), where CDK4/6 inhibitors have been successful but CDK2-driven resistance to therapy can develop; and metastatic castration-resistant prostate cancer (mCRPC).
Patient enrollment and dosing is ongoing in the Phase 1/2 study of NUV-422 in adult patients with recurrent or refractory high-grade gliomas, including glioblastoma multiforme (GBM); recurrent GBM, hormone receptor-positive breast cancer and mCRPC. The Phase 1 dose escalation part of the study is designed to evaluate safety and tolerability and determine a recommended Phase 2 dose based on the tolerability profile and pharmacokinetic properties of NUV-422. The Phase 2 dose expansion part of the study is expected to initially focus on patients with high-grade gliomas and is designed to evaluate overall response rate, duration of response and survival. Data from the Phase 1 portion of this study is expected in 2022.
NUV-868, a selective oral small molecule BET (bromodomain and extra-terminal) inhibitor, specifically inhibits BRD4, a key a key member of the BET family that epigenetically regulates proteins that control tumor growth and differentiation.
These proteins are believed to be important regulators of the oncogene c-myc, which has been implicated as a driver of tumor growth in up to 70% of cancers. NUV-868 is designed to avoid the therapeutic limiting toxicities of other BRD4 inhibitors and is almost 1,500 times more selective for BD2 than BD1, avoiding the toxicities associated with other non-BD2 selective inhibitors.
We are currently in preclinical development and intend to initiate a Phase 1 trial of NUV-868 in patients with Acute Myeloid Leukemia (AML) and/or solid tumors in the first half of 2022.
NUV-569 is a differentiated oral small molecule selective inhibitor of Wee1 kinase, an important regulator of DNA damage repair. Wee1 inhibitors synergize with DNA-damaging therapies like radiation and certain types of chemotherapy to increase anti-tumor activity.
We have designed NUV-569 to avoid off-target effects by improving its kinase selectivity, that could increase the therapeutic window for this class of therapeutic candidates and have wide applicability to treating many different types of cancer. NUV-569 is highly potent against Wee1 and is also designed to have low inhibition of PLK1, thus potentially reducing the toxicity.
We intend to submit an IND for NUV-569 in the first half of 2022 and initiate Phase 1 trials in patients with pancreatic cancer and/or other solid tumors in the second half of 2022.
NUV-1182 is an adenosine receptor inhibitor designed to have high affinity for the A2A adenosine receptor, which plays multiple critical roles in human physiology and pathophysiology including anti-cancer immunity.
We also designed NUV-1182 to have a reduced affinity for the adenosine A1 receptor, which may potentially improve tolerability.
We are exploring immuno-oncology combination preclinical studies, which have so far demonstrated a desirable pharmacokinetic profile, for NUV-1182 to support the initiation of a Phase 1 trial in the second half of 2022.
Our proprietary Drug-Drug Conjugate (DDC) platform leverages a novel therapeutic approach within the DDC class of anti-cancer therapies designed to selectively deliver potent targeted therapeutics to cancer cells to exert greater toxicity against these target cells than against healthy non-target tissues.
Utilizing this platform, we are able to conjugate tissue-selective targeted small molecules with anti-tumor agents to create unique therapeutic candidates.
Our first DDC program is focused on targeting a poly ADP ribose polymerase (PARP) inhibitor to androgen receptor (AR), or AR-expressing cancer cells in patients with prostate cancer. AR expression is significantly higher in prostate cancer cells than in the GI tract and bone marrow, which are the major sites of current commercial PARP inhibitor toxicities. By fusing a PARP inhibitor to an AR-targeting drug, we believe we may be able to achieve better on-target anti-cancer effects and lower off-target adverse effects.
Our second DDC program is focused on targeting a PARP inhibitor to ER-expressing breast and ovarian cancers cells and avoid adverse effects commonly seen with non-specific, non- targeted PARP inhibitors including bone marrow and gastrointestinal toxicity.
Similar to our PARP-AR DDC program, we believe that our PARP-ER DDC could be broadly applicable, ranging from treatment of advanced stage to early-stage breast and ovarian cancers. We intend to nominate clinical development candidates in the second half of 2022.