Orphagen Pharmaceuticals is taking a first-in-class approach to cancer drug development by focusing on a largely unexplored group of biological targets: orphan nuclear receptors. Founder and CEO Scott Thacher believes these targets could open new therapeutic opportunities in cancers where existing treatments have delivered limited benefit.
The San Diego-based biopharmaceutical company has built three first-in-class small-molecule programmes through a combination of grant funding and strategic partnerships. Its work draws on the broader nuclear receptor family, which already includes well-established therapeutic targets in breast cancer, prostate cancer and inflammatory disease.
“Our core mission has been to identify and validate novel or unexplored targets from the nuclear receptor family,” Thacher explains. For Orphagen, that means not simply finding new targets, but determining whether they can be effectively addressed with drug-like small molecules.
Addressing a major unmet need in adrenocortical cancer
Orphagen’s lead programme, OR-449, is being developed initially for adrenocortical cancer, a rare and aggressive cancer of the adrenal gland.
Treatment options remain extremely limited. Thacher notes that the existing approved therapy is decades old, while approaches including immunotherapies and tyrosine kinase inhibitors have so far failed to produce transformative results for patients.
Orphagen is targeting steroidogenic factor 1 (SF-1), a nuclear receptor that plays an important role in adrenal gland development and appears to be a critical driver in both adult and paediatric forms of adrenocortical cancer.
For patients with metastatic disease, where prognosis remains poor, a drug capable of directly targeting the underlying biology could represent a significant advance.
The challenge of developing a first-in-class drug
The potential of novel nuclear receptor targets comes with substantial scientific and development risk.
According to Thacher, the first hurdle is establishing that a previously unexplored target is genuinely druggable. The next is finding preclinical models that accurately reflect the proposed clinical mechanism — models that may not already exist.
A further challenge is translating compelling preclinical evidence into sufficient confidence and funding to reach the clinic.
“Finding money, finding validation that makes sense to people” can be particularly difficult for genuinely novel programmes, he says, because a first-in-class asset does not necessarily resemble the programmes investors or partners have backed previously.
Non-dilutive funding has therefore been important to Orphagen’s development strategy. The Cancer Prevention and Research Institute of Texas (CPRIT) has offered the company $10.2 million, subject to matching funding, to support the remaining work required for an IND filing and a Phase I clinical trial.
Phase I as the critical value-creation milestone
Orphagen’s immediate objective is to move OR-449 into the clinic.
The Phase I study will be designed to establish safety while also looking for target engagement and early evidence of efficacy. For Thacher, achieving those milestones could materially change the company’s strategic options.
Positive initial clinical data could support either a pharmaceutical partnership or a substantial Series B financing, potentially giving Orphagen the capital required to accelerate development.
The commercial opportunity is also meaningful despite the rarity of the disease. Successful rare oncology drugs can command premium pricing, making therapies with relatively small patient populations capable of generating significant global revenues.
That combination — a serious unmet medical need, differentiated biology and potentially attractive economics — could ultimately make OR-449 both a valuable therapeutic programme and a compelling strategic asset.
For Orphagen, however, the next inflection point is clear: demonstrating in patients that targeting an orphan nuclear receptor can translate from innovative science into a clinically meaningful cancer therapeautics.
