Having written about hedgehog signaling in cancer a few times on this blog (see here, here and here for examples), including it's potential role in CML, it came as no surprise to see some very exciting new data presented in the New England Journal this month.
The other week, while attending the excellent Rodman and Renshaw Healthcare conference in NY, I was fascinated by one particular presentation by Curis, whose hedgehog inhibitor (GDC-0449) is being developed with Genentech/Roche, not to be confused with their pan PI3K inhibitor (GDC-0941). The initial promising indications include basal cell carcinoma and medullablastoma, both rare but fatal diseases. Curis illustrated their development program, including the hedgehog inhibitor as thus:
In the NEJM articles, phase I data in basal cell carcinoma (BCC) and medullablstoma (MB) was reported by van Hoff et al., and Rudin et al., respectively.
The BCC patients had locally advanced and metastatic disease and received either 150mg or 270mg per day and showed a median of 9.8 months on study at the time of reporting. Of the 33 patients, 18 had an objective response (2 CR, 16PR), giving an ORR of 55%. Typical drug related adverse events seen in 6 of the patients included fatigue (4), hyponatremia (2), muscle spasm (1) and atrial fibrillation (1).
Medullablastoma is the most common malignant brain cancer seen in children, with a typical diagnosis around 5 years of age. Rudin et al., reported on a case study of the cancer found in a 26 yo man who was refractory to multiple therapies. Analysis of tumor specimens suggested activation of the hedgehog pathway. Treatment with GDC-0449 resulted in rapid but transient regression of the tumor and reduction in symptoms. A trial in children with medullablastoma was therefore recommended, since use of a targeted inhibitor of a pathway implicated in malignant transformation may prove a useful new approach.
In their succinct editorial, Dlugosz and Talpaz highlighted some important points. In particular, they noted that blockade of the hedgehog pathway could lead to a greater degree of selectivity and fewer side effects in the treatment of cancer compared with conventional chemotherapy. The pathway is also involved with numerous processes associated with embryogenesis but becomes largely inactivated in adults, except in some cancers when it appears to be reactivated. Overall, they described hedgehog inhibition as a promising new approach in BCC and medullablastoma that are well worth pursuing.
From a marketing standpoint, this approach continues the concept applied by others such as Novartis viz Gleevec in CML and GIST and Ilaris in Muckle Wells Syndrome, where the drug targets the actual cause of the disease and has a high efficacy rate, yet the market itself may initially not look particularly large or attractive. However, I would argue that it is easier to own a high share of a small market than try and achieve a small share of a very large and competitive market. Of course, the commercial value also increases significantly if the therapy becomes chronic or larger new markets evolve after the initial fast track approval. Neither basal cell carcinoma nor medulloblastoma offer Curis and Genentech larger cancer markets initially, but the elegance in the proof of concept for targeting the hedgehog pathway is an important one and more opportunities may follow later.
Von Hoff, D., LoRusso, P., Rudin, C., Reddy, J., Yauch, R., Tibes, R., Weiss, G., Borad, M., Hann, C., Brahmer, J., Mackey, H., Lum, B., Darbonne, W., Marsters, J., de Sauvage, F., & Low, J. (2009). Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma New England Journal of Medicine, 361 (12), 1164-1172 DOI: 10.1056/NEJMoa0905360
Rudin, C., Hann, C., Laterra, J., Yauch, R., Callahan, C., Fu, L., Holcomb, T., Stinson, J., Gould, S., Coleman, B., LoRusso, P., Von Hoff, D., de Sauvage, F., & Low, J. (2009). Treatment of Medulloblastoma with Hedgehog Pathway Inhibitor GDC-0449 New England Journal of Medicine, 361 (12), 1173-1178 DOI: 10.1056/NEJMoa0902903
Dlugosz, A., & Talpaz, M. (2009). Following the Hedgehog to New Cancer Therapies New England Journal of Medicine, 361 (12), 1202-1205 DOI: 10.1056/NEJMe0906092