News announcing that small biotech firms are filing for approval of breakthrough drugs targeting deadly diseases is worth admiration, not cynicism. Humans look for miracles. Yet, they impassively overlook hundreds of human handmade marvels taking place every second around them. Serendipity does not make miracles. Human curiosity, learning and determination to erase whatever obstacles might block the road to great accomplishments create marvels.
Discovering the structure of the DNA is a miracle, mapping the human genome is a miracle, switching genes on and off with a pill is working on a miracle and the advancement in biological sciences in the past two decades is a basket full of miracles. The miracle of miracles, though, was that in spite of labeling the biotechnology industry high risk since its inception, investors never abandoned investing in it. Thousands generated lots of profit on it, especially those who managed to select the best of the best of the stocks and stick to them. Those investors, no doubt, contributed a great deal in creating many of the miracles that are filling what a quarter of a century ago was an empty basket.
The following two firms were not walking in place as some advocated. They were working hard on unearthing precious realities that would benefit millions of sufferers from all age groups. They were researching, analyzing, innovating, validating information and discoveries and spending tremendous efforts and most of their time solving difficult problems on the road to realizing big dreams. Big dreams are not easy to materialize. Otherwise many would achieve them and the reward wouldn’t be so big.
It is always refreshing hearing that struggling small biotech firms have overcome tons of scientific problems, financial, regulatory, bureaucratic and media bias problems and reached the finish line to filed their first NDA. Wednesday‘s news announced that Exelixis has completed the filing of its rolling New Drug Application (NDA) with the FDA for the first approval of a drug, cabozantinib, designed and developed by this struggling firm. Cabozantinib is in clinical trials for various cancers. The filed NDA, though, is for progressive, unresectable, locally advanced, or metastatic medullary thyroid cancer (MTC).
Aveo, another cancer specialized firm, has had successful trial results of its lead drug Tivozanib. This firm and its collaborator Astellas decided to submit an NDA for renal cell carcinoma (RCC) in the third quarter of 2012 and to follow it with MAA submission.
Aveo (AVEO): Three weeks ago, Aveo and its collaborator Astellas Pharma announced positive detailed results from the TIVO-1 (Tivozanib Versus Sorafenib) in first line advanced renal cell carcinoma (RCC) superiority study. The results demonstrated statistically significant progression-free survival’s (PFS) vs. sorafenib and superiority over the same drug in the overall (intent To treat) study population as well as in objective response rate (ORR). The results have also demonstrated consistent efficacy advantage of tivozanib over sorafenib across subgroups in the study. This is called advancement.
Based on the promising results, it is said that AVEO and its collaborator Astellas decided to submit the tivozanib NDA in RCC in the third quarter of 2012, with the MAA submission to follow.
Today, Aveo announced that its management will host a conference call on June 4, 2012, at 7:30 a.m. (CT) to review Tivozanib Phase 3 TIVO-1 data that will be presented at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO). This is exciting news for Aveo. With regard to the conference call, we believe it is worth listening to what the firm has decided to tell before the ASCO. Could it be an announcement of an NDA filing? We wish it were. But regardless of the message’s contents, we will listen because we are tilted to believe that tivozanib is a breakthrough drug expected to improve the management of renal cell carcinoma and other cancers in the near future.
Exelixis (EXEL) has already completed the filing of its rolling New Drug Application (NDA) with the FDA for cabozantinib as a treatment for patients with progressive, unresectable, locally advanced, or metastatic medullary thyroid cancer (MTC). The NDA was submitted under the FDA’s Fast Track designation.
We cannot call this but good news. It should silence the circulating rumors that the NDA filing was past due, raising concerns in investors’ minds about possible negative reasons behind the delays. Exelixis has not only filed for approval, but requested “Priority Review” designation from the FDA. If granted, the FDA’s would be announcing its decision in six months.
The NDA filing depended on data from the EXAM trial - a phase 3 pivotal clinical trial of cabozantinib in patients with advanced MTC. When results were announced, it was obvious that they were positive, as the trial has met its primary endpoint of improving PFS compared to placebo. Indeed, Cabozantinib PFS was 11.2 months versus 4.0 months for the placebo.
Cabozantinib inhibits MET, VEGFR2 and RET. MET is upregulated in many tumor types, facilitating tumor cell escape by promoting the formation of more aggressive phenotypes, resulting in metastasis. MET-driven metastasis may be further stimulated by hypoxic (low oxygeneted) conditions in the tumor environment, which is often exacerbated by selective prior VEGF-pathway inhibitors. In preclinical studies, cabozantinib has shown powerful tumoricidal, antimetastatic and antiangiogenic effects, including extensive apoptosis (suicide) of cancer cells, decreased tumor invasiveness and metastasis, decreased tumor and endothelial cell proliferation, blockade of metastatic bone lesion progression and disruption of tumor vasculature.
More good news came also about the same multipurpose drug cabozantinib, but this time targeting advanced castrate-resistant prostate cancer. This is the indication that stirred most oncologists', patients’ and investors’ excitement. Yes, it was cabozantinib that made bone metastasis disappear like magic in early trials. But this was not enough. More trials were to be conducted to confirm these results, in addition to figuring out, or confirming that cabozantinib would prolong patients’ survival.
Phase 2 studies of cabozantinib provided evidence of impressive effects on measurable tumor, progression-free survival, bone scan response, pain alleviation and circulating tumor cell (CTC) counts. Several of these measures, including reduction in pain and CTC counts, are associated with improved overall survival in mCRPC. Still, more confirmation has been required through other trials for overall survival (OS).
In a press release issued by the firm on Wednesday, Exelixis announced it initiated COMET-1, a Phase 3 double-blind, placebo-controlled study that will include up to 240 international sites. The trial is designed to enroll 960 mCRPC patients who have previously been treated with docetaxel and abiraterone acetate and/or MDV3100. All patients will have bone metastases. Patients will be randomized 2:1 to receive cabozantinib (60 mg daily, N=640) or prednisone (5 mg twice daily. The trial has 90% power to detect a 25% reduction in the risk of death. A single interim analysis is planned after 387 events. The primary endpoint for the study is, of course, overall survival (OS) and the secondary endpoint is bone scan response as assessed by an independent radiology facility (IRF). COMET-1. Final data is expected to become available in the first half of 2014.
Comments: From the above, we can see why we are enthusiastic to the initiation of the COMET-1 trial, which is focused on demonstrating the potential for cabozantinib to improve overall survival in mCRPC patients. If the data from this trial and the ongoing COMET-2 pivotal trial confirm the early findings and demonstrate survival benefit, in addition to all the other benefits, prostate cancer specialists and castration resistant prostate cancer patients would definitely celebrate the birth of the dragon killer. In this case, Exelixis would be celebrating the transformation of cabozantinib from an investigational drug costing millions of dollars/year to a blockbuster filling the firm’s coffers with billions of deserved income.
Disclosure: Long the mentioned firms.