Cabozantinib (s)-Malate

Following formal sign-off from the FDA, Handa Pharmaceuticals’ branded drug reformulation strategy has paid off for a third time. On Friday, the U.S. and Taiwan-headquartered company announced final FDA approval for its Omcazio capsules, a laurylsulfate salt formulation of Exelixis’ cancer med Cabometyx that uses cabozantinib, the same tyrosine kinase inhibitor active ingredient. The novel formulation of Exelixis’ patent-protected med was devised by the company’s Handa Oncology subsidiary and shifts a prior tentative approval into a formal green light, clearing the way for the drug to be marketed in the United States. Omcazio now joins two other branded reformulated medicines in Handa’s portfolio, Phyrago, a modified version of Bristol Myers Squibb’s oncology medicine Sprycel (dasatinib) that can be used alongside proton pump inhibitors and H2 receptor antagonists, and Tascenso ODT, an orally disintegrating tablet formulation of Novartis’ relapsing multiple sclerosis therapy Gilenya (fingolimod). Both of those products are being commercialized in the U.S. under licensing agreements with Cycle Pharmaceuticals. As for Omcazio, Handa said Friday that it plans to provide additional information on the drug’s U.S. commercial availability in a forthcoming announcement. The capsule’s key advantage, according to a statement from Handa CEO Bill Liu, is that it can be taken with or without food, which he said gives both doctors and patients “added flexibility in treatment.” The medicine can be used in adults with advanced renal cell carcinoma and as a first-line treatment in those patients in combination with BMS’ Opdivo, as well as in hepatocellular carcinoma patients previously treated with Bayer’s Nexavar and in adults and children 12 and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated extra-pancreatic neuroendocrine tumors. Meanwhile, the 60-, 40- and 20-mg once-a-day doses of Cabometyx correspond to 34.5-, 23- and 11.5-mg daily doses of Omcazio, respectively, Handa noted. Cabometyx, which won its first approval more than a decade ago, is among the most commonly used oral targeted therapies in cancer treatment, per Handa. Last year, Exelixis reported a 17% sales bump for the medicine to $2.11 billion in the U.S. As for what Handa’s nod means for Exelixis, analysts at William Blair wrote to clients Friday that they don’t view the full approval of Omcazio as a threat. They cited the apparent gap between approval and commercial availability and further asserted that they believe Handa’s drug is “not equivalent to Cabometyx.” Omcazio was approved using bioavailability and bioequivalence data via the FDA’s 505(b)(2) pathway, the William Blair team pointed out. This pathway enables developers to rely in part on existing data supporting a previously approved drug, and is often used when a company is developing a new formulation or novel combination of an already-approved medicine. Nevertheless, Omcazio’s labeling specifically states that the drug is not substitutable on a milligram-to-milligram basis with other cabozantinib products. The William Blair analysts said they therefore believe Handa will “likely have to build a sales force to fully commercialize Omcazio,” adding that the lack of data also leads them to suspect “minimal” uptake of Omcazio in the U.S. The reformulation game has been picking up traction of late, as multiple developers look to retool versions of already-approved medicines in hopes of delivering a new, patent-protected product that fills some lingering unmet need. One prominent example is Veradermics, the buzzy hair-loss biotech that has continued to generate positive data —and investor excitement—around its lead candidate VDPHL01, which is an extended-release oral formulation of minoxidil. Minoxidil is likely better known by most as the topical hair loss treatment Rogaine, first approved in 1988. Meanwhile, an oral version of the drug was approved in the late 1970s as a blood pressure medicine, but it has not been approved in that format for hair loss.

BioNTech has linked gotistobart to median overall survival (OS) of 18.5 months in relapsed lung cancer patients, adding to evidence that the anti-CTLA-4 antibody is better than the standard of care. The data come from Preserve-003, a two-stage phase 3 trial comparing gotistobart to docetaxel in metastatic squamous non-small cell lung cancer (sqNSCLC) patients without actionable genomic alterations. Checkpoint inhibitors work in the first-line population, but the chemotherapy docetaxel, with or without the VEGFR2 antibody ramucirumab, is still the standard of care for patients who relapse. BioNTech used the World Conference on Lung Cancer in Seoul to share updated data from the trial, revealing that the median OS on gotistobart in the first stage of the trial was 18.5 months. Median OS on docetaxel was 10 months, as reported previously. The results confirm the survival advantage that gotistobart appeared to hold over docetaxel at the prior analysis, when OS data on the CTLA-4 antibody were immature. If replicated in the second stage of the trial, the OS result could establish gotistobart as the first breakthrough in the indication in years. BioNTech's co-founder and outgoing chief medical officer Özlem Türeci, M.D., said the data “underscore gotistobart’s potential to redefine treatment for patients with hard-to-treat squamous NSCLC whose disease has progressed after initial therapy and who face limited options.” “In second- and later lines of treatment, the clinical relevance of novel therapeutic options depends on the ability to re-engage a suppressed or exhausted anti-tumor immune response and overcome acquired resistance,” Türeci added in a Monday release. “This update highlights gotistobart’s unique mode of action and our ambition to translate our deep understanding of the immune system into meaningful survival benefit for patients with lung cancer—particularly in areas where patients still need more.” Multiple drugmakers have failed to improve on docetaxel in the population. Gilead’s Trodelvy achieved an OS of 11.1 months, while AstraZeneca and Daiichi Sankyo linked a rival antibody-drug conjugate, Datroway, to an OS of 12.9 months. The combination of Exelixis’ Cabometyx and Roche’s Tecentriq also fell short, delivering an OS of 10.7 months. Median OS on docetaxel in the three trials was 10 to 12 months. Gotistobart’s seemingly superior efficacy comes with safety and tolerability challenges. BioNTech saw serious treatment-related adverse events in 44.4% of patients taking gotistobart, compared to 29.3% for docetaxel. Treatment-related adverse events led 15.6% of people on gotistobart to discontinue therapy, versus 4.9% for docetaxel. Colitis was the most common grade 3 or worse adverse event on gotistobart. Safety and tolerability are long-standing challenges for CTLA-4 antibodies, an immuno-oncology class led by Bristol Myers Squibb’s Yervoy. While gotistobart has inherited some of the issues, the efficacy results suggest work to achieve differentiated outcomes has paid off. The pH-sensitive mechanism is designed to boost depletion of regulatory T cells in the tumor microenvironment, increasing anticancer activity. BioNTech is closing in on data that could confirm that gotistobart has a future in second-line sqNSCLC. On an earnings call last month, Türeci, M.D., said she expected to conduct the first interim analysis from the pivotal stage of the trial toward the end of this year.