publication date: Feb. 8, 2019
Drugs & Targets
FDA approves therapy for adult patients with blood clotting disorder
FDA has approved Cablivi (caplacizumab-yhdp) injection in combination with plasma exchange and immunosuppressive therapy, for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura.
The FDA granted the approval to Ablynx.
“Patients with aTTP endure hours of treatment with daily plasma exchange, which requires being attached to a machine that takes blood out of the body and mixes it with donated plasma and then returns it to the body. Even after days or weeks of this treatment, as well as taking drugs that suppress the immune system, many patients will have a recurrence of aTTP,” Richard Pazdur, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products, said in a statement. “Cablivi is the first targeted treatment that inhibits the formation of blood clots. It provides a new treatment option for patients that may reduce recurrences.”
Cablivi was studied in a clinical trial of 145 patients who were randomized to receive either Cablivi or a placebo. Patients in both groups received the current standard of care of plasma exchange and immunosuppressive therapy.
The results of the trial demonstrated that platelet counts improved faster among patients treated with Cablivi, compared to placebo. Treatment with Cablivi also resulted in a lower total number of patients with either aTTP-related death and recurrence of aTTP during the treatment period, or at least one treatment-emergent major thrombotic event.
The proportion of patients with a recurrence of aTTP in the overall study period (the drug treatment period plus a 28-day follow-up period after discontinuation of drug treatment) was lower in the Cablivi group (13 percent) compared to the placebo group (38 percent), a finding that was statistically significant.
The FDA granted this application Priority Review designation. Cablivi also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
Pfizer given positive CHMP opinion for Vizimpro in NSCLC
The Committee for Medicinal Products for Human Use of the European Medicines Agency has adopted a positive opinion recommending Vizimpro (dacomitinib) 45 mg, as monotherapy, be granted marketing authorization in the European Union for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer with epidermal growth factor receptor-activating mutations. The CHMP’s opinion will now be reviewed by the European Commission
The agent is sponsored by Pfizer.
Vizimpro was approved by FDA in 2018 for the first-line treatment of patients with metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test. It was also recently approved in Japan for EGFR gene mutation-positive, inoperable or recurrent NSCLC.
The Marketing Authorization Application for Vizimpro was based on results from ARCHER 1050, a randomized, multicenter, multinational, open-label, phase III study conducted in patients with locally advanced unresectable, or metastatic NSCLC harboring EGFR exon 19 deletion or exon 21 L858R substitution mutations, an Eastern Cooperative Oncology Group performance status of 0 or 1; with no prior therapy for metastatic disease or recurrent disease with a minimum of 12 months disease-free after completion of systemic therapy. A total of 452 patients were randomized 1:1 to Vizimpro 45 mg (n=227) or gefitinib 250 mg (n=225).
Vizimpro is an oral, once-daily, irreversible pan-human epidermal growth factor receptor kinase inhibitor for first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer with epidermal growth factor receptor-activating mutations.
Vizimpro is approved in the U.S. for the first-line treatment of patients with metastatic non-small cell lung cancer with epidermal growth factor receptor exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test. Vizimpro is also approved in Japan for EGFR gene mutation-positive, inoperable or recurrent NSCLC. The applications in the US and Japan were reviewed and approved under the Priority Review program.
In 2012, Pfizer and SFJ Pharmaceuticals entered into a collaborative development agreement to conduct ARCHER 1050 across multiple sites. SFJ is a global drug development company, which provides a unique and highly customized co-development partnering model for the world’s top pharmaceutical and biotechnology companies. Under the terms of this agreement, SFJ Pharmaceuticals provided the funding and conducted the trial to generate the clinical data used to support this application. Pfizer retains all rights to commercialize Vizimpro globally.
The efficacy of Vizimpro was demonstrated in ARCHER 1050, a global phase III head-to-head trial conducted in patients with locally advanced unresectable, or metastatic non-small cell lung cancer harboring epidermal growth factor receptor exon 19 deletion or exon 21 L858R substitution mutations, with no prior therapy for metastatic disease or recurrent disease with a minimum of 12 months disease-free after completion of systemic therapy.
A total of 452 patients were randomized 1:1 to Vizimpro 45 mg (n=227) or gefitinib 250 mg (n=225). Randomization was stratified by region and EGFR mutation status. The primary endpoint of the study was progression-free survival as determined by blinded Independent Radiology Central review. Key secondary endpoints included objective response rate, duration of response, overall survival, and patient-reported outcomes.
Genentech submits sBLA for Kadcyla for breast cancer
Genentech has submitted a supplemental Biologics License Application to the FDA for Kadcyla (ado-trastuzumab emtansine) for adjuvant treatment of people with HER2-positive early breast cancer with residual disease after neoadjuvant treatment.
Genentech is a member of the Roche Group.
The FDA is reviewing the application under the Real-Time Oncology Review and Assessment Aid pilot programs, which aim to explore a more efficient review process to ensure safe and effective treatments are available to patients as early as possible.
For this indication, Kadcyla was also granted Breakthrough Therapy Designation, which is designed to expedite the development and review of medicines intended to treat serious or life-threatening diseases.
This application is based on results of the phase III KATHERINE study showing Kadcyla significantly reduced the risk of invasive breast cancer recurrence or death from any cause (invasive disease-free survival) by 50 percent (HR=0.50, 95% CI 0.39-0.64, p<0.0001) compared to Herceptin (trastuzumab) as an adjuvant treatment in people with HER2-positive EBC who have residual disease present following neoadjuvant treatment.
People who have residual disease after neoadjuvant treatment have a worse prognosis than those with no detectable disease. At three years, 88.3 percent of people treated with Kadcyla did not have their breast cancer return compared to 77.0 percent treated with Herceptin, an absolute improvement of 11.3 percent.
KATHERINE is an international, multi-center, two-arm, randomized, open-label, Phase III study evaluating the efficacy and safety of Kadcyla versus Herceptin as an adjuvant therapy in people with HER2-positive EBC who have pathological invasive residual disease in the breast and/or axillary lymph nodes following neoadjuvant therapy that included Herceptin and taxane-based chemotherapy.
The primary endpoint of the study is iDFS, which in this study is defined as the time from randomization free from invasive breast cancer recurrence or death from any cause. Secondary endpoints include disease-free survival and overall survival.
Kadcyla is an antibody-drug conjugate engineered to deliver potent chemotherapy directly to HER2-positive cells. It is designed to limit damage to healthy tissues, although it can still affect them. Kadcyla can cause serious side effects.
It combines two anti-cancer agents using a stable linker: the HER2-targeting trastuzumab (the active ingredient in Herceptin) and the chemotherapy agent DM1. Kadcyla is the only ADC approved for the treatment of HER2-positive metastatic breast cancer. In the U.S., Genentech licenses technology for Kadcyla under an agreement with ImmunoGen, Inc.
Kadcyla, as a single agent, is indicated for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either:
Received prior therapy for metastatic disease, or
Developed disease recurrence during or within six months of completing adjuvant therapy.
Merck KGaA and GSK to co-develop immunotherapy M7824
Merck KGaA and GSK have agreed to jointly develop and commercialize M7824 (bintrafusp alfa). M7824 is an investigational bifunctional fusion protein immunotherapy that is currently in clinical development, including potential registration studies, for multiple difficult-to-treat cancers.
This deal includes a phase II trial to investigate M7824 compared with pembrolizumab as a first-line treatment in patients with PD-L1 expressing advanced NSCLC.
M7824 is designed to simultaneously target two immuno-suppressive pathways, transforming growth factor-β trap and an anti-programmed cell death ligand-1, that are commonly used by cancer cells to evade the immune system. Bifunctional antibodies aim to increase efficacy above and beyond that achieved with individual therapies or combinations of individual therapies. M7824 has the potential to offer new ways to fight difficult-to-treat cancers beyond the established PD-1/PD-L1 class. In addition to use as a single agent, M7824 is also being considered for use in combination with other assets from the pipelines of both companies.
Merck KGaA will receive an upfront payment of €300 million and is eligible for potential development milestone payments of up to €500 million triggered by data from the M7824 lung cancer program.
Merck KGaA will also be eligible for further payments upon successfully achieving future approval and commercial milestones of up to €2.9 billion. The total potential deal value is up to €3.7 billion. Both companies will jointly conduct development and commercialization with all profits and costs from the collaboration being shared equally on a global basis.
Bintrafusp alfa is the proposed International Nonproprietary Name for the bifunctional immunotherapy M7824. Bintrafusp alfa is currently under clinical investigation and not approved for any use anywhere in the world.
M7824 is an investigational bifunctional immunotherapy that is designed to combine a TGF-β trap with the anti-PD-L1 mechanism in one fusion protein. M7824 is designed to combine co-localized blocking of the two immuno-suppressive pathways—targeting both pathways aims to control tumor growth by potentially restoring and enhancing anti-tumor responses.
M7824 is currently in phase I studies for solid tumors, as well as a randomized phase II trial to investigate M7824 compared with pembrolizumab as a first-line treatment in patients with PD-L1 expressing advanced NSCLC. The multicenter, randomized, open-label, controlled study is evaluating the safety and efficacy of M7824 versus pembrolizumab as a monotherapy treatment.
To-date, nearly 700 patients have been treated with M7824 across more than 10 tumor types in phase I studies. Encouraging data from the ongoing phase I studies indicates M7824’s potential safety and clinical anti-tumor activity across multiple types of difficult-to-treat cancers, including advanced NSCLC, human papillomavirus-associated cancers, biliary tract carcinoma and gastric cancer.
In addition, in pre-clinical studies M7824 demonstrated superior anti-tumor activity, compared with anti-PD-L1 alone or with anti-PD-L1 and TGF-β trap when co-administered. In total, eight high priority immuno-oncology clinical development studies are ongoing or expected to commence in 2019, including studies in NSCLC and biliary tract cancers.
FDA pursues order to bar some retailers from selling tobacco in efforts to target tobacco use by minors
FDA has initiated enforcement action against several retail locations of Walgreen Co. and Circle K Stores Inc. for repeated violations of restrictions on the sale and distribution of tobacco products, including sales of cigars and menthol cigarettes to minors.
The agency filed complaints seeking No-Tobacco-Sale Orders, which seek to bar the two retail locations from selling tobacco products for 30 days. The two retail outlets that are the subject of these NTSO actions are a Walgreens store in Miami and a Circle K store in Charleston, South Carolina.
Notably, Walgreens is currently the top violator among pharmacies that sell tobacco products, with 22 percent of the stores inspected having illegally sold tobacco products to minors.
FDA Commissioner Scott Gottlieb said he will request a meeting with corporate management of Walgreens to “discuss whether there is a corporate-wide issue related to their stores’ non-compliance.”
“[I will] put them on notice that the FDA is considering additional enforcement avenues to address their record of violative tobacco sales to youth,” FDA Commissioner Scott Gottlieb, said in a statement. “I’m also deeply disturbed that a single pharmacy chain racked up almost 1,800 violations for selling tobacco products to minors across the country.”
An estimated 4.9 million middle and high school students reported current (past 30 days) use of any tobacco product in 2018, according to preliminary results of the 2018 National Youth Tobacco Survey.
An “epidemic-level rise” in e-cigarette use over the last year has led overall tobacco product use to increase by 38 percent among high school students (to 27.1 percent) and by 29 percent among middle school students (to 7.2 percent) in the last year, reversing the declines seen in the last few years, the survey said.
The NTSO action against this Walgreens outlet follows the issuance of more than 1,550 warning letters and 240 civil money penalty actions against Walgreens stores nationwide for unlawful tobacco product sales to minors. This is, however, the first NTSO action taken against a Walgreens store.
While the NTSO action against Circle K is not its first, it marks the first time the agency has initiated an NTSO complaint for the sale of deemed products (cigars) to minors. Since 2010, the FDA has issued over 1,045 warning letters and 205 civil money penalty actions to retailers doing business as Circle K for sales to minors.
Retailers who receive an NTSO complaint from the FDA may enter into a settlement agreement or respond with an answer and contest the allegations before an administrative law judge. If an NTSO goes into effect, a retailer is responsible for ensuring that the establishment does not sell tobacco products during the specified period.
FDA said it plans to conduct unannounced compliance check inspections during that period to check whether each establishment is complying with the terms of the order and will take further action if necessary.