Products

Date: 2016-06-29

Type of information: Product launch

Product name: Envarsus® (previously LCP-Tacro™)

Compound: tacrolimus

Therapeutic area: Transplantation

Action mechanism: immunosuppressive agent. Envarsus® XR is an extended release formulation of tacrolimus designed for once-daily dosing, with flatter pharmacokinetics and greater bioavailability compared to twice-daily tacrolimus.

Company: Veloxis Pharmaceuticals (Denmark)

Disease: prevention of organ rejection in kidney transplant patients

Latest news:

• • On June 29, 2016, Veloxis Pharmaceuticals announced that once-daily Envarsus XR® (tacrolimus extended-release tablets), indicated for the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations, in combination with other immunosuppressants, received FDA approval for label enhancements. These enhancements are related to the pharmacokinetics (PK) and pharmacogenomics (PG) studied in the ASERTAA trial, one of the largest trials of tacrolimus PK in African-American kidney transplant patients ever conducted. African-American kidney transplant patients historically experience poorer outcomes as compared to other ethnic groups and this has been associated in part due to their expression of the CYP3A5*1 genotype, which codes for a cytochrome p450 enzyme that metabolizes tacrolimus, and shown to be present in approximately 80% of African-Americans. Patients expressing this genotype metabolize tacrolimus much more rapidly and as a result typically require higher tacrolimus doses. This may hinder efforts to obtain a therapeutic level potentially increasing the risk of organ rejection. As previously reported, The ASERTAA trial demonstrated that patients on Envarsus achieved therapeutic drug levels with a 30% lower peak concentration and 20% lower average dose compared to tacrolimus immediate-release regardless of genotype status. Importantly, patients expressing the CYP3A5*1 genotype on tacrolimus immediate-release reached a peak concentration as high as 26 ng/mL. Based upon these findings, the FDA-approved label now contains ethnicity-specific dosing and unique genotyping guidance to Envarsus XR as shown below: - The PK of Envarsus XR® converted from tacrolimus immediate-release to Envarsus XR® indicated that an 80% dose conversion factor is appropriate for African-American patients; - Regardless of genotype status, the PK data collected for Envarsus XR® demonstrated similar exposure, lower Cmax, prolonged Tmax, and increased bioavailability when compared to tacrolimus immediate-release. The importance of these label enhancements is that the dosing recommendations and expected PK profile even for these difficult populations remain the same as with other populations.
• • On December 7, 2015, Veloxis announced the U.S. launch of Envarsus® XR (tacrolimus extended-release tablets) for the prophylaxis of rejection in kidney transplant patients who require or desire conversion from immediate release tacrolimus products to once-daily Envarsus® XR. Envarsus® XR has Orphan Drug status in the U.S. and has been issued a unique reimbursement J-code by the Centers for Medicare and Medicaid Services (CMS) for 2016 onwards. Veloxis will be marketing and selling Envarsus XR through its own dedicated specialty sales force in the U.S.
• • On July 10, 2015, Veloxis Pharmaceuticals announced FDA approval of Envarsus® XR (tacrolimus extended-release tablets) for the prophylaxis of rejection in kidney transplant patients who require or desire conversion from other twice-daily tacrolimus products to once-daily Envarsus® XR. The FDA marketing approval is based on the review of two Phase III trials and several Phase II trials in kidney transplant recipients. In all of the clinical trials, Envarsus® XR dosed once daily demonstrated significantly higher bioavailability and a flatter PK profile, compared to the current leading transplant drug, Prograf® (immediate release tacrolimus), dosed twice-daily. Veloxis expects Envarsus® XR to be available to patients in the United States and their physicians in 4Q2015. Veloxis Pharmaceuticals also announced that Envarsus® XR was granted Orphan Drug status by the FDA for prophylaxis of organ rejection in patients who convert from immediate-release tacrolimus.
• • On December 19, 2014, Veloxis Pharmaceuticals issued the following statement regarding an order issued by the U.S. District Court for the District of Columbia in connection with the action Veloxis filed on December 16, 2014 against the FDA, seeking an order requiring the FDA to grant final approval to Envarsus® XR: "We are pleased that the Court recognizes our need for an expedited resolution of this matter, and has indicated that it will set a briefing timetable that will result in the matter being fully briefed in a timely fashion. We had previously requested and anticipated that approximately 2 months would be required to achieve a full briefing under the strategy Veloxis had proposed, and we are pleased to see the court Order reflecting consistency with this timeline. Although Envarsus XR has been found to be safe and effective, FDA determined that the period of statutory exclusivity granted to another extended-release tacrolimus product, Astagraf XL®, blocks Envarsus XR from being sold in the United States until that exclusivity period expires (July 2016) as previously announced by the Company on October 31, 2014. Veloxis believes that FDA's action is contrary to the requirements of the controlling statute, its regulations and longstanding agency precedent. Its lawsuit seeks a determination by the Court that Envarsus XR should be immediately approved for sale in the United States. There can be no assurance that Veloxis will be successful in its action against FDA.
• • On October 31, 2014, Veloxis Pharmaceuticals announced that the FDA has informed Veloxis of the tentative approval of Envarsus® XR. FDA stated that the final approval of Envarsus XR will be delayed until expiration of the exclusivity period for Astellas' Astagraf XL®. Veloxis understands that this expiry is anticipated to occur July 19, 2016. FDA's approval notice stated that it is "subject to change on the basis of any new information that may come to FDA's attention." Veloxis disagrees that exclusivity for Astagraf XL®, which was not identified as a listed drug or relied upon to support approval of Envarsus XR, should require delay in the formal approval of Envarsus XR. Veloxis plans to immediately appeal this decision within FDA, and will pursue all options available to it. The tentative approval notification received from FDA included agreement with manufacturing post-marketing commitments as previously proposed by Veloxis during NDA review as well as agreement on final labeling for the product. There were no other conditions attached to the NDA approval.
• • On July 28, 2014, Veloxis Pharmaceuticals and Chiesi Farmaceutici announced that the European Commission (EC) has granted marketing authorization for Envarsus® for the prevention of organ rejection in adult kidney and liver transplant patients in the European Union (EU). Veloxis' New Drug Application (NDA) for Envarsus® XR for the prevention of organ rejection in kidney transplant patients is under regulatory review by the FDA and has a PDUFA action date of October 30, 2014. Veloxis does not expect to receive the additional liver indication in the U.S. Envarsus® XR received Orphan Drug Designation by the FDA for prophylaxis of organ rejection in patients receiving allogeneic kidney transplants.
• • On May 22, 2014,  Veloxis Pharmaceuticals announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending the granting of a marketing authorization for Envarsus® for the prevention of organ rejection in adult transplant patients in the European Union (EU). The positive opinion is for both kidney and liver transplant recipients and includes both the de novo transplant and "switch" settings, as well as for treatment of rejection episodes resistant to treatment with other immunosuppressive products in adult patients.  The positive opinion of the CHMP is based on review of the favorable results of the Envarsus® Phase III 3001 study in stable kidney transplant patients and 3002 study in de novo kidney transplant recipients as well as data from an extensive Phase I and II clinical program, which included both kidney and liver transplant patients. Studies 3001 and 3002 demonstrated that Envarsus® dosed once-daily was not inferior to the current leading transplant drug, Prograf® (tacrolimus), dosed twice-daily. The Phase I pharmacokinetic and Phase II efficacy data that was submitted in the MAA enabled extrapolation into the broader populations of both kidney and liver transplant recipients.
• • On March 14, 2014, Veloxis Pharmaceuticals has announced the  FDA accepted for standard review the company's New Drug Application (NDA) for Envarsus® for the prevention of organ rejection in adult kidney transplant patients. FDA has set a target review date under the Prescription Drug User Fee Act (PDUFA) of October 30, 2014. The NDA was submitted to the FDA on 30 December, 2013. The NDA is based on two Phase III studies, 3001 and 3002, in which Envarsus demonstrated non-inferiority compared to twice daily tacrolimus (Prograf®) based on a composite endpoint of treatment failure at one year. The clinical program comprised 25 studies and enrolled over 1,000 patients
• • On December 30, 2013, Veloxis Pharmaceuticals has announced that it has submitted a New Drug Application (NDA) to the FDA seeking approval for the marketing and sale of Envarsus® (formerly LCP-Tacro™) for the prevention of organ rejection in kidney transplant recipients. The submission is based on the entire data set from the company's clinical development program that comprised 25 studies and enrolled over 1000 patients, including two pivotal clinical trials, studies 3001 and 3002. In the two pivotal trials, Envarsus® given once-daily met the primary endpoint of demonstrating comparable efficacy and safety compared to twice-daily tacrolimus (Prograf®, Astellas Pharma, Inc.). In the largest study, Study 3002, Envarsus® was shown to have a primary efficacy failure rate of 18.3% vs 19.6% with Prograf® therapy.  The differences between the treatments was well-within the pre-defined 10% non-inferiority margin. The study was conducted under a Special Protocol Agreement with the FDA. Veloxis'commercial preparation activities in the U.S. are underway. The company will build a sales force of approximately 20 representatives for the marketing of Envarsus®.Outside the U.S., Veloxis plans to launch and commercialize Envarsus® through partnering arrangements. In Europe, Turkey and the CIS countries, Envarsus® will be commercialized by Veloxis' partner Chiesi Farmaceutici.
• • On December 24, 2013, Veloxis Pharmaceuticals has announced that Envarsus® was granted Orphan Drug status by the FDA for prophylaxis of organ rejection in patients receiving allogenic kidney transplants.
• • On May 21, 2013, Veloxis Pharmaceuticals has announced that the European Medicines Agency (EMA) accepted for review the company’s Marketing Authorization Application (MAA) to market LCP-Tacro® for the prevention of organ rejection in kidney transplant patients in the European Union. Veloxis expects th decision from the European Union in 2014.
• • On April 29, 2013, Veloxis Pharmaceuticals has announced that it has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) seeking approval to market LCP-Tacro™ for the prevention of organ rejection in kidney transplant patients in the European Union. The MAA submission is based on the favorable results of the LCP-Tacro Phase III 3001 study in stable kidney transplant patients and data from an extensive Phase I and II clinical program.  The 3001 study demonstrated that LCP-Tacro dosed once-daily was not inferior to the current leading transplant drug, Prograf® (tacrolimus), dosed twice-daily. Non-inferiority was determined by a composite endpoint, measured over a year of follow up that included death, graft failure, biopsy-proven acute rejection or loss to follow-up. In addition, over the 12 month study, the daily dose of LCP-Tacro could be lowered significantly compared to the baseline Prograf dose, while the target blood levels remained stable and within the target range. This reflected the enhanced bioavailability provided by Veloxis' proprietary MeltDose® formulation. The technology optimizes the formulation and delivery characteristics of the LCP-Tacro product to permit once daily dosing.
• In addition, Veloxis is awaiting results from a Phase III clinical trial in de novo kidney transplant patients, the 3002 study, which are expected mid-2013. Patient enrolment was completed in the first quarter of 2012, with 543 patients enrolled in this randomized, double-blind, multicenter study that compares once-daily LCP-Tacro against twice-daily Prograf in de novo adult kidney transplant patients. This study is not part of the current MAA submission.

Patents:

• • On January 8, 2014, Veloxis Pharmaceuticals has announced that United States Patent and Trademark Office (USPTO) has issued a Notice of Allowance for U.S. Application Serial Number 13/167,420, a patent which covers the diurnal-independent administration of Envarsus®. The subject patent covers a method of administering Envarsus®, Veloxis' once-daily formulation of tacrolimus employing the company's proprietary MeltDose® technology, once-daily in the evening (as opposed to morning dosing) to a kidney transplant patient.

Submission of marketing authorization application USA : 2013-12-30

Submission of marketing authorization application UE: 2013-04-29

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2015-07-10

UE authorization: 2014-07-28

Favourable opinion UE: 2014-05-22

Favourable opinion USA:

Orphan status USA: 2013-12-20

Orphan status UE:

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes