Products

Date: 2017-03-06

Type of information: Acceptation for review of a NDA

Product name: Translarna®

Compound: ataluren - 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazole-3-yl]-benzoic acid

Therapeutic area: Genetic diseases - Neuromuscular diseases - Rare diseases

Action mechanism:

• protein restauration therapy/inducer of ribosomal readthrough on nonsense mutation mRNA stop codons. Ataluren (3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazole-3-yl]-benzoic acid) is an investigational new drug designed to enable the production of functional dystrophin protein in the muscle cells of patients with genetic disorders due to a nonsense mutation. Ataluren is designed to allow the ribosome to ignore the premature stop signal and continue translation of the mRNA, resulting in formation of a functioning protein. Ataluren does not cause the ribosome to read through the normal stop signal.
• On May 16, 2014, PTC Therapeutics announced that the results of a Phase 3 study of ataluren in patients with nonsense mutation cystic fibrosis (nmCF) were published in Lancet Respiratory Medicine. The results demonstrated positive trends in both the primary endpoint, lung function as measured by relative change in % predicted FEV1 (forced expiratory volume in one second) and in the secondary outcome measure, rate of pulmonary exacerbations. The collective data from this trial, including retrospective and subgroup analyses support the conclusion that ataluren was active and showed clinically meaningful improvements over placebo in these trials. The Phase 3 double-blind, placebo-controlled study, which was conducted across 11 countries, compared ataluren (n=116) to placebo (n=116) in nmCF patients. The primary endpoint, the relative change from baseline in %-predicted FEV1 at 48 weeks, showed a positive trend favoring ataluren versus placebo, and a larger effect in patients not receiving chronic inhaled tobramycin. In the intent-to-treat population, there was a 3% difference in the relative change from baseline in %-predicted FEV1 between the ataluren and placebo groups at Week 48 (-2.5% change on ataluren vs. -5.5% change on placebo; p=0.12) which was not statistically significant. An analysis of the relative change from baseline in %-predicted FEV1 across all post-baseline study visits demonstrated an average difference between ataluren and placebo of 2.5% (-1.8% average change on ataluren vs. -4.3% average change on placebo; p= 0.048). There were 23% fewer pulmonary exacerbations in the ataluren group compared to placebo (p=0.0992). Further results from a post hoc analysis of the subgroup of patients not receiving chronic inhaled tobramycin showed a 5.7% difference in relative change from baseline in % predicted FEV1 favoring ataluren, with a mean change from baseline of -0.7% in the ataluren arm, and – 6.4% in the placebo arm (nominal p=0.0082). In addition, there were 40% fewer exacerbations in ataluren-treated patients in this subgroup. The outcomes observed in multiple endpoints between the subgroup of patients who were not prescribed chronic inhaled tobramycin and the subgroup of patients who were prescribed chronic inhaled tobramycin as well as post-hoc in vitro testing showing the interference of aminoglycoside antibiotics with ataluren activity support the hypothesis that inhaled tobramycin may interfere with ataluren's mechanism of action. Safety results indicate that ataluren was generally well tolerated. The overall incidence of adverse events through Week 48 was similar in the ataluren and placebo groups, except for the occurrence of creatinine elevations that occurred more frequently in the ataluren group in connection with concomitant treatment with systemic aminoglycosides. Most treatment emergent adverse events were of mild (Grade 1) or moderate (Grade 2) severity, and no life-threatening adverse events were reported. Most serious adverse events reported in this study were CF pulmonary exacerbations and were considered unrelated to ataluren treatment. Eight patients in the ataluren arm and three patients in the placebo arm discontinued treatment due to an adverse event. (Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial. Eitan Kerem et al. The Lancet Respiratory Medicine, Early Online Publication, 16 May 2014 doi:10.1016/S2213-2600(14)70100-6)

Company: PTC Therapeutics (USA - NJ)

Disease: nonsense mutation Duchenne muscular dystrophy (nmDMD)

Latest news:

• • On June 6, 2017, PTC Therapeutics announced that the FDA has notified the company of the tentative scheduling of a Peripheral and Central Nervous Systems Drugs Advisory Committee meeting on September 28, 2017 to review the new drug application (NDA) for ataluren for the treatment of nonsense mutation dystrophinopathy, including nonsense Duchenne muscular dystrophy (nmDMD).
• • On March 6, 2017, PTC Therapeutics announced that the FDA has acknowledged the filing over protest of PTC's New Drug Application (NDA) for Translarna™ (ataluren) for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD). The company is seeking approval to market the drug for the treatment of nmDMD patients in the United States. The FDA has granted standard review and assigned a Prescription Drug User Fee Act (PDUFA) date of October 24, 2017. The PDUFA date is the target date for the FDA to complete its review of the NDA.
• PTC used the FDA's file over protest regulations to file the NDA. These regulations allow a company to have its NDA filed and reviewed following receipt of a refuse to file determination.
• • On January 9, 2017, PTC Therapeutics announced that it received notification from the European Commission of its adoption of a positive decision granting annual renewal of the conditional marketing authorization for Translarna™ (ataluren). The positive decision is based on the recent renewal recommendation by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). As a specific obligation of the renewal, the Company will conduct an additional trial of Translarna in nmDMD.
• • On November 10, 2016, the CHMP announced that it had completed its scientific assessment of the annual renewal of the conditional marketing authorisation for Translarna® (ataluren) and recommended that the conditional authorisation be renewed. The committee also requested PTC Therapeutics to conduct a new 18-month randomised, placebo-controlled study in patients with Duchenne muscular dystrophy, followed by an 18-month peiod where all patients will be switched to  Translarna®. Study results are expected to be available in the first quarter of 2021.
• • On October 17, 2016, PTC Therapeutics provided a regulatory update on Translarna™  for the treatment of nonsense mutation Duchenne muscular dystrophy. PTC Therapeutics announced that at the end of last week, the Office of Drug Evaluation I (ODE-I) of the FDA denied the company's first appeal of the refuse to file letter issued by the FDA's Division of Neurological Products (DNP) on February 22, 2016 regarding PTC's New Drug Application (NDA) for Translarna™ for the treatment of nonsense mutation Duchenne muscular dystrophy. PTC Therapeutics intends to escalate its appeal to the next supervisory level of the FDA. This is an iterative process and the company anticipates that multiple cycles of appeals to progressively higher levels of the FDA may be required.
• PTC continues to assert that a proper assessment of the data and analyses from multiple clinical studies, including two of the largest placebo-controlled trials ever conducted in DMD, can only be accomplished in the context of a full and fair review by the FDA. This would include an advisory committee meeting that allows clinical experts and representatives of the patient community to express their views on Translarna™ for the treatment of nmDMD. The company believes that Translarna is the only therapy in clinical development designed to target the underlying cause of nmDMD. In addition, a favorable safety profile has been consistently demonstrated in PTC's clinical trials, which have enrolled over 1,000 individuals to date. In addition, the company maintains its position that PTC should, under existing law and in fairness to patients, be provided the same opportunity for full review that the DNP gave to other recent applicants for products in development for different subsets of the DMD population.
• PTC recently participated in an oral explanation meeting before the CHMP in connection with the company's ongoing annual renewal of its marketing authorization for Translarna for the treatment of nmDMD in ambulatory patients aged five years and older. Following conclusion of this explanation, the CHMP issued a request for supplemental information (RSI), including a request categorized as a major objection. Generally speaking, renewal of a marketing authorization requires a company to adequately address the points raised in a major objection. As with prior RSIs received by the company during this renewal process, the major objection relates to the efficacy and overall risk-benefit profile of Translarna as well as the design and conduct of an additional clinical trial that would provide comprehensive clinical data. The RSIs also include requests categorized as other concerns, which do not rise to the level of a major objection, and are generally associated with the primary pharmacology of Translarna™ and label matters. PTC anticipates that an opinion regarding its marketing authorization renewal request will be adopted by the CHMP before the end of 2016. The company expects that its current marketing authorization will remain valid while the EMA's assessment is ongoing and until it is concluded with a decision from the European Commission.
• • On July 25, 2016, PTC Therapeutics announced global regulatory updates on Translarna™ for the treatment of nonsense mutation Duchenne muscular dystrophy. Over the last several months, PTC has been engaged in constructive discussions with the CHMP regarding the renewal of Translarna™'s marketing authorization. The company has been informed that the renewal assessment procedure cannot be completed by mid-year 2016, however PTC expects that Translarna's current marketing authorization status will remain valid until a decision is adopted by the European Commission. The CHMP has agreed to the proposal by PTC to submit a draft clinical trial protocol for further discussion, which includes seeking scientific advice from the EMA. The company is optimistic that these interactions will support the renewal of the marketing authorization of Translarna coupled with an obligation to conduct an agreed upon clinical trial. Translarna™ initially received marketing authorization in the European Economic Area for the treatment of nmDMD in 2014, subject to annual renewal and certain conditions. Translarna™ is currently available to patients in more than 20 countries outside of the U.S. commercially or through early access programs. As part of PTC's ongoing commitments under the European marketing authorization and to support the potential expansion of Translarna™'s label to younger patients, the company has initiated a pediatric clinical study of Translarna for the treatment of nmDMD in patients two to five years of age. This Phase 2, open-label, multiple-dose study will evaluate the safety and pharmacokinetics of Translarna™ in pediatric patients. PTC also recently participated in discussions with the FDA to discuss the Refuse to File (RTF) letter issued on February 22, 2016 with respect to the company's New Drug Application (NDA) for Translarna ™ for the treatment of nmDMD. PTC recently submitted an appeal to escalate continuing discussions about the RTF decision to the next level of FDA management via the formal dispute resolution process within FDA's Center for Drug Evaluation and Research (CDER). This process exists to encourage open, prompt discussion of scientific and procedural disputes that arise during the drug development process between FDA and companies. Within the dispute resolution process, PTC is willing to consider multiple paths to advance a potential FDA approval, including the possibility of conducting an additional clinical trial under accelerated approval.
• • On July 7, 2016, PTC Therapeutics announced that the company and NHS England have successfully negotiated a Managed Access Agreement (MAA) for Translarna™ (ataluren) for ambulatory patients aged five years and older with nonsense mutation Duchenne muscular dystrophy. This decision provides reimbursed patient access to Translarna™ in England via a five-year MAA. Translarna™ previously received a positive recommendation from the National Institute for Health and Care Excellence (NICE) in April of 2016, subject to PTC and NHS England finalizing the terms of the MAA. NICE is expected to issue final guidance later this month following execution of the MAA, with implementation soon after. PTC and NHS England have now finalized the outstanding aspects of the MAA which include a confidential financial arrangement and the collection of further data on the efficacy of Translarna™ for the treatment of nmDMD over a five-year period with NICE guidance to be reviewed again at the end of that period, before future funding decisions are taken.
• • On April 15, 2016, PTC Therapeutics announced that the National Institute for Health and Care Excellence (NICE) has recommended Translarna® for ambulatory patients aged five years and older with nonsense mutation Duchenne muscular dystrophy (nmDMD) in connection with a Managed Access Agreement (MAA) with NHS England. The provision of patient access is subject to the finalization of the NICE draft guidance, which the agency expects in May of 2016. PTC and NHS England are in the process of finalizing an MAA outlining financial and clinical details surrounding the use of Translarna®, including a confidential financial arrangement. The MAA is expected to allow PTC to collect further data on the efficacy of Translarna® for the treatment of nmDMD over a five-year period with NICE guidance to be reviewed again at the end of that period.
• • On March 14, 2016, PTC Therapeutics announced that the company intends to submit the results of the recently completed Phase 3 ACT DMD study for review by Health Canada as part of the New Drug Submission (NDS) for Translarna™ (ataluren) to treat nonsense mutation Duchenne muscular dystrophy (nmDMD). In order to submit this additional data for review, PTC will withdraw the current NDS from Health Canada and resubmit the NDS with the ACT DMD results. As a result, the company no longer expects Health Canada review of the NDS in the first half of 2016.
• • On February 26, 2016, PTC Therapeutics announced that the company has had multiple discussions with the German Federal Association of the Statutory Health Insurances (GKV-SV) over the last several months to come to agreement on pricing and reimbursement. Recently, these discussions transitioned into an arbitration process, which did not lead to an acceptable agreement. As a result, PTC is considering delisting Translarna™ from the German pharmacy ordering system. Under these circumstances, patients and healthcare professionals may be able to access Translarna™ through a reimbursed importation pathway possible under German law, thus minimizing any access issues for German patients while maintaining a sustainable price. In May of 2015, Germany's Federal Joint Committee (G-BA), the highest decision-making body in the healthcare sector, granted Translarna™ an Early Benefit Assessment rating of 3, which signifies that the drug provides a quantifiable added benefit to patients. Additionally, in recognition of its innovative mechanism-of-action, Translarna™ was awarded the 2015 Prix Galien as the most innovative new product in the Orphan Drug category in Germany. Translarna™ has been commercially available in Germany since December 1, 2014, and is currently available on a commercial basis to patients in 23 countries.
• • On February 23, 2016, PTC Therapeutics  announced that it received a Refuse to File letter from the FDA regarding its New Drug Application (NDA) for Translarna™ for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD). The FDA states in the Refuse to File letter that the application was not sufficiently complete to permit a substantive review. PTC first learned of the Refuse to File decision via this letter and is reviewing its content to determine the appropriate next steps.
• • On January 8, 2016, PTC Therapeutics announced the completion of its rolling submission of a New Drug Application (NDA) to the FDA for Translarna™ for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD). PTC has also fulfilled the principal requirement of the European Medicines Agency (EMA) in connection with its approval of Translarna™ in August 2014 by submitting the results of its Phase 3 ACT DMD clinical trial to the agency.
• • On December 23, 2014, PTC Therapeutics announced that it has commenced a rolling submission of a New Drug Application (NDA) to the FDA for Translarna™ for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD). A rolling submission allows completed portions of the application to be submitted and reviewed by the FDA on an ongoing basis. PTC expects to finalize the application in the fourth quarter of 2015 following the completion of the ACT DMD confirmatory Phase 3 clinical trial.
• • On November 3, 2014, PTC Therapeutics announced that Translarna™ has been approved to be included in the list of drugs reimbursable by the Italian National Health System under Law 648/96. The decision is expected to be formalized through its publication in the official Italian journal, Gazzetta Ufficiale in the coming weeks. AIFA's Technical and Scientific Committee gave a positive opinion for the inclusion of Translarna® to be available and reimbursed to patients at its recent October meeting. The approval is based on the request of specialist physicians and Parent Project Onlus to gain access to Translarna® prior to its commercial availability in Italy. Law 648/96 allows a cohort of patients access to drugs which have demonstrated clear benefit while under clinical investigation, including drugs that have obtained a marketing authorization abroad but are not yet marketable in Italy. Translarna® has been approved in the European Economic Area but is not yet commercially available in Italy.
• • On August 4, 2014, PTC Therapeutics announced that the European Commission has granted conditional marketing authorization for Translarna™ in the European Union (EU) for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD) in ambulatory patients aged five years and older. The authorization allows PTC to market Translarna™ in the 28 countries that are Member States of the European Union, as well as European Economic Area members Iceland, Liechtenstein and Norway. As part of the conditional marketing authorization, PTC is obligated to complete its confirmatory Phase 3 trial in nmDMD (ACT DMD) and submit additional efficacy and safety data from the trial. The approval is based on the safety and efficacy results from a randomized double-blind multicenter study in 174 nmDMD patients for 48 weeks and our additional retrospective analyses of study data. The primary endpoint evaluated the effect of Translarna on ambulation as assessed by the change in distance walked (six-minute walk distance - 6MWD) during a six-minute walk test (6MWT). The post-hoc analysis showed that from baseline to Week 48, patients receiving Translarna™ (40 mg/kg/day given in 3 doses) had a 12.9 meter mean decline in 6MWD, and patients receiving placebo had a 44.1 meter mean decline in 6MWD. Thus the mean change in observed 6MWD from baseline to Week 48 was 31.3 meters better in the Translarna™ group than in the placebo group (p=0.056). Furthermore, in more severely affected patients whose baseline 6MWD was less than 350 meters, the mean change in observed 6MWD from baseline to Week 48 was 68 meters better in the Translarna™ group than in the placebo group. Patients on Translarna also showed a slower rate of decline in ambulation based on an analysis of time to 10 percent worsening in 6MWD. The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency found that these results suggest that Translarna™ slows the loss of walking ability in nmDMD patients.
• Additionally, based on a retrospective analysis, patients receiving treatment also trended better in secondary endpoints such as stair climb and stair descend time-function tests, which the CHMP also found to suggest slowing of nmDMD progression relative to placebo. Safety results showed that Translarna™ was generally well tolerated. Serious adverse events were infrequent, and none was considered to be related to Translarna™. The most frequent adverse reactions at the recommended dose were nausea, vomiting, and headache. These adverse reactions generally did not require medical intervention, and no patients discontinued Translarna™ treatment due to any adverse reaction.
• • On July 9, 2014, PTC Therapeutics announced the initiation of a reimbursed expanded access program (EAP). PTC's EAP program is intended to make Translarna™  available to patients before commercial availability in certain countries. Where mechanisms exist and in accordance with local regulations, PTC will make Translarna available to nonsense mutation Duchenne muscular dystrophy (nmDMD) patients through funded EAP programs. Funded Named Patient Programs have already been authorized in Turkey and Spain. The French National Agency for Medicines and Health Products Safety (ANSM), has also granted a Temporary Authorization for Use (Autorisation Temporaire d'Utilisation de cohorte). Government allocations to hospitals will allow payment for Translarna® for patients included in the ATU cohort program.
• • On May 23, 2014, PTC Therapeutics announced that CHMP's positive opinion is based on data and subsequent analysis submitted from a 48-week, 174-patient Phase 2b double-blind, placebo controlled trial which demonstrated that nmDMD patients treated with Translarna® (40 mg/kg given daily) walked on average 31.3 meters farther than patients on placebo, as measured by the change in six-minute walk distance (6MWD) from baseline to Week 48. Patients receiving Translarna® also demonstrated a slower rate of decline in ambulation, based on an analysis of time to 10 percent worsening in 6MWD. Safety results showed that Translarna® was generally well tolerated. Serious adverse events were infrequent and none were considered to be related to Translarna®. PTC's global Phase 3 ACT DMD clinical trial is ongoing with full enrollment expected mid-2014. The outcome of this trial is critical for achieving full approval in the EU as well as the US.
• • On 22 May 2014, the CHMP recommended the granting of a conditional marketing authorisation for Translarna® for the treatment of Duchenne muscular dystrophy. On 23 January 2014, the CHMP had originally adopted a negative opinion for Translarna, but at the request of the applicant the CHMP started a re-examination of its opinion. Following the re-examination, the CHMP adopted a final positive opinion on 22 May 2014 recommending the granting of a conditional marketing authorisation for Translarna®, while further confirmatory data on the benefits of this medicine are being generated. During the re-examination the CHMP looked again at the data from the main study and also at additional analyses of these data provided by the company. The Committee re-considered whether enough data were available to support a conditional marketing authorisation, and whether it would be feasible to obtain further data from a confirmatory study which is currently recruiting patients. During the re-examination, the CHMP took the view that there was some evidence of effectiveness when Translarna® is used at a dose of 40 mg/kg/day, and that the way the medicine works is plausible. The CHMP considered that the data available are sufficient to recommend a conditional marketing authorisation. Under the terms of the authorisation, the company will be required to provide comprehensive data from an ongoing confirmatory study. In recommending a conditional marketing authorisation, the CHMP also considered the safety profile of Translarna®, which was not of concern, and acknowledged the seriousness of Duchenne muscular dystrophy and the unmet medical need of patients with this condition. Therefore, the CHMP concluded that the benefits of Translarna® outweigh its risks and recommended that the medicine be granted a conditional marketing authorisation.
• • On January 24, 2014, PTC Therapeutics has announced that the response from the CHMP is consistent with the Company's previous guidance concerning the substantial risks regarding conditional EMA approval and underscores the importance of PTC's work in completing the ongoing confirmatory Phase 3 clinical trial. In April 2013, PTC initiated a 48-week, 220-patient confirmatory Phase 3 clinical trial of ataluren for the treatment of nmDMD. The trial is on track to complete enrollment in mid-2014 with top-line data expected in mid-2015. PTC intends to request a re-examination of the CHMP opinion with a final outcome expected in the second quarter of 2014, when the confirmatory study is expected to be more fully enrolled. Stuart W. Peltz, Ph.D., Chief Executive Officer of PTC, added, "We understood and communicated that there was a substantial risk that the EMA would not grant us conditional approval when we began this process 15 months ago. However, we pursued this approach because we believe ataluren has shown a clinically meaningful benefit for nmDMD patients in our trials, has been generally well tolerated and should be made available to patients as soon as possible. Furthermore, we have made meaningful progress both in validating the 6-minute walk distance as an outcome measure in DMD clinical studies and in sharing an understanding of the natural history of this disorder as its relates to changes in ambulation."
• • On 23 January 2014, the CHMP has adopted a negative opinion, recommending the refusal of the marketing authorisation for Translarna®, intended for the treatment of Duchenne muscular dystrophy. Translarna® was expected to be used to treat patients aged 5 years and older with Duchenne muscular dystrophy. This small molecle is intended to interact with the ribosome to enable it  to read through premature nonsense stop signals on mRNA and allow the cell to produce a full-length, functional dystrophin. PTC Therapeutics presented the results of one main study in 174 patients with Duchenne muscular dystrophy, where Translarna® was compared with placebo (a dummy treatment). The main measure of effectiveness was the change in the distance the patient could walk in six minutes after 48 weeks of treatment. The CHMP noted that the main study failed to show that patients taking Translarna® could walk in six minutes a greater distance than patients taking placebo. Although the company performed additional analyses of the data, the CHMP considered that these were insufficient to provide enough evidence of effectiveness. When other measures of effectiveness were considered, including those directly linked to patients daily activities, these provided only limited supportive evidence of the beneficial effects of Translarna®. Finally, insufficient data had been provided to determine how the medicine works in the body and how its effects change with the dose. Therefore, at that point in time, the CHMP was of the opinion that the benefits of Translarna did not outweigh its risks and recommended that it be refused marketing authorisation.
• • On December 6, 2012, PTC Therapeutics has announced that the European Medicines Agency (EMA) has validated a Marketing Authorization Application (MAA) seeking conditional approval for ataluren for the treatment of patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). The MAA's submission was accepted by EMA for review on the basis of a 48-week, 174-patient Phase 2b study showing that nmDMD patients treated with ataluren (10, 10, 20 mg/kg given daily) walked on average 31.3 meters farther than patients on placebo, as measured by the change in six-minute walk distance (6MWD) from baseline to Week 48. Patients receiving ataluren demonstrated a slower rate of decline in ambulation, based on an analysis of time to 10 percent worsening in 6MWD. While 44 percent of patients receiving placebo declined 10 percent or more in walking as measured by the 6-minute walk test (6MWT), only 26 percent of patients receiving ataluren declined 10 percent or more. Safety results showed that ataluren was generally well tolerated and adverse events were similar to placebo. Serious adverse events were infrequent and none were considered to be related to ataluren. PTC also announced the design of a confirmatory Phase 3 clinical trial of ataluren in patients with nmDMD that would support conditional approval and is expected to be initiated in the first quarter of 2013. The primary objective of the multicenter, randomized, double-blind, placebo-controlled Phase 3 study is to confirm the ability of ataluren to slow disease progression as assessed by ambulatory ability based on the 6MWD in patients with nmDMD. Secondary endpoints related to physical function and quality of life will also be assessed. Approximately 220 patients are expected to be enrolled in this global study.

Patents:

Submission of marketing authorization application USA : 2014-12-23

Submission of marketing authorization application UE:

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization:

UE authorization: 2014-08-05 (conditional approval)

Favourable opinion UE: 2014-05-22

Favourable opinion USA:

Orphan status USA: 2005-01-10

Orphan status UE: 2007-05-27

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes