Adlyxin (Lixisenatide) Vs. Victoza (Liraglutide) and Byetta (Exenatide) August 4, 2016

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Drug Evidence Review: Adlyxin (lixisenatide) vs. Victoza (liraglutide) and Byetta (exenatide) August 4, 2016

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Actionable Intelligence: Based on analysis of clinical trial evidence glargine 100 Units/mL and lixisenatide is also submitted for FDA for on Advera’s Evidex platform, Sanofi’s Adlyxin (lixisenatide) showed approval, and FDA decision is anticipated in August 2016. a slightly safer profile compared to Victoza (liraglutide) based on a lower serious AE rate in head-to-head trials, and no associated thyroid GLP-1 agonists increase the incretin effect in patients with type 2 cancer risk which has been tied to Victoza in rare cases. Adlyxin diabetes, stimulating the release of insulin by mimicking the actions (lixisenatide) improved glycemic control both as monotherapy and as of naturally occurring GLP-1 hormone that is released after a meal. an add-on therapy to oral anti-diabetic drugs and insulin and showed They induce significant reductions in glycosylated haemoglobin a safe cardiovascular profile in patients in a cardiovascular safety trial, (HbA1c) and weight loss, and have a low risk of hypoglycaemia, but but showed inferior efficacy in reducing Hb1Ac and FPG in head-to- are also reported to be possibly associated with increased risk of head trials vs. Victoza (liraglutide) and Byetta (exenatide). pancreatitis and pancreatic cancers, acute renal failure and thyroid Considering the label warning against anaphylactic reactions carcinomas. associated with usage of Adlyxin (lixisenatide), close post-marketing surveillance will reveal the extent of this and other safety issues for Adlyxin’s (lixisenatide) approval is based on clinical trials called this drug. GETGOAL trials, which include various double-blind placebo Drugs Covered: Adlyxin (lixisenatide), Victoza (liraglutide) and controlled studies and open-label, head-to-head trials against Byetta (exenatide) exenatide (Byetta), liraglutide (Victoza), or insulin glulisine (Apidra). Patients mostly received 20g Adlyxin (lixisenatide) once daily as a Indications Covered: Type 2 Diabetes monotherapy, or as an add-on to other oral diabetic drugs or insulin. Drug Classes Covered: Other blood glucose lowering drugs, excl. Table 1 shows the demographic details, efficacy and safety of these insulins clinical trials in detail. Table 1a shows the results of GETGOAL- Mono, a trial exploring the efficacy and safety of Adlyxin MoA Covered: GLP-1 agonists (lixisenatide) as a monotherapy, and two head on trials against Byetta (exenatide) (GETGOAL-X) and Victoza (liraglutide) (LIRA-LIX). Adlyxin (lixisenatide) showed non-inferior reductions in HbA1c, Overview slightly lower mean weight loss, lower incidence of hypoglycemia, a On 27th July, 2016, FDA approved Adlyxin (lixisenatide, Sanofi) a similar serious AE rates and better gastrointestinal tolerability once daily glucagon-like peptide-1 receptor agonist (GLP-1 RA) compared with exenatide (Byetta) twice daily. In the head-on LIRA- indicated as an adjunct to diet and exercise for the treatment of LIXI trial, Victoza (liraglutide) appeared to have better efficacy adults with type 2 diabetes. It was approved in Europe in 2013 under (Hb1Ac reduction, Fasting plasma glucose (FPG) levels, weight loss), the name Lyxumia for the “treatment of adults with type 2 diabetes but Adlyxin (lixisenatide) showed lower serious AE rate than Victoza mellitus to achieve glycaemic control in combination with oral (liraglutide). Table 1B and 1C show the GETGOAL trials where glucose-lowering medicinal products and/or basal insulin when Adlyxin (lixisenatide) was used as an add-on to metformin, sulfonyl these, together with diet and exercise, do not provide adequate urea and pioglitazone and insulin. In all these trials Adlyxin glycaemic control” and is presently approved in more than 50 (lixisenatide) appeared to improve the Hb1Ac, FPG and body weight countries including most EU countries, Japan, Brazil, Mexico and of the patients, with an acceptable safety profile. Table 1D details the other markets. Sanofi re-submitted Adlyxin (lixisenatide) for FDA cardiovascular safety trial of Adlyxin (lixisenatide), ELIXA, and approval in the third quarter of 2015, after data from the ELIXA trial Victoza (liraglutide), LEADER. demonstrated no change in the rate of major cardiovascular events compared to placebo in people with type 2 diabetes and high cardiovascular risk. In 2008 FDA mandated cardiovascular safety studies of all newer drugs for the treatment of type 2 diabetes before approval. LixiLan, a fixed-ratio combination of basal insulin www.adverahealth.com © 2016 Advera Health Analytics 1

Both of these drugs established their cardiovascular safety: Adlyxin did not increase or decrease the cardiovascular risk whereas Victoza reduced the risk of death due to cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Overall through the clinical trials, Adlyxin (lixisenatide) showed comparable efficacy to Byetta and slightly lower efficacy compared to Victoza in head-on trials, and improved the glycemic control as an add-on to both oral diabetic drugs and insulin therapy. The most frequently reported adverse reactions during clinical studies were nausea, vomiting, and diarrhea. These reactions were mostly mild and transient. In the present article, we compare the safety and efficacy of Adlyxin (lixisenatide) with other GLP-1 agonists Victoza (liraglutide) and Byetta (exenatide). Table 2 below shows the Important Medical Event (IME)-Serious terms (as designated by EudraVigilance Expert Working Group (EV-EWG)) found in the latest drug labels of Adlyxin (lixisenatide), Victoza (liraglutide) and Byetta (exenatide), their incidence rates through the clinical trials, and their corresponding incidence rates in FAERS reports. The data is taken from Evidex™, our proprietary web-based platform that combines annotated data from curated clinical trial results with structured real-world drug evidence. The Adlyxin (lixisenatide) label warns about serious anaphylactic reactions (due to immunogenicity against the drug) and pancreatitis and kidney injury (associated with GLP-1 agonists) and did not show thyroid tumours which appear on Victoza’s label or haemorrhage due to drug-interaction with warfarin that appears on Byetta’s label. Overall, Adlyxin (lixisenatide) seems to have a slightly less risky safety profile compared to its comparator Victoza (liraglutide) and a similar safety profile as Byetta (exenatide).

Table 3 depicts the “Active” and “Watchlist” RxSignals1 identified by our RxSignal analytic for Victoza and Byetta. Table 4 shows the RxCosts2 of top 5 labeled and non-labeled AEs of these drugs, based on the post-market reporting of adverse events by patients. The RxScores of Victoza and Byetta were 54.28 and 64.79 respectively, and the RxCost per prescription was calculated as $3.76 for Victoza and $8.76 for Byetta.

Safety Comparison to Existing Treatments Clinical trials

Tables 1a, 1b, 1c and 1d below give a detailed overview of selected clinical trials of Adlyxin (lixisenatide), Victoza (liraglutide) and Byetta (exenatide). The side-by-side tabulation is done to simplify presentation across trials that are all conducted in differing trial designs. The data of individual trials was procured from the www.clinicaltrials.gov and the references indicated therein.

TABLE-1A: CLINICAL TRIAL EXPERIENCE OF ADLYXIN (LIXISENATIDE) Description Head to head trial Monotherapy

Name of trial GETGOAL-X LIRA-LIXI GETGOAL-MONO GETGOAL-MONO-Japan

*24 week main treatment Trial duration 26 weeks 12 weeks 72 week (*24 week) +≥52 week extension

Adlyxin Byetta Adlyxin Adlyxin Adlyxin Adlyxin Adlyxin Victoza PBO Arms (lixisenatide) (exenatide) (lixisenatide) -2 (lixisenatide) -1 (lixisenatide) -2 (lixisenatide) -1 (ixisenatide) (liraglutide) combined (20ug OD) (10ug BID) step regimen** step regimen** step regimen step regimen Demographics Number of Participants (n) Mean age (years) Male (%)

Basal Hemoglobin A1c % Basal FPG (mmol/l) Body weight (kgs) Efficacy Mean Change From Baseline for Hemoglobin A1c (HbA1c) Mean Change From Baseline for FPG (mmol/l) Percentage of Participants Achieving an A1C Goal <7.0% Change in body weight (kg) AE rates Serious adverse events Other non-serious adverse events Discontinuation Nausea Vomiting Diarrhea Symptomatic hypoglycemia * Primary outcome duration ** Lixisenatide-2 step regimen: 10 μg once daily for 1 week, 15 μg once daily for 1 week then the maintenance dose of 20 μg once daily; Lixisenatide-1 step regimen: 10 μg once daily for 2 weeks then 20 μg once daily www.adverahealth.com © 2016 Advera Health Analytics 2

Evidex™ is a web-based platform that provides insights using annotated data from curated clinical trials results and structured real-world evidence. Full data tables are reserved for Evidex™ subscribers. To learn more and request a trial of the Evidex platform, please contact [email protected] for more information.

Label comparison Table 2 below shows the IME serious AEs that appear in the latest labels of Adlyxin (lixisenatide), Victoza (liraglutide) and Byetta (exenatide). An ROR4 value of >1.0 indicates that there is a higher than expected reporting rate for a given AE / drug combination.

Boxed Warning Victoza (liraglutide) has a boxed warning alerting patients about possible risk of thyroid c−cell tumours. Byetta (exenatide) does not have any boxed warning. Adlyxin (lixisenatide) does not have any Boxed warning on its label.

REMS Victoza (liraglutide) has a Risk Evaluation Mitigation Strategies (REMS program) to inform healthcare providers about the thyroid c−cell tumors. Byetta (exenatide) and Adlyxin (lixisenatide) do not have any REMS associated with their usage.

RxSignal Table 3 below shows the Active and Watchlist RxSignals for Victoza (liraglutide) and Byetta (exenatide). Any RxSignal tagged with DR5 indicates an AE that could potentially be related to the disease the medication is FDA-approved to treat. Paste text here. Align left

RxCost Table 4 below shows the top 5 costliest non-labeled and labeled AEs associated with Victoza (liraglutide) and Byetta (exenatide).

RxScore

Disclaimer

Neither Advera Health, nor its officers or analysts currently hold a direct or indirect investment position (long or short) in any of the securities of the companies who own a financial interest in the drugs mentioned in this Drug Evidence Review (“DER”).

DERs are independent research pieces. Opinions provided by Advera Health analyst team in all DERs are based upon data and insight generated by the analytical tools of Evidex™ and other pertinent information gathered at the time of publication. DERs have never been, nor will ever be, sponsored or influenced by any third party, including any clients of Advera Health. The inclusion of a particular company, drug, adverse event, class or indication in this report is determined wholly by our quantitative signaling and analytic systems along with our qualitative analysis work. The inclusion or exclusion of any drug, company, adverse event, class or indication has not, and will not, be influenced by any third party, including any clients of Advera Health.

Advera Health executes advisory projects for its clients from time to time. Employees of Advera Health who provide opinions on these advisory projects have not contributed to this DER if it contains drugs that were part of an advisory project.

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RxFilter results, disproportionality measures, RxSignals, RxScores, RxCosts, and Outcome rates change over time as a result of new case report procurement. As a result, the data you see in this report might not reflect the latest update. Clients may access updated results through their Evidex™ subscription. If you are not a client, you can contact us for more information.

Footnotes

1RxSignal uses a refined version of disproportionality analysis (DA) in order to make predictions regarding future FDA label changes. The key issue for developing a relevant signaling platform is being able to properly identify and track AEs that are of significant interest to FDA. RxSignal was developed by identifying key AEs from over one thousand past FDA alerts.

An Active RxSignal term must be an RxSignal-eligible term that is not listed on the drugs prescribing information. Our new methodology closely monitor 3 AEs - progressive multifocal leukoencephalopathy, Stevens-Johnson syndrome, and toxic epidermal necrolysis, which are noted by the FDA as inherently serious and often drug-related DMEs. An Active RxSignal is triggered for these adverse reactions with at least 1 primary suspect case.

For all other RxSignal-eligible AEs, an Active RxSignal is generated when at least 5 primary suspect cases are reported and the ROR is 2.0 or greater, or when the primary suspect case count is between 2 and 5, and the lower end of the 95% confidence interval for the ROR is 2.0 or greater. We use ROR values of 2.0 and above as a benchmark for an Active RxSignal to help avoid false positive signals.

A Watchlist RxSignal has the same criteria with the exception of having an ROR value between 1.0 and 2.0, if the AE has at least 5 primary case reports. When the primary suspect case count is between 2 and 5, a Watchlist RxSignal is generated if the lower end of the 95% confidence interval for the ROR value is between 1.0 and 2.0.

2ROR is a disproportionality analysis known as the Reporting Odds Ratio. An ROR score greater than 1 indicates that there is a higher than expected reporting rate for a given AE/drug combination. While there is no widely accepted benchmark regarding the numerical level at which disproportionality analysis yields a safety signal, many in the drug industry assume that results above 2.0 warrant attention.

3Potential Disease-Related

Occasionally, disease-related (DR) symptoms are listed in the “adverse event” field by the person who submitted the FAERS case report. When such events are clearly related to the underlying disease those “AEs” are designated as DR and excluded from further analysis, including our RxCost and RxScore methods. Additionally, when an AE could reasonably be associated with 1) the disease itself, 2) the administration of a drug to treat the disease, or 3) unknown causes, we designated such AEs as "potential DR" and they are included in our cost and scoring methods. While we are careful to omit all DR AEs from analysis, it cannot be stated that our methods identify and exclude them all.

RxFilter makes post-marketing adverse event (AE) case reports contained in FDA's Adverse Event Reporting System (FAERS) accessible by using a combination of computer algorithms and in-house data analysis. The system accurately standardizes and normalizes ~5 million AE case reports, from 1997 on, linked to over ~2,000 FDA approved drugs and feeds those clean data into our other analytics.

RxScore is a proprietary algorithmic model that ranks the potential risk of each drug in our coverage universe on a 1-100 scale. The model is based on the average downstream cost of serious AEs and outcomes per patients exposed to a particular medication.

RxCost is a proprietary algorithm that calculates downstream medical costs associated with AE/drug combinations. We obtained FAERS case reports of all the AEs that occurred during the previous five year period, pertaining to a particular drug. These AEs were mapped to MedDRA (Medical Dictionary for Regulatory Activities) terms and the MedDRA terms were matched to the corresponding ICD-9 codes (International Statistical Classification of Diseases and Related Health Problems). An average RxCost per AE is calculated by normalizing the five-year cost of treating a particular AE listed according to Healthcare Cost and Utilization Project (HCUP).

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