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The Discovery of Lesinurad

 

At Ironwood, innovation for patients drives all that we do. We are inspired by and proud to play a part in bringing important medicines to patients in need of new or additional treatment options, regardless of whether that innovation originates in our own labs or not.

In 2016, Ironwood entered into a license agreement with AstraZeneca PLC for exclusive U.S. rights to all products containing lesinurad, including ZURAMPIC® (lesinurad) and the fixed-dose combination of lesinurad and allopurinol, DUZALLO®. Lesinurad was initially discovered and developed by Ardea Biosciences, which was later acquired by AstraZeneca. Interestingly, the discovery of lesinurad was not associated with a medicinal chemistry effort directed at finding a URAT1 inhibitor. Instead, an unanticipated finding during phase 1 clinical trials in a different therapeutic area led to the identification of this compound.

Lesinurad is a selective uric acid reabsorption inhibitor that inhibits the urate transporter URAT1, and was shown in early phase studies to reduce reabsorption of serum uric acid (sUA) and increase its excretion. As underexcretion of sUA was a serious issue for gout patients and with a limited number of treatment options existing to increase sUA excretion, Ardea decided to develop lesinurad for the treatment of hyperuricemia in gout patients.

Gout is the most common form of inflammatory arthritis that develops in some people who have hyperuricemia or high levels of uric acid in the blood1. Lesinurad showed promise as a potential piece in the puzzle of treatment of hyperuricemia associated with gout. Previously approved therapies, allopurinol and febuxostat, are xanthine oxidase inhibitors (XOIs), which work by reducing the production of uric acid. But overproduction of uric acid is not the only cause of hyperuricemia in gout; underexcretion of uric acid also results in elevated sUA levels. The Ardea team researched the potential of lesinurad to complement the effect of XOIs by addressing underexcretion.

The FDA approved lesinurad 200 mg tablets as ZURAMPIC® in 2015 to be taken in combination with an XOI (either allopurinol or febuxostat) based on the results of three clinical studies2.

In 2017, the FDA approved the fixed-dose combination of lesinurad plus allopurinol as DUZALLO. Approval of DUZALLO was based on bioequivalence of DUZALLO to co-administered lesinurad and allopurinol, as efficacy of the combination of allopurinol and lesinurad was shown in trials leading to the approval of ZURAMPIC.

The use of lesinurad in combination with XOIs has therefore provided an additional treatment for patients with hyperuricemia associated with gout.

______________________
1) “What is gout?” Arthritis Foundation®.
2) ZURAMPIC Prescribing Information. Section 14.
 

 

DUZALLO® (lesinurad and allopurinal) Indications and Usage
For hyperuricemia in gout when goal sUA levels are not achieved with a medically appropriate daily dose of allopurinol alone. Not recommended for asymptomatic hyperuricemia.

IMPORTANT SAFETY INFORMATION

WARNING: RISK OF ACUTE RENAL FAILURE
Acute renal failure has occurred with lesinurad, one of the components of DUZALLO
Contraindications
Severe renal impairment (estimated creatinine clearance [eCLcr] <30 mL/min), end-stage renal disease, kidney transplant recipients, or patients on dialysis
Tumor lysis syndrome or Lesch-Nyhan syndrome
Known hypersensitivity to allopurinol, including previous occurrence of skin rash
Warnings and Precautions
Renal events
Adverse reactions related to renal function, including acute renal failure, can occur after initiating DUZALLO. Renal function should be evaluated prior to initiation of DUZALLO and periodically thereafter, as clinically indicated. More frequent renal function monitoring is recommended in patients with eCLcr <60 mL/min or with serum creatinine elevations 1.5 to 2 times the value when lesinurad treatment was initiated. DUZALLO should not be initiated in patients with an eCLcr <45 mL/min. Interrupt treatment with DUZALLO if serum creatinine is elevated to >2 times the pretreatment value or if there are symptoms that may indicate acute uric acid nephropathy, including flank pain, nausea, or vomiting. DUZALLO should not be restarted without another explanation for the serum creatinine abnormalities
Skin rash and hypersensitivity
Skin rash is a frequently reported adverse event in patients taking allopurinol. In some instances, a skin rash may be followed by more severe hypersensitivity reactions associated with exfoliation, fever, lymphadenopathy, arthralgia, and/or eosinophilia including Stevens-Johnson syndrome and toxic epidermal necrolysis. Associated vasculitis and tissue response may be manifested in various ways including hepatitis, renal impairment, seizures, and on rare occasions, death. Hypersensitivity reactions to allopurinol may be increased in patients with decreased renal function who are receiving thiazide diuretics and DUZALLO concurrently. DUZALLO should be discontinued immediately at the first appearance of skin rash or other signs that may indicate an allergic reaction, and additional medical care should be provided as needed
Hepatotoxicity
A few cases of reversible clinical hepatotoxicity have been reported in patients taking allopurinol and, in some patients, asymptomatic rises in serum alkaline phosphatase or serum transaminase have been observed. If anorexia, weight loss, or pruritus develops in patients taking DUZALLO, evaluation of liver function should be performed. In patients with preexisting liver disease, periodic liver function tests are recommended
Cardiovascular events
In clinical trials, major adverse cardiovascular events (defined as cardiovascular deaths, nonfatal myocardial infarctions, and nonfatal strokes) were observed with DUZALLO. A causal relationship has not been established
Bone marrow depression
Bone marrow depression has been reported in patients receiving allopurinol, most of whom received concomitant drugs with the potential for causing this reaction. This has occurred as early as 6 weeks to as long as 6 years after the initiation of allopurinol therapy. Rarely, a patient may develop varying degrees of bone marrow depression, affecting one or more cell lines, while receiving allopurinol alone. Patients taking allopurinol and mercaptopurine or azathioprine require a reduction in dose to approximately one-third to one-fourth of the usual dose of mercaptopurine or azathioprine
Increase in prothrombin time
It has been reported that allopurinol prolongs the half-life of dicumarol, a coumarin anticoagulant. The prothrombin time should be reassessed periodically in patients receiving coumarin anticoagulants (dicumarol, warfarin) concomitantly with DUZALLO
Drowsiness
Occasional occurrence of drowsiness was reported in patients taking allopurinol. Patients should be alerted to the need for caution when engaging in activities where alertness is mandatory
Adverse Reactions
The most common adverse reactions in controlled studies (occurring in 2% or more of patients on lesinurad in combination with allopurinol and at least 1% greater than observed in patients on allopurinol alone) were headache, influenza, blood creatinine increased, and gastroesophageal reflux disease
The most common adverse reactions identified during post-approval use of allopurinol are skin rash, nausea, and diarrhea
Indication and Limitations of Use
DUZALLO, a combination of lesinurad, a URAT1 inhibitor, and allopurinol, a xanthine oxidase inhibitor, is indicated for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a medically appropriate daily dose of allopurinol alone.
DUZALLO is not recommended for the treatment of asymptomatic hyperuricemia
Please see full Prescribing Information including Boxed Warning, and Medication Guide. »

 

ZURAMPIC® (lesinurad and allopurinal) Indications and Usage
ZURAMPIC is a URAT1 inhibitor indicated in combination with an XOI for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with an XOI alone.

  • ZURAMPIC is not recommended for the treatment of asymptomatic hyperuricemia
  • ZURAMPIC should not be used as monotherapy

IMPORTANT SAFETY INFORMATION

WARNING: RISK OF ACUTE RENAL FAILURE, MORE COMMON WHEN USED WITHOUT A XANTHINE OXIDASE INHIBITOR (XOI)<br/>
<ul><li>Acute renal failure has occurred with ZURAMPIC and was more common when ZURAMPIC was given alone</li>
<li>ZURAMPIC should be used in combination with an XOI</li></ul>
Contraindications
Severe renal impairment (eCLcr less than 30 mL/min), end-stage renal disease, kidney transplant recipients, or patients on dialysis
Warnings and Precautions
Renal events
Adverse reactions related to renal function have occurred after initiating ZURAMPIC. A higher incidence was observed at the 400-mg dose, with the highest incidence occurring with monotherapy use. Monitor renal function at initiation and during therapy with ZURAMPIC, particularly in patients with eCLcr below 60 mL/min or with serum creatinine elevations 1.5 to 2 times the pre-treatment value, and evaluate for signs and symptoms of acute uric acid nephropathy. Interrupt treatment with ZURAMPIC if serum creatinine is elevated to greater than 2 times the pre-treatment value or if there are symptoms that may indicate acute uric acid nephropathy. ZURAMPIC should not be restarted without another explanation for the serum creatinine abnormalities. ZURAMPIC should not be initiated in patients with an eCLcr less than 45 mL/min
Cardiovascular events
In clinical trials, major adverse cardiovascular events (defined as cardiovascular deaths, non-fatal myocardial infarctions, or non-fatal strokes) were observed with ZURAMPIC. A causal relationship has not been established.
Adverse Reactions
Most common adverse reactions with ZURAMPIC (in combination with an XOI and more frequently than on an XOI alone) were headache, influenza, blood creatinine increased, and gastroesophageal reflux disease
Indication and Limitations of Use for ZURAMPIC:
ZURAMPIC is a URAT1 inhibitor indicated in combination with an XOI for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with an XOI alone.
ZURAMPIC is not recommended for the treatment of asymptomatic hyperuricemia
ZURAMPIC should not be used as monotherapy
Please see full Prescribing Information including Boxed Warning, and Medication Guide. »