Keeping Track: US FDA Clears Esperion’s Nexletol, Baudax’ Anjeso, Agile’s Twirla

The latest drug development news and highlights from the Pink Sheet’s US FDA Performance Tracker.

The US Food and Drug Administration closed out the week with a late-Friday approval of Esperion Therapeutics Inc.’s Nexletol, a new oral non-statin LDL-cholesterol lowering agent.

Earlier in the week, FDA’s new product approvals included a new formulation of an NSAID as an IV treatment for pain, a new transdermal contraceptive patch, and a prescription laxative formulation of a molecule also known as a low-calorie sweetener.

FDA declined to approve Merck & Co. Inc.’s application for a more convenient dosing interval for its flagship immuno-oncologic Keytruda, issuing a complete response letter. The oncology review queue saw new applications for Genentech Inc.’s Tecentriq in lung cancer and Epizyme Inc.’s Tazverik in follicular lymphoma. And Seattle Genetics Inc. and Astellas Pharma Inc.’s recently approved Padcev received a second breakthrough therapy designation in bladder cancer – this time in combination with Keytruda.

Esperion’s Nexletol Is CDER’s 5th Novel Approval Of 2020

Nexletol (bempedoic acid), a first-in-class inhibitor of ATP citrate lyase, is indicated as an adjunct to diet and maximally tolerated statin therapy for treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD).

Esperion emphasized that “Nexletol is the first oral, once-daily, non-statin LDL-C lowering medicine approved since 2002 for indicated patients.” The convenience is expected to be an asset when competing with the PCSK9 inhibitors, which have demonstrated strong cholesterol-lowering efficacy but have been hampered in the market by their injectable administration and high cost.

In the Phase III trials that supported the NDA, Nexletol “provided an average of 18% placebo corrected LDL-C lowering when used with moderate or high intensity statins,” Esperion reported.

As is usual for drugs approved on the basis of cholesterol-lowering effect, Nexletol labeling notes that its effect on CV morbidity and mortality has not been determined. The company started a CV outcomes trial, known as CLEAR, in 2016; the study completed enrollment of 14,032 patients in August 2019. Esperion has touted the design of CLEAR, which is longer than the PCSK9 inhibitor CVOTs, and conservatively powered to show a significant risk reduction in major CV events. (Also see "Ex-US FDA Director John Jenkins Sketches Regulatory Path For Esperion's Bempedoic Acid" - Pink Sheet, 11 Jul, 2018.)

The FDA is still reviewing Esperion’s second NDA for bempedoic acid, in a fixed-dose combination with ezetimibe. The combo has a 26 February user fee goal.

In Acute Pain, One Step Forward And One Step Slower

One of the many fronts in the campaign against opioid overuse has been a burst of development of intravenous formulations of non-opioid drugs like the NSAID meloxicam that are designed for treatment of acute pain in hospitals and medically supervised settings.

More than two-thirds of inpatients treated with IV analgesia now receive IV opioid monotherapy, according to Baudax Bio, a specialty company with a focus on non-opioid analgesics for hospital and acute care settings that was spun out of Recro Pharma Inc. in November 2019.

FDA approved Baudax Bio’s IV meloxicam product Anjeso on 20 February as a once-daily IV bolus push for management of moderate to severe pain, alone or in combination with other non-NSAID analgesics.

Anjeso is the “first and only once-daily IV analgesic,” Baudax said. The IV meloxicam is formulated with Alkermes’ NanoCrystal technology, which “enables enhanced bioavailability of poorly water-soluble drug compounds.”

“Because of delayed onset of analgesia, Anjeso alone is not recommended for use when rapid onset of analgesia is required,” labeling notes. The limitation of use statement reflects one of FDA’s concerns cited in the second complete response letter issued for Anjeso.

When Recro announced the CRL in March 2019, the company said the letter “focused on onset and duration of IV meloxicam, noting that the delayed onset fails to meet the prescriber expectations for IV drugs.” (Also see "Keeping Track: Thumbs Up For Zulresso And Sunosi, Thumbs Down For Zynquista And IV Meloxicam" - Pink Sheet, 24 Mar, 2019.)

Recro disputed the CRL using FDA’s formal dispute resolution process, and FDA granted its appeal in October 2019. The company resubmitted the NDA in December 2019. The class 1 resubmission carried a 20 February goal date.

Competition may soon be coming, though. Heron Therapeutics Inc. combines a low dose of meloxicam with bupivacaine in its product HTX-011, an extended-release local anesthetic for postoperative pain control that holds a breakthrough therapy designation (BTD) from FDA. Heron resubmitted the NDA in September 2019 after receiving a CRL earlier in the year, on 30April, citing issues relating to chemistry, manufacturing and controls and non-clinical information. (Also see "Keeping Track: US FDA, Industry Roar Into Fourth Quarter With Bevy Of Regulatory Announcements" - Pink Sheet, 5 Oct, 2019.)

The user fee goal for HTX-011 has been extended from 26 March to 26 June, Heron announced on 19 February, calling the extension “very disappointing.”

Heron reported that the contract manufacturing site for HTX-011 “has been reinspected by the FDA with no Form 483 observations issued and with a recommendation by the FDA inspector for approval of the site.”

Twirla’s Third Review Cycle Is The Charm

The FDA’s 14 February 2020 approval of Agile Therapeutics Inc.’s transdermal contraceptive patch comes nearly eight years and two complete response letters after the NDA was submitted in April 2012.

Twirla, a weekly patch delivering a 30mcg daily dose of ethinyl estradiol with a 120mcg daily dose of the progestin levonorgestrel, is indicated for use in women of reproductive potential with a BMI <30 kg/m2. Twirla is contraindicated for women with a BMI ≥ 30, who saw “reduced effectiveness” and “may have a higher risk” of venous thromboembolism (VTE) compared with women with a lower BMI, labeling explains.

A limitation of use statement in the indication advises prescribers to “consider Twirla’s reduced effectiveness in women with a BMI > 25 to < 30 kg/m2 before prescribing.”

The agency appears to have listened to the advisory committee after a 30 October 2019 meeting where advisors voted 14-1, with one abstention, to recommend approval despite a scathing FDA review of the NDA. (Also see "Twirla Gets Strong Advisory Cmte. Endorsement Even After US FDA Pans Application" - Pink Sheet, 30 Oct, 2019.)

Labeling presents data on pregnancy rates broken down by categories – BMI of up to 25, of 25 up to 30, and of 30 or more – as well as in a graph showing estimated pregnancy rates in Twirla patients as BMI increases. The presentation follows the advice of advisory committee members including Sally Hunsberger, a mathematical statistician in the National Institute of Allergy and Infectious Disease's Division of Clinical Research, who recommended that the label include "a curve with confidence intervals, not just cut points of obese or non-obese."

The Twirla approval comes with a post-marketing requirement for a controlled, non-interventional, prospective, observational cohort study comparing the risk of fatal and non-fatal VTE and arterial thromboembolism (ATE) in new Twirla users, compared primarily with new users of oral combined hormonal contraceptives and secondarily with new users of Mylan NV’s Xulane (ethinyl estradiol and norelgestromin), a branded generic weekly transdermal contraceptive patch equivalent to Johnson & Johnson’s Ortho Evra.

Braintree Notches An NME

FDA approved Braintree Laboratories Inc.’s Pizensy, an osmotic laxative for treatment of chronic idiopathic constipation (CIC) in adults, on 12 February. Pizensy is an oral solution formulation of the sugar alcohol lactitol, which is also used as a very low-calorie sweetener – but its use as a sugar replacement has been limited in use by side effects, notably diarrhea.

Pizensy is the first use of lactitol as a drug, so it is considered a new molecular entity. Braintree nonetheless used the 505(b)(2) NDA pathway allowing use of information from studies not conducted by or for the applicant. The NDA was based on two pivotal controlled trials, one testing Pizensy against placebo and the other against lubiprostone, with support from what labeling calls published studies “of varying design describing the efficacy of lactitol in increasing the frequency of bowel movements during short-term treatment of less than 4 weeks in patients with symptoms of CIC.”

Braintree, a gastrointestinal specialty company, became part of privately-held Sebela Pharmaceuticals in mid-2018.

Keytruda Six-Week Dosing Regimen Must Wait

FDA has issued a complete response letter for Merck’s supplemental BLAs for a new, less frequent dosing regimen for PD-1 inhibitor Keytruda (pembrolizumab), the company announced 18 February.

The sBLAs would add a 400mg dose infused over 30 minutes every six weeks (Q6W) in multiple cancers, based on “pharmacokinetic modeling and simulation data,” Merck said. Keytruda is currently indicated for adults as a 200mg dose infused over 30 minutes every three weeks.

The shorter regimen has been approved in Europe for nearly a year. (Also see "EU & US At Odds Over Merck’s Keytruda " - Pink Sheet, 20 Feb, 2020.)

Tazverik Strives For Second Indication On Heels Of Its First

The FDA has assigned an 18 June 2020 priority review user fee goal for a new indication for Epizyme’s methyltransferase inhibitor Tazverik (tazemetostat) for treatment of relapsed or refractory follicular lymphoma (FL) patients who have received at least two prior lines of systemic therapy.

Tazverik only recently cleared FDA for its first indication, to treat a rare subtype of soft tissue sarcoma, epithelioid sarcoma, in patients 16 and older who are ineligible for complete resection. FDA granted accelerated approval on 23 January. (Also see "Keeping Track: Approvals For Tazverik And Tepezza, Priority Reviews For Belantamab Mafodotin And Lynparza" - Pink Sheet, 25 Jan, 2020.)

Epizyme is also seeking accelerated approval for the follicular lymphoma sNDA, which is based on Phase II data showing clinical benefit in 45 patients with EZH2 activating mutations and 54 patients with wild-type EZH2.

The company is already conducting the safety run-in portion of an adaptive Phase Ib/III trial that is designed to support full approval of Tazverik for FL, and expects to start the efficacy portion in 2020. The confirmatory trial will evaluate Tazverik in combination with Revlimid and Rituxan (the chemo-free “R2” regimen) in second-line or later FL, Epizyme said, and is expected to enroll 500 patients stratified by EZH2 mutation status.

Tecentriq Bids To Go it Alone In First-Line NSCLC

Genentech is looking to extend Tecentriq’s presence in earlier stage lung cancer patients with an sBLA for first-line monotherapy in advanced non-squamous and squamous non-small cell lung cancer (NSCLC) patients who do not have EGFR or ALK mutations and who do have high PD-L1 expression (TC3/IC3 wild-type), as determined by PD-L1 biomarker testing.

The sBLA has a 19 June priority review user fee goal date.

The first-line monotherapy indication rests on the Phase III IMpower110 study, which compared Tecentriq monotherapy with chemotherapy -- cisplatin or carboplatin and pemetrexed or gemcitabine – in 572 PD-L1-selected, chemo-naïve NSCLC patients without ALK or EGFR mutations.

Patients in IMpower110 receiving Tecentriq monotherapy saw a 7.1 month improvement in overall survival compared with chemotherapy, Genentech reported.

Padcev/Keytruda Combo Earn BTD In First-Line Bladder Cancer

Seattle Genetics and Astellas announced the second breakthrough therapy designation awarded to the anti-Nectin 4 antibody-drug conjugate Padcev (enfortumab vedotin-ejfv) on 19 February, providing a boost to the clinical program to bring Padcev to earlier-stage bladder cancer patients.

The new BTD covers Padcev in combination with Merck's PD-1 inhibitor Keytruda (pembrolizumab) for treatment of patients with unresectable locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy in the first-line setting.

Padcev earlier received a BTD, and then approval on 18 December 2019, for adults with locally advanced or metastatic urothelial cancer who have previously received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. (Also see "Keeping Track Of The US FDA's Final Novel Approvals, CRLs Of 2019" - Pink Sheet, 5 Jan, 2020.)

The Padcev/Keytruda combo BTD is based on data from the ongoing Phase Ib/II EV-103 trial in cisplatin-ineligible first-line mUC patients. Interim EV-103 data from 45 patients reported 11 February 2020 found median progression-free survival of 12.3 months and a 12-month overall survival rate of 81.6%. The study found a confirmed objective response rate of 73.3%.

Astellas, Seattle Genetics and Merck announced a clinical collaboration in December 2019 to support a Phase III trial of the Padcev/Keytruda combination in previously untreated mUC. The EV-302 trial started in early 2020.