Keeping Track: Rebuff Of Iclaprim Creates Early Pileup Of CRLs For Novel Drugs

The latest drug development news and highlights from our US FDA Performance Tracker.

The US FDA's Center for Drug Evaluation and Research (CDER) approved its third novel product of the year with a Feb. 13 blessing for Novartis AG's Egaten (triclabendazole), which also resulted in a priority review voucher for the Swiss drug giant. (See sidebar for related story.)

But the weak start for approvals this year continued to drag on, as the agency also issued its third complete response letter (CRL) for a novel product in 2019. The recipient was Motif Bio PLC's antibiotic iclaprim, which continues to have issues clearing FDA's review hurdles.

Nevertheless, a steady stream of breakthrough therapy designations (BTDs) continue to roll in, with the most recent going to CymaBay Therapeutics Inc.'s primary biliary cholangitis (PBC) therapy seladelpar.

Speaking of BTDs, Harmony Biosciences LLC’s breakthrough-designated narcolepsy treatment pitolisant is positioned for a mid-August approval decision from FDA after reeling in priority review status. Set for June action with priority reviews, meanwhile, are two separate supplemental biologics license applications (sBLAs) for renal call carcinoma treatments from Pfizer Inc./Merck KGAA and Merck & Co. Inc..

Now, here's your news in less brief:

Embattled Iclaprim Joins Novel CRL Pileup

While Egaten came in as the third novel approval of 2019, so did the year's third rebuff of a novel drug. The victim this time was the embattled acute bacterial skin and skin structure infections (ABSSSI) antibiotic iclaprim, which received a second CRL after seemingly battling back from a checkered regulatory history.

In a Feb. 14 announcement, the sponsor Motif said that the agency is calling for additional data to evaluate the risk of liver toxicity. The company said it will request a meeting with FDA to further discuss the deficiencies.

Iclaprim first ran into an FDA stop sign in 2008 when it was sponsored by the now-bankrupt Arpida Ltd., as FDA requested additional data to demonstrate non-inferiority to the then-comparator linezolid. An advisory panel also raised concerns about a series of safety issues, such as QT prolongation and bone marrow suppression. (Also see "US panel knocks efficacy of Arpida's iclaprim for skin infections" - Scrip, 21 Nov, 2008.)

But Motif appeared to right the ship by conducting clinical trials using a different dosage and a narrower definition of infections suitable for study. The company also used vancomycin as a comparator rather than linezolid, and the result was two successful Phase III trials. (Also see "Motif A Step Closer To Succeeding With Iclaprim After Phase III Success" - Scrip, 18 Apr, 2017.) and (Also see "Motif Bio Poised For Filings As Iclaprim Succeeds Again In Phase III" - Scrip, 4 Oct, 2017.)

Motif is now faced with commercial uncertainty following the setback. The company said in its press release that it had $12.3 million in cash and $15 million in debt at the end of 2018, adding that, "The Company is financed into the second quarter of 2019 but will need to raise capital in the near term."

More broadly, it's been a rough start to the year for novel product developers, who have so far received as many CRLs as they have approvals just midway through February. Iclaprim joined Immunomedics Inc.'s sacituzumab govitecan and Alkermes PLC's ALKS 5461 (samidorphan and buprenorphine) as the novel products to get rejected so far in 2019. (Also see "Keeping Track: FDA's Review Actions Carry On During Shutdown" - Pink Sheet, 20 Jan, 2019.) and (Also see "Keeping Track: FDA Approves First Generic Advair, But Alkermes And Sunovion Land CRLs" - Pink Sheet, 2 Feb, 2019.)

In 2018, conversely, it took the Center for Drug Evaluation and Research (CDER) until May to issue its first CRL of the year for a novel drug, and the second didn't come until June. (Also see "Achaogen Questioning Whether Others Will Pursue LPAD Pathway After Zemdri Misses Out " - Pink Sheet, 26 Jun, 2018.)

Alkaline Phosphatase Reductions Land BTD For CymaBay's PBC Treatment

The primary biliary cholangitis (PBC) landscape has no shortage of candidates, but CymaBay's seladelpar looks to be the first to land a BTD for the chronic liver disease, building on FDA's endorsement of an alkaline phosphatase (AP) reduction as a surrogate endpoint.

Specifically covering early-stage PBC, seladelpar's BTD is based on data from an ongoing Phase II trial (CB8025-21629), "which indicates that seladelpar may demonstrate substantial improvement over existing therapy based on a reduction in alkaline phosphatase," CymaBay said in a Feb. 15 announcement.

According to the data presented at The Liver Meeting 2018 in November, patients receiving 5 mg/10 mg or 10 mg doses of the drug experienced mean decreases in AP of 47% and 46%, respectively. Additionally, 59% of 5 mg/10 mg patients and 71% of 10 mg patients achieved the key secondary outcome of composite responder rate at week 52, defined as "a patient with AP <1.67 x [upper limit of normal], ≥15% decrease in AP, and total bilirubin ≤[upper limit of normal]."

FDA first gave the thumbs up to the use of a reduction in the level of AP as a surrogate endpoint for PBC when the agency granted accelerated approval to Intercept Pharmaceuticals Inc.'s Ocaliva (obeticholic acid) in 2016. (Also see "Keeping Track: FDA Approval Activity Heats Up With Ocaliva, Zinbryta And More" - Pink Sheet, 6 Jun, 2016.) and (Also see "Full Data For Intercept's Liver Disease Drug Show Rivals Where To Differentiate" - Scrip, 18 Aug, 2016.) The only other treatment for PBC cleared in the US is Amneal Pharmaceuticals LLC's URSO Forte (ursodeoxycholic acid), which was approved in 1997.

However, there is a rich pipeline of candidates in Phase II or later, and the BTD likely positions seladelpar at the front of the pack. (Also see "Genkyotex Plans 'Solo' Pivotal Trials After Lead Product Hits Phase II PBC Targets" - Scrip, 9 Nov, 2018.) Seladelpar, an orally administered peroxisome proliferator-activated receptor delta agonist, is now being evaluated in the pivotal Phase III ENHANCE trial, which is evaluating composite responder rate as the primary endpoint.

The other candidate in Phase III development is Alibero's A4250, according to Biomedtracker, whose late-stage trial was initiated in 2018. (Also see "Pipeline Watch: Phase III Progress With Burosumab, Duvelisib And Galcanezumab" - Scrip, 18 May, 2018.)

Harmony’s Pitolisant Aims To Wake Up Narcolepsy Market

Harmony Biosciences’ new drug application (NDA) for pitolisant seeks a broad claim for treatment of both excessive daytime sleepiness (EDS) and cataplexy symptoms of narcolepsy in adults. FDA assigned the NDA priority review, the company announced Feb. 12, putting the likely user fee goal in mid-August.

Pitolisant holds a BTD for the cataplexy claim in narcolepsy patients. Up to two-thirds of narcolepsy patients have cataplexy, an intrusion of elements of REM sleep state into wakefulness that is characterized by sudden temporary loss of muscle tone, Harmony reported. Pitolisant is the first, and to date only, product to receive a BTD for sleep medicine. (Also see "Keeping Track: Thumbs Up For Doptelet And Palynziq, Thumbs Down For Methylene Blue MMX And Meloxicam" - Pink Sheet, 28 May, 2018.)

FDA is reviewing another new molecular entity (NME) for narcolepsy patients, Jazz Pharmaceuticals PLC’s solriamfetol, but it is seeking an indication for EDS only in both narcolepsy and obstructive sleep apnea patients. Solriamfetol, a dopamine and norepinephrine reuptake inhibitor, is receiving standard review; it has a March 20, 2019 user fee goal after a three-month extension.

Pitolisant would be the first drug in the histamine 3 (H3) receptor antagonist/inverse agonist class. “It enhances the activity of histaminergic neurons in the brain that function to improve a patient’s wakefulness and inhibit attacks of cataplexy,” Harmony explained. The company, which was founded in late 2017 to focus on rare CNS disorders, licensed pitolisant from Bioprojet .

Bioprojet has marketed pitolisant as Wakix in Europe following its 2016 EMA approval for use in narcolepsy patients, with or without cataplexy. The market experience appears to have helped boost the safety database: Harmony reported that the NDA included safety data in over 1,500 patients from multiple populations. The clinical program submitted in the NDA includes more than 300, who were treated for as long as five years. In the US, pitolisant has been available through the PEACE Expanded Access Program for EDS associated with narcolepsy, with or without cataplexy.

Two Inlyta Combos Set For Mid-Year Showdown In RCC

Two additional first-line renal cell carcinoma (RCC) treatments are positioned to hit the market this June, as FDA awarded priority review status to two different Inlyta (axitinib) combinations.

The first went to Pfizer and Merck KGaA, which are seeking a supplemental approval for the tyrosine kinase inhibitor in combination with Pfizer's PD-L1 inhibitor Bavencio (avelumab). FDA awarded a June 2019 user fee goal date, the companies said in a Feb. 11 announcement. In the pivotal Phase III JAVELIN Renal 101 study, the breakthrough-designated combination achieved a median progression-free survival (PFS) of 13.8 months compared with 7.2 months for patients on Pfizer's Stutent (sunitinib). (See sidebar for related story.)

JAVELIN Renal 101 will continue to complete the final analysis for overall survival (OS), the other primary endpoint, the companies added.

However, coming in strong with OS data on hand is Merck's sBLA, which scored a priority review of its own for Keytruda (pembrolizumab) in combination with Inlyta for the first-line treatment of RCC. The combination, which has a user fee goal date of June 20, demonstrated a statistically significant improvement in OS and PFS compared with Sutent in the Phase III KEYNOTE-426 trial. (Also see "Pfizer Well-Placed To Lead First-Line Advanced RCC Market" - Scrip, 30 Oct, 2018.) Merck will present the data Feb. 16 at the 2019 Genitourinary Cancers Symposium in San Francisco. The sBLA will also include supporting data from the Phase Ib KEYNOTE-035 trial, the company added.

But it wasn't Keytruda's only priority status for the week. Merck also announced that its PD-1 inhibitor will get an expedited review in combination with platinum and 5-fluorouracil (5-FU) chemotherapy for the first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).

The sBLA will be supported by in part by data from the 882-patient Phase III KEYNOTE-048 trial, where Ketruda demonstrated a significant improvement in OS both as a monotherapy and in combination with chemotherapy compared to the EXTREME regimen, the current standard of care. (Also see "Merck Recasts Keytruda Regulatory Strategy In Head & Neck Cancer To Capitalize On KEYNOTE-048" - Pink Sheet, 30 Oct, 2018.) The user fee goal date for the sBLA is June 10.

Janssen Adds Dosing Flexibility To Darzalex Label

Janssen Pharmaceutical Cos. is touting new flexibility in the infusion of its multiple myeloma drug Darzalex (daratumumab), as the Johnson & Johnson unit has added a split-dosing regimen to the label allowing health providers the option to separate the first infusion over two consecutive days.

"The first infusion of Darzalex is an important first step in a patient's course of therapy, and this approval provides added flexibility for how patients may receive initial treatment," Craig Tendler, vice president of clinical development and global medical affairs at Janssen, said in a Feb. 12 statement. 

In the Phase Ib EQUULEUS trial supporting the Feb. 8 approval, pharmacokinetic concentrations of Darzalex were similar in patients who received a split dose versus those who received a single infusion.

"Splitting the first dose of DARZALEX over two consecutive days effectively reduced the duration of the first infusion and resulted in a similar rate and pattern of infusion reactions," Janssen explained.

Separately, Janssen waiting on an FDA decision on a Darzalex supplemental biologics license application (sBLA) filed under the Real-Time Oncology Review (RTOR) pilot program, which would add an indication for use in combination with Celgene Corp.'s Revlimid (lenalidomide) and the corticosteroid dexamethasone for the treatment of newly diagnosed multiple myeloma patients who are not candidates for high dose chemotherapy and autologous stem cell transplant (HSCT).  (Also see "Keeping Track: Bad News For Bristol And Lilly, Good News For TG Therapeutics" - Pink Sheet, 27 Jan, 2019.)