Keeping Track: A Quintet Of Novel Approvals

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

Here's your news in brief: It was by far the US Food and Drug Administration's busiest week of the year for novel drug approvals with five such products getting the green light from the agency: Genentech Inc.'s Rozlytrek (entrectinib), Celgene Corp.'s Inrebic (fedratinib), the Global Alliance for TB Drug Development's pretomanid, Harmony Biosciences LLC’s Wakix (pitolisant) and AbbVie Inc.’s Rinvoq (upadacitinib).

The Center for Drug Evaluation and Research's novel drug approval count has now jumped to 23 for the year.

The FDA also handed out a few expedited pathway designations. AstraZeneca PLC snagged a breakthrough therapy designation (BTD) for Calquence (acalabrutinib) in chronic lymphocytic leukaemia (CLL), while Daré Bioscience scored a qualified infectious disease product (QIDP) designation for its bacterial vaginosis (BV) candidate DARE-BV1.

Now here's your news in less brief:

Rozlytrek Approval Comes With Pazdur's Praise Of Pediatric Development Program

Barriers to enrollment of pediatric patients in clinical trials continue to persist despite legislative efforts to facilitate inclusion, but FDA's Oncology Center of Excellence director Rick Pazdur made clear with the FDA's approval of Genentech's Rozlytrek the agency would love to see sponsors make the effort. Especially early in the clinically development program.

A kinase inhibitor, Rozlytrek nabbed a 15 August accelerated approval to treat adults and pediatric patients 12 and older with neurotrophic tyrosine receptor kinase (NTRK) gene fusion, making it the third drug to get a tissue-agnostic indication from the FDA. Tissue-agnostic therapies are based on a common biomarker across different types of tumors rather than the place in the body the tumor originated.

Rozlytrek's label specifically covers patients with solid tumors who have an NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity and have progressed following treatment or have no satisfactory alternative therapy.

Padzur offered praise for the label's pediatric indication, which he noted relied on efficacy information obtained primarily from adults. He also pushed for other sponsors to follow suit.

"The FDA continues to encourage the inclusion of adolescents in clinical trials," Pazdur said. "Traditionally, clinical development of new cancer drugs in pediatric populations is not started until development is well underway in adults, and often not until after approval of an adult indication."

In 54 adult patients with solid tumors with an NTRK gene fusion across four clinical trials (the Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 pivotal trials with data from the Phase I/II STARTRK-NG study), Rozlytrek demonstrated an overall response rate (ORR) of 57%. Of the 31 patients who exhibited tumor shrinkage, 61% had their shrinkage persist for nine months or longer. Safety was demonstrated in 30 pediatric patients, Pazdur noted.

The approval also drew the attention of acting FDA commissioner Ned Sharpless. The former director of the National Cancer Institute, Sharpless said in the FDA's release that tissue agnostic therapies "have the potential to transform cancer treatment."

"We’re seeing continued advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine,” Sharpless said. "Using the FDA’s expedited review pathways, including breakthrough therapy designation and accelerated approval process, we’re supporting this innovation in precision oncology drug development and the evolution of more targeted and effective treatments for cancer patients."

In addition to accelerated approval, Rozlytrek garnered a slew of other regulatory benefits from the FDA for the NTRK indication, including a BTD, orphan drug status and a priority review.

Merck & Co. Inc.'s Keytruda (pembrolizumab) picked up the first tissue-agnostic cancer indication in the US in May 2017 with a supplemental indication for microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors. Loxo Oncology Inc. and Bayer AG’s Vitrakvi (larotrectinib) followed as the first novel tissue-agnostic approval with an FDA green light in November 2018 for solid tumors with an NTRK gene fusion regardless of tumor type. (Also see "Biomarker-Led Claim Is Small Step For Merck's Keytruda, Giant Leap For Cancer Indications" - Pink Sheet, 23 May, 2017.) and (Also see "Vitrakvi, Daurismo Approvals Put US FDA On Brink Of Another Record " - Pink Sheet, 27 Nov, 2018.)

The FDA also awarded a full approval to Rozlytrek 15 August for adults with metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1-positive. The drug demonstrated a 78% ORR in 51 patients, with 5.9% of patients experiencing a complete response.

Genentech is pricing Rozlytrek at $17,050 per month for adults, but the price for NTRK gene fusion-positive pediatric patients is based on the dose. (Also see "Roche/Genentech Set Lower Rozlytrek Price To Catch Up With Bayer’s Vitrakvi" - Scrip, 15 Aug, 2019.)

Inrebic Secures MF Indication Similar To Jakafi's, But With Black Box

In becoming the second FDA-approved myelofibrosis (MF) drug, Celgene's Inrebic won a similar indication to that in the label of Incyte Corp.'s Jakafi (ruxolitinib).

The agency cleared Inrebic, a JAK2 inhibitor, on 16 August to treat adults with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF. Jakafi's indication appears to be slightly broader, covering all intermediate and high-risk adults with MF.

Celgene has noted that some of the patients in the single-arm, open-label Phase II JAKARTA2 trial were diagnosed with intermediate-1 risk MF, although the randomized, double-blind, placebo-controlled Phase III JAKARTA trial only included intermediate-2 and high-risk primary MF subjects.

Importantly, the company did manage to get a front-line indication, as labeling does not restrict its use to patients who have relapsed on, or are refractory/intolerant, to Jakafi. In JAKARTA, 37% of patients treated with the now-labeled 400 mg daily dose of Inrebic experienced a 35% reduction from baseline in spleen volume at the end of cycle 6 (week 24) versus just 1% of placebo recipients. (Also see "Keeping Track: Accelerated Approval For Tecentriq And A Burst Of Filings And Submissions" - Pink Sheet, 10 Mar, 2019.)

But cutting against Inrebic is the inclusion of a boxed warning in its label for encephalopathy, including Wernicke's encephalopathy. Serious cases were reported in 1.3% of patients treated with Inrebic in clinical trials, while 0.16% of patients experienced fatal cases.

"Assess thiamine levels in all patients prior to starting Inrebic, periodically during treatment, and as clinically indicated," the black box states. "Do not start Inrebic in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue Inrebic and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize."

Conversely, Jakafi, which was first approved in 2011, does not contain a boxed warning in its label.

Pazdur commented in the agency's release that Inrebic "provides another option for patients" with MF.

Approval for Inrebic was an important box for Celgene to check ahead of its merger with Bristol-Myers Squibb Co., as the drug was one of five Celgene products that have been touted in justifying the big purchase. (Also see "Celgene Gives Reassurances That Key Products And Programs Remain On Track" - Scrip, 31 Jan, 2019.)

Two Ongoing Trials Highlight Pretomanid Postmarketing Requirements

The TB Alliance will have to complete a series of postmarketing requirements as part of its FDA approval for the non-profit's pretomanid regimen for tuberculosis (TB).

The FDA backed pretomanid 14 August in combination with Janssen Pharmaceutical Cos.'s Sirturo (bedaquiline) and Pfizer Inc.'s Zyvox (linezolid) for the treatment of adults with pulmonary extensively drug resistant (XDR), treatment-intolerant or nonresponsive multidrug-resistant (MDR) TB. (See sidebar.)

Two of the TB Alliance's postmarketing requirements include ongoing clinical trials to assess a hepatotoxicity signal. One is the Phase III ZeNix trial "to evaluate various doses and treatment durations of linezolid plus bedaquiline and Pretomanid Tablets for treatment of extensively drug-resistant pulmonary tuberculosis," according to the approval letter.

Meanwhile, the Phase II/III SimpliciTB trial will evaluate "Pretomanid Tablets, bedaquiline, moxifloxacin, and pyrazinamide for treatment of drug-resistant pulmonary tuberculosis," the approval letter adds.

ZeNix and SimpliciTB are scheduled for completion by March 2023 and June 2023, respectively.

The approval letter also lists five more minor postmarketing requirements, including studies to evaluate the pharmacokinetics and safety in subjects with renal impairment and subjects with hepatic impairment.

Harmony Wakix Is First Narcolepsy Therapy That Isn’t A Controlled Substance

FDA approval on 14 August made Harmony Biosciences’ Wakix the “first and only treatment approved for patients with narcolepsy that is not scheduled as a controlled substance,” the company stated. Unlike available (and scheduled) psychostimulants available for narcolepsy, Wakix works to “increase the synthesis and release of histamine, a wake-promoting neurotransmitter in the brain,” Harmony explained.

Wakix is indicated for treatment of excessive daytime sleepiness (EDS) in adults with narcolepsy.

The indication does not address occurrence of cataplexy, another common symptom in narcolepsy patients, and one that is not well-addressed by psychostimulant medicines. Pitolisant was awarded a BTD for treatment of cataplexy associated with narcolepsy in May 2018. (Also see "Keeping Track: Rebuff Of Iclaprim Creates Early Pileup Of CRLs For Novel Drugs" - Pink Sheet, 18 Feb, 2019.)

The Phase III Wakix clinical trials, HARMONY and HARMONY 1bis, enrolled patients with or without cataplexy, according to labeling. Nonetheless, cataplexy, which is characterized by sudden temporary loss of muscle tone, was common. In the pivotal trials, HARMONY and HARMONY 1bis, a history of cataplexy was recorded for 80% and 75% of the clinical trial population, respectively.

EDS was the primary endpoint for both HARMONY trials, a measured by the least square mean final Epworth Sleepiness Scale (ESS) score compared to placebo after an eight-week treatment period. The studies randomized a total of 261 patients to Wakix, placebo or active control with modafinil.

The HARMONY1 and 1bis trials were sponsored by Bioprojet, the French company that developed the drug and has marketed Wakix in Europe, where it received European Medicines Agency approval in 2016. According to the US clinicaltrials.gov database, Bioprojet also sponsored HARMONY2 and HARMONY CTP Phase III trials that used measurements of cataplexy attacks as the primary endpoint. Harmony licensed US development and marketing rights from Bioproject in 2017. (Also see "Harmony Biosciences Raises $270m; Acquires US Rights To Narcolepsy Drug " - Scrip, 6 Oct, 2017.)

AbbVie Invokes Data Depth, Breadth In Rinvoq Label

AbbVie’s investment in a priority review voucher (PRV) for its Janus kinase inhibitor Rinvoq paid off with an approval on 16 August – four months ahead of the December user fee goal date that the drug would have had under the standard review absent the PRV.

Rinvoq is indicated to treat moderate to severely active rheumatoid arthritis in adults who have had an inadequate response or intolerance to methotrexate. The drug may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying anti-rheumatic drugs (DMARDs), labeling notes, but use with “other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.”

The indication rests on five studies with almost 4,400 patients in what AbbVie calls “one of the largest registrational Phase III program in rheumatoid arthritis.” The SELECT trials included patients “who failed or were intolerant to biologic disease-modifying anti-rheumatic drugs and who were naïve or inadequate responders to methotrexate,” AbbVie said, noting that “Rinvoq is not indicated for methotrexate-naïve patients.” Some of the studies included both the approved 15 mg dose and an unapproved 30 mg dose of upadacitinib.

“Across the SELECT Phase III studies, Rinvoq met all primary and ranked secondary endpoints,” AbbVie stated. “Patients treated with Rinvoq 15 mg, alone or in combination with cDMARDs, achieved higher ACR [American College of Rheumatology] response rates compared to MTX monotherapy or placebo, respectively, at the primary efficacy timepoint,” labeling summarized.

In addition to measuring clinical response with ACR scores, AbbVie highlighted upadacitinib data on clinical remission “even without methotrexate,” reporting that approximately 30% of patients in SELECT-COMPARE and SELECT-MONOTHERAPY trials achieved clinical remission compared to 6% and 8% of placebo and methotrexate comparator patients. In SELECT-EARLY, 36% of Rinvoq and 14% of MTX patients achieved clinical remission.

“Durable remission rates were observed up to week 26,” AbbVie said. “Forty-eight percent of patients treated with Rinvoq alone in SELECT-EARLY and 41% of patients treated with Rinvoq plus methotrexate in SELECT-COMPARE achieved clinical remission at weeks 24 and 26, compared to 9% with placebo plus methotrexate and 18% with methotrexate, respectively.”

Rinvoq labeling carries a black box, akin to the warnings on labeling for the other Janus kinase inhibitors approved for rheumatoid arthritis, Eli Lilly & Co.'s Olumiant (baricitinib) and Pfizer’s Xeljanz (tofacitinib). The black box warns of risk of serious infections, malignancy and thrombosis.

With potential competition from Gilead Sciences Inc.’s filgotinib moving up rapidly – Gilead plans to submit its JAK1 inhibitor for RA in 2019 – AbbVie is hoping to establish Rinvoq in the market quickly. Rinvoq will be available in the US in late August 2019, AbbVie said. At the same time, the company is working to deepen its clinical trial evidence, including longer-term data with an eye on remission. (Also see "AbbVie Ups The Ante For Upadacitinib At EULAR" - Scrip, 17 Jun, 2019.)

Extra Speedy Review Possible For Calquence In CLL Following Late-Stage BTD

A fast FDA review might be in the cards for AstraZeneca's Bruton tyrosine kinase inhibitor Calquence after landing a late-stage BTD for adults with CLL.

AstraZeneca announced the BTD, the company's 10^th overall, on 14 August, just months after it released results from the pivotal Phase III ELEVATE-TN and ASCEND trials, in which Calquence demonstrated statistically significant improvements in progression-free survival (PFS) versus active comparators (Also see "AZ’s Calquence Hits Endpoint In Second CLL Phase III Study" - Scrip, 6 Jun, 2019.)

With the BTD coming after the completion of clinical development, the benefits of the pathway will be concentrated in the submission and review phases. The company is planning regulatory submissions later this year.

Calquence first picked up an accelerated approval in 2017 for the second-line or greater treatment of adults with mantle cell lymphoma. (Also see "Keeping Track: New MCL Treatment Calquence, Submissions Galore, And A Breakthrough Designation For GSK" - Pink Sheet, 3 Nov, 2017.)

Daré Touts Thermosetting Hydrogel Formulation Of BV Drug With QIDP Score

Daré reeled in a QIDP designation for its thermosetting hydrogel formulation of the lincosamide antibacterial clindamycin phosphate, DARE-BV1, which the company believes can help improve delivery of the drug to treat BV in women.

The clinical-stage biopharma describes the treatment as "a viscous liquid designed to undergo solution to gel (sol-to-gel) transition using body temperature as the trigger."

"This property allows the product to be more easily directed to the site of infection," the company added. "Pre-clinical studies demonstrated that, by the process of 'reverse thermal gelation,' the viscosity of the base matrix increases up to four-fold upon reaching normal body temperature when compared to its viscosity at room temperature."

According to data from a Phase II proof of concept study presented at the 2019 Annual Meeting of the Infectious Diseases Society for Obstetrics and Gynecology on 9 August, DARE-BV1 demonstrated an 86% clinical cure rate in evaluable subjects (24 of 28 patients) at the test-of-cure visit (day 7-14). In a 12 August statement announcing the QIDP, Daré President and CEO Sabrina Martucci Johnson noted that clinical cure rates of currently approved BV products range from 37%-68%.

Daré added that it expects to launch a Phase III study in roughly 250 women in the fourth quarter of 2019, which the company believes would be sufficient to support an approval.