Keeping Track: US FDA, Industry Roar Into Fourth Quarter With Bevy Of Regulatory Announcements

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

The fourth quarter of 2019 kicked off with no shortage of drug development announcements from the US Food and Drug Administration and industry. Here's your news in brief:

The FDA issued a supplemental approval Gilead Sciences Inc.'s Descovy (emtricitabine 200 mg and tenofovir alafenamide 25 mg), making it the second drug with an indication for HIV-1 pre-exposure prophylaxis (PrEP) in at-risk adults and adolescents.

But Descovy was just one of several drugs to earn supplemental indications, as Novartis AG's Entresto (sacubitril and valsartan) and Janssen Pharmaceutical Cos.'s Invokana (canagliflozin) also expanded their labels.

Sponsors were especially busy on the submissions front. Nippon Shinyaku Co. Ltd.'s viltolarsen submission was the most notable, as the drugmaker is looking to beat out Sarepta Therapeutics Inc. for first FDA approval of an exon 53-skipping Duchenne muscular dystrophy (DMD) drug.

In terms of resubmissions, Heron Therapeutics Inc. and IntelGenyx are each taking another crack at am approval for their respective products HTX-011 (bupivacaine and meloxicam) and Rizaport (rizatriptan benzoate).

Janssen also nabbed a breakthrough therapy designation (BTD) for Zejula (niraparib) for a BRCA1/2 gene-mutated metastatic castration-resistant prostate cancer (mCRPC) indication.

The week appeared to have one blemish with a complete response letter (CRL) for AstraZeneca PLC, which failed to garner approval for its chronic obstructive pulmonary disease (COPD) treatment PT010 (budesonide/glycopyrronium/formoterol fumarate).

Now, here's your news in less brief:

Gilead Descovy PrEP Approval In Men Comes With Post-Marketing Commitment For Women

The FDA’s 3 October approval of Gilead’s Descovy for HIV PrEP follows the advice of the agency’s advisory committee, which recommended limiting the indication to men and transgender women who have sex with men (MSM/TGW). The new indication reads for “at risk adults and adolescents weighing at least 35kg for pre-exposure prophylaxis (PrEP) to reduce the risk of HIV-1 from sexual acquisition, excluding individuals at risk from receptive vaginal sex.”

The indication reflects the population of the pivotal DISCOVER trial, which enrolled 5,387 MSM/TGW subjects at risk of HIV-1 infection. Gilead had pursued an extrapolation strategy to extend the indication to cisgender women; the company told the 7 August advisory committee meeting that cisgender women were not included because of low HIV incidence rates in women at the DISCOVER sites. (Also see "Gilead, US FDA Ponder Innovative Designs For Descovy HIV Prevention Study In Women" - Pink Sheet, 12 Aug, 2019.)

A postmarketing commitment (PMC) directs Gilead to conduct a randomized comparative trial examining the safety and efficacy of Descovy PrEP in cisgender women and adolescent girls weighing at least 35kg who are at risk of sexually acquired HIV-1. (See sidebar.)

“The trial should employ two distinct methods to estimate the background HIV-1 incidence rate as external controls,” FDA’s approval letter states. The final protocol for the PMC study is due in May 2020; the trial is expected to complete in December 2024.

The postmarketing trial should include an arm providing Gilead’s Truvada (emtricitabine/tenofovir disoproxil fumarate), the FDA said. Truvada, the only other antiretroviral with a PrEP indication, is not limited by gender.

Truvada also served as the control for DISCOVER. Gilead is working to convert patients from Truvada to Descovy in advance of Teva’s generic version of emtricitabine/TDF, which can be marketed in the US starting in September 2020 – a deadline that may have spurred Gilead to use a priority review voucher for the supplemental new drug application, bringing the FDA review to six months instead of the 10 months it would have received as standard review.

The advisory committee also discouraged Gilead’s attempts to use DISCOVER to show advantages for Descovy over the older Truvada. (Also see "Gilead’s Marketing Of Descovy For HIV Prevention Should Not Suggest Superiority To Truvada" - Scrip, 9 Aug, 2019.) On the primary outcome of DISCOVER, the incidence of documented HIV-1 infection per 100 person-years, Descovy patients had an 0.16 rate of HIV infections per 100 person-years, labeling shows. Truvada patients had an 0.34 rate. Nonetheless, the DISCOVER findings show that “Descovy was similar to Truvada in reducing the risk of acquiring HIV-1 infection,” FDA said.

Gilead has long touted the renal and bone safety advantages of tenofovir alafenamide (TAF) over TDF. Labeling notes the superior lab measurements, but states the long-term clinical significance is not known.

Sarepta's Vyondys 53 Whiff Looks Costly As Nippon Shinyaku Submits Viltolarsen

Sarepta's failure to score an approval for its exon 53-skipping DMD drug Vyondys 53 (golodirsen) might end up being costly for the company, as Japanese drugmaker Nippon Shinyaku has brought a new such candidate to the FDA.

Nippon Shinyaku announced 2 October that it completed its rolling submission of an NDA for viltolarsen (NS-065/NCNP-01), which is also designed for the treatment of DMD amenable to exon 53 skipping. The drugmaker began the rolling submission in late 2018.

There is currently no FDA-approved drug for exon-53 skipping DMD. Vyondys 53 would have been the first, although Sarepta received a complete response letter (CRL) for the NDA in August. (Also see "Golodirsen Rebuff: Did Exondys 51 Review Strife Influence US FDA's Decision?" - Pink Sheet, 20 Aug, 2019.)

Viltolarsen, which carries a rare pediatric disease designation, orphan drug designation and fast track designation, could garner an approval by June 2020 if it receives a priority review. The timeline for the Vyondys 53 resubmission remains unclear, although Sarepta plans to meet with the FDA before the end of the year to discuss the application's deficiencies. (Also see "Golodirsen Rebuff: Did Exondys 51 Review Strife Influence US FDA's Decision?" - Pink Sheet, 20 Aug, 2019.)

Like Vyondys 53 and Sarepta's approved DMD drug Exondys 51 (eteplirsen), viltolarsen was evaluated in clinical development using the primary endpoint of a mean increase of dystrophin protein from baseline. Eight of the 16 patients in a US/Canada Phase II trial conducted by Nippon Shinyaku subsidiary NS Pharma Inc. received 40mg/kg of viltolarsen, while the other eight patients received 80mg/kg; the respective mean increases were 5.7% and 5.9%.

These mean increases are higher than those demonstrated by Exondys 51 (0.3%) and Vyondys 53 (1.019%). Although they didn't meet the 10% threshold advocated by Office of Drug Evaluation I director Ellis Unger, Biomedtracker analysts noted that that some patients did have increases of dystrophin protein to over 10% of normal.

Viltolarsen also doesn't appear to have any significant safety issues. There were no severe treatment-related events and no adverse events leading to treatment discontinuation observed during the Phase II study.

AstraZeneca Will Submit ETHOS Data Following PT010 CRL

The FDA declined to approve AstraZeneca's PT010 (budesonide/glycopyrronium/formoterol fumarate) for COPD, and the drugmaker said in a 1 October announcement that an NDA resubmission will include data from the Phase III ETHOS trial.

AstraZeneca initially submitted the NDA for PT010 (approved as Breztri Aerosphere in Japan) in the first quarter of 2019 only with data from Phase III trial KRONOS trial, as the ETHOS data were not yet available. In KRONOS, PT010 met eight of the nine primary lung function endpoints and also demonstrated a statistically significant 52% reduction in the rate of moderate or severe COPD exacerbations compared with AstraZeneca's own dual combination therapy Bevespi Aerosphere (glycopyrrolate and formoterol fumarate).

ETHOS, however, enrolled 8,500 patients, which is more than four times greater than the 1,900 enrolled patients in KRONOS. AstraZeneca announced results from ETHOS in August, noting that PT010 demonstrated a statistically significant reduction in the rate of moderate or severe exacerbations compared with Bevespi Aerosphere and the company's PT009 (budesonide/formoterol fumarate).

PT010 is a fixed-dose triple combination of the inhaled corticosteroid budesonide, the long-acting muscarinic agonist glycopyrronium and the long-acting beta2-agonist formoterol fumarate, delivered in a pressurized metered-dose inhaler.

The treatment is supposed to help AstraZeneca compete in the COPD space with GlaxoSmithKline PLC, which markets Trelegy Ellipta (fluticasone/umeclidinium/vilanterol) as a triple combination therapy for the disease. (Also see "Blow To AZ As FDA Rejects COPD Contender" - Scrip, 1 Oct, 2019.)

Six-Month Review Likely For Resubmitted HTX-011 NDA

Heron is expecting a six-month review for its breakthrough-designated, non-opioid pain drug HTX-011, which is back at the FDA after landing a CRL just over five months earlier.

The company announced 1 October that it resubmitted the NDA, which is seeking an approval for the management of postoperative pain with labeling reflecting a reduced need for opioids. (Also see "Keeping Track: FDA Starts November With A Bang" - Pink Sheet, 2 Nov, 2018.)

HTX-011, which combines an extended-release formulation of the local anesthetic bupivacaine with the anti-inflammatory meloxicam, was rejected by the FDA in April with the agency requesting, according to Heron, “additional CMC and non-clinical information." Company officials said at the time of the CRL that they felt the issues could have been addressed during the review cycle. (Also see "Keeping Track: US FDA Approves Sanofi’s Dengvaxia, But Heron’s HTX-011 And Nabriva’s Contepo Fall Short" - Pink Sheet, 5 May, 2019.)

On 2 October, Heron announced results from top-line results from a Phase III study of HTX-011 in 51 patients undergoing total knee arthroplasty (TKA) surgery. Mean pain scores remained in the mild range through 72 hours post-surgery, median consumption of opioids was 4-5 pills of oxycodone and 75% of patients were discharged from the hospital without an opioid prescription, the company said.

Heron is using two Phase III studies in hernia repair and bunionectomy to support the HTX-011 NDA, noting that the positive TKA data "complement" those results.

IntelGenx Takes A Fourth Try At Rizaport Approval

IntelGenyx is refusing to strike out on its acute migraine treatment Rizaport. The company announced on 26 September that it resubmitted the NDA, marking the company's fourth swing at landing an approval.

An oral thin-film formulation of Merck & Co. Inc.'s 5-HT1 receptor agonist Maxalt (rizatriptan benzoate), Rizaport has already been the subject of two CRLs involving CMC issues. The first came back in 2014, while the second came earlier in 2019. (Also see "Keeping Track: Industry Channels Inner Gottlieb As Commissioner Departs US FDA" - Pink Sheet, 5 Apr, 2019.)

Sandwiched in between the CRLs was a refuse-to-file, which came when IntelGenyx tried to first resubmit the NDA in November 2017. (Also see "Keeping Track: US FDA Enters Year's Final Stretch With Tsunami Of Novel Approvals " - Pink Sheet, 1 Dec, 2018.)

Now the company is hoping to clear the review hurdle on its fourth try. IntelGenx CEO Horst Zerbe said in a statement that, “Over the past several months, we have been working diligently to address the FDA’s questions and resubmit this NDA in a timely manner.”

Psychiatric Emergencies Are Next Frontier For J&J’s Spravato

Johnson & Johnson is seeking a second breakthrough-designated indication for its Spravato (esketamine) nasal spray with an sNDA submission announced on 2 October for rapid reduction of depressive symptoms in adults with major depressive disorder (MDD) who have active suicidal ideation with intent.

The two pivotal trials supporting the sNDA, ASPIRE I and II, “are the first global clinical studies in this severely ill patient population, who are typically excluded from antidepressant treatment studies,” J&J said.

Spravato was introduced earlier this year after FDA approval on 5 March 2019 to treat treatment-resistant depression in adults in conjunction with an oral antidepressant. The treatment-resistant depression indication also holds a BTD; Spravato was the first approval in the treatment-resistant setting in 10 years. (Also see "Janssen’s Spravato Enters US Market With Enhanced REMS And Plans For A Monotherapy Trial" - Pink Sheet, 6 Mar, 2019.)

The psychiatric emergency setting placed constraints on the ASPIRE trial design that contributed to the trials’ failure to show a benefit in severity of suicidality, a key secondary endpoint that includes suicidal ideation and behavior. “In order to safely and ethically conduct the study in this vulnerable patient population, all patients were treated with the comprehensive [standard of care], which included initial hospitalization and a newly initiated and/or optimized antidepressant regimen,” J&J explained in its announcement of ASPIRE trial results in September. (Also see "J&J Looks To Expand Spravato Label To Suicidal Ideation" - Scrip, 10 Sep, 2019.)

Both the Spravato and placebo arms showed an improvement on the revised Clinical Global Impression of Severity of Suicidality (CGI-SS-R) at 24 hours after first dose, reflecting the “substantial beneficial effects of comprehensive SOC utilized in the clinical trial, including the immediate impact of inpatient psychiatric hospitalization in diffusing the acute suicidal crisis in patients in both treatment groups,” the company said.

The rapid reduction of depressive symptoms part of the proposed new indication is supported by the primary endpoint of ASPIRE I and II, the Montgomery-Åsberg Depression Rating Scale (MADRS) total score measured 24 hours after first study medication. The mean difference observed in reduction in depressive symptoms between the Spravato and placebo arms was 3.8 points in ASPIRE I and 3.9 points in ASPIRE II.

Spravato plus SOC’s effect on MDD symptoms was “apparent at four hours after first dose,” J&J said. The magnitude of difference was generally maintained through the 25-day double-blind period. In ASPIRE I, 54% of the Spravato patients achieved remission, defined as a MADRS score ≤ 12, at 25 days; 47% of the Spravato patients in ASPIRE II achieved remission.

GALAHAD Wins Niraparib A BTD In BRCA-Mutated Prostate Cancer

J&J's 2016 agreement to license Tesaro Inc.’s niraparib in prostate cancer is bearing fruit with a BTD for treatment of patients with BRCA1/2 gene-mutated mCRPC who have received prior taxane chemotherapy and androgen receptor (AR)-targeted therapy. Tesaro, now a part of GlaxoSmithKline, markets the PARP inhibitor as Zejula for ovarian cancer.

While BRCA mutations are more commonly associated with breast and ovarian cancers, “BRCA1/2 mutations are the most common DNA-repair gene defects (DRD) in patients with mCRPC,” J&J said.

The BTD rests on findings from the Phase II GALAHAD trial of mCRPC patients and DRD with disease progression on taxane and androgen receptor-targeted therapy, the company reported. Interim data from 165 patients in the ongoing study was presented at the ESMO congress on 29 September 2019, including 81 patients with biallelic DRD; only 46 of the biallelic DRD patients had BRCA1/2 mutations.

The BRCA1/2 patients posted an objective response rate (ORR) of 41% in the interim data, compared with 9% in the non-BRCA biallelic DRD patients on the primary endpoint.  A key secondary endpoint measured composite response rate, which incorporates ORR, conversion of circulating tumor cells and decline in prostate specific antigen. The CRR was 63% in the BRCA patients and 17% in the non-BRCA DRD patients.

While the GALAHAD Phase II study continues, J&J is also evaluating niraparib in in a broader prostate cancer population in the MAGNITUDE study in front-line mCRPC. MAGNITUDE is testing niraparib in combination with J&J’s Zytiga (abiraterone) and prednisone.

Entresto Adds Pediatric HF IndicationWith Assist From Adult Data

With the help of clinical trial data from adults, Novartis successfully tacked on a pediatric heart failure (HF) indication to the label of Entresto on 1 October.

A combination of the neprilysin inhibitor sacubitril and the angiotensin II receptor blocker valsartan, Entresto is now indicated for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients ages 1 and older. Labeling states that Entresto has demonstrated reductions in the cardiac biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP) and that the drug is expected to improve cardiovascular outcomes.

The approval is based on an analysis at 12 weeks from the 52-week PANORAMA-HF trial of 110 pediatric patients. Entresto recipients experienced a 44% reduction from baseline in NT-proBNP compared with a 33% reduction among patients receiving the active comparator enalapril (Merck's Vasotec).

These results, however, were boosted by data from Novartis' PARADIGM-HF study, which supported the approval of Entresto's initial indication to reduce the risk of cardiovascular death and hospitalization for HF in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. PARADIGM-HF studied 8,842 adult patients with symptomatic chronic heart failure and systolic dysfunction.

Labeling explains that although the differences among NT-proBNP reductions between the Entresto and enalapril groups were not statistically significant, "they were similar to or larger than what was seen in adults."

"Because Entresto improved outcomes and reduced NT-proBNP in PARADIGM-HF, the effect on NT-proBNP was considered a reasonable basis to infer improved cardiovascular outcomes in pediatric patients," labeling adds.

Invokana Adds Key Diabetic Nephropathy Indication

Janssen's sodium-glucose co-transporter 2 (SGLT2) inhibitor Invokana (canagliflozin) became the second drug approved with a diabetic nephropathy to
Sanofi's Avapro (irbesartan).

But the J&J unit explained that Invokana is now "the only type 2 diabetes medicine indicated to both treat diabetic kidney disease and reduce the risk of hospitalization for heart failure in patients with [type 2 diabetes] and [diabetic nephropathy]."

With the 27 September approval, Invokana specifically carries an indication to reduce the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria. (Also see "Keeping Track: Novartis Scores Big Ahead Of US Memorial Day With Approvals For Gene Therapy Zolgensma, Oncologic Piqray" - Pink Sheet, 26 May, 2019.)

Approval is supported by the Phase III CREDENCE study, which was stopped early after meeting the pre-specified criteria for efficacy. (Also see "J&J's Invokana Slows CKD Progression In Diabetes" - Scrip, 17 Jul, 2018.)

INBUILD Trial Produces Broad Ofev sNDA Submission

Boehringer Ingelheim International GmbH is eyeing the addition of broad range of progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF) to the label of its kinase inhibitor Ofev (nintedanib).

"Chronic hypersensitivity pneumonitis, autoimmune ILDs such as rheumatoid arthritis-associated ILD, systemic sclerosis-associated ILD (SSc-ILD), mixed connective tissues disease-associated ILD, sarcoidosis and idiopathic forms of interstitial pneumonias, i.e. non-specific interstitial pneumonia, and unclassified idiopathic interstitial pneumonia, are among these diseases," Boehringer said in a 30 September announcement.

The sNDA submission is supported by data from the Phase III INBUILD trial, where Ofev slowed lung function decline by 57% across the overall study population, as measured by the annual rate of decline in forced vital capacity (FVC) over 52 weeks. INBUILD enrolled a total of 663 patients with progressive fibrosing interstitial lung disease.

Ofev recently scored an indication for slowing the rate of decline in pulmonary function in patients with SSc-ILD following a narrow vote in favor of approval from an advisory committee. (Also see "Boehringer's Ofev Likely Needs More Data For SSc-ILD, But Might Get It Postapproval" - Pink Sheet, 25 Jul, 2019.) The drug is also labeled for the treatment of IPF.

Merck Aims To Grow Dificid Franchise With Pediatric Expansion

Merck is seeking to bring its macrolide antibiotic Dificid (fidaxomicin) for Clostridium difficile infection to pediatric patients with a new oral suspension formulation and a new indication for treatment of C diff infections in children aged six months and older. The oral suspension NDA and pediatric indication sNDA both have 24 January 2020 user fee goals.

Dificid was approved as an oral tablet to treat C difficile-associated diarrhea in adults in 2011, with a postmarketing requirement (PMR) for a prospective 10-day trial in at least 32 pediatric patients with CDAD to evaluate safety and pharmacokinetics. That PMR was fulfilled and labeling was updated in 2015, but the indication has remained for adults only.

The new NDA and sNDA are based on the Phase III SUNSHINE trial, which compared fidaxomicin with vancomycin. The trial enrolled 148 pediatric patients; children from birth to six years old received fidaxomicin oral suspension or vancomycin oral liquid, while patients from six to 18 years old received tablets or capsules.

GSK Hopes To Score Asthma Win With Triple Combo Trelegy Ellipta

GlaxoSmithKline hopes to extend use of its triple combination inhaler Trelegy Ellipta into asthma with an sNDA submission announced on 2 October. Trelegy Ellipta was approved for COPD in September 2017.

Trelegy uses GSK’s dry powder Ellipta inhaler to deliver a once-daily, single inhalation that contains a long-acting muscarinic antagonist (umeclidinium), a long-acting beta₂ adrenergic agonist (vilanterol) and the inhaled corticosteroid fluticasone furoate.

The asthma sNDA is based on 2,436-patient Phase III CAPTAIN trial, which compared Trelegy with GSK’s Breo Ellipta (fluticasone/vilanterol). CAPTAIN met the primary endpoint, demonstrating a statistically significant improvement in lung function, as measured by change from baseline in trough forced expiratory volume (FEV1) at 24 weeks of treatment.

Treatment with Trelegy also resulted in a 13% reduction in exacerbations versus Breo, although the result of the secondary endpoint was not statistically significant. (Also see "AstraZeneca’s COPD Triple Combo Drug Succeeds in ETHOS Phase III, Setting Up GSK Showdown " - Scrip, 28 Aug, 2019.)