Keeping Track: Pfizer’s Talzenna Ensures Record Year For Novel US Approvals; Novartis Submits SMA Gene Therapy

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

Here's your US review and approval news this week in brief: The FDA’s Center for Drug Evaluation and Research matched 2017’s record novel approval count on Oct. 16 with the approval of Pfizer Inc.’s oncologic Talzenna.

Talzenna brings CDER’s new molecular entity and novel therapeutic biologic approval tally to 46 for 2018. Barring an unprecedented spurt of complete response letters for the rest of the year, FDA will close out 2018 with the most novel approvals in the modern era.

FDA also approved one new ophthalmic corticosteroid formulation (EyePoint Pharmaceuticals Inc.’s Yutiq) and received an NDA for another (Kala Pharmaceuticals Inc.’s KPI 121). ViiV Healthcare  submitted a two-drug HIV combination, and Bristol-Myers Squibb Co. received a review extension for a first-line lung cancer claim for the double immuno-oncology regimen of Opdivo and Yervoy in patients with high tumor mutation burden.

Novartis AG’s third-quarter earnings call provided news of a complete response letter for a canakinumab indication for cardiovascular risk reduction and the submission of a gene therapy for spinal muscular atrophy.

And two new breakthrough therapy designations were announced, for Loxo Oncology Inc.and Kadmon Corp. LLC.

Now here's your news in less brief:

Pfizer’s Talzenna Becomes Second PARP Inhibitor Approved For Breast Cancer

Pfizer’s Talzenna (talazoparib) cleared FDA Oct. 16, almost two months before the poly (ADP-ribose) polymerase (PARP) inhibitor’s Dec. 6 priority review user fee goal.

Talzenna is indicated for patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2‑negative locally advanced or metastatic breast cancer, as detected by an FDA-approved test. Myriad Genetics Inc.'s BRACAnalysisCDx, which was used in the pivotal trial, was cleared the same day for use as a companion diagnostic. (Also see "Pfizer Expands In Breast Cancer With Talazoparib Approval" - Scrip, 16 Oct, 2018.)

BRCA1 and BRCA2 mutations account for 20%-25% of hereditary breast cancers and about 5%-10% of all breast cancers.

Talzenna is the fourth PARP inhibitor to reach the market, but only the second approved for breast cancer – behind AstraZeneca PLC/
Merck & Co. Inc.'s Lynparza (olaparib). Tesaro Inc.'s Zejula (niraparib) and Clovis Oncology Inc.'s Rubraca (rucaparib) are approved for ovarian cancer, as Lynparza is as well.  

The Talzenna approval rests on the pivotal EMBRACA trial, which enrolled patients with a known or suspected deleterious gBRCA mutation who had received no more than three prior chemotherapy regimens for locally advanced or metastatic disease, and who had received an anthracycline and/or a taxane in the neoadjuvant, adjuvant or metastatic treatment setting. The open-label trial randomized 431 patients who were treated with talazoparib or physician’s choice of chemotherapy.

The talazoparib arm had a median progression-free survival, the primary endpoint, of 8.6 months versus 5.6 months for the chemotherapy arm.

While Talzenna was approved based on a PFS benefit, AstraZeneca/Merck already have overall survival data for Lynparza. Although the Phase III OlympiAD study wasn’t powered to show a statistically significant effect on OS, the companies are able to point out that Lynparza had a median OS of 19.3 months, compared to 17.1 months in patients on chemotherapy. (Also see "Encouraging Survival Data For Lynparza in Metastatic Breast Cancer" - Scrip, 16 Apr, 2018.)

Talzenna is the second novel oncology approval for Pfizer this year, coming on the heels of FDA’s Sept. 27 clearance of the kinase inhibitor Vizimpro (dacomitinib) in non-small cell lung cancer patients. (Also see "Keeping Track: Three Oncologics, A New Migraine Preventive, And First LPAD Antibiotic Clear US FDA" - Pink Sheet, 30 Sep, 2018.) Goal dates for Pfizer’s NDAs for two more novel oncologics, lorlatinib and glasdegib, are coming up in November and December, respectively. (Also see "10 Things For Pfizer's New CEO To Worry About" - Pink Sheet, 16 Oct, 2018.)

Dupixent Nabs Broad Asthma Approval, Including Eosinophil-Neutral Claim

FDA’s Oct. 20 approval of Sanofi and Regeneron Pharmaceuticals Inc.’s interleukin-4 receptor alpha antagonist Dupixent (dupilumab) for uncontrolled asthma could bring biologic therapy to a broader population.

Dupixent’s approval comes after three novel antibody approvals since 2015, backed by the substantial commercial resources of GlaxoSmithKline PLC (Nucala), Teva Pharmaceutical Industries Ltd. (Cinqair), and AstraZeneca PLC (Fasentra). However, all three of those antibodies, which target interleukin-5 (IL-5), are indicated only for severe asthma patients with an “eosinophilic phenotype.” (Also see "Severe Asthma Market Snapshot: A Competitive Therapy Area That Will Test Payers' Influence" - Scrip, 23 May, 2018.)

Dupixent, which intervenes upstream of the anti-IL-5 products by inhibiting overactive signaling of IL-4 and IL-13, is indicated for moderate as well as severe asthma patients with an eosinophilic phenotype, and for patients with oral corticosteroid-dependent asthma regardless of baseline eosinophil levels. Dupixent is approved for patients aged 12 years and older. 

All three of the pivotal LIBERTY ASTHMA trials supporting Dupixent’s approval enrolled asthma patients without requiring a minimum baseline eosinophil count. In the third trial, patients were also dependent on daily oral corticosteroids. 

Sanofi’s approval announcement emphasized the results of the LIBERTY ASTHMA QUEST trial, the largest of the Phase III trials with an enrollment of 1,902 adult and adolescent patients who were receiving inhaled corticosteroids and one to two additional asthma controller medications. The trial is known as Trial 2 in labeling. 

“Prespecified subgroup analyses of AS Trials 1 and 2 demonstrated that there were greater reductions in severe exacerbations in subjects with higher baseline blood eosinophil levels,” labeling states.

In the QUEST study, “Dupixent reduced exacerbations and improved lung function in the overall population,” Sanofi said. “Benefits in exacerbations were seen in patients with eosinophil counts greater than or equal to 150 cells/microliter, which represented 70% of the patients enrolled.”

Nonetheless, “efficacy improved in patients with higher eosinophil counts,” Sanofi continued. “For example, in patients with blood eosinophils of 300 cells/microliter or greater, Dupixent reduced severe exacerbations by 67% compared to placebo, and improved FEV1 (lung function) by 29%-33% compared to 14%-16% for placebo. In patients with eosinophil counts less than 150 cells/microliter, there was no difference in severe exacerbation rates for Dupixent versus placebo.”

Labeling highlights exacerbation rates and FEV1 findings for patients with eosinophils ≥300 cells/mcL, summarizing the findings of from Trials 1 and 2 in charts. The label presents relative risk data from Trial 2 graphically across baseline eosinophil levels. 

Trial 3, also known as LIBERTY ASTHMA VENTURE, had a different focus.  (Also see "Not To Be Sniffed At: Dupixent Success In Rhinosinusitis Could Open Up Large Additional Market" - Scrip, 16 Oct, 2018.)  

The trial’s primary endpoint was reduction oral corticosteroid dose after 24 weeks while maintaining asthma control. Mean daily oral steroid use declined by 70% for Dupixent patients vs. 42% with placebo, labeling reports. OCS dose was reduced by 50% or more in 80% of Dupixent and 53% of placebo patients; OCS was eliminated in 52% and 29% of patients, respectively. 

“Effects on lung function and on oral steroid and exacerbation reduction were similar for Dupixent irrespective of baseline blood eosinophil levels,” Sanofi stated. 

FDA reviewed Dupixent for asthma under standard review. The biologic was originally approved in March 2017 for atopic dermatitis with priority review and a breakthrough therapy designation. Sanofi and Regeneron are studying Dupixent for a range of diseases also driven by Type 2 inflammation, including rhinosinusitis with nasal polyps. SC124010

More Responder Data Needed For Novartis’ Canakinumab In CV Risk Reduction

Novartis announced that it had received a complete response letter for canakinumab for cardiovascular risk reduction during its Oct. 18 earnings call. (Also see "Eight Things To Know From Novartis' Third Quarter Call " - Scrip, 18 Oct, 2018.)

"We presented our case to the FDA. The FDA has asked additional questions and has requested additional data with respect to the responder population, and we're evaluating now what would be the appropriate next steps," CEO Vasant Narasimhan said.

Canakinumab, a monoclonal antibody targeting interleukin-1beta, is approved as Ilaris for rare inherited disease indications.

Novartis studied canakinumab’s potential to prevent major adverse cardiovascular events in patients with recent myocardial infarction and elevated levels of high sensitivity C-reactive protein (hsCRP), an inflammatory biomarker, in the CANTOS trial. The Phase III enrolled more than 10,000 patients, who all received standard care; patients were randomized to one of three doses of canakinumab or placebo.

The CANTOS trial showed a statistically significant but modest benefit, with a relative risk reduction of 15% seen at 48 months with the 150mg dose of canakinumab (given as a subcutaneous injection every three months). Novartis, however, suggested that patients whose CRP levels dropped quickly appeared to have better outcomes than those whose did not, and that it would be quick, cheap and easy to identify them using a simple and cheap biomarker test. (Also see "Novartis Aims Canakinumab At Targeted CV Patients" - Scrip, 13 Nov, 2017.)

Novartis Brings First SMA Gene Therapy To FDA

Novartis is betting big on gene therapy. The big pharma paid almost $9bil. to acquire AveXis Inc. earlier this year. (Also see "Novartis Goes Big On Gene Therapy With $8.7bn AveXis Acquisition" - Scrip, 9 Apr, 2018.)

Now the lead candidate from that acquisition, a one-time survival motor neuron (SMN) gene replacement therapy for spinal muscular atrophy, is now under FDA review, Novartis told the quarterly call. Novartis is planning to launch AVXS-101 in the middle of 2019.

The US BLA filing was matched by simultaneous submissions in the EU and Japan. AVXS-101 already holds a trifecta of expedited review designations from the regulatory bodies – FDA’s breakthrough therapy designation, the EMA’s PRIME scheme, and SAKIGAKE designation in Japan.

The BLA seeks approval for type 1 SMA based on the Phase I START study and data from the ongoing Phase III STR1VE trial. “Our expectation is that the initial label will be for intravenous (IV) use of AVXS-101 for infants with SMA type 1, as IV dosing has only been studied in clinical trials in infants,” AveXis said in an Oct. 18 statement to the SMA community released by the organization Cure SMA.

AveXis presented 24-month data from the Phase I study to the American Academy of Neurology annual meeting in April. Researchers found that 15 of 15 patients alive without need for permanent ventilation two years after gene transfer with AVXS-101. “Natural history indicates only 8% of untreated patients with SMA type 1 survive event-free at 20 months of age,” the company stated. Eleven of the Phase I patients have enrolled in the long-term follow-up (LTFU) trial for ongoing evaluation.

During the earnings call, Novartis described START as demonstrating “transformational efficacy,” with more than 90% of patients able to site unassisted two years after receiving the gene therapy.

AveXis also presented initial data from the STR1VE trial at the AAN meeting. The trial had enrolled 11 patients aged less than six months old (out of a target population of 20), with six at least one month post gene therapy treatment. Scores on the CHOP-INTEND scale, a measure of infant neuromuscular disorders, increased by an average of 7.8 at one month after gene transfer. “Early CHOP-INTEND increases have been observed to be associated with eventual milestone achievement,” the company said.

The STR1VE trial’s co-primary efficacy endpoints include developmental milestones at 18 months of age and event-free survival at 14 months of age.

AveXis is also testing AVXS-101 for SMA type 2, using intrathecal injection delivery. “IT delivery of gene therapy has shown promise for reducing the amount of drug required for larger and older patients,” the company explained. “This could eventually make the treatment accessible to a wider population.”

The Phase I STRONG study in SMA type 2 is fully enrolled with patients aged six months to five years old. “Data from that study will help determine the final study design for the planned study in children up to 18 years of age (REACH),” the company said.

Once Again, ViiV Takes PRV Path In HIV

ViiV Healthcare’s second, two-drug combination pill for treatment of HIV-1 infection will get a speedy US FDA review, thanks to the company’s redemption of a priority review voucher for the dolutegravir/lamivudine combination.

On Oct. 18, ViiV announced submission of a new drug application (NDA) for a single-tablet regimen combining Tivicay (dolutegravir), an integrase strand transfer inhibitor, and Epivir (lamivudine), a nucleoside analogue.

The HIV/AIDS specialist company – which is majority owned by GlaxoSmithKline, with Pfizer and Shionogi & Co. Ltd. – redeemed a priority review voucher, thereby giving the NDA a six-month review with a mid-April user fee date instead of the standard 10-month timeline.

ViiV obtained the voucher from GSK, which earned it with the July 20 approval of the malaria drug Krintafel (tafenoquine), according to GSK.

GSK beat out [60 Degrees Pharmaceuticals LLC] in securing the tropical disease priority review voucher for tafenoquine. (Also see "GSK Wins First-Ever Voucher Race With Anti-Malarial Approval" - Pink Sheet, 23 Jul, 2018.)

Under FDA’s priority review voucher programs, a sponsor seeking to redeem a voucher must notify FDA of its plans to do so at least 90 days prior to NDA submission. The timing of the ViiV NDA just barely met this window.

Given that ViiV’s application for the combination product was submitted to the European Medicines Agency in mid-September, the company may have had to await expiration of the 90-day voucher notification window before submitting to FDA.

Priority review vouchers have become a go-to strategy to speed the route to market in the HIV space.

In June 2017, GSK and ViiV redeemed a voucher, purchased for $130m, with the submission of Juluca, a single-tablet regimen of dolutegravir and Janssen Pharmaceutical Cos.’s Edurant (rilpivirine) for the maintenance treatment of HIV-1 infection. FDA approved Juluca Nov. 21, 2017. (Also see "Keeping Track: Flurry Of Approvals Rolls Over Into Holiday Season" - Pink Sheet, 1 Dec, 2017.)

Also in June 2017, Gilead Sciences Inc. redeemed a voucher for Biktarvy, a fixed-dose combination of bictegravir, a novel investigational integrase strand transfer inhibitor, and emtricitabine/tenofovir alafenamide, a dual nucleoside reverse transcriptase inhibitor (NRTI) backbone, for the treatment of HIV-1 infection. FDA approved Biktarvy Feb. 7, 2018. (Also see "After Hep C Patent Battle, Gilead Faces ViiV Suit Over Its New HIV Drug" - Pink Sheet, 8 Feb, 2018.)

As with Juluca, the dolutegravir/lamivudine dual regimen is part of ViiV's plan to take market share from rival Gilead by simplifying HIV therapies and reducing treatment costs. (Also see "ViiV CEO: "We Aim To Be Top HIV Player By Mid-2020s"" - Scrip, 25 Jun, 2018.)

The NDA is based on data from the GEMINI 1 and 2 studies encompassing more than 1,400 HIV-1 infected adults with baseline viral loads up to 500,000 c/mL. The study results showed the two-drug regimen to be effective across high and low viral loads and non-inferior to a three-drug regimen comprising Tivicay and tenofovir disoproxil fumarate/emtricitabine. (Also see " ViiV Steals A March On Gilead with HIV Doublet Data" - Scrip, 24 Jul, 2018.)

Importantly, the data, which were presented at AIDS 2018 in Amsterdam in July, appeared to address two main concerns inherent in HIV treatment with doublet-therapy as opposed to three-drug regimens – lower efficacy and higher risk of resistance. Rates of virologic failure were ≤1% across all arms of the GEMINI studies, and no patient who experienced virologic failure in either treatment arm developed treatment-emergent resistance.

“ViiV Healthcare believes that a two-drug regimen has the potential to be an important option for many who may spend their lifetime taking drugs to control their virus,” ViiV CEO Deborah Waterhouse said. “This regulatory submission is the next step in the two-drug regimen journey and reinforces our belief that many patients can control their disease with two drugs instead of three or more.”

FDA Extends Goal For Opdivo/Yervoy In NSCLC To Review OS Data

FDA assigned a new user fee goal date of May 20, 2019 to Bristol-Myers Squibb Co.’s IO/IO combination of Opdivo (nivolumab) and low-dose Yervoy (ipilimumab) for first-line treatment of non-small cell lung cancer patients with a tumor mutational burden (TMB) ≥10 mutations/megabase.

The extension reflects Bristol’s submission of overall survival data for the subgroup of patients with TMB <10 mut/Mb in the Phase III CheckMate-227 trial, which constitutes a major amendment, the company said Oct. 19. The trial compares the Opdivo/Yervoy regimen with platinum doublet chemotherapy.

The application is the first submitted to FDA using the TMB biomarker. Bristol submitted the sBLA in April with data from CheckMate-227, which had been amended to feature progression-free survival (PFS) as a co-primary endpoint in a subset of patients with a high level of TMB, along with OS in trial patients stratified by PD-L1 expression. (Also see "Keeping Track: Bristol Tests US FDA’s TMB Tolerance, Celltrion Resubmits Herceptin Biosimilar, Nocdurna Approved At Last" - Pink Sheet, 24 Jun, 2018.)

Following the submission, Bristol continued to analyze the OS findings from CheckMate-227. The median OS in patients with TMB ≥10 mut/Mb was 23.03 months for Opdivo+Yervoy arm and 16.72 months for chemotherapy, the company reported. In patients with TMB <10 mut/Mb the median OS was 16.20 months and was 12.42 months on the combination and chemotherapy arms, respectively. 

EyePoint Adds Yutiq To Back-Of-The-Eye Disease Armamentarium

FDA cleared EyePoint’s posterior uveitis therapy Yutiq on Oct. 12, three weeks ahead of the NDA’s Nov. 5 user fee goal date – and ahead of the world’s largest gathering of ophthalmologists, the American Association of Ophthalmology annual meeting, at the end of October.

“We planned meticulously for this meeting in anticipation of a possible early approval,” EyePoint CEO Nancy Lurker told an Oct. 15 call on the approval. FDA cleared Yutiq for treatment of chronic non-infectious uveitis affecting the posterior segment of the eye. (Also see "Early Yutiq Approval Gives EyePoint Two Ophthalmic Drugs To Launch In 2019" - Scrip, 15 Oct, 2018.)

Yutiq, an intravitreal implant, is administered in physician’s office. The “micro-insert” product uses EyePoint’s Durasert injectable polymer-based drug delivery system to release the steroid fluocinolone acetonide continually over 36 months.

“Today, patients with posterior uveitis are typically treated with systemic steroids, but over time frequently develop serious side effects that can limit effective dosing,” EyePoint said.

EyePoint was created by the merger of pSivida Inc. and Icon Bioscience Inc. in March. “With the approval of Yutiq, the company has developed four of only five FDA-approved sustained-release treatments for back-of-the-eye diseases,” EyePoint noted.

Yutiq is the first in-house product using pSivida’s Durasert miniaturized injectable implant technology. Durasert is used in two other marketed ophthalmic fluocinolone acetonide formulations – Alimera Sciences Inc.’s Iluvien implant for diabetic macular edema and Bausch & Lomb Inc.’s Retisert, which like Yutiq is indicated for chronic non-infectious posterior uveitis. Retisert contains a higher dose of steroid (0.59mg vs. Yutiq’s 0.18mg) and a shorter 30-month duration. B&L’s antiviral Vitrasert (ganciclovir) also uses Durasert.

Kala Submits Dry Eye Drug KPI-121 While Seeking More Symptom Data

Kala will collect additional symptom-focused endpoint data from a third Phase III study while FDA reviews its NDA for KPI-121 0.25% for temporary relief of the signs and symptoms dry eye disease.

KPI-121 is an ophthalmic formulation of the steroid loteprednol etabonate that uses Kala’s AMPPLIFY mucus-penetrating particle (MPP) delivery technology to enhance penetration of the steroid into ocular tissue. KPI-121 0.25% is given four times a day for two weeks; if approved, it would be the first short-term treatment for dry eye flares. 

The NDA submission, announced Oct. 16, 2018, is based on the Phase III STRIDE 1 and STRIDE 2 trials, both of which met the primary sign endpoint of conjunctival hyperemia. The primary symptom endpoint – ocular discomfort severity at day 15 – was achieved by STRIDE 1, but fell short of statistical significance in STRIDE 2, although Kala points to trends toward treatment effect.

Kala’s “comprehensive analysis” of the data in the NDA identified what the company believes are “key factors that contributed to the differences observed in the results from STRIDE 2 compared to those of STRIDE 1 and Phase II.”

“Based upon the recommendation of the FDA,” Kala started the Phase III STRIDE 3 trial in July 2018. “The STRIDE 3 trial design reflects specific modifications to the inclusion/exclusion criteria of our previous trials to address key factors which we believe will improve the probability of success,” Kala said.

The primary endpoint of the 900-patient STRIDE 3 trial is day 15 ocular discomfort severity. Topline data are expected in the fourth quarter of 2019. (Also see "Kala Hopes To Stride Into Dry Eye Market This Year" - Scrip, 20 Jun, 2018.)

LIBRETTO-001 Results Land Third BTD For LOXO-292

Loxo Oncology's selective RET inhibitor LOXO-292 has landed its third breakthrough therapy designation in two months, all of which have come on the back of the company's Phase I/II LIBRETTO-001 trial.

The company reported Oct. 15 that the new designation covers the treatment of patients with advanced RET fusion-positive thyroid cancer who require systemic therapy, have progressed following prior treatment and have no acceptable alternative treatment options.

Seven of nine (78%) of patients with RET fusion-positive thyroid cancer in the trial demonstrated an objective response, Loxo announced at the American Society of Clinical Oncology (ASCO) annual meeting in June.

The company additionally scored two breakthrough therapy designations in September, both of which were supported by data from LIBRETTO-001. One was for the treatment of patients with metastatic RET-fusion-positive non-small cell lung cancer (NSCLC) who require systemic therapy and have progressed following platinum-based chemotherapy and an anti-PD-1 or anti-PD-L1 therapy, and the other was for treatment of patients with RET-mutant medullary thyroid cancer who require systemic therapy, have progressed following prior treatment and have no acceptable alternative treatment options.  (Also see "US FDA’s Latest Breakthrough Therapy Awards Include Asthma, Alopecia Areata, And (Of Course) Oncology Therapies" - Pink Sheet, 10 Sep, 2018.)

A new drug application (NDA) submission for patients with RET fusion solid tumors and RET-mutant medullary thyroid cancer is expected in late 2019, Loxo announced on its Q2 earnings call in August.  (Also see "Bayer Files Larotrectinib In EU As LOXO-292 Hurtles Towards The Market " - Scrip, 29 Aug, 2018.)

Kadmon KD025 Nabs BTD As It Enters Pivotal Trial

Kadmon’s KD025, a selective oral inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2), is having a busy October, thanks to a breakthrough therapy designation (BTD) and the start of a pivotal trial.

Kadmon announced the BTD for treatment of patients with chronic graft-versus-host disease (cGVHD) after failure of two or more lines of systemic therapy on Oct. 17. The ROCK2 inhibitor already holds orphan drug designation for cGVHD, which occurs in close to half of patients who receive allogeneic hematopoietic stem cell transplant (HSCT).

The BTD supported by data from the Phase II trial KD025-208, an ongoing dose-finding study in adults with steroid-dependent or steroid-refractory cGVHD and active disease. Data from the first two cohorts (17 patients on 200mg once daily and 16 patients on 200mg twice daily) show that “KD025 was well tolerated and demonstrated clinical activity in approximately two-thirds of patients,” Kadmon said. A 21-patient third cohort receiving a 400mg once daily dose is underway.

In addition to overall response rates of 65% and 69% for cohorts 1 and 2, the Phase II study found durable responses (sustained for 20 or more weeks) in 47% of cohort 1 and 38% of cohort 2 patients, Kadmon reported in an Oct. 17 corporate presentation. Corticosteroid doses were reduced in 66% of all patients.

Enrollment is also underway in another Phase II trial, KD025-213, that will act as the pivotal trial for adults with cGVHD who have received at least two prior lines of systemic therapy. The open label trial will randomize 126 patients to KD025 200mg once daily or twice daily. The trial design incorporates FDA’s guidance from a type C meeting in March 2018.

Kadmon pointed to KD025’s safety profile in an Oct. 17 corporate presentation. The drug was “well-tolerated in clinical trials, with no drug-related [serious adverse events],” Kadmon said, underlining the “potential for long-term use.” Approved therapies for cGVHD – steroids and AbbVie Inc.’s BTK inhibitor Imbruvica (ibrutinib) – are associated with immunosuppression and high rates of discontinuation due to adverse events, respectively.