Keeping Track: Turalio, Nubeqa And Accrufer Mark Trio Of Novel Drug Approvals

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

Novel approvals are likely to pick up at the US Food and Drug Administration over the next several weeks, and the agency commenced its busy string of activity with green lights for Daiichi Sankyo Co. Ltd.'s Turalio (pexidartinib), Bayer HealthCare Pharmaceuticals AG's Nubeqa (darolutamide) and Shield Therapeutics PLC's Accrufer (ferric maltol).

On the submissions front, Ultragenyx Pharmaceutical Inc.'s UX007 (triheptanoin) is headed to the FDA, as the company is seeking an indication for the treatment of long-chain fatty acid oxidation disorders (LC-FAOD).

Meanwhile, Sunovion Pharmaceuticals Inc.'s dasotraline officially stamped its place in the agency's review pipeline by securing a May 2020 standard review user fee date.

Additionally, Orchard Therapeutics Ltd. picked up a regenerative medicine advanced therapy (RMAT) designation for its ex vivo autologous hematopoietic stem cell-based gene therapy for the treatment of Wiskott-Aldrich Syndrome (WAS).

Now, here's your news in less brief:

FDA Backs Pexidartinib With Expected Safety Measures

The FDA agreed with its Oncologic Drugs Advisory Committee (ODAC) in approving Daiichi's Turalio on 2 August for the treatment of tenosynovial giant cell tumor (TGCT), which will come to the US market with some expected safety restrictions.

A first-in-class kinase inhibitor of the colony stimulating factor 1 receptor (CSFIR), the KIT proto-oncogene receptor tyrosine kinase (KIT) and the FMS-like tyrosine kinase 3 (FLT3) pathways, Turalio's specific indication is for the treatment of adults with symptomatic TGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery. It is the first FDA-approved product for the rare disease.

Labeling includes a black box warning for hepatoxicity, which was proposed by the FDA during the review cycle. The warning instructs prescribers to monitor liver tests prior to initiation of Turalio and at specified intervals during treatment. Turalio was also approved with a risk evaluation and mitigation strategy (REMS) that requires patients sign and complete an enrollment form for inclusion in a patient registry, which was another FDA proposal. (Also see "Daiichi's Pexidartinib Likely Needs REMS For Liver Safety Concerns" - Pink Sheet, 13 May, 2019.)

TGCT is a rare tumor affecting the synovium and tendon sheaths. Although the tumor is rarely malignant, it can cause the synovium and tendon sheaths to thicken and overgrow, and subsequently cause damage to surrounding tissue. ODAC overwhelmingly felt Turalio demonstrated a transformative effect in clinical development, voting 12-3 that the benefits outweigh the risks. (Also see " Daiichi's Pexidartinib: Potential Patient Impact Drives Advisory Cmte. Recommendation" - Pink Sheet, 14 May, 2019.)

In the Phase III ENLIVEN trial, Turalio demonstrated an overall response rate of 38% after 25 weeks of treatment, including a complete response rate of 15% and a partial response rate of 23%, while no placebo recipients demonstrated a response.

Nubeqa Lands Fastest Novel Approval Of 2019 (So Far)

There are still five months to go in 2019, but Bayer's Nubeqa has clocked in as the Center for Drug Evaluation and Research's fastest approval of a novel agent so far this year.

It took just 5.1 months for the FDA to give the nod to Nubeqa, an androgen receptor inhibitor Bayer licensed from Orion Corp. in 2014, on 30 July for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC). The 5.1-month review time just edges out the 5.2-month review time for Novartis AG's Piqray (alpelisib), which became the first novel drug approved under the agency's Real-Time Oncology Review pilot program. (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.)

Nubeqa's clean safety profile observed in clinical trials is reflected in its label. While Pfizer Inc./Astellas Pharma Inc.'s Xtandi (enzalutamide) and Johnson & Johnson's Erleada (apalutamide), the other two agents approved in the US for nmCRPC, each have a warning for an increased risk of fall or fracture, Nubeqa's label is devoid of such a warning. (Also see "Keeping Track Of Oncology: US FDA Approves Herceptin Hylecta, Reviews Darolutamide And Pexidartinib" - Pink Sheet, 3 Mar, 2019.)

The only warning in Nubeqa's label is for embryo-fetal toxicity. Safety is an especially important consideration in the nmCRPC space, as the population is largely asymptomatic. (Also see "Bayer Sees Room For Third-To-Market Darolutamide In Prostate Cancer" - Scrip, 14 Feb, 2019.)

In terms of efficacy, Nubeqa plus androgen deprivation therapy (ADT) demonstrated metastasis-free survival (MFS) of 40.4 months compared with 18.4 moths for placebo plus ADT (p < 0.0001). Secondary endpoints were overall survival (OS) and time to pain progression, although the OS data were not mature at the time of final MFS analysis. (Also see "Positive Phase III For Darolutamide In Prostate Cancer Could Improve Options For Orion" - Scrip, 24 Oct, 2018.)

Bayer will submit the OS data to the FDA by December 2010 for its sole 506B postmarketing commitment, according to the approval letter.

A company spokesperson told the Pink Sheet that Nubeqa will have a wholesale acquisition cost of $11,550 for a 30-day supply of 300 mg tablets but declined to comment on a timeline for launch plans. Bayer is also seeking an approval for Nubeqa in the EU.

Shield Eyes New Iron Deficiency Anemia Treatment Paradigm With Accrufer Approval

In addition to securing a broad approval for its iron replacement product Accrufer on July 25 for the treatment of iron deficiency in adults, Shield also sees the drug as potentially shifting the treatment paradigm for iron deficiency anemia.

Shield has positioned Accrufer, which is approved under the brand name Ferracru in the EU, as a more tolerable oral alternative to approved salt-based oral iron therapies, which can cause gastrointestinal tract adverse events.

Two of the studies supporting the new drug application evaluated Accrufer in patients with patients with inflammatory bowel disease. AEGIS 1 and AEGIS 2 enrolled 128 total patients, and the drug met the primary endpoint of mean difference in hemoglobin concentration from baseline to week 12 compared with placebo.

AEGIS 3 enrolled 167 patients with non-dialysis dependent chronic kidney disease (CKD), where Accrufer demonstrated statistical significance on the primary endpoint of mean difference in hemoglobin levels from baseline to week 16 versus placebo.  It was the CKD trial that initially appeared to be a setback for Shield, as news of the drug failing a preliminary topline data analysis led to the company making cuts to its workforce. (Also see "Jobs Go At Shield Therapeutics As Failed Study Fallout Hits" - Scrip, 23 Feb, 2018.)

However, a detailed analysis showed that Accrufer did demonstrate statistical significance on the primary endpoint in CKD patients. (Also see "Keeping Track: US FDA Approves Novel Tetracyclines Nuzyra And Seysara; Hemlibra Indication Expands" - Pink Sheet, 7 Oct, 2018.)

“The broad label that the FDA has granted provides a very strong signal as to the tolerability and efficacy profile of Feraccru/Accrufer and provides a novel and convenient treatment alternative to the millions of US patients who routinely suffer with iron deficiency," said Jackie Mitchell, vice president of regulatory affairs at Shield, stated 26 July.

Shield didn't hide its grand vision on the prospects of Accrufer's reach.  In its approval statement, the drugmaker also pointed to results from its AEGIS-H2H study announced in March, where Accrufer demonstrated non-inferiority to Injectafer (ferric carboxymaltose injection) on the endpoint of hemoglobin response.

Between the non-inferiority trial results, Accrufer's efficacy profile and its tolerability profile, the company believes that the drug "might remove the need for patients to progress to intravenous iron therapy, leading to a change in the current paradigm for the treatment of iron deficiency anaemia."

A company spokesperson declined to provide US pricing and launch plans for Accrufer, noting that Shield is in discussions with potential commercial partners. (Also see "Shield Therapeutics Looking At US Options For Feraccru" - Scrip, 24 Jan, 2019.)

Ultragenyx's Triheptanoin Submission Features Expanded Access Data

Ultragenyx's triheptanoin NDA submission is supported by a broad array of data sources, including expanded access data, as the company seeks an approval for the treatment of LC-FAOD.

LC-FAOD is a group of genetic disorders where the body is unable to convert long-chain fatty acids into energy.

In a 1 August announcement, Ultragenyx said the NDA is supported by a "Phase II study of UX007 in 29 patients, a long-term safety and efficacy extension study in 75 patients including 20 patients who were previously naïve to UX007, a retrospective medical record review of 20 original compassionate use patients, 67 patients treated through expanded access, and a randomized controlled investigator-sponsored study of 32 patients showing an effect on cardiac function."

Data from the 29-patient Phase II study were published in Molecular Genetics and Metabolism in April 2017. Eight eligible patients demonstrated a 28% increase from baseline in the 12-minute walk test, and seven eligible patients showed a 60% increase in watts generated over baseline for the exercise tolerance test at week 24.

In the long-term extension study, patients had a 67% reduction in median annualized event rate and a 66% reduction in the median annualized duration rate over the entire treatment period, and the safety profile was consistent with what has been previously observed with UX007.

Ultragenyx noted that triheptanoin carries a rare pediatric disease designation. A priority review would position a user fee date for 1 April 2020 or earlier.

Notably, triheptanoin is only one of two drugs in the development pipeline for LC-FAOD, according to Biomedtracker. The other is Recro Pharma Inc.'s REN001, which is in Phase I development.

Sunovion Tries Again With Dasotraline – For A Different Indication

Sunovion has brought dasotraline back to the FDA, but not but not for the attention-deficit hyperactivity disorder (ADHD) indication which the agency rejected last year. The firm is now gunning for an approval to treat patients with moderate-to-severe binge eating disorder, announcing 30 July that the agency assigned a user fee goal date of 14 May 2020 to the NDA.

In two randomized, double-blind trials, dasotraline demonstrated a statistically significant decrease in the number of binge days per week at week 12. Binge days were defined as days during which at least one binge episode occurred. One of the trials was a Phase II/III flexible-dose study (SEP360-221), while the other was a Phase III fixed-dose study (SEP360-321). However, only the higher 6mg/day dose met the primary endpoint in SEP360-321, while the 4mg/day dose did not.

Sunovion also says the drug was well tolerated across clinical trials, including the long-term safety study SEP360-322, which assessed BED patients for up to one year.

Last year, it was notably the safety and tolerability that appeared to derail dasotraline's in the ADHD indication, as Sunovion said the FDA requested additional such clinical data in the complete response letter. (Also see "Keeping Track: Busy August Ends With Approval For Doravirine, CRLs For Dasotraline And Waylivra " - Pink Sheet, 3 Sep, 2018.)

Biomedtracker analysts have also questioned whether dasotraline will be able to compete with Shire PLC's central nervous system stimulant Vyvanse (lisdexamfetamine dimesylate) in binge eating disorder. The analysts noted in July 2018 that dasotraline demonstrated a -0.99 difference in binge eating days compared with placebo SEP360-221, while data from Vyvanse's two pivotal trials showed differences of -1.36 days and -1.66 days compared with placebo. Sunovion did not disclose the specific data from SEP360-321.

Orchard Adds An RMAT To Its Expedited Review Designations List

Orchard further solidified its presence in the top tier of gene therapy companies with an RMAT designation announced 29 July for OTL-103, the company’s autologous hematopoietic stem cell (HSC) gene therapy for the rare inherited immune disorder WAS. To make OTL-103, a patient’s HSCs are modified ex vivo to add a functional WASP gene using a lentiviral vector. The gene-modified cells are infused back into the patient in a single IV infusion after a conditioning regimen.

The WAS gene therapy was developed by the San Raffaele Telethon Institute for Gene Therapy in Milan; Orchard acquired it as part of a broad gene therapy deal with GlaxoSmithKline PLC in April 2018. (Also see "Orchard To Use Divested GSK Rare Disease Gene Therapies To Grow Globally" - Scrip, 12 Apr, 2018.)

As of September 2018, eight patients have been treated with OTL-103 in an ongoing registrational trial and eight patients in a compassionate use program, with a maximum follow-up of up to approximately eight years post-treatment. All the patients were below the age of 12 years with a diagnosis of severe, classical WAS and were ineligible for hematopoietic stem cell transplant (HSCT) treatment due to the absence of an appropriate donor.

Orchard pointed to the publication of an interim analysis of the registration trial in Lancet Haematology in May 2019, which showed “recovery of the immunological and platelet abnormalities associated with WAS, with a consequent significant reduction in the major complications of the disease.” The frequency of severe infections decreased in patients with follow up ranging from 0.5 to 5.6 years, the company said. “In addition, severe bleeding episodes were eliminated and moderate bleeding episodes were greatly reduced.”

Orchard indicated that the full registrational trial data set will be presented later this year, including the primary endpoint data, collected when all patients are three years post-treatment with gene therapy. The trial was conducted at San Raffaele Hospital in Milan, Italy, using freshly produced cells. Orchard hopes to market a cryopreserved formulation, and is conducting a supportive study to support analytical comparability between the fresh and cryopreserved drug products.

Orchard already holds a breakthrough therapy designation (BTD) for its lead US gene therapy candidate, OTL-101 for adenosine deaminase severe combined immunodeficiency (ADA-SCID), which is headed for a rolling BLA submission in the first half of 2020. The OTL-103 BLA submission is targeted for 2021.

PIVOT-02 Nets Opdivo/Bempegaldesleukin Combo BTD In First-Line Melanoma

Bristol-Myers Squibb Co. and Nektar Therapeutics got a late-stage development boost for their Opdivo (nivolumab)/ NKTR-214 (bempegaldesleukin) combination, which scored a BTD for the first-line treatment of unresectable or metastatic melanoma, the drugmakers announced 1 August.

The BTD is based on data from the ongoing Phase I/III PIVOT-02 study data presented at the American Society of Clinical Oncology annual meeting. (Also see "Nektar/Bristol Show Promise With Double IO Combo, But Numbers Are Small" - Scrip, 19 Feb, 2019.)

But the drugmakers are now recruiting for an open-label pivotal Phase III study to assess the combination in the first-line melanoma indication. According to clinicaltrials.gov, enrollment is estimated to be 764 participants, and the primary endpoints will be ORR, progression-free survival and OS. 

Opdivo currently carries an indication as a monotherapy and in combination with Yervoy (ipilimumab) for the first-line treatment of unresectable or metastatic melanoma.

Bempegaldesleukin, a novel agent, works by binding to the CD122 receptor on the surface of cancer-fighting immune cells to stimulate their proliferation. Bristol and Nektar are studying the Opdivo/bempegaldesleukin combination in a variety of indications and tumor types. (Also see "Nektar's IL-2 Impresses In Combination With Bristol's Opdivo" - Scrip, 14 Nov, 2017.)

Keytryda Adds Esophageal Cancer Indication

Merck & Co. Inc.'s Keytruda (pembrolizumab) has entered yet another oncologic arena: esophageal cancer.

The PD-1 inhibitor picked up an approval 30 July for the second-line or greater treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 as determined by an FDA-approved test.

Jonathan Cheng, vice president of oncology clinical research at Merck, said in a statement that Keytruda is the first anti-PD-1 therapy approved for the indication.

Eton Cites Pediatric Advantage In Liquid Lamotrigine NDA Filing

Eton Pharmaceuticals Inc. announced that its oral liquid formulation of lamotrigine will receive a standard review user fee date of 17 March 2020, pointing to the advantage that ET-105 brings to pediatric patients.

Lamotrigine, the widely-used anti-epilepsy medication, was first approved in 1998 as a tablet formulation (GSK's Lamictal). But Eton says that pediatric patients require precision dosing at levels below the currently available tablet strengths, and that the liquid formulation of ET-105 is designed to address this unmet need.

According to Eton, the ET-105’s precision dosing delivery system allows for measurements down to 1mg, while the lowest strength tablet available on the market is 5mg.