Keeping Track Of Approvals: Two Novel Drugs (Givlaari And Xcopri), A Project Orbis Collaboration (Calquence) And Another Humira Biosimilar
Executive Summary
The latest news on US FDA drug approvals.
For the third straight year, the US Food and Drug Administration has reached a mark of at least 40 approvals of novel drugs and therapeutic biologics after greenlighting Alnylam Pharmaceuticals Inc.'s Givlaari (givosiran) SK Life Science Inc.'s Xcopri (cenobamate) for the US market.
A major supplemental approval went to AstraZeneca PLC's Calquence (acalabrutinib) for a chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) indication, which was cleared under the FDA's Project Orbis and Real-Time Oncology Review (RTOR) programs.
Additionally, Pfizer Inc. picked up the fifth agency approval for a biosimilar to AbbVie Inc.'s Humira (adalimumab), although the US launch of the copycat product is not planned until 2023.
Now, here's your news in less brief:
Givlaari Is Latest In String Of Early Novel Approvals
The FDA's review divisions are continuing to operate in fifth gear with the 20 November approval of Alnylam's Givlaari, marking the third time over a one-month stretch that the agency has backed a novel drug after a less than six-month review.
An aminolevulinate synthase 1-directed small interfering RNA, the subcutaneously-administered Givlaari labeled for the treatment of adults with acute hepatic porphyria (AHP), the first drug approved for the indication. It's also the second-ever RNAi-based therapeutic approved by the FDA behind Alnylam's own Onpattro (patisiran). (Also see "Alnylam's Onpattro Carries Narrower hATTR Indication Without Cardiac Data" - Pink Sheet, 13 Aug, 2018.)
According to the approval letter, Alnylam submitted the new drug application 4 June, meaning the review took just 5.5 months; the approval came 2.5 months ahead of the 4 February 2020 priority review user fee date. Givlaari received a breakthrough therapy designation (BTD) for AHP, a rare genetic disorder involving the buildup of toxic porphyrin molecules, which can lead to severe pain, paralysis, respiratory failure, seizures and mental health issues.
"Prior to today’s approval, treatment options have only provided partial relief from the intense unremitting pain that characterizes these attacks," said Richard Pazdur director of the Oncology Center of Excellence and acting director of the Office of Oncologic Diseases. "The drug approved today can treat this disease by helping to reduce the number of attacks that disrupt the lives of patients."
Alnylam CEO John Maraganore added in a statement that, "We believe today’s news reinforces the promise and potential of RNAi therapeutics as a whole new class of medicines."
The NDA was supported by the 94-patient, Phase III ENVISION trial, where patients treated with Givlaari experienced 70% fewer porphyria attacks compared with placebo recipients. The drug also demonstrated statistical significance on five of nine secondary endpoints, including urinary aminoleyulinic acid (ALA) levels at three and six months. (Also see "Alnylam Ramps Up Commercial Planning For Givosiran Based On Phase III Data " - Scrip, 6 Mar, 2019.)
Alnylam was initially planning to submit the NDA for accelerated approval in 2018 based on interim data from ENVISION trial, although reports of adverse events impacting the kidney and liver delayed those plans. (Also see "Keeping Track: First RMAT Approval On The Horizon; Big Weeks For Merck, Lilly And Celgene" - Pink Sheet, 7 Jun, 2019.)
Givlaari is the third novel drug since late October to win the FDA's approval blessing following a review period of less than six months. BeiGene Ltd.'s mantle cell lymphoma (MCL) drug Brukinsa (zanubrutinib) scored an approval 14 November after just 4.5 months of review. (Also see "Keeping Track Of User Fee Decisions And Filings: Adakveo, Brukinsa And Fetroja Mark Massive Week Of Novel Approvals" - Pink Sheet, 17 Nov, 2019.)
And on 21 October, Vertex Pharmaceuticals Inc. got the agency's nod to market Trikafta (elexacaftor, tezacaftor and ivacaftor) for cystic fibrosis just three months following the NDA submission date. (Also see "Keeping Track: Vertex’ Trikafta Speeds To US Approval; New Indications For AZ’s Farxiga, J&J’s Stelara, GSK’s Zejula" - Pink Sheet, 24 Oct, 2019.)
Approvals for these drugs will provide a boost for CDER's 2019 novel approval count, as all three had 2020 goal dates.
Alnylam will price Givlaari, its second commercial product, at roughly $575,000-per-patient-per-year. (See sidebar.)
Second Project Orbis Approval Goes To Calquence
AstraZeneca's Calquence became the second drug to score an approval under the FDA's Project Orbis collaboration, as the Bruton tyrosine kinase inhibitor picked up a broad indication for the treatment of CLL or SLL on 21 November.
Project Orbis, an initiative of the Oncology Center of Excellence, involves a collaboration between the FDA, Health Canada and the Australian Therapeutic Goods Administration that allows for a simultaneous submission and review of oncology drugs. (Also see "Keeping Track: A Duo Of RTOR Approvals, Thumbs Up For First Oral GLP-1 Treatment, And First Ebola Vaccine Nears US Market" - Pink Sheet, 21 Sep, 2019.)
The first approval under the program came in September with an accelerated approval for Eisai Co. Ltd.'s Lenvima (lenvatinib) in combination with Merck & Co. Inc.'s Keytruda (pembrolizumab) for the treatment of patients with advanced endometrial carcinoma. (Also see "US FDA’s Project Orbis Could Streamline Global Clinical Trials In Cancer" - Pink Sheet, 17 Sep, 2019.)
Like the Lenvima/Keytruda combination, Calquence was also reviewed under the FDA's RTOR pilot and was part of the accompanying Assessment Aid pilot. Both of these programs "facilitated discussions among the regulatory agencies," the agency said. Calquence is now the 13th drug approval that was reviewed under the RTOR pilot.
The supplemental NDA evidently received a two-month review. The FDA noted in its press release that the sNDA was approved four months in advance of the user fee date, and supplemental applications with priority review status are awarded a user fee date six months from the date of submission. Calquence's two-month review time is faster than the average and median review times for RTOR applications, both of which are three months.
But the speed of the review was also likely boosted by a late-stage BTD for Calquence in CLL, which came after the drug demonstrated statistically significant improvements in progression-free survival (PFS) versus active comparators in the Phase III ELEVATE-TN and ASCEND trials. (Also see "Keeping Track: A Quintet Of Novel Approvals" - Pink Sheet, 17 Aug, 2019.)
Labeling features data from both ELEVATE-TN and ASCEND, which evaluated Calquence, respectively, in previously untreated patients with CLL and patients with relapsed or refractory CLL after at least one prior therapy. (Also see "AZ’s Calquence Hits Endpoint In Second CLL Phase III Study" - Scrip, 6 Jun, 2019.)
Xcopri Cleared With Warning For DRESS
The FDA gave the thumbs up to Korea-based SK Life Science on 21 November to market Xcopri (cenobamate) for the treatment of partial-onset seizures in adults with labeling that includes language in the warning and precautions section about drug reaction with eosinophilia and systemic symptoms (DRESS).
DRESS, also known as multiorgan hypersensitivity, was first observed in one of the two pivotal Phase II trials supporting approval, prompting the SK to conduct a 1,339-patient, Phase III open-label safety study. The company reported at the American Epilepsy Society 2018 annual meeting that there were no cases of DRESS identified in the trial, with a lower starting dose and slower titration being key mitigating factors. (Also see "New Option For Uncontrolled Epilepsy On Horizon As US Accepts Cenobamate NDA" - Scrip, 12 Feb, 2019.)
But the FDA cautions in labeling that, "This finding does not establish that the risk of DRESS is prevented by a slower titration; however, Xcopri should be initiated at 12.5 mg once daily and titrated every two weeks."
In one of the pivotal studies, Study 013, Xcopri 200mg/day demonstrated a statistically significant 56% reduction in median seizure frequency per 28 days compared to a 22% reduction with placebo. Study 017 evaluated doses of 100mg/day, 200mg/day and 400mg/day, which achieved 36%, 55% and 55% reductions in median seizure frequency, respectively, versus placebo's 24% reduction. (Also see "Keeping Track: US FDA Enters Year's Final Stretch With Tsunami Of Novel Approvals " - Pink Sheet, 1 Dec, 2018.)
“Patients can have different responses to the various seizure medicines that are available," Billy Dunn, director of the FDA's Office of Neuroscience, said in a statement. "This approval provides an additional needed treatment option for people with this condition.”
Xcopri's label also contains contraindications for patients with hypersensitivity to the drug's active ingredient or any of its inactive ingredients, as well as for patients with familial short QT syndrome.
SK Life Science said in a statement that it expects to launch Xcopri in the US in the second quarter of 2020 following scheduling review by the Drug Enforcement Administration, which generally occurs within 90 days of FDA approval. The company added that the approval "marks the first time a Korean company has independently brought a compound from discovery to U.S. FDA approval."
With Launch Years Away, FDA Touts Approval Of Fifth Humira Biosimilar
Even though the launch of Pfizer’s newly approved Humira (adalimumab) biosimilar Abrilada (adalimumab-afzb) won't happen until 2023, the approval still came with a lengthy statement from Sarah Yim, acting director of the Office of Therapeutic Biologics and Biosimilars (OTBB).
The 15 November FDA green light made Abrilada the fifth agency-approved biosimilar to Humira and the 25th overall.
Yim described the approval as "another step to further foster biologics competition," adding that, "I’m pleased to see this progress and am confident that the market for these therapies will continue to grow."
However, due to patent settlements with the reference product sponsor AbbVie, none of the five approved Humira biosimilars will be able to launch until 2023. Pfizer will be able to launch Abrilada in November 2023 under its agreement with AbbVie. (Also see "Pfizer’s FDA-Approved Adalimumab Faces Four-Year Wait" - Generics Bulletin, 18 Nov, 2019.)
Abrilada's label, like those of the other Humira biosimilars, currently carries seven of 10 of the reference product's indications: rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, ulcerative colitis and plaque psoriasis.
Pfizer noted that the approval is supported by the REFLECTIONS B538-02 clinical comparative study. According to clinicaltrials.gov, the Phase III trial enrolled 597 patients.
Yim also pointed to several of the FDA's other activities on biosimilars in her statement, such as the development and implementation of new biosimilar-specific review templates and the upcoming 23 March 2020 transition date for certain biological products, including insulin. (Also see "US FDA's Stein: 'Cognitive Dissonance' Exists Between Review Divisions In Regulation Of Biosimilars" - Pink Sheet, 19 Nov, 2019.)