Keeping Track: US FDA Set For Speed With Approvals Of Inqovy, Rukobia, Dojolvy, Phesgo; Keytruda Loses Chance At AA In HCC

The latest drug development news and highlights from the Pink Sheet’s FDA Performance Tracker.

The US Food and Drug Administration continues to defy the constraints of the pandemic by not only meeting but exceeding user fee goal dates for a steady, high volume of approval actions.

The speed of FDA review can be seen particularly for the novel agents, a closely-watched regulatory metric. Three of the four recent new molecular entity approvals came at least one month before the user fee goal date.

Another approval, a new indication for Merck & Co., Inc.’s Keytruda, came less than one month after the sBLA was submitted, as the FDA’s Real-Time Oncology Review (RTOR) pilot and other regulatory initiatives continue to trim reviews to racing speed.

The FDA’s ongoing efforts to reduce the potential SARS-CoV-2 exposure of patients receiving cancer treatment saw two more approvals that could allow at-home administration.

Inqovi, Rukobia And Dojolvy In The Fast Lane

Unmet medical need remains a primary driver of FDA assessments that come in ahead of the user fee goal date, FDA’s recent approvals show.

Otsuka subsidiary Astex Pharmaceuticals, Inc.’s Inqovi (decitabine/cedazuridine), an oral treatment for myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), was approved on 7 July, five weeks before the 11 August user fee goal. ViiV Healthcare’s Rukobia (fostemsavir), the first in a new class of antiretroviral drug, was approved 2 July for heavily treatment-experienced, multidrug-resistant HIV; it had a 4 August goal.

Both Inqovi and Rukobia received priority review, as do most of the agency’s faster-than-goal approvals. Rukobia also hold a breakthrough therapy designation. The approval of Ultragenyx Pharmaceutical Inc.’s Dojolvi (triheptanoin), a source of calories and fatty acids for patients with long-chain fatty oxidation disorders (LC-FAOD), on 30 June was notable for coming about one month before the expected standard review user fee goal on 31 July. 

While it did not receive priority review, Dojolvi does hold an orphan drug designation. Inqovi is also an orphan drug. While Rukobia does not hold an orphan designation, it is intended as a last resort.

FDA described Rukobia as a treatment for HIV patients “who have tried multiple HIV medications and whose HIV infection cannot be successfully treated with other therapies because of resistance, intolerance or safety considerations.”

Cosmo Pharmaceuticals N.V.’s Byfavo (remimazolam), on the other hand, received a standard review for a widely applicable use as a “very rapid onset/offset” IV benzodiazepine sedative during invasive medical procedures lasting 30 minutes or less, a category including colonoscopy and bronchoscopy. Byfavo was approved on 2 July, after the goal date was extended three months from 5 April 2020.

[For more detail on NME and novel biologic approvals, see the Pink Sheet FDA Performance Tracker’s Novel CDER Approvals chart.]

Keytruda Snaps Up MSI-H CRC Claim, But Loses AA Eligibility With Lenvima In HCC

Merck’s Keytruda (pembrolizumab) franchise earns approvals at a steady – and fast – clip, but the FDA’s 29 June clearance of an sBLA that had just been submitted on 1 June 2020 is still remarkable.

The approval made Keytruda the first immunotherapy approved for first-line treatment of unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer, the FDA noted.

The approval took advantage of a full range of FDA’s regulatory initiatives, including the popular Real-Time Oncology Review (RTOR) pilot program that has been behind most of the agency’s most eyebrow-raising quick reviews, the Assessment Aid submission template, and the international collaboration Project Orbis. (Also see "Keytruda And FDA’s Oncology Center of Excellence: The Regulatory Milestones Keep Coming" - Pink Sheet, 1 Jul, 2020.)

The Keytruda MSI-H or dMMR CRC approval is also only the third to use the Summary Level Review program, which “allows FDA to rely on qualified data summaries to support approval of a supplemental application,” FDA said.

Summary Level Review was previously used in the approval of ibrutinib for Waldenstom macroglobulinemia in August 2018 and Faslodex monotherapy for HR-positive, HER2-negative advanced breast cancer in postmenopausal women not previously treated with endocrine therapy in August 2017.

A complete response letter announced 8 July for the combination of Keytruda and Lenvima in first-line unresectable hepatocellular carcinoma (HCC) appears to be more about the technicalities of accelerated approval than it is about deficiencies in the Keytruda/Lenvima applications.

The sBLAs used the AA process to rely on data from a single-arm Phase Ib trial, KEYNOTE-524/Study 116, that measured objective response rate and duration of response, the companies said, and also earned a breakthrough therapy designation.

However, Before the Merck and Eisai Co., Ltd. applications reached their user fee goal, “another combination therapy was approved based on a randomized, controlled trial that demonstrated overall survival,” Merck and Eisai explained.

FDA approved Genentech, Inc.’s Tecentriq (atezolizumab) and Avastin (bevacizumab) together for HCC patients without prior systemic therapy on 29 May 2020 (about two months before the Genentech sBLAs’ user fee goal), on the basis of a Phase III trial comparing Tecentriq/Avastin with Bayer AG’s Nexavar (sorafenib). (Also see "Keeping Track: Tecentriq, Cyramza Celebrate ASCO With New Indications; Brilinta Moves Earlier In Coronary Artery Disease" - Pink Sheet, 7 Jun, 2020.)

“Consequently, the CRL stated that Merck’s and Eisai’s applications do not provide evidence that Keytruda in combination with Lenvima represents a meaningful advantage over available therapies for the treatment of unresectable or metastatic HCC with no prior systemic therapy for advanced disease,” the companies said.

Merck and Eisai already have a well-controlled Phase III trial fully enrolled and underway to meet the demands of regular approval. The LEAP-002 trial is comparing the Keytruda/Lenvima combination against Lenvima monotherapy, which is approved for first-line HCC.

Eisai has experience with the unusual circumstance of having a candidate for accelerated approval derailed by a new therapeutic landscape after approval of a different agent. Its breast cancer drug Halaven (eribulin) lost its chance at accelerated approval when Bristol-Myers Squibb’s Ixempra (ixabepilone) in the same highly refractory population, but was later approved with Phase III data showing an overall survival benefit. (Also see "Halaven Survival Data Was Gold-Standard Lining In Forced Shift From Accelerated To Full Approval" - Pink Sheet, 1 May, 2011.)

[Follow the progress of both new and supplemental applications for FDA approval with the Pink Sheet FDA Performance Tracker’s User Fee Goal Dates chart.]

Dosing Improvements In The Spotlight

At-home administration was highlighted by the FDA in approval announcements for Genentech’s Phesgo (pertuzumab, trastuzumab and hyaluronidase-zzxf) for early HER2-positive breast cancer on 29 June and Otsuka’s Inqovi on 7 July.

Inqovi combines the established hypomethylating agent decitabine (Otsuka’s IV Dacogen) with cedazuridine, a cytidine deaminase inhibitor that permits oral delivery of decitabine. “The FDA is making available an oral outpatient treatment option that can reduce the need for frequent visits to health care facilities,” Oncology Center of Excellence director Richard Pazdur stated in FDA’s press release. “At this critical time, we continue to focus on providing options to patients with cancer, including regimens that can be taken at home.”

Approval of Inqovi was based on ASCERTAIN, a 138-patient clinical trial that found similar drug concentrations between IV decitabine and Inqovi. “Additionally, about half of the patients who were formerly dependent on transfusions were able to no longer require transfusions during an eight-week period,” FDA said. The safety profile was also similar to IV decitabine.

The Inqovi review used the OCE’s Assessment Aid, and is also one of the first to use the Office of Pharmaceutical Quality’s Assessment Aid. FDA also collaborated internationally under Project Orbis.

Genentech’s Phesgo was approved about four months ahead of its goal date, the FDA noted. “Currently, most patients with HER2-positive breast cancer receive trastuzumab and pertuzumab at infusion centers,” FDA said. “Phesgo is initially used in combination with chemotherapy and could continue to be administered at home by a qualified health care professional once the chemotherapy regimen is finished.”

Phesgo was approved on the basis the Phase III FeDeriCa trial, a non-inferiority study which demonstrated comparable efficacy and safety to IV pertuzumab (Perjeta) and IV trastuzumab (Herceptin) in patients with HER2-positive early breast cancer. Administration-related reactions were higher with Phesgo “due to the subcutaneous route of administration,” FDA reported. Phesgo combines the oncologic MAbs with Halozyme’s hyaluronidase-based Enhanze technology.

Genentech reported that a cross-over Phase II trial, PHranceSCa, found that 85% of its 160 subjects preferred the subcutaneous to the IV route.