Keeping Track: Bad News For Bristol And Lilly, Good News For TG Therapeutics

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

Here's your US drug review and approval news news in brief: Industry may have some relief on the horizon with President Trump and congressional leaders agreeing to a three-week continuing resolution to re-open the government, but it was a bad week for two big pharmas in Bristol-Myers Squibb Co. and Eli Lilly & Co.

For Bristol, it was another disappointment for its PD-1 inhibitor Opdivo (nivolumab). The drugmaker has withdrawn its supplemental biologics license application (sBLA) for its Opdivo/Yervoy (ipilimumab) combination in the first-line treatment of non-small cell lung cancer (NSCLC) as it waits for a fuller dataset from the CheckMate 227 trial.

Lilly, meanwhile, disclosed that its soft tissue sarcoma (STS) therapy Lartruvo (olaratumab) failed to confirm its benefit in a postmarketing trial after receiving accelerated approval. The drug now risks joining the small list of cancer drugs that have had an accelerated approval indication withdrawn.

In better news, TG Therapeutics Inc. scored what appears to be the first breakthrough therapy designation awarded to a marginal zone lymphoma (MZL) treatment for its PI3K delta inhibitor umbralisib.

Additionally, Janssen Biotech Inc. and Genmab AS have initiated a Darzalex (daratumumab) sBLA submission for a first-line indication in multiple myeloma under the FDA Oncology Center of Excellence’s Real-Time Oncology Review (RTOR) pilot program.

Now, here's your news in less brief:

Opdivo/Yervoy sBLA Withdrawal Delays Bristol's Quest For First-Line Lung Cancer Indication

An overall survival (OS) analysis was not enough for Bristol to bring Opdivo into the first-line NSCLC arena, as the drugmaker announced in a Jan. 24 earnings release that it voluntarily withdrew the sBLA for the PD-1 inhibitor in combination and Yervoy.

Bristol was specifically seeking an approval for Opdivo and low-dose Yervoy for the first-line treatment of advanced NSCLC in patients with tumor mutational burden (TMB) ≥10 mutations/megabase (mut/Mb). (Also see "Bristol Stuck In Waiting Game As Opdivo TMB Gamble Fails To Pay Off" - Scrip, 24 Jan, 2019.) FDA extended the combination's goal date to May 20, 2019 after Bristol submitted an exploratory OS analysis for the TMB <10 mut/Mb subgroup from CheckMate 227. (Also see "Keeping Track: Pfizer’s Talzenna Ensures Record Year For Novel US Approvals; Novartis Submits SMA Gene Therapy" - Pink Sheet, 21 Oct, 2018.)

However, "After recent discussions with the FDA, the company believes further evidence on the relationship between TMB and PD-L1 is required to fully evaluate the impact of Opdivo plus Yervoy on OS in first-line NSCLC patients," the company said in reporting its 2018 financial results.

Bristol continued it will need the final data from Part 1a of CheckMate 227, which is evaluating Opdivo plus low-dose Yervoy or Opdivo monotherapy versus chemotherapy in patients whose tumors express PD-L1. The results are anticipated in the first half of 2019, although the company noted that, "Since these data from Checkmate -227, Part 1a, will not be available within the review cycle of the current application the company decided to withdraw."

While Bristol has stumbled in first-line NSCLC development, Merck & Co. Inc.'s PD-1 inhibitor Keytruda (pembrolizumab) has surged ahead in this space. (Also see "Merck's Keytruda Enjoys Clean Sweep In Lung Cancer, At Bristol's Expense" - Scrip, 17 Apr, 2018.) and (Also see "First-Line Chemo Combo Data Help Merck's Keytruda Power Past Opdivo" - Scrip, 29 Jul, 2018.)

Bristol, meanwhile, has continued to prop up the scientific importance of TMB, which refers to the number of mutations in tumor cells. But the most recent setback has raised more questions about its viability as a biomarker. (Also see "Bristol Stuck In Waiting Game As Opdivo TMB Gamble Fails To Pay Off" - Scrip, 24 Jan, 2019.) and (Also see "TMB Biomarker Is A Winding Path Rather Than Straight Road" - Scrip, 14 Jun, 2018.)

Lilly's Lartruvo Could Be Headed For Rare Accelerated Approval Withdrawal

With Lilly announcing that its STS therapy Lartruvo failed to confirm its clinical benefit in a confirmatory trial, the platelet-derived growth factor receptor alpha (PDGFR-α) blocking antibody could be the first oncology drug to have an accelerated approval indication withdrawn since 2013.

FDA first awarded accelerated approval to Lartruvo in October 2016 in combination with the chemotherapy drug doxorubicin for the treatment of adults with STS who cannot be cured with radiation or surgery and who have a type of STS for which chemotherapy is appropriate. The combination demonstrated an overall survival benefit in a 133-patient Phase II study. (Also see "Lilly's Lartruvo Scores Broad FDA Approval In Orphan Sarcomas" - Pink Sheet, 19 Oct, 2016.)

But on Jan. 18, Lilly reported that both the overall study population and the leiomyosarcoma (LMS) sub-population receiving Lartruvo/doxorubicin failed to meet the OS primary endpoint in the Phase III ANNOUNCE trial. According to Lilly, "there was no difference in survival between the study arms for either population."

FDA said Jan. 24 that it is "currently reviewing the data and working with the company to determine appropriate next steps." Both Lilly and the agency instructed patients to consult their physician about the continued use of Lartruvo as the next steps are assessed, and cautioned against initiating any new treatment with the drug.

Lartruvo would be joining rare company if the approval is withdrawn. The last oncology drug to have an accelerated approval rescinded was GlaxoSmithKline PLC's non-Hodgkin's lymphoma Bexxar (tositumomab) in October 2013, specifically for a supplemental indication for patients who had not previously received Genentech Inc.’s Rituxan (rituximab). GSK did not complete the confirmatory trial and voluntarily withdrew the indication, and ultimately discontinued manufacturing the drug entirely. (Also see "The ABCs Of Accelerated Approval Withdrawals" - Pink Sheet, 28 Oct, 2013.)

In total, there have only been five accelerated approval indications withdrawn for oncology or hematology drugs since the pathway's inception in 1992. FDA issued a total of 93 accelerated approval indications to such drugs through May 2017. (Also see "Accelerated Approval: US FDA Defends Size Of Premarket Safety Databases, Confirmatory Endpoints" - Pink Sheet, 5 Mar, 2018.)

TG Lands BTD For Umbralisib With Eye On Full Approval

TG Therapeutics appears to have its eye on landing the first full approval for a marginal zone lymphoma (MZL) treatment after receiving a breakthrough therapy designation for its PI3K delta inhibitor umbralisib.

The company noted in a Jan. 22 announcement that there are no fully approved agents for the treatment of MZL, which involves a group of slow growing B-cell non-Hodgkin lymphomas (NHLs) that begin forming in the marginal zone of lymphoid tissue.

The only product with a labeled indication for MZL is AbbVie Inc./Johnson & Johnson's Imbruvica (ibrutinib), a Bruton's tyrosine kinase (BTK) inhibitor that received accelerated approval in 2017 for the treatment of patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy. (Also see "Keeping Track: Trulance Is First Novel Drug Of 2017; Vantrela ER Is Year's Second Abuse-Deterrent Opioid" - Pink Sheet, 22 Jan, 2017.)

TG's breakthrough status is also for patients who have received at least one prior anti-CD20 regimen. The designation is based on interim data from the MZL cohort of the open-label UNITY-NHL Phase IIb registration-directed trial, which is evaluating umbralisib as a monotherapy in subjects who have received at least one prior anti-CD20 regimen. Other cohorts in the trial are evaluating umbralisib regimens in patients with relapsed or refractory diffuse large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma and mantle cell lymphoma.

TG CEO Michael Weiss said in a statement that the company will report top-line results from the umbralisib monotherapy cohort of UNITY-NHL by mid-year and present the data at a major medical meeting later this year.

According to clinicatrials.gov, the primary endpoint of the trial is overall response rate (ORR), while the secondary endpoint is progression-free survival (PFS). Imbruvica received accelerated approval for the MZL based on a response rate endpoint, although AbbVie and J&J did not use PFS as an endpoint. Instead, FDA required the companies assess PFS as the primary endpoint in the confirmatory trial. The approval letter for Imbruvica's MZL indication states that the required completion date for the confirmatory trial is May 2019 and the final report submission is due by August 2019.

The breakthrough status for umbralisib appears to be the first such designation for an MZL product.

Celgene Corp., recently acquired by Bristol, is also pursuing an approval in MZL for its thalidomide analogue Revlimid (lenalidomide) in combination with rituximab. The drugmaker announced results from the AUGMENT trial in July 2018, where the combination achieved a statistically significant improvement in PFS compared with rituximab plus placebo. (Also see "Pipeline Watch: Top-line Phase III Results For KX2-391, Dasotraline And Brigatinib" - Scrip, 30 Jul, 2018.) Celgene said at the time that it is preparing for global regulatory submissions in the first quarter of 2019.

Darzalex MAIA Data To Take Real-Time Oncology Review Pathway To Label

Janssen Biotech and Genmab are hoping for a quick route to an expanded first-line indication in multiple myeloma for the CD38-targeting monoclonal antibody Darzalex. Genmab announced that Janssen had submitted the first part of an sBLA under the FDA Oncology Center of Excellence’s RTOR pilot program on Jan. 22.

The application, based on the Phase III MAIA (MY3008) study, would add an indication for use of Darzalex in combination with lenalidomide (Celgene’s Revlimid) and dexamethasone (a regimen known a D-Rd) to treat newly diagnosed multiple myeloma patients who are not candidates for high dose chemotherapy and autologous stem cell transplant (HSCT)

The RTOR pilot program, which was unveiled by FDA Commissioner Scott Gottlieb at the 2018 American Society of Clinical Oncology (ASCO) meeting in June, allows sponsors to submit key efficacy and safety tables/figures and datasets, proposed labeling and other information, prior to complete dossier submission. The pilot is open to supplemental applications for oncologics deemed likely to demonstrate substantial improvements over available therapies, that have straightforward study designs and endpoints that can be easily interpreted. (Also see "Real-Time Oncology Review Has Sponsors Rethinking What Data To Share With US FDA And When" - Pink Sheet, 26 Nov, 2018.)

FDA has approved four applications under RTOR, including expanded indications for Kisqali (ribociclib), Kyprolis (carfilzomib) and Adcetris (brentuximab vedotin) and conversion of a Keytruda accelerated approval to full approval. Thanks to the early access to data under the pilot program, the RTOR approvals have come after some eye-popping short reviews – Adcetris’ approval for newly diagnosed peripheral T-cell lymphoma on Nov. 16 came less than two weeks after submission. (Also see "Keeping Track Of Approvals: Cancer, Cancer, And A Two-Week Cancer Review" - Pink Sheet, 18 Nov, 2018.)

FDA is already familiar with Darzalex as a treatment for multiple myeloma. The antibody is approved for first-line use in HSCT-ineligible myeloma patients in combination with bortezomib, melphalan, and prednisone. That background regimen is used more commonly in Europe than in the US, where the lenalidomide and dexamethasone (Rd) regimen used in MAIA is the standard of care. Darzalex is indicated for use with the Rd regimen for multiple myeloma patients who have had at least one prior therapy, and for monotherapy in heavily pretreated patients.

The MAIA trial enrolled 737 patients, 44% of who were aged 75 years or older. Data presented at the December 2018 American Society of Hematology meeting showed that with a median follow-up of 28 months, the primary progression-free survival endpoint had not been met in the D-Rd arm but was 31.9 months in the Rd control arm, significantly reducing risk of death by 44%. (Also see "Imbruvica Replaces Chemo, Darzalex Boosts Standard Of Care In Front-Line CLL, Myeloma" - Scrip, 4 Dec, 2018.)

Merck's Pifeltro, Delstrigo sNDAs Land September Goal Dates

Merck is moving right along in pursuing broader use for its HIV drugs Pifeltro (doravirine) and Delstrigo (doravirine, lamivudine and tenofovir disoproxil fumarate), as the drugmaker reeled in two Sept. 20, 2019 standard review goal dates for its supplemental new drug applications (sNDAs).

The company is seeking a new indication for both products in treating people living with HIV-1 who are switching from a stable antiretroviral regimen and whose virus is suppressed.

The Phase III DRIVE-SHIFT trial "met its primary endpoint, demonstrating non-inferior efficacy of switching to DELSTRIGO (doravirine/lamivudine (3TC)/tenofovir disoproxil fumarate (TDF)) compared with continuing on a baseline regimen of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a boosted protease inhibitor, boosted elvitegravir, or NNRTI," Merck said in a Jan. 22 statement.

"Non-inferior efficacy was measured by the proportion of participants who switched to DELSTRIGO and had plasma HIV-1 RNA levels <50 copies/mL at Week 48 compared to the proportion of participants who continued on their baseline regimen and had HIV-1 RNA levels <50 copies/mL at Week 24," the company continued.

Pifeltro, which contains doravirine monotherapy, and Delstrigo, a fixed-dose combination tablet that features doravirine, lamivudine and tenofovir disoproxil fumarate, were first cleared by FDA in August 2018 for the treatment of HIV-1 infection in adults with no prior antiretroviral treatment experience. (Also see "Keeping Track: Busy August Ends With Approval For Doravirine, CRLs For Dasotraline And Waylivra " - Pink Sheet, 3 Sep, 2018.)

Sanofi Pasteur Touts Convenience With New Fluzone Quadrivalent Dose Approval

Sanofi Pasteur says a broader approval for its 0.5 mL Fluzone Quadrivalent (influenza vaccine) dose will be more convenient for pediatricians by providing a single option for all patients.

FDA extended the use of the vaccine's 0.5 mL dose to children ages 6 months to 35 months, who were previously only eligible for the 0.25 mL dose.

"Offering pediatricians, the convenience of the same 0.5 mL dose option for children, may help streamline immunization efforts," said David Greenberg, Sanofi Pasteur's regional medical head for North America.

Approval was based on a Phase IV safety and immunogenicity study conducted in nearly 2,000 children. According to the company, the vaccine "demonstrated that one or two doses of 0.5 mL of vaccine in children 6 through 35 months of age had a safety profile that was comparable to one or two doses of 0.25 mL of vaccine with no new safety concerns observed, and induced a robust immune response."