Keeping Track: Oncology Submissions From Blueprint, Y-mAbs, BMS/bluebird; Approvals For BMS’ Reblozyl, LFB’s SevenFact

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

Oncology products took center stage last week, thanks to submissions for Blueprint Medicines Corp.’s targeted therapy pralsetinib, Y-mAbs’ antibody therapeutic naxitamab, bluebird bio Inc. and Bristol-Myers Squibb Co.’s CAR-T immunotherapy idecabtagene vicleucel, and, for the second time, Aveo Pharmaceuticals Inc.’s targeted therapy tivozanib.

Zealand Pharma AS and Rhythm Pharmaceuticals Inc. also announced new submissions, for rescue pen to treat hypoglycemia in diabetics and a new drug for two ultra-rare inherited obesity conditions.

But first, here’s your approval (or not) news in brief:

The Center for Biologics Evaluation and Research approved its third novel agent of 2020 on 1 April: Sevenfact, a recombinant analog of human coagulation factor VII expressed in the milk of genetically engineered rabbits. “During purification and processing of the milk, FVII is converted into activated FVII (FVIIa),” the FDA explained.

Sevenfact is the first US biologic approval for Laboratoire Francais du Fractionnement et des Biotechnologies S.A., a French company known as LFB SA that is focused on therapeutic proteins both plasma-derived and recombinant.

“Sevenfact is the first product for hemophilia treatment that contains an active ingredient obtained from rabbits genetically engineered to produce a protein necessary for blood coagulation,” CBER director Peter Marks stated in the FDA approval announcement. “This approval is an example of our efforts to advance safe biotechnology innovations."

Sevenfact is indicated for treatment and control of bleeding episodes occurring in adults and adolescents aged 12 years and older with hemophilia A or B with inhibitors (neutralizing antibodies). The BLA rests on a 27-patient study that included 465 mild or moderate bleeding episodes and three severe episodes.

The Center for Drug Evaluation and Research posted approvals for new indications for AstraZeneca PLC’s immuno-oncologic Imfinzi and Bristol-Myers Squibb and Acceleron Pharma Inc.’s erythroid maturation agent Reblozyl, Curium’s lung imaging agent Pulmotech MAA, and a new IV formulation of Rockwell Medical Inc.’s iron replacement product Triferic.

Data from the Phase III CASPIAN trial supported the FDA’s 27 March approval of Imfinzi (durvalumab) for first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) in combination with standard of care chemotherapy with etoposide plus a platinum agent (cisplatin or carboplatin). The CASPIAN trial found that addition of Imfinzi to SoC reduced the risk of death by 27%.

“Imfinzi is the only immunotherapy to show both a significant survival benefit and improved response rate in combination with chemotherapy for these patients,” AstraZeneca said.

BMS/Acceleron’s Reblozyl (luspatercept-aamt) received FDA approval on 3 April for treatment of anemia in patients failing an erythropoiesis stimulating agent and requiring two or more red blood cell (RBC) units over 8 weeks in adults with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).

Reblozyl was originally approved in November 2019 for treatment of anemia in adults with beta thalassemia who require regular RBC transfusions. The new indication is based on the Phase III MEDALIST trial, which met the primary endpoint when “a significantly greater proportion of patients receiving Reblozyl achieved independence from RBC transfusions for at least eight weeks during the first 24 weeks of the trial compared with those receiving placebo,” the companies said.

Pulmotech MAA (technetium Tc 99m albumin aggregated injection) cleared FDA on 20 March 2020, but Curium notes that is has “marketed a similar version of MAA (macroaggregated albumin) in Europe for more than a decade.”

The FDA granted two claims for the radioactive diagnostic agent: use in lung scintigraphy as an adjunct in the evaluation of pulmonary perfusion and to aid in the evaluation of peritoneovenous shunt patency. The pulmonary perfusion claim includes adult and pediatric patients; the shunt patency claim is for adults only.

Rockwell’s new formulation of Triferic (ferric pyrophosphate citrate), known as Triferic AVNU, expands the administration options for the physiologic iron maintenance product, which is used to maintain hemoglobin in adults with hemodialysis-dependent chronic kidney disease. Triferic was approved in 2015 for delivery with liquid bicarbonate via dialysate.

The new formulation, approved 27 March, is given direct intravenous infusion and thus can be used regardless of the way a clinic generates bicarbonate. (Also see "Keeping Track: A Busy Week For Regenerative Medicine, A Surprise Priority Review For Vascepa, And Tazemetostat Aims For Accelerated Approval" - Pink Sheet, 1 Jun, 2019.)

IntelGenx has been pursuing approval of Rizaport, an orally dissolving film formulation of rizatriptan to treat acute migraine therapy, since 2013. On 27 March, the company announced that FDA had issued a complete response letter – Rizaport’s third. The first two letters raised chemistry, manufacturing and controls issues. The new CRL requests “additional information, but no new bioequivalence study,” IntelGenx said.

Four Breakthrough Therapies, Three Fast Track Drugs Stand Out In Flurry Of Submissions

Bristol-Myers Squibb and bluebird bio are hoping for a perch in the increasingly active multiple myeloma space from idecabtagene vicleucel (ide-cel), which became the first B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T cell therapy to reach FDA with a BLA submission announced 31 March. Ide-cel holds a BTD for previously treated multiple myeloma.

The ide-cel BLA seeks an indication for treated of adults with multiple myeloma who have received at least three prior therapies, including an immunomodulatory drug, a proteasome inhibitor and an anti-CD38 antibody. The submission rests on the Phase II KarMMa study.

Blueprint Medicines announced the completion of a rolling NDA submission for pralsetinib on 1 April, in line with predictions. (Also see "Keeping Track: Ayvakit Approval, Keytruda Supplement, NME Submissions " - Pink Sheet, 12 Jan, 2020.)

Pralsetinib was “specifically designed for highly potent and selective targeting of oncogenic RET alterations.

The company seeks an indication for treatment of RET fusion-positive non-small cell lung cancer. Pralsetinib holds a BTD for patients who have progressed following platinum-based chemotherapy, but the NDA appears to include first-line patients as well. In the pivotal ARROW trial, 80 patients with RET-fusion NSCLC who had received prior platinum chemo posted a 61% overall response rate, while the 26 patients with no prior systemic therapy had a 73% ORR, Blueprint reported on a February investor call.

Y-mAbs is seeking accelerated approval for naxitamab, an monoclonal antibody that targets the cell surface antigen GD2 licensed from Memorial Sloan-Kettering Cancer Center, for treatment of patients with relapsed or refractory high-risk neuroblastoma. Naxitamab holds a BTD in combination with CM-CSF for high-risk NB patients older than 12 months who are refractory to initial therapy or with incomplete response to salvage therapy and who have persistent, refractory disease limited to bone marrow.

Y-mAbs completed the rolling BLA submission on 1 April. The application draws on the pivotal Phase II studies 201 and 12-230. NB is an almost exclusively pediatric cancer, and FDA has issued a rare pediatric disease designation for naxitamab. If approved, Y-mAbs will earn a priority review voucher. (Also see "Keeping Track, Oncology Edition: Biologic Breakthroughs And BLAs" - Pink Sheet, 10 Dec, 2019.)

The company highlighted the potential advantages of naxitamab over United Therapeutics’ approved GD2-targeting Unituxin (dinutuximab). “Unlike currently approved GD2‑targeting therapies for NB, which require 10 to 20 hours of infusion and hospitalization for several days, naxitamab is administered in approximately 30 minutes in an outpatient setting,” Y-mAbs said. “We believe this significantly shorter administration time is an important advantage considering the overall pain associated with treatment.”

Rhythm Pharmaceuticals announced the completion of its first NDA submission on 30 March. The company is seeking priority review of setmelanotide, a melanocortin-4 receptor (MC4R) agonist, for treatment of two ultra-rare genetic disorders, pro-opiomelanocortin (POMC) deficiency obesity and leptin receptor (LEPR) deficiency obesity. The user fee goal is likely to fall in late November.

In addition to the fast track status that allowed a rolling NDA submission, setmelanotide holds a BTD for treatment of obesity associated with genetic defects upstream of the MC4R in the central melanocortin pathway, which includes both of the conditions included in the NDA. Phase III trials found reductions in weight, body mass index and BMI z-scores (standard deviation) compared with historical controls. (Also see "Keeping Track: Biosimilars, Novel Approvals, And Ebola" - Pink Sheet, 10 Nov, 2019.)

Zealand Pharma submitted an NDA for a HypoPal rescue pen formulation of its glucagon analog dasiglucagon for treatment of hypoglycemia in people with diabetes. The drug has “a unique stability profile in a ready-to-use aqueous solution,” the company said in its 31 March announcement. In three Phase III trials, the median time to blood glucose recovery was 10 minutes following dasiglucagon injection.

Seven years after receiving a complete response letter, Aveo Oncology is trying again for FDA approval of the VEGFR tyrosine kinase inhibitor tivozanib to treat relapsed or refractory renal cell carcinoma (RCC). The new NDA submission, announced 31 March, includes a new Phase III trial, the TIVO-3 study, in addition to data from the TIVO-1 trial that supported the earlier NDA. (Also see "Aveo Eyes Role For Tivozanib In US Kidney Cancer Market, Against The Odds" - Scrip, 6 Nov, 2018.)

Mixed top-line results from the TIVO-3 trial, which compared tivozanib with Bayer’s Nexavar (sorafenib), raised concerns with regulators in Europe, where the drug is approved as Fotivda, and the US. (Also see "Aveo's Tivozanib Under CHMP Spotlight If Negative OS Trend Continues In TIVO-3" - Scrip, 4 Apr, 2019.)

A final analysis based on a 1 May 2020 data cutoff date could be decisive: FDA and Aveo agreed that if the final analysis yields an overall survival hazard ratio (OS HR) above 1.00, “the company will withdraw its NDA.”