Keeping Track Of Breakthroughs: AZ Farxiga, ImmunoGen ADC For Hematologic Cancer, Inventiva NASH Candidate Earn Designation
Executive Summary
The latest breakthrough therapy designation news and highlights from the Pink Sheet’s US FDA Performance Tracker.
The US Food and Drug Administration’s recent grants of breakthrough therapy designations stand in very different therapeutic spaces. AstraZeneca PLC’s established antidiabetic Farxiga (dapagliflozin) won its first BTD for treatment of patients with chronic kidney disease, a common condition with more than 4 million diagnosed cases in the US. Inventiva S.A.'s lanifibranor was tapped for treatment of non-alcoholic steatohepatitis, which affects 3% to 12% of US adults, according to the US National Institutes of Health
ImmunoGen, Inc.’s antibody-drug conjugate candidate IMGN632, on the other hand, earned a BTD for treatment of relapsed or refractory blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare hematologic cancer that the NIH estimates accounts for less than 1% of all acute leukemias.
Farxiga BTD Rests On Renal Outcomes Trial DAPA-CKD
Data showing Farxiga’s potential to slow the progression of CKD in the DAPA-CKD study, a 4,304-patient renal outcomes trial, supported the FDA’s award of a BTD to the sodium-glucose co-transporter 2 (SGLT2) inhibitor, AstraZeneca announced 2 October.
The DAPA-CKD trial was stopped early in March 2020 because of “overwhelming efficacy.” Results of the trial, showed that Farxiga on top of standard of care reduced the risk of a primary endpoint event – a composite of worsening renal function, cardiovascular death or renal death – by 39% compared to placebo plus SoC. “The absolute risk reduction (ARR) was 5.3% over the median time in study of 2.4 years,” AstraZeneca said. The results were presented at the virtual European Society of Cardiology meeting on 30 August.
The trial also found that Farxiga reduced the relative risk of all-cause death, a key secondary endpoint, by 31%. (Also see "DAPA-CKD Data Put AstraZeneca’s Farxiga Out Front" - Scrip, 31 Aug, 2020.)
The DAPA-CKD results were consistent between patients with and without type 2 diabetes, and the BTD specifies use both groups of CKD patients. Indeed, AZ noted that the trial makes Farxiga “the first SGLT2 inhibitor proven to significantly prolong the survival of patients with chronic kidney disease with and without type 2 diabetes.”
ImmunoGen’s IMGN632 Is Second CD123-Targeting BPDCN Therapy With BTD
ImmunoGen can expect a boost to the development of the antibody-drug conjugate IMGN632 from a BTD announced 5 October, a potential boon as it follows Menarini Group’s Elzonris (tagraxofusp-erzs, SL-401) in the BPDCN space.
Elzonris, which also holds a BTD for BPDCN, became the first approved therapy for the cancer when it was approved in December 2018 based on a single-arm trial in 13 treatment-naïve and 15 relapsed or refractory BPDCN patients. (Also see "Keeping Track Of The US FDA's Final Approvals Of 2018" - Pink Sheet, 2 Jan, 2019.)
The IMGN632 BTD specifies treatment of relapsed or refractory BPDCN patients. The designation is supported by the BPDCN cohort in the first-in-human Phase I/II study of IMGN632; another cohort enrolled relapsed or refractory acute myeloid leukemia patients.
Interim data from the IMGN632 trial showed responses in three of nine BPDCN patients. All the responding patients had received prior Elzonris, and two had also received intense chemotherapy.
Updated data from a IMGN632 monotherapy dose expansion cohort in BPDCN will be presented at the American Society of Hematology meeting in December, ImmunoGen said.
Both Elzonris and IMGN632 target CD123, also known as the interleukin-3 receptor. The ImmunoGen antibody-drug conjugate uses the company’s novel indolino-benzodiazepine (IGN) payload, which the company says can “alkylate DNA without crosslinking.” Elzonris is comprised of human IL-3 recombinantly fused to truncated diphtheria toxin.
BTD Confirms Lanifibranor As Leader Of The NASH Pack (For Now)
A breakthrough therapy designation for its lead product candidate, lanifibranor, will give Inventiva a boost as it prepares for a Phase III trial expected to begin in the first half of 2021.
Inventiva’s 12 October announcement of a BTD for lanafibranor for was the first such announcement for a treatment of non-alcoholic steatohepatitis (NASH) since 2015, Inventiva noted. Intercept Pharmaceuticals, Inc., the recipient of that 2015 BTD for obeticholic acid (OCA), announced a complete response letter for its NASH NDA 29 June.
The paucity of BTDs for NASH does not reflect the crowded R&D landscape for the liver disorder, although it does suggest the clinical challenges in the space. Genfit SA’s elafibranor became the latest drug to fail a high-profile NASH trial when it missed the primary endpoint in the Phase III RESOLVE-IT trial in May. (Also see "RESOLVE-IT Failure Dashes Genfit's NASH Hopes" - Scrip, 12 May, 2020.)
Elafibranor, like lanifibranor, belongs to the widely studied peroxisome proliferator-activate receptor (PPAR) agonist class. However, Inventiva points out that lanifibranor targets all three PPAR isoforms; elafibranor is a dual PPAR alpha/delta agonist. “While there are other PPAR agonists that target only one or two PPAR isoforms for activation, lanifibranor is the only pan-PPAR agonist in clinical development,” Inventiva said.
Inventiva emphasizes the “balanced” and “moderately potent” PPAR binding profile of lanifibranor. The drug’s “moderate and balanced pan‑PPAR binding profile contributes to the favorable tolerability profile that has been observed” in development, the company said.
The BTD rests on the Phase IIb NATIVE trial, which randomized 247 NASH patients to lanifibranor or placebo. Inventiva announced in June that lanifibranor met the primary endpoint – reduction in the steatosis activity fibrosis (SAF) score from baseline at six months with no worsening of fibrosis – in topline data. (Also see "Inventiva Moves Up In NASH, Hitting Multiple Phase IIb Endpoints" - Scrip, 17 Jun, 2020.) Phase IIb results will be presented at the Liver Meeting Digital Experience, to be held virtually on 13-16 November 2020.
“The main purpose of the trial was to assess the efficacy of lanifibranor in improving liver inflammation and ballooning, the two histological markers included in the definition of the regulatory endpoint of NASH resolution,” Inventiva said. The SAF score “combines assessments of hepatocellular inflammation and ballooning,” the company noted. NASH resolution is among the NATIVE secondary endpoints.
“In particular, lanifibranor achieved statistically significant effects on NASH resolution with no worsening of fibrosis and improvement of fibrosis with no worsening of NASH, the US Food and Drug Administration (FDA) and European Medicine Agency (EMA) primary endpoints relevant for seeking accelerated approval during future Phase III clinical development,” Inventiva said.