CFB

Novartis' Fabhalta may be the first approved for complement 3 glomerulopathy, but it may not be the only one soon, as Apellis is also angling its Empaveli for the same kidney disease. Novartis’ kidney disease troika keeps marching forward.With a new FDA approval, the company’s Fabhalta has become the first treatment endorsed by the agency for the ultrarare kidney disease complement 3 glomerulopathy (C3G). But analysts spotted several shortfalls in the drug’s label, leaving more to be desired—and potential room for improvement for rival Apellis.Thursday’s approval clears Fabhalta to reduce excessive protein in the urine—a phenomenon called proteinuria—in adults with C3G.“This approval of Fabhalta is historic for the entire C3G community as now, for the first time, we have a therapy that is believed to treat the underlying cause of the disease, providing the potential for a new standard of care for patients,” Carla Nester, M.D., at the University of Iowa, said in a statement.About one to two people per million worldwide are diagnosed with C3G each year, according to a Novartis estimate based on a 2020 study. The disease is marked by the buildup of C3 protein in the kidney glomeruli as a result of overactivation of the alternative complement pathway, triggering inflammation and kidney damage. Fabhalta works by inhibiting complement factor B, blocking activation of C3.Data from the phase 3 Appear-C3G trial initially showed that treatment with Fabhalta led to a statistically significant 35% relative reduction in proteinuria from baseline, as measured by 24-hour urine protein-to-creatinine ratio (UPCR), compared with placebo after six months. Nester was an investigator of the study.Then 12-month data found that Fabhalta’s proteinuria benefit was maintained after one year. And in patients who switched from placebo to Fabhalta, the magnitude of 24-hour UPCR improvement, at 31%, was similar to the outcome seen in the original Fabhalta group during a six-month testing period.C3G marks Fabhalta’s third U.S. indication, following its approval in paroxysmal nocturnal hemoglobinuria (PNH) in 2023 and IgA nephropathy (IgAN) last year.“It’s a molecule nephrologists already know, and we’re going to fully synergize our launch with the presence that we already have amongst these nephrologists,” Victor Bulto, president of Novartis U.S., said in an interview with Fierce Pharma ahead of the latest FDA approval. While Fabhalta is the first drug to enter the C3G field, it may soon have company. Apellis is also angling its Sobi-partnered C3 inhibitor Empaveli (pegcetacoplan) for a C3G nod. And by analysts’ observations, Apellis has better efficacy data.In the phase 3 Valiant trial, Empaveli led to a 68% relative reduction in proteinuria versus placebo after six months.Despite differences in trial design and baseline patient characteristics, analysts at Citi and William Blair view Empaveli as the winning C3G med between the two. And according to the team at William Blair, so too did Nester.Nester presented both trials’ results at the 2024 American Society of Nephrology Kidney Week conference in October. When asked about her expectation of commercial uptake for the two drugs, “she noted that physicians will be choosing based on efficacy, and pegcetacoplan has shown the best efficacy so would likely get the majority of patients,” William Blair analysts wrote in an October note.Novartis’ Bulto argued that C3G is a very heterogeneous disease, and the measurements of proteinuria can be highly variable, making cross-trial comparisons difficult.Rather than precise proteinuria numbers, doctors are really hoping to see stabilization of patients’ estimated glomerular filtration rate (eGFR), which is a key measurement of kidney function, Bulto argued.In Appear-C3G, Fabhalta appeared to confer eGFR stability through one year, compared with disease progression prior to treatment. However, the mean improvement of 1.3 mL/min/1.73m2 at six months was not statistically different from the 0.9 mL/min/1.73m2 deterioration seen with placebo.As the Fabhalta label now states, “there was no difference between arms in the proportion of patients with stable or improved eGFR compared to baseline at 6 months (90% in Fabhlata vs 89% in placebo).”That might be why the FDA’s approved indication for Fabhalta in C3G has specific language stating that it’s used “to reduce proteinuria.”In contrast, in Valiant, Empaveli showed a relative eGFR improvement of 6.3 mL/min/1.73m2 over placebo after six months. This represents an opportunity for Empaveli to earn a broader label without the proteinuria language, Evercore ISI analysts said in a Thursday note.However, to Bulto’s point of heterogeneity among C3G patients, Empaveli patients actually logged a 1.5 mL/min/1.73m2 eGFR decline from baseline in Valiant, although that was better than the 7.8 mL/min/1.73m2 drop seen in the placebo group. The Empaveli eGFR showing was not formally significant in Valiant thanks to the trial’s statistical design. Apellis’ study included adolescents. Novartis’ only enrolled adults, leading to an adult-only FDA label; Novartis has noted that the average age of diagnosis is around 23 years old. In addition, in the efficacy section, the FDA label specifies that Fabhalta’s profile has not been established in C3G patients following kidney transplant, whereas Empaveli has data in that population.“Overall, it looks to us like FDA label for [Novartis] includes specific language keeping the door open for [Apellis] to have a clearly differentiated label—on both breadth and efficacy,” the Evercore team said.There’s one potential advantage for Fabhalta, though—it’s an oral drug, while Empaveli is an injection.“We also hear from the patient community, if they can achieve that efficacy with an oral therapy, that's always a layer of preference as well,” Bulto said.Fabhalta is one of three meds that Novartis is developing against kidney diseases from different mechanisms of action. The company is also expecting an FDA decision on endothelin A receptor antagonist atrasentan in IgAN and is working on anti-APRIL antibody zigakibart.Commercially, Novartis is bringing “several products” and “several capabilities” in kidney diseases, Bulto noted. Apellis, in contrast, has one single asset here.

In 2024, China approved several new drugs, and more blockbuster drugs are expected to be launched in 2025, covering oncology, autoimmune diseases, rare diseases, and other therapeutic areas.   Drug Name Mechanism of Action Indications Development Institutions Evantuzumab c-Met/EGFR bispecific antibody Non-small cell lung cancer Johnson & Johnson; Genmab Taqetuzumab CD3/GPRC5D bispecific antibody Multiple myeloma Johnson & Johnson; Genmab Zenidatuzumab Anti-HER2 bispecific antibody Biliary tract cancer Zymeworks; Jazz Pharmaceuticals; BeiGene Inalises PI3Kα inhibitor HR-positive breast cancer Roche; Chugai Pharmaceutical Asunitinib STAMP allosteric inhibitor Speculated use for chronic myeloid leukemia treatment Novartis Tazemetostat EZH2 inhibitor Follicular lymphoma Epizyme; Huadong Medicine; Eisai Relatuzumab-alpha PDL1/TGF-β bispecific antibody Stomach cancer; gastroesophageal junction cancer Hengrui Medicine; Dong-A Pharma Vabysmo EGFR antibody-drug conjugate Nasopharyngeal cancer Lepu Biopharma Tenapanor NHE3 inhibitor Chronic kidney disease hyperphosphatemia Ardelyx; Kyowa Kirin; Fosun Pharma; AstraZeneca Mersutide OXM analog; GLP-1R/GCGR agonist Obesity Eli Lilly; Innovent Biologics Vusirumab IL-1β monoclonal antibody Gouty arthritis Junshi Biosciences Romosozumab SOST monoclonal antibody Osteoporosis Astellas; Amgen; UCB Teplizumab CD3 monoclonal antibody Type 1 diabetes Ligand Pharmaceuticals; Johnson & Johnson; Sanofi Solrepinib Syk inhibitor Immune thrombocytopenic purpura Huadong Medicine BBM-H901 Factor IX gene therapy Hemophilia B Gene Therapy Fitusiran RNAi therapy Hemophilia A; Hemophilia B Sanofi; Alnylam Andexanet alfa Recombinant factor Xa Factor Xa inhibitor antidote Portola Pharmaceuticals Lisocabtagene maraleucel IL-23p19 monoclonal antibody Crohn's disease Boehringer Ingelheim; AbbVie Lemborexant & Daridorexant OX1R antagonist; OX2R antagonist Insomnia Eisai & Idorsia; Sihuan Pharmaceutical; Nxera Pharma Highlights of new drug approvals in 2024 include: 1. Oncology: The world’s first antibody-drug conjugate (ADC) targeting folate receptor alpha (FRα) for ovarian cancer: Mirvetuximab soravtansine. PD-1/VEGF bispecific antibody envafolimab and Nectin-4 ADC enfortumab vedotin. 2. Autoimmune diseases: IL-17A/F monoclonal antibody bimekizumab for ankylosing spondylitis. 3. Rare diseases: Novartis’ complement factor B inhibitor for paroxysmal nocturnal hemoglobinuria (PNH).   Blockbuster drugs expected to be approved in 2025 include: Oncology: Amivantamab (Q1) The world’s first c-Met/EGFR bispecific antibody. Highlight: Phase III study showed significant extension of median progression-free survival (mPFS). Talquetamab (Q2) A CD3/GPRC5D bispecific antibody and the world’s first drug targeting GPRC5D. Clinical results: Objective response rate (ORR) in Chinese patients was 69.0%-73.6%. Zanidatamab (Q2) A HER2-targeting bispecific antibody based on Azymetric™ technology. Indication: HER2-positive biliary tract cancer (BTC) with an ORR of up to 52%. Inavolisib (Q3) Roche’s highly selective PI3Kα inhibitor for PIK3CA-mutated breast cancer. Asciminib (Q3) Novartis’ Bcr-Abl allosteric inhibitor for Philadelphia chromosome-positive chronic myeloid leukemia (CML). SHR-1701 (Q4) A PD-L1/TGF-βRII bifunctional fusion protein for first-line treatment of gastric cancer. Phase III study demonstrated significant extension in median overall survival. MRG003 (Q4) China’s first EGFR-targeting ADC with remarkable efficacy in nasopharyngeal carcinoma. Endocrinology and Metabolism: Tenapanor (Q1) The world’s only approved NHE3 inhibitor for controlling hyperphosphatemia in chronic kidney disease patients. Trend Analysis: Continued Innovation in Oncology: The emergence of multiple bispecific antibodies and ADC drugs is making targets and treatment options more precise and diverse. Breakthroughs in Autoimmune and Rare Diseases: New biologics are gradually addressing drug resistance and limited treatment options in previous therapies. Emergence of Domestic Innovative Drugs: Examples include SHR-1701 and MRG003, highlighting the growing research and development capabilities of Chinese pharmaceutical companies.   The sequential launch of these drugs will provide new therapeutic options for Chinese patients and enhance China’s position in the global pharmaceutical market.

– Interim data from Phase 1/2a study demonstrate near complete inhibition in hemolytic activity and functional activity of alternative complement pathway PASADENA, CA, USA I December 11, 2024 I Arrowhead Pharmaceuticals, Inc. (NASDAQ: ARWR) today announced interim results from a Phase 1/2a clinical study of ARO-CFB, the company’s investigational RNA interference (RNAi) therapeutic targeting complement factor B being developed as a potential treatment for complement mediated diseases. The data were presented today, December 11, 2024, at the 8th Complement-Based Drug Development Summit being held in Boston. “Dysregulated activation of the complement system can lead to progression of certain renal diseases, either by playing a directly pathogenic role, or by amplifying or exacerbating the inflammatory and damaging impact of non-complement disease triggers. In a Phase 1/2a clinical study, ARO-CFB treatment in healthy volunteers achieved deep and durable reductions in the liver production of complement factor B (CFB), which is involved in alternative complement pathway activation and associated with pathogenesis of diseases involving complement activation. Circulating levels of CFB protein were reduced by a mean of up to 90% to date, with additional data from higher doses levels pending, and a duration of response greater than 3 months,” said James Hamilton, M.D., MBA, Chief of Discovery and Translational Medicine at Arrowhead. “ARO-CFB also demonstrated dramatic reductions in measures of alternative complement pathway activation, with mean reductions at or approaching 100% in AH50 and Wieslab AP at multiple dose levels. These interim results in healthy volunteers give us confidence in the potential of ARO-CFB as we seek to complete Part 1 of the study over the coming months, and subsequently look ahead to Part 2 of the study in patients with immunoglobulin A nephropathy, which is the most common glomerular disease worldwide.” Select ARO-CFB Results In the ongoing AROCFB-1001 study, ARO-CFB achieved the following key results in normal healthy volunteers as of the interim data cutoff – 15 November 2024: Safety and Tolerability Results ARO-CFB has been generally well-tolerated to date with safety data supportive of further clinical development. There have been no treatment emergent adverse events (TEAE) leading to study or study drug discontinuation with most TEAEs being mild in severity. About ARO-CFB ARO-CFB is designed to reduce hepatic expression of complement factor B (CFB), which plays an important regulatory role in amplifying complement alternative pathway activation and has been identified as a promising therapeutic target. ARO-CFB is being developed as a potential treatment for complement mediated kidney diseases such as immunoglobulin A nephropathy (IgAN), which is the most common glomerular disease worldwide and carries a high lifetime risk of progression to end-stage renal disease. Additionally, ARO-CFB may have clinical applications in non-renal diseases involving complement activation. About the AROCFB-1001 Phase 1/2 Study AROCFB-1001 ( NCT06209177 ) is an ongoing Phase 1/2a dose-escalating study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO-CFB in up to 66 normal healthy volunteers (NHV) and patients with complement mediated kidney disease. In Part 1 of the study, NHVs will receive either one or two doses of ARO-CFB or placebo. In Part 2 of the study, adult patients with IgAN will receive 3 open-label doses of ARO-CFB. The study is designed to assess safety and tolerability and key pharmacodynamic parameters, including the change and percent change from baseline over time in serum CFB, and alternative complement pathway activity via AH50 and Wieslab AP. About Arrowhead Pharmaceuticals Arrowhead Pharmaceuticals develops medicines that treat intractable diseases by silencing the genes that cause them. Using a broad portfolio of RNA chemistries and efficient modes of delivery, Arrowhead therapies trigger the RNA interference mechanism to induce rapid, deep, and durable knockdown of target genes. RNA interference, or RNAi, is a mechanism present in living cells that inhibits the expression of a specific gene, thereby affecting the production of a specific protein. Arrowhead’s RNAi-based therapeutics leverage this natural pathway of gene silencing. For more information, please visit www.arrowheadpharma.com , or follow us on X (formerly Twitter) at @ArrowheadPharma , LinkedIn , Facebook , and Instagram . To be added to the Company’s email list and receive news directly, please visit http://ir.arrowheadpharma.com/email-alerts . SOURCE: Arrowhead Pharmaceuticals