Pharmaceutical Business Review International’s Post

Novartis has shared positive results from a late-stage trial of its factor B inhibitor Fabhalta (iptacopan) in patients with the ultra-rare kidney disease complement 3 glomerulopathy (C3G). Approximately one to two people per million worldwide are diagnosed every year with C3G, which occurs when an over-activation of the alternative complement pathway causes deposits of C3 protein to build up in kidney glomeruli. This triggers inflammation and glomerular damage that results in proteinuria (protein in urine), haematuria (blood in urine) and reduced kidney function, with about 50% of C3G patients progressing to kidney failure within ten years of diagnosis. The ongoing phase 3 APPEAR-C3G study has been evaluating the safety and efficacy of a twice-daily 200mg dose of Fabhalta in C3 patients. Results, which were presented at this year’s European Renal Association Congress, showed that patients treated with Fabhalta in addition to supportive care achieved a 35.1% reduction in proteinuria at six months, compared to placebo plus supportive care. Data on the secondary endpoint of estimated glomerular filtration rate, a measure of kidney function, also showed improvements over six months with Fabhalta compared to placebo, and Novartis’ therapy demonstrated a favourable safety profile with no new safety signals observed. APPEAR-C3G steering committee member, David Kavanagh, Newcastle University, said: “Fabhalta is the first potential treatment that targets the alternative complement pathway in C3G, and its impact on measures of kidney damage and kidney function in this study, in addition to its safety profile, is encouraging for patients and the clinical community.” The trial will continue with an additional six-month, open-label period, in which all patients will receive Fabhalta, including those who were in the placebo cohort of the double-blind period. Read more: https://lnkd.in/eZKzTw5T

Bristol Myers Squibb: phase 3 trials, enrolled 251 patients, promising outcome Long-Term Follow-Up Data from Phase 3 Study of CAMZYOS® (mavacamten) Underscores Established Efficacy and Safety Profile in Patients with Symptomatic Obstructive Hypertrophic Cardiomyopathy (oHCM) Cumulative analysis of data up to 3.5 years from EXPLORER-LTE showed consistent and sustained improvements in echocardiographic measures and symptoms, with no new safety signals observed CAMZYOS is the first and only approved cardiac myosin inhibitor that targets the source of symptomatic obstructive hypertrophic cardiomyopathy At the data cutoff, 211 of 231 patients who enrolled in MAVA-LTE, of which EXPLORER-LTE is a cohort, were on CAMZYOS; 185 and 99 patients had reached Week 156 and 180, respectively. Key findings from the EXPLORER-LTE data analysis showed sustained improvements from baseline to Weeks 156 and 180 in echocardiographic measures and biomarkers. In echocardiographic markers, patients experienced a reduction of 55.3 mmHg in Valsalva LVOT gradient at both Week 156 and 180 and a reduction of 40.2 mmHg and 40.3 mmHg in mean resting LVOT gradient at Week 156 and 180, respectively. Improvements from baseline to Weeks 144 and 180 were sustained in mean left atrial volume index, with patients experiencing a reduction of 3.5 mL/m2 and 5.5 mL/m2, respectively. The mean left ventricular ejection fraction (LVEF) decreased by 11% from baseline to Week 180, and the mean (63.9%) remained within normal range. Evaluation of biomarker data showed that median NT-proBNP levels decreased by 504 ng/L at Week 156 and 562 ng/L by Week 180. At Week 180, most patients (66.3%) were NYHA class I. Overall, 108 patients (46.8%) achieved a complete response — defined as achieving NYHA class I and a Valsalva LVOT gradient of ≤30 mmHg during the study and retained a complete response until the data cutoff. Patient-reported outcomes as measured by the HCM Symptom Questionnaire (HCMSQ) found improvement in shortness of breath score from baseline with treatment during the first 12 weeks and was sustained through Weeks 156 and 180. “These results, representing the longest duration of follow up of the Phase 3 EXPLORER study to date, further reinforce the established safety and efficacy profile of CAMZYOS,” said Roland Chen, MD , senior vice president and head of Immunology, Cardiovascular & Neuroscience (ICN) Development at Bristol Myers Squibb. https://lnkd.in/e2G_Dfj3

Sanofi and Regeneron’s Dupixent (dupilumab) has been approved by the European Commission (EC) to treat eosinophilic oesophagitis (EoE) in young patients. The drug has been specifically authorised for use in children aged one to 11 years who weigh at least 15kg and are inadequately controlled by, intolerant to, or are not candidates for conventional medicinal therapy. Dupixent, which is already approved by the regulator to treat EoE in patients aged 12 years and older, is now the first and only medicine in the EU indicated for use in this younger patient population. EoE is a chronic inflammatory disease that results in a range of symptoms, including difficulty swallowing, vomiting and pain. The EC’s decision follows a recent recommendation from the European Medicines Agency’s human medicines committee and was based on positive results from the phase 3 EoE KIDS trial, in which 68% of children aged one to 11 years receiving Dupixent achieved histological disease remission at week 16 compared to 3% in the placebo group, with results sustained for up to one year. Dupixent demonstrated an 86% reduction in peak oesophageal intraepithelial eosinophil count from baseline compared to a 21% increase for placebo, and showed reductions in abnormal endoscopic findings, as well as disease severity and extent. Improvements in the frequency and severity of EoE signs were also observed in Dupixent-treated patients, and safety results were generally consistent with the known safety profile of the drug in adult and adolescent patients. Dupixent is designed to inhibit the signalling of the interleukin-4 and interleukin-13 pathways, shown in the Dupixent development programme to be central drivers of the type 2 inflammation that plays a major role in multiple related diseases, including EoE. Read more: https://lnkd.in/eeMtiRif Stay in touch with all the leading stories, events and opportunities by subscribing to my weekly LinkedIn Newsletter here:  https://bit.ly/3KQs0mD

Adicet Bio, Inc. today announced the opening of enrollment for the Phase 1 clinical trial evaluating ADI-001 in autoimmune diseases. “The favorable safety profile, cellular kinetics and B cell depletion in peripheral blood and secondary lymphoid tissue demonstrated with ADI-001 clinical experience to date, positions ADI-001 to potentially bring a paradigm shift in the treatment of autoimmune diseases,” said Francesco Galimi, MD PhD, M.D., Ph.D., Senior Vice President and Chief Medical Officer of Adicet Bio. “We expect to have several additional sites open for enrollment by the end of the fourth quarter of 2024, and further increase the number of active sites during the first quarter of 2025. At this time, our sites are open to enroll patients with LN, and we plan to initiate enrollment of patients with SLE, SSc, and AAV in the fourth quarter of this year. We look forward to reporting preliminary clinical data from this trial of ADI-001 in LN as well as SLE, SSc, and AAV in the first half of 2025.” This announcement follows the U.S. Food and Drug Administration’s (FDA) decision to grant Fast Track Designation to ADI-001 for the treatment of relapsed/refractory class III or class IV LN and clearance from the FDA to develop ADI-001 in four autoimmune indications, including LN, SLE, SSc, and AAV. The Phase 1 study has three separate arms, enrolling LN and SLE patients into one arm, SSc patients into a second arm and AAV patients into a third arm. Enrolled patients will receive a single dose of ADI-001. The dose-limiting toxicity window is 28 days with response and safety assessments conducted on Day 28 and during the follow up period on months 3, 6, 9, 12, 18 and 24. The primary objectives of the study are to evaluate the safety and tolerability of ADI-001. Secondary objectives include measuring cellular kinetics, pharmacodynamics, changes in autoantibody titers, and appropriate disease activity scores in each indication.

Sanofi’s Sarclisa (isatuximab) has been approved by the US Food and Drug Administration (FDA) as part of a first-line combination treatment for adults with newly diagnosed multiple myeloma (NDMM). The anti-CD38 therapy has been authorised alongside standard-of-care bortezomib, lenalidomide, and dexamethasone (VRd) to treat NDMM patients who are not eligible for autologous stem cell transplant. The FDA’s decision was supported by positive results from the late-stage IMROZ trial, in which Sarclisa plus VRd followed by Sarclisa/Rd reduced the risk of disease progression or death by 40% compared to VRd followed by Rd. Median progression-free survival (PFS) with the Sarclisa/VRd combination was not reached after a median follow up of 59.7 months versus 54.3 months with Vrd, and the estimated PFS at 60 months was 63.2% for patients treated with Sarclisa/VRd compared to 45.2% for those receiving VRd. Benefits were also seen across the trial’s secondary endpoints, with approximately 74.7% of patients in the Sarclisa/VRd cohort achieving a complete response (CR) compared to 64.1% of those in the VRd group, and 55.5% of Sarclisa/VRd-treated patients reaching minimal residual disease negative CR compared to 40.9% of those receiving Vrd. Multiple myeloma (MM) is the second most common haematological malignancy, with approximately 32,000 people in the US diagnosed with the disease every year. Despite available treatments, MM remains incurable and newly diagnosed patients have a five-year survival rate of about 52%. Read more: https://lnkd.in/gBWxnNRw Stay in touch with all the leading stories, events and opportunities by subscribing to my weekly LinkedIn Newsletter here:  https://bit.ly/3KQs0mD

"🎉 Congratulations to the team on this significant achievement! Your research on optimizing vancomycin therapeutic drug monitoring compliance in pediatric oncology is a vital step towards personalized medication management. The dedication and collaborative effort from all the authors are commendable. This work highlights the importance of precision in medication management to improve patient outcomes. We are proud to support and celebrate your contributions to advancing healthcare standards. Well done! 👏 #HealthcareExcellence #PersonalizedMedicine #Pharmacovigilance #PediatricOncology **Interactive Questions:** 1. **Why is therapeutic drug monitoring (TDM) important in pediatric oncology?** - **Answer:** TDM is crucial in pediatric oncology to ensure the correct dosage of medication is administered, optimizing therapeutic effects while minimizing toxicity, especially in vulnerable populations like children. 2. **How does personalized medication management improve patient outcomes?** - **Answer:** Personalized medication management tailors treatment to individual patient needs, leading to more effective therapy, reduced side effects, and improved overall patient outcomes. 3. **What are the challenges in optimizing vancomycin TDM compliance in pediatric patients?** - **Answer:** Challenges include varying pharmacokinetics in children, ensuring adherence to monitoring protocols, and the need for frequent blood sampling, which can be difficult in pediatric patients. 4. **What impact does research like this have on global healthcare standards?** - **Answer:** This research contributes to setting higher standards for precision in medication management, influencing global healthcare practices to improve patient care and safety. Share your thoughts and join the discussion! How can we further enhance therapeutic drug monitoring in pediatric care? #ResearchImpact #HealthcareInnovation الف مبروك 🎉 https://lnkd.in/dzmQiiUP https://lnkd.in/dSpuv5GH

Nearly 40K in the US have PAH 🫁 Which often leads to death.  But a new medicine did well in Phase 3…! 👍 “In the phase 3 ZENITH study, Merck’s activin signaling inhibitor Winrevair, also known as sotatercept, met its primary endpoint of time to first morbidity or mortality event—which included all-cause death, lung transplantation, or hospitalization for at least 24 hours linked to disease worsening—and helped reduce the risk of morbidity or mortality events versus placebo in adults with pulmonary arterial hypertension (#PAH) in functional class III or IV. (Patients in the trial’s study drug and control arms both received background PAH therapy.) The World Health Organization ranks the severity of patients’ PAH according to functional classes I through IV, with I being the mildest and IV the most severe form of the disease. Winrevair’s original FDA approval in late March leveraged data from the late-phase STELLAR trial, which assessed the drug in PAH patients in functional groups II or III. In PAH, the blood vessels narrow in the lungs, which causes blood pressure to increase, leading to heart failure. Roughly 40,000 people in the U.S. have the disorder, which often leads to death and strikes more women than men. Based on the latest results from ZENITH, which enrolled 172 patients, an independent data monitoring committee urged Merck to stop the study early and offer Winrevair to all patients via its SOTERIA open-label extension trial. With a positive readout in hand, Merck says it plans to present the detailed PAH data at an upcoming medical meeting and submit the results to global regulators. Following Winrevair’s U.S. approval earlier this year, the drug has picked up green lights in an additional 36 countries. By assessing Winrevair in PAH patients at functional class III or IV, Merck looked at the drug in people at high risk of mortality from their disease. Aside from the primary composite endpoint measuring time to first morbidity or mortality event, the study also assessed Winrevair on secondary outcome measures like overall survival, transplant-free survival and more. “PAH is a serious, progressive disease with a high incidence of morbidity and mortality," Eliav Barr, M.D., SVP and head of global clinical development and CMO for Merck Research Laboratories, said in a statement. "These findings are impressive, set a high evidentiary bar for studies of future candidates developed for the treatment of PAH and support the potential of Winrevair to be practice-changing in the management of PAH.” To make a name for itself in PAH, #Winrevair will need to compete with Johnson & Johnson’s prostacyclin receptor (IP) agonist blockbuster #Uptravi, as well as the New Jersey drug giant’s endothelin receptor agonist #Opsumit, which itself garnered $2 billion in 2023 revenue." Thanks to Fraiser Kansteiner for Fierce Pharma - links to news item & press release in the comments! #clinicaltrials 

Tolerability of Daratumumab Amongst Asian Patients with Plasma Cell Dyscrasias – A Single Centre Experience. Daratumumab is increasingly incorporated into the standard treatment regimens for patients with plasma cell dyscrasias in Asia, especially with cost-containment measures implemented by various regional health authorities. This analysis aimed to study daratumumab’s tolerability amongst Asian patients. This is a retrospective medical records review of patients who received daratumumab between November 2016 and August 2021 as part of routine clinical care. Sixty-two patients were included in the study: 62.9% had renal impairment, and 27.4% had creatinine clearance (CrCl) <30ml/min. Forty-five patients (72.6%) received daratumumab combination therapy, with a median 1 line of prior therapy. The median duration of follow-up was 12.4 months, and the median duration patients were on treatment with daratumumab was 12.3 months. Twenty-one of 62 (33.9%) patients experienced infusion-related reactions (IRRs) after the first dose of intravenous daratumumab. Seven developed mostly grades 1 and 2 respiratory events, and 14 showed grades 1 and 2 non-respiratory IRRs. Only one patient experienced a grade 1 IRR with the second infusion, with none developing any IRRs in the third or subsequent infusions. Eight (12.9%) patients were affected by hematological adverse events (AEs), mostly grades 2 and 3, with one experiencing grade-4 neutropenia without sepsis. Six (9.7%) patients experienced non-hematological AEs, the commonest being pneumonia and other infections, with one developing Nocardia pneumonia (grade 4) 14 months after the initiation of daratumumab. In conclusion, daratumumab is tolerable amongst Asian patients, including the elderly and patients with severe renal impairment and chronic lung diseases. https://lnkd.in/eNfYSsUr

Novo Nordisk has shared positive results from a late-stage study of its haemophilia A therapy, Mim8, which the company hopes to submit for regulatory approval towards the end of this year. Haemophilia A, a rare inherited bleeding disorder caused by a missing or defective clotting factor VIII, accounts for 80 to 85% of the 1,125,000 global haemophilia cases. Up to 30% of haemophilia A patients have inhibitors, an immune system response to the clotting factors in replacement therapy that causes treatment to stop working. Administered subcutaneously, Mim8 is designed to replace the function of the missing clotting factor VIII. The phase 3a FRONTIER 2 trial has been evaluating the efficacy and safety of a once-weekly and once-monthly dose of the candidate against both no prophylaxis and prior coagulation factor prophylaxis treatment in patients aged 12 years and older with or without inhibitors. The trial achieved its co-primary endpoints by demonstrating a statistically significant and superior reduction of treated bleeding episodes with both once-weekly and once-monthly Mim8 versus no prophylaxis and prior coagulation factor prophylaxis treatment. In patients with no prior prophylaxis treatment, once-weekly and once-monthly Mim8 demonstrated reductions of 97% and 99% in treated bleeds, respectively, compared to no prophylaxis treatment. In addition, 86% of patients with no prior prophylaxis treatment who received once-weekly Mim8 and 95% of those treated with once-monthly Mim8 experienced zero treated bleeds, compared to 0% of those treated with no prophylaxis. In the intra-patient analysis of patients with prior coagulation factor prophylaxis, once-weekly and once-monthly Mim8 demonstrated reductions of 48% and 43% in treated bleeds, respectively, compared to those who received only prior coagulation factor prophylaxis. Additionally, 66% of patients treated with once-weekly Mim8 and 65% of those receiving once-monthly Mim8 experienced zero treated bleeds. Read more: https://lnkd.in/eCjzr4S6 Stay in touch with all the leading stories, events and opportunities by subscribing to our LinkedIn Newsletter:https://bit.ly/3RbdKtc or joining some of the largest groups most relevant to you: https://bit.ly/4caKquL (A-Z list)

Results of the AQUILA trial were published in the NEJM after ASH.  This was a phase III trial which looked at 3 years of daratumumab vs observation in high-risk smoldering myeloma patients.  The trial met its primary endpoint of PFS.  There are several issues I would like to point out. First, the subsequent therapy was inferior.  If daratumumab was good enough to be compared to observation, it should be used as first-line therapy after observation.  Only 35/105 patients on the observation arm received a CD38 antibody.  That's not enough crossover, considering that daratumumab likely has a small carryover effect.  In the CASSIOPEIA trial, which randomized patients to daratumumab or placebo before transplant, and then re-randomized after transplant, patients who received daratumumab only before transplant did just as well as patients who received daratumumab before and after transplant for the first 3-4 years after transplant.  That could explain why PFS after first progression and overall survival trended in favor of the daratumumab. Second, the definition of high-risk smoldering myeloma keeps changing.    If you look at their subgroup analysis, the patients drove the PFS benefit were the high-risk Mayo 2018 patients, which was about 40% of the patients in this trial.  And even then, for the high-risk Mayo patients, 2 in 5 patients did not have a progression event or death.  The definition of high-risk in this trial, which does not match how we define high-risk today, is probably too broad. Third, in the discussion, the authors state that "close monitoring alone may not prevent the occurrence of clinically significant end-organ damage in patients with high-risk smoldering multiple myeloma."  That was not demonstrated in this publication, as end-organ damage data was not presented.  There's other information missing in this publication, like the proportion of patients who received a transplant after first progression.  Quality of life data appears to be only have been tracked until the first progression event.  If the argument is that patients have worse quality-of-life earlier, possibly issues after transplant, there is no data presented in this publication for that. Overall, this trial doesn't answer the question as to whether we should treat high-risk smoldering myeloma or not.  For any trials that compare against observation, the experimental arm should be mandated as subsequent therapy.  It's not a surprise that an agent that works in the first line setting works in smoldering, compared against nothing.  If we gave daratumumab to everyone in the world, it would probably reduce progression events to myeloma.  That's not the question to ask in trials that compare to observation.   #darzalex #darzalexfaspro #myeloma #multiplemyeloma #ash24 #ash2024 https://lnkd.in/eDUiqdcC