Justify Durvalumab dose: CDSCO Panel Tells AstraZeneca on Study of Dato-DXd and Durvalumab

New Delhi: Reviewing the drug major AstraZeneca’s Phase III clinical trial protocol of the anti-cancer drug of Dato-DXd and Durvualumab, the Subject Expert Committee (SEC) functional under the Central Drug Standard Control Organisation (CDSCO) has recommended the firm to submit supportive documents for the selection of Durvalumab dose of 1120mg every three weeks instead of 1500mg.

Furthermore, the expert panel suggested to include more geographically distributed government sites.

This came after the drug major AstraZeneca presented Phase III clinical trial protocol No. D7630C00001. This study is a phase III study of Dato-DXd with or without Durvalumab compared with the investigator’s choice of chemotherapy in combination with Pembrolizumab in patients with PD-L1 positive locally recurrent inoperable or Metastatic Triple-negative Breast Cancer (TNBC).

This is a Phase III, randomised, open-label, 3-arm, a multicentre, international study assessing the efficacy and safety of Dato-DXd with or without durvalumab compared with investigator’s choice chemotherapy in combination with pembrolizumab in participants with PD-L1 positive locally recurrent inoperable or metastatic TNBC.

Datopotamab Deruxtecan (Dato-DXd), a Novel TROP2-directed Antibody–drug Conjugate, demonstrates potent antitumor activity by efficient drug delivery to tumor cells. The pharmacologic activity and mechanism of action of Dato-DXd were investigated in several human cancer cell lines and xenograft mouse models including patient-derived xenograft (PDX) models.

Durvalumab injection is in a class of medications called monoclonal antibodies. It works by helping the immune system to slow or stop the growth of cancer cells.

Durvalumab is used alone to treat non-small cell lung cancer (NSCLC) that spreads to nearby tissues and cannot be removed by surgery but has not worsened after being treated with other chemotherapy medications and radiation treatments. It is also used in combination with tremelimumab-actl (Imjudo) and platinum-based chemotherapy to treat a certain type of NSCLC that has spread throughout the lungs and to other parts of the body.

Durvalumab injection is also used in combination with chemotherapy agents to treat extensive-stage small cell lung cancer (ES-SCLC) in adults whose cancer has spread throughout the lungs and to other parts of the body. It is also used in combination with chemotherapy agents to treat biliary tract cancer (BTC; cancer in the organs and ducts that make and store bile, the liquid made by the liver) in adults whose cancer has spread to nearby tissues or to other parts of the body.

At the recent SEC meeting for Oncology and Hematology held on 21st and 22nd December 2023, the expert panel reviewed the Phase III clinical trial protocol No. D7630C00001.

After detailed deliberation, the committee opined that the firm should submit supportive documents for the selection of Durvalumab dose of 1120mg every three weeks instead of 1500mg and include more geographically distributed Govt. sites for further review by the committee.

Also Read: Justify Clinical Relevance of Higher Strength of Caroverine Capsules: CDSCO Panel Tells Lincoln Pharma

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Use of intra-articular vancomycin safe in primary hip and knee arthroplasty

The use of a single dose of intra-articular antibiotic (IAA) has been reported in reducing the rate of prosthetic joint injection after total hip and knee arthroplasty. A.W.R. Burns et al examined the safety of IAA in primary hip and knee replacement surgery and the blood levels and joint fluid levels of vancomycin utilising this technique. It has been published in “Journal of Orthopaedics.”

From August to October 2021, 68 patients undergoing primary total joint arthroplasty (THA & TKA) were given 1g vancomycin intra-articularly (IA) after closure of the fascia. All patients received 2g cefazolin intravenously (IV) 30 min prior to the procedure as is the standard prophylaxis, and 21 of the patients (IA + IV) were also administered an additional 1 gm vancomycin IV. Post-operative blood vancomycin, creatinine and eGFR level monitoring was performed day1 and day3. To determine the post-operative intra-articular vancomycin levels, surgical drain fluid was sampled at day 1 and 2, in 10 patients.

Key findings of the study were:

• In the group where vancomycin was injected after fascial closure, the average blood vancomycin level day 1 was 5.2 μg/ml (range 2.0–10.9) and day 3 was < 1.4 μg/ml.

• The average pre-op creatinine levels were 69.4 μmol/L (56.1–82.6) compared to 70.2 μmol/L (57.0–83.4) on day 1 and 66.1 μmol/L (52.6–79.6) on day 3, (p = 0.663).

• The average pre-op eGFR levels (ml/ min/1.73 m2) were 82.2 (76.0–88.3) compared to 81.7 (75.6–87.8) on day 1 and 83.0 (76.8–89.2) on day 3 (p = 0.736).

• Samples of joint fluid aspirated from surgical drains on day 1 and day 2 showed average vancomycin levels of 224 μg/ml and 51 μg/ml respectively, significantly higher than the MIC for Staph aureus.

The authors concluded that – “The use of IA vancomycin in TJA is appears safe, providing high antibiotic levels within the joint itself, with no renal or auditory complications in our investigation. Whilst role of IA antibiotics is evolving and its position in total joint replacement has not yet been fully determined, these finding may stimulate further study in this area of clearly significant importance in the prevention of PJI.”

Further reading:

The use of intra-articular vancomycin is safe in primary hip and knee arthroplasty

Alexander W.R. Burns, Tat Chao et al

Journal of Orthopaedics 46 (2023) 161–163

https://doi.org/10.1016/j.jor.2023.10.017

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Direct Percutaneous Endoscopic Jejunostomy Effective Alternative to surgical jejunostomy for Feeding Access

A recent retrospective study by John Locke and team suggests important inputs on the efficacy and safety of various methods for jejunostomy tube placements which provides enteral access for patients who are unable to meet nutritional needs orally. The findings were published in the journal of Gastrointestinal Endoscopy.

The study was conducted to compare procedural success rates and complications by examining three approaches: direct percutaneous endoscopic jejunostomy (DPEJ), laparoscopic (lap-J), and open laparotomy (open-J). These methods are imperative for patients who require alternative feeding routes due to their inability to consume sufficient nutrients orally.

The research was based on data from 201 patients which was classified into DPEJ, lap-J, and open-J cohorts, demonstrated comparable procedural success rates among the three groups (DPEJ 96.9%, Lap-J 99.1%, Open-J 100%, p=0.702). The infection and bleeding rates were also similar across the board with no reported cases of gastrointestinal perforation.

This study uncovered significant findings related to tube dysfunction within 90 days. The cases requiring complete removal and/or replacement were notably lower in the DPEJ group (0%) when compared to the surgical groups (lap-J 35.1%, open-J 40.0%, p<0.001). This discrepancy was primarily from increased incidents of tube clogging and dislodgement in the surgical approaches.

The findings of the study concludes that DPEJ emerges is a safe and effective alternative to surgical jejunostomy for eligible patients. DPEJ might offer a potential advantage beyond its efficacy by significantly reducing the complication rates at the critical 90-day mark. This outcomes are important for medical practitioners and patients who seek optimal enteral access solutions when considering the postoperative recovery and maintenance aspects of the jejunostomy tube placements.

Reference:

Locke, J., Norwood, D., Forrister, N., Ahmed, A. M., Aryan, M., Oster, R., Reddy, S., Kabir Baig, K. K., & Peter, S. (2023). Safety and Efficacy of Direct Percutaneous Endoscopic Jejunostomy Tube Placement Compared with Surgical Jejunostomy: A Tertiary Care Analysis. In Gastrointestinal Endoscopy. Elsevier BV. https://doi.org/10.1016/j.gie.2023.12.013

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Can transcranial magnetic stimulation damage or interact with implanted cardiac devices?

Germany: A recent study showed a low risk of implantable cardioverter-defibrillator (ICD) damage or overheating during transcranial magnetic stimulation (TMS), used for treating several neuropsychiatric disorders, even when stimulation was much stronger than normal. The findings were published online in JACC: Clinical Electrophysiology on January 3, 2024.

Multiple experiments indicated that electromagnetic therapy for depression shouldn’t damage a person’s pre-existing implantable cardioverter-defibrillator.

Felix Wegner, MD, of University Hospital Muenster, Germany, and colleagues had several Biotronik ICDs hooked up to an arrhythmia simulator and exposed ex vivo to magnetic stimulation, using MagStim equipment, with an increasing gradient during continuous device telemetry:

  • Biotronik Intica Neo 7 DR-T ICD programmed to the device’s MRI mode and asynchronous pacing (DOO 80/min): No interaction between magnetic stimulation and the device even at the maximum output. There were no significant changes in sensing amplitude, lead impedance, or thresholds.
  • Biotronik Intica Neo 7 DR-T ICD programmed to a dual-chamber mode: Atrial oversensing occurred at an output of 25% of maximum, leading to a pacemaker tachycardia which was correctly identified and terminated by the device. No significant changes in sensing amplitude, lead impedance, or thresholds were observed.
  • Biotronik Itrevia 7 VR-T Dx ICD programmed in a single-chamber mode: No signal interference detected up to an output of 50% of maximum. At the maximum possible output, intermittent ventricular oversensing of the stimulation impulse occurred. No significant changes in sensing amplitude, lead impedance, or thresholds were observed.

A last experiment revealed that a Biotronik Rivacor 5 VR-T Dx ICD, connected to a Medtronic Sprint Quattro Secure MRI SureScan 6947M dual-coil defibrillator lead and immersed in saline solution, stayed undamaged when it was programmed to a single-chamber mode and exposed to magnetic stimulation at an output of 70% of maximum and a repetition rate of 0.9 Hz for 15 minutes. Also, there was no change in the temperature of the saline bath.

“Our proof-of-principle experiments suggest that the risk of damage to an ICD and heating of an ICD may be low during magnetic stimulation, even when stimulation is delivered directly to the device,” the researchers wrote.

“We consistently used a far greater output at a far closer distance to the ICD than would be realistic for TMS/TCMS [transcutaneous magnetic stimulation].”

They suggested that in light of the high comorbidity of depression in cardiovascular disease and its distinct effect on outcomes and prognosis, this might add therapeutic options for a significant proportion of cardiac patients.

“Our data could encourage investigators using TMS/TCMS to include device patients in future studies after careful individual risk/benefit analysis,” they concluded.

They added that “Because only Biotronik ICD and Medtronic defibrillator leads were studied, research on pacemakers, ICD, and magnetic stimulation coils and generators of all types and manufacturers in more physiologic models of magnetic device interference is warranted.”

Reference:

Wegner, F. K., Bietenbeck, M., Suntrup-Krueger, S., Markman, T. M., Eckardt, L., & Wolters, C. (2024). Transcranial/Transcutaneous Magnetic Stimulation Interacts With But Does Not Damage Implantable Cardioverter-Defibrillators. JACC: Clinical Electrophysiology. https://doi.org/10.1016/j.jacep.2023.10.021

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Less dosage of Brexpiprazole efficient to treat agitation in dementia

Agitation in dementia is commonly reported and has a negative effect on patient functioning, health outcomes, and quality of life increases caregiver distress and time spent caring and may contribute to the patient being institutionalized. Brexpiprazole is a rarely prescribed antipsychotic that acts on noradrenergic, serotonergic, and dopaminergic neurotransmitter systems, which are implicated in the neurochemistry of agitation in Alzheimer disease.

Daniel Lee, MD and a team of researchers in a recent trial aimed to evaluate the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer dementia. They report that brexpiprazole, 2 mg/d or 3 mg/d, demonstrated a statistically significant reduction in agitation against placebo over 12 weeks. No treatment emergent showed adverse events with an incidence of 5% or greater with brexpiprazole and greater than placebo, and the discontinuation rates due to adverse events were similar across the groups. The findings of the trial are published in JAMA Neurology.

Researchers designed a randomized clinical trial was a 12-week, double-blind, placebo-controlled, fixed-dose, parallel-arm trial that ran from May 2018 to June 2022 at 123 clinical trial sites in Europe and the United States. Participants included patients with agitation in Alzheimer dementia in a care facility or community-based setting. Stable Alzheimer disease medications were permitted. In this 2-arm trial, patients were randomized to receive oral brexpiprazole or placebo (2:1 ratio) for 12 weeks. Within the brexpiprazole arm, patients were further randomized to receive fixed doses of 2 mg/d or 3 mg/d in a 1:2 ratio.

The primary end point was change in Cohen-Mansfield Agitation Inventory total score (which measures the frequency of 29 agitated behaviors) from baseline to week 12 for brexpiprazole, 2 or 3 mg, vs placebo. Safety was assessed by standard measures, including treatment-emergent adverse events.

The key findings of the trial are

• Out of 345 patients 288 were randomized to receive brexpiprazole and 117 placebo; completion rates were 198 (86.8%) for brexpiprazole and 104 (88.9%) for placebo.

• 225 patients receiving brexpiprazole, 2 or 3 mg, demonstrated statistically significantly greater improvement than those 116 taking placebo in Cohen-Mansfield Agitation Inventory total score from baseline to week 12 (brexpiprazole baseline, 80.6, mean change, −22.6; placebo baseline, 79.2, mean change, −17.3; least-squares mean difference, −5.32; 95% CI, −8.77 to −1.87; P = .003; Cohen d effect size, 0.35).

• No treatment-emergent adverse events had an incidence of 5% or more with brexpiprazole and greater incidence than placebo.

• The proportion of patients who discontinued because of adverse events was 12 of 226 (5.3%) for brexpiprazole and 5 of 116 (4.3%) for placebo.

Researchers concluded that “ In this study, patients with Alzheimer dementia who took brexpiprazole, 2 or 3 mg, showed a statistically significant improvement vs placebo in agitation over 12 weeks. Brexpiprazole was generally well tolerated over 12 weeks in this vulnerable patient population.”

Reference: Lee D, Slomkowski M, Hefting N, et al. Brexpiprazole for the Treatment of Agitation in Alzheimer Dementia: A Randomized Clinical Trial. JAMA Neurol. Published online November 06, 2023. doi:10.1001/jamaneurol.2023.3810

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GERD has no causal impact on susceptibility and prognosis of idiopathic pulmonary fibrosis

China: The link between gastroesophageal reflux disease (GERD) and its potential impact on susceptibility to idiopathic pulmonary fibrosis (IPF) may not be of a direct causal nature; it could be impacted by factors such as smoking, a recent Mendelian randomization (MR) study has revealed.

The findings published in BMC Pulmonary Medicine did not reveal any evidence of a causal relationship between GERD and the diffusing capacity of the lung for carbon monoxide (DLco), forced vital capacity (FVC), and transplant-free survival (TFS) of patients with IPF.

Idiopathic pulmonary fibrosis is a severe and progressive fibrotic lung disease. IPF patients have an abysmal prognosis, with a median survival of 3-5 years following the diagnosis and a survival rate of only 66% at three years after lung transplantation. GERD encompasses a constellation of distressing complications and symptoms that arise due to the reflux of stomach contents into the oesophagus.

Previous studies have shown a relationship between GERD and the susceptibility as well as the prognosis of IPF, with the potential confounding factor of smoking not adequately addressed. In light of this, Di Sun & Qiao Ye from Capital Medical University in Beijing, China, conducted an MR study to investigate the causal effects of GERD on the prognosis and susceptibility of IPF while excluding smoking.

GERD was chosen as the exposure variable and genome-wide association data was employed to examine its association with forced vital capacity, susceptibility, transplant-free survival, and diffusing capacity of the lung for carbon monoxide in IPF patients as the outcome variables.

The inverse variance weighted (IVW) method was used to perform MR analyses, and sensitivity analyses were conducted using the MR-Egger intercept test, MR-PRESSO outlier test, Cochran’s Q test, and leave-one-out sensitivity analysis. Additionally, a multivariable MR (MVMR) analysis by adjusting for smoking was conducted to mitigate the potential effects of smoking on MR estimates.

The study led to the following findings:

· The univariable MR analysis demonstrated no causal effect of GERD on FVC (βIVW = 26.63, SE = 48.23), DLco (βIVW = 0.12, SE = 0.12), and TFS (HRIVW = 0.87) in patients with IPF.

· Sensitivity analysis revealed no evidence of heterogeneity, horizontal pleiotropy, or outlier single nucleotide polymorphisms.

· The MVMR analysis showed no causal effect of GERD on susceptibility to IPF after adjusting for smoking (ORIVW = 1.30). These findings were consistent in the replication cohort.

“Our findings indicate that the association of GERD with susceptibility to IPF may not be directly causal and could be explained by confounding factors, particularly smoking,” the researchers wrote. “Furthermore, no observed causal effect of GERD on DLco, FVC, and TFS of idiopathic pulmonary fibrosis was found.”

Reference:

Sun, D., Ye, Q. Mendelian randomization analysis suggests no causal influence of gastroesophageal reflux disease on the susceptibility and prognosis of idiopathic pulmonary fibrosis. BMC Pulm Med 23, 517 (2023). https://doi.org/10.1186/s12890-023-02788-8

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Fortis Healthcare launches institute for specialised treatment of blood cancer, CAR T Therapy

New Delhi:  A well-known private healthcare group, Fortis on Friday inaugurated a state-of-the-art facility for the specialised treatment of blood cancers and disorders, which it said “represented a critical step” in addressing the urgent need for comprehensive holistic care.

The Fortis Institute of Blood Disorders also integrates paediatric and geriatric care, advanced transplant procedures, and hematopathology expertise, all under one roof, Fortis Healthcare said in a release. 

The Institute also launched CAR-T cell therapy to its extensive network of Bone Marrow Transplant centres in Mohali, Delhi, Gurgaon, Noida, Mumbai and Bangalore, the statement said.

Also Read: Fortis Healthcare to divest Fortis Malar Hospital, Chennai to MGM Healthcare for Rs 128 crores

This initiative is supported by a commercial collaboration with ImmunoACT, an IIT-Bombay spin-off and pioneer in India’s first fully indigenous and commercially approved gene-modified cell therapy.

The NexCAR19, India’s first market-authorised CAR-T cell therapy, offers a new ray of hope for treating B-cell lymphomas and B-acute lymphoblastic leukaemia in patients aged 15 and above, who have previously found limited success with other treatments.

Dr Ashutosh Raghuvanshi, MD and CEO, Fortis Healthcare, said, “The establishment of the Fortis Institute of Blood Disorders is a reflection of our unwavering commitment to medical excellence and patient-focused care. The integration of advanced CAR-T cell therapy across our Bone Marrow Transplant centres in India sets a new benchmark in the treatment of complex blood cancers.” “This initiative is a key part of our mission to offer the highest standard of care in precision medicine and comprehensive healthcare solutions,” he said. 

Medical Dialogues team had earlier reported that continuing with the aim of saving and enriching lives, Fortis Healthcare had joined hands with Coal India Limited (CIL) to treat underprivileged children suffering from thalassemia, under CIL’s flagship CSR Initiative ‘Thalassemia Bal Sewa Yojana’.

Also Read: IHH healthcare unit drags Daiichi Sankyo to court over Fortis Healthcare deal, claims 20 billion yen as damages

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NEET PG 2024 exam likely in July: Report

Not the National Exit Test (NExT), but the National Eligibility-cum-Entrance Test Postgraduate (NEET-PG) examination will continue to be the way of admission into post-graduate courses in 2024 also, sources have informed PTI.

The current PG medical entrance examination i.e. the NEET PG exam is likely to be held in the first week of July and the counselling is likely to be held in the first week of August, sources informed PTI on Saturday. Further, they informed that the NExT exam will not be held this year.

For more news & updates, check out the link given below:

No NExT This Year, NEET PG 2024 Exam Likely In July: Report

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Medical Colleges to be fined Rs 1 crore per seat, 2-year bar on admissions for violation: NMC PGMER 2023

New Delhi: Aiming to put an end to backdoor entries to PG medical courses, the National Medical Commission (NMC) has clarified that medical colleges and institutes will have to pay a fine for illegal admission, in violation of the rules and regulations.

If any student is admitted to a postgraduate course in any other way than counselling, or in violation of the Post-Graduate Medical Education Regulations (PGMER) 2023, then the concerned medical institute granting admission to such students shall have to pay a fine of Rs 1 crore per seat for non-compliance.

Further, if the medical institute continues such a practice, then the concerned institute shall be barred from granting admissions to any student in the subject for a minimum of two academic years from the next academic year.

The Commission also specified that the student, who gets admitted in such an illegal manner shall also be discharged from the medical college and double the number of seats shall be reduced from the concerned medical institute for one or more years.

Medical Dialogues had earlier reported that the final Post-Graduate Medical Education Regulations, 2023 (PGMER 2023), which were published in the official Gazette on 29.12.2023, lay down the rules and regulations regarding admission, counselling, and other details related to the postgraduate medical courses.

Also Read: NMC’s new rules spell out harsh penalties for Misrepresentation by Medical Teachers

Section 4.5 of the PGMER 2023 clarified that any student seeking admission to PG medical courses in any other way than Counselling shall be prohibited. It stated, “No medical institution shall admit any candidate to the Post-Graduate Medical Education courses (including super-speciality medical courses) in contravention of these regulations. Provided the medical institution granting admission to any student in contravention of these Regulations, shall be fined rupees one crore per seat for non-compliance.”

“For any subsequent non-compliance or continued contravention, the medical institution shall be barred from granting admissions to any student in the subject for minimum two academic years from the next academic year. Provided further that such Student admitted in contravention of this mandate shall be discharged from the Medical College and double the number of seats shall be reduced for one or more years,” further stated the regulations.

Several other ways have been prescribed by the National Medical Commission (NMC) to bring transparency in the admission process. Releasing the PGMER 2023, NMC has also made it mandatory to conduct counselling for postgraduate medical admissions via online mode only.

NMC clarified that all the rounds of counselling for all seats will be held via online mode by the State or Central Counselling Authority. Further, the Commission has specified that the medical colleges must mention the fees for each course while entering the details in the Seat Matrix.

Also Read: Final PGMER 2023 Regulations released in Gazette

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Dr Reddy’s Labs recalls over 8000 bottles of generic medication in US over packaging error

New Delhi: Dr Reddy’s Laboratories is recalling over 8,000 bottles of a generic medication used to prevent rejection of a transplanted organ from the US market due to a packaging error, according to the US Food & Drug Administration. The Hyderabad-based drug major is recalling 8,280 bottles of Tacrolimus capsules from the US market for “presence of foreign tablets/capsules” in the affected lot.

One 0.5 mg Tacrolimus capsule was found in a bottle of 1 mg Tacrolimus capsules, the USFDA stated in its latest Enforcement Report.
The affected lot was produced at Dr Reddy’s Bachupally-based plant near Hyderabad.
New Jersey-based Dr Reddy’s Laboratories, Inc has initiated the nationwide (US) Class II recall on December 15, 2023.
As per the USFDA, a Class II recall is initiated in a situation in which use of, or exposure to, a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote.
Dr Reddy’s had recalled 4,000 bottles of the same drug in March last year as well. The company had initiated the recall on February 8, 2023.
Established in 1984, Dr. Reddy’s Laboratories Ltd. is a global pharmaceutical company headquartered in Hyderabad, India. The Company offer a portfolio of products and services including APIs, generics, branded generics, biosimilars and OTC. Its major therapeutic areas of focus are gastrointestinal, cardiovascular, diabetology, oncology, pain management and dermatology. Dr Reddy’s major markets include – USA, India, Russia & CIS countries, China, Brazil and Europe.

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