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CHMP recommends approval of Xenpozyme, first & only treatment for ASMD

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CHMP recommends approval of Xenpozyme, first & only treatment for ASMD

May 20, 2022: “The European Medicines Agency’ CHMP has adopted a positive opinion for Xenpozyme® (olipudase alfa), recommending that this investigational enzyme replacement therapy be approved in the European Union for the treatment of non-central nervous system (non-CNS) manifestations of acid sphingomyelinase deficiency (ASMD) in pediatric and adult patients with ASMD type A/B or ASMD type B.

The positive CHMP opinion is based on data from the ASCEND and ASCEND-Peds clinical trials, demonstrating that Xenpozyme showed robust and clinically relevant improvement in lung function (as measured by diffusing capacity of the lung for carbon monoxide, or DLco) and reduced spleen and liver volumes, with a well-tolerated safety profile in adults and children with ASMD.

The EMA previously awarded olipudase alfa the PRIority MEdicines designation, also known as PRIME, and the application was reviewed under the EMA’s accelerated assessment, intended to aid and expedite the regulatory process for investigational medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options.

The European Commission will review the CHMP recommendation and is expected to make a final decision in the coming months.

About Xenpozyme

Xenpozyme® (olipudase alfa) is an enzyme replacement therapy designed to replace deficient or defective acid sphingomyelinase (ASM), an enzyme that allows for the breakdown of sphingomyelin.

Accumulation of sphingomyelin in cells can cause harm to the lungs, spleen, and liver, as well as other organs, potentially leading to early death.

Xenpozyme is currently being investigated in pediatric and adult patients to treat non-CNS manifestations of ASMD.

Xenpozyme has not been studied in ASMD type A patients.

In March 2022, Xenpozyme was approved in Japan under the SAKIGAKE (or “pioneer”) designation, marking the first approval for olipudase alfa anywhere in the world.

In the United States, where olipudase alfa received Breakthrough Therapy designation, the FDA has extended its review of the Biologics License Application (BLA) by three months, with a new target action date for the FDA decision (PDUFA date) of October 3, 2022.

https://www.sanofi.com/en/media-room/press-releases/2022/2022-05-20-07-00-00-2447427

FDA Urges Drug Manufacturers to Develop Risk Management Plans to Promote a Stronger, Resilient Drug Supply Chain

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FDA Urges Drug Manufacturers to Develop Risk Management Plans to Promote a Stronger, Resilient Drug Supply Chain

May 19, 2022: “Drug shortages pose a significant public health threat as they can delay, and in some cases, even deny critically needed care for patients.

Over the past decade, the FDA’s efforts have contributed to fewer new drug shortages and reduced the time to resolve existing drug shortages.

This is due, in part, to authorities the agency now has, including those added by the  Food and Drug Administration Safety and Innovation Act. 

But despite mitigating or preventing hundreds of new drug shortages, disruptions in the U.S. drug supply continue to occur due to drug quality problems, vulnerabilities in the global supply chain, unanticipated increases in demand, market withdrawals of drugs or natural disasters.  

In 2019, in an effort to address the national drug shortage problem, the federal Drug Shortages Task Force released a report that called for the adoption of risk management plans to proactively assess risk and to predict and prevent supply disruptions that could potentially lead to a drug shortage.

Then in 2020, Congress passed the CARES Act to require certain manufacturers to develop, maintain, and implement, as appropriate, risk management plans that identify and evaluate risks to a drug’s supply.

To further assist manufacturers with these requirements, we are issuing a draft guidance, Risk Management Plans to Mitigate the Potential for Drug Shortages, intended to help with the development, maintenance and implementation of risk management plans.

The draft guidance describes a framework for stakeholders to consider when developing risk management plans that aligns with principles stated in the International Council for Harmonisation guidance for industry, Q9 Quality Risk Management, and identifies risk factors to consider when developing the content of risk management plans.

The steps needed to reduce risks of a disruption in drug supply may vary among the different manufacturers in the supply chain for a given drug. 

Today’s draft guidance is an important step in what the nation needs to achieve an increasingly secure and resilient drug supply.

For Americans to have access to an uninterrupted supply of safe, effective and high-quality drugs, all entities involved in the manufacture of a drug should take every step available to reduce risks and threats to the drug supply chain.

Risk management plans can serve as a safeguard, helping manufacturers prepare for and respond to hazards that could lead to drug supply disruptions and shortages.”

https://www.fda.gov/news-events/press-announcements/fda-urges-drug-manufacturers-develop-risk-management-plans-promote-stronger-resilient-drug-supply

New FDA Draft Guidance Aims to Increase Safety Information About Dietary Supplement Marketplace

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New FDA Draft Guidance Aims to Increase Safety Information About Dietary Supplement Marketplace

May 19, 2022: “The U.S. FDA announced the availability of a draft guidance aimed at increasing the amount of safety information the agency has about the dietary supplement marketplace by providing the industry an opportunity to submit late new dietary ingredient (NDI) notifications.

The FDA wants consumers who use dietary supplements to know that today’s draft guidance, if finalized, will advise the dietary supplement industry that the agency intends to exercise enforcement discretion, for a limited time and in limited circumstances, to encourage manufacturers and distributors to correct any past failures to submit a required NDI notification.

By providing industry with an opportunity to correct past failures to submit required safety information, the FDA can gain more safety information about the dietary supplement marketplace and better protect public health. 

“We remain committed to a flexible framework for dietary supplements that ensures the safety of these products for consumers,” said Cara Welch, Ph.D., director of the Office of Dietary Supplement Programs in the FDA’s Center for Food Safety and Applied Nutrition (CFSAN).

“The resulting notifications the agency receives through this period of enforcement discretion will help increase the amount of safety information we have about NDI-containing dietary supplements in the marketplace.” 

The Dietary Supplement Health and Education Act of 1994 (DSHEA) requires manufacturers and distributors who wish to market a dietary supplement containing an NDI to notify the FDA before marketing, unless a legal exception applies.

The notification must contain the safety information that a manufacturer relied upon to conclude the dietary supplement containing the NDI is reasonably expected to be safe.  

The NDI notification process is the FDA’s only chance to evaluate the safety of a dietary supplement before it becomes available to consumers.  

For dietary supplements that do not contain an NDI, the law does not require manufacturers to submit safety information to the FDA before marketing.  

The FDA is aware that in the more than 27 years since the requirement was established, some dietary supplement firms have marketed products for which a premarket NDI notification was required, but never submitted.

The enforcement discretion policy proposed in this draft guidance relates solely to the failure to submit an NDI notification.

For example, it would not extend to NDI-containing dietary supplements that are adulterated for safety reasons or that violate any other regulatory requirements that pertain to dietary supplements.

This temporary policy also should help facilitate enforcement actions against those that remain out of compliance with the NDI notification requirements after the enforcement discretion period ends.

In a February 2019 statement about new efforts to strengthen the regulation of dietary supplements through modernization and reform, the FDA emphasized the need to ensure that our regulatory framework is flexible yet comprehensive enough to effectively evaluate product safety, while promoting innovation.

The FDA also stated that fostering the submission of NDI notifications would be key to this effort. This draft guidance is a critical first step toward encouraging those submissions.

If the draft guidance is finalized without change, the enforcement discretion period to submit a late notification would start when the guidance is published, would last 180 days, and would apply only to products on the market when the Federal Register notice announcing the draft guidance was published.

Along with this draft guidance, the FDA is also developing a new submission type through the CFSAN Online Submission Module to provide a dedicated pathway for stakeholders to electronically submit their late notifications.”

https://www.fda.gov/news-events/press-announcements/new-fda-draft-guidance-aims-increase-safety-information-about-dietary-supplement-marketplace

Lilly to Participate in UBS Global Healthcare Conference 2022

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Lilly to Participate in UBS Global Healthcare Conference 2022

May 16, 2022: “Eli Lilly and Company will attend the UBS Global Healthcare Conference on Tuesday, May 24, 2022. Michael Mason, senior vice president, president of Lilly Diabetes, will participate in a fireside chat at 8:30 a.m., Eastern time.

A live audio webcast will be available on the “Webcasts & Presentations” section of Lilly’s Investor website at https://investor.lilly.com/webcasts-and-presentations. A replay of the presentation will be available on this same website for approximately 90 days.”

https://investor.lilly.com/news-releases/news-release-details/lilly-participate-ubs-global-healthcare-conference-2022

FDA Expands Eligibility for Pfizer-BioNTech COVID-19 Vaccine Booster Dose to Children 5 through 11 Years

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FDA Expands Eligibility for Pfizer-BioNTech COVID-19 Vaccine Booster Dose to Children 5 through 11 Years

May 17, 2022: “The U.S. FDA amended the emergency use authorization for the Pfizer-BioNTech COVID-19 Vaccine, authorizing the use of a single booster dose for administration to individuals 5 through 11 years of age at least five months after completion of a primary series with the Pfizer-BioNTech COVID-19 Vaccine. 

“While it has largely been the case that COVID-19 tends to be less severe in children than adults, the omicron wave has seen more kids getting sick with the disease and being hospitalized, and children may also experience longer term effects, even following initially mild disease,” said FDA Commissioner Robert M. Califf, M.D.

“The FDA is authorizing the use of a single booster dose of the Pfizer-BioNTech COVID-19 Vaccine for children 5 through 11 years of age to provide continued protection against COVID-19.

Vaccination continues to be the most effective way to prevent COVID-19 and its severe consequences, and it is safe.

If your child is eligible for the Pfizer-BioNTech COVID-19 Vaccine and has not yet received their primary series, getting them vaccinated can help protect them from the potentially severe consequences that can occur, such as hospitalization and death.”   

On Jan. 3, the FDA authorized the use of a single booster dose of the Pfizer-BioNTech COVID-19 Vaccine for administration to individuals 12 through 15 years of age after completion of primary vaccination with the Pfizer-BioNTech COVID-19 Vaccine.

Today’s action expands the use of a single booster dose of the vaccine for administration to individuals 5 through 11 years age at least five months after completion of a primary series of the Pfizer-BioNTech COVID-19 Vaccine.

The FDA has authorized the Pfizer-BioNTech COVID-19 Vaccine for use in individuals 5 years of age and older and has approved Comirnaty (COVID-19 Vaccine, mRNA) for use in individuals 16 years of age and older.

“The Pfizer-BioNTech COVID-19 Vaccine is effective in helping to prevent the most severe consequences of COVID-19 in individuals 5 years of age and older,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research.

“Since authorizing the vaccine for children down to 5 years of age in October 2021, emerging data suggest that vaccine effectiveness against COVID-19 wanes after the second dose of the vaccine in all authorized populations.

The FDA has determined that the known and potential benefits of a single booster dose of the Pfizer-BioNTech COVID-19 Vaccine for children 5 through 11 years of age at least five months after completing a primary series outweigh its known and potential risks and that a booster dose can help provide continued protection against COVID-19 in this and older age groups.”

Data Supporting Effectiveness

The EUA for a single booster dose of the Pfizer-BioNTech COVID-19 Vaccine for children 5 through 11 years of age is based on FDA’s analysis of immune response data in a subset of children from the ongoing randomized placebo-controlled trial that supported the October 2021 authorization of the Pfizer-BioNTech COVID-19 Vaccine primary series in this age group.

Antibody responses were evaluated in 67 study participants who received a booster dose 7 to 9 months after completing a two-dose primary series of the Pfizer-BioNTech COVID-19 Vaccine.

The antibody level against the SARS-CoV-2 virus one month after the booster dose was increased compared to before the booster dose.

FDA Evaluation of Safety

The safety of a single booster dose of the Pfizer-BioNTech COVID-19 Vaccine in this age group was assessed in approximately 400 children who received a booster dose at least five months (range 5 to 9 months) after completing a two-dose primary series.

The most commonly reported side effects were pain, redness and swelling at the injection site, as well as fatigue, headache, muscle or joint pain and chills and fever.

The FDA did not hold a meeting of its Vaccines and Related Biological Products Advisory Committee on today’s action, as the agency previously convened the committee for extensive discussions regarding the use of booster doses of COVID-19 vaccines and, after review of Pfizer’s EUA request, the FDA concluded that the request did not raise questions that would benefit from additional discussion by committee members.

The FDA will make available on its website relevant documents regarding today’s authorization. 

The amendment to the EUA was granted to Pfizer Inc.”

https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-expands-eligibility-pfizer-biontech-covid-19-vaccine-booster-dose

AstraZeneca signs licence agreement with RQ Biotechnology for monoclonal antibodies against COVID-19

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AstraZeneca signs licence agreement with RQ Biotechnology for monoclonal antibodies against COVID-19

May 17, 2022: “AstraZeneca has entered into a licence agreement with RQ Biotechnology Ltd (RQ Bio) for a portfolio of early-stage monoclonal antibodies (mAbs) targeted against SARS-CoV-2, the virus that causes COVID-19.

Under the agreement, AstraZeneca has acquired an exclusive worldwide licence to develop, manufacture and commercialise mAbs against SARS-CoV-2.

Iskra Reic, Executive Vice President, Vaccines & Immune Therapies, AstraZeneca, said: “The COVID-19 pandemic has changed the landscape for immune therapies, including the use of monoclonal antibodies to protect vulnerable patients who can’t respond adequately to vaccination alone.

Scientific innovation is rapidly accelerating, and this agreement reflects our continued commitment to the discovery and development of new medicines to help prevent and treat infectious disease, including COVID-19.”

RQ Bio is a UK-based biotechnology company focused on developing treatments and preventative therapies based on potent broad-spectrum mAbs to address areas of unmet need in vulnerable patient populations.”

https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2022/astrazeneca-signs-licence-agreement-with-rq-biotechnology-for-monoclonal-antibodies-against-covid-19.html

What Is CDISC and What Are CDISC Data Standards?

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What Is CDISC and What Are CDISC Data Standards?

Introduction

Clinical trials are relatively simple to conduct. We want to know if a new drug is effective and, if so, how effective it is. We will test this medicine on a few thousand people to see how they respond.

We capture their thoughts, examine them for a dozen health indicators, then examine a ton of tables containing collected data before arriving at a conclusion.

All of these procedures are primarily dependent on one thing: data. And how thoroughly it’s documented, gathered, compiled, and analysed. For the most phase, humanity has done a good job working with data. However, as we grow older, our need expand.

Data sharing and accessibility are two of today’s most important aspects of clinical research. We looked at the most common drug data APIs previously. Now we’ll look at the CDISC guidelines and how they affect scientists.

The “Clinical Data Interchange Standards Consortium,” or CDISC, is a global non-profit organisation that actively develops data standards based on the combined knowledge and experience of volunteers in the pharmaceutical industry.

CDISC standards are open source, global, and universal.

The medical community benefits in the following ways.

For researchers, clear and straightforward data management at all stages of clinical research means speedier discoveries and easier sharing and understanding of study results by the community.

For Pharma companies, CDISC standards are required by FDA, PMDA, and EMA, thus the submission and review procedure is simple and quick.

For technology vendors, the ability to design solutions that meet the needs of the research community and employ standardised datasets for machine learning in the pharmaceutical industry.

Overall, standards make it easier to interpret massive amounts of data, ranging from patient questionnaires to information regarding laboratory samples. Let’s go over the different CDISC standards.

CDISC standards fall into four categories: fundamental or Data content standards  (SEND, PRM, CDASH, SDTM, ADaM).

These are the foundation standards for a number of other CDISC standards that assist data collection, management, analysis, and reporting throughout the clinical trial process.

Standards for data exchange (SDM-XML, ODM-XML, Define-XML, CTR-XML). CDISC uses a standard XML for data interchange that is accompanied by industry-specific requirements.

The core requirements for many disease areas are specified in these standards. Here’s an example of a user guide that explains how to collect data and perform COVID-19 trials.

What Does CDISC Do & Why Is CDISC Important?

CDISC develops and disseminates standards for the collecting, exchange, submission, and archiving of data for the development of medical and biopharmaceutical products.

The consortium collaborates with international organisations such as the U. S. FDA, the European Medicines Agency (EMA), Japan’s Pharmaceuticals and Medical Devices Agency (PMDA), and China’s National Medical Products Administration (NMPA) to develop guidelines and requirements that influence clinical and nonclinical data standards.

CDISC standards evolve and change in accordance with worldwide rules. CDISC standards have numerous advantages.

Implementing CDISC data standards has a number of advantages, including:

• CDISC standards promote transparency throughout the medical research process, from protocol development to data and result reporting.

• By speeding regulatory processes during medication development, CDISC standards can reduce timeframes and costs, resulting in a faster marketing authorisation.

• CDISC standards allow FDA reviewers to spend more time on the science of drug development by reducing the amount of time they spend reviewing data.

• When CDISC data standards are implemented, CROs and Sponsors can exchange high-quality, interpretable data quickly and easily.

CDISC Data Standards in Clinical Research & Clinical Studies

CDISC datasets assist in providing clear and standardised clinical trial data to regulatory organisations.

When data is poorly organised or difficult to interpret, it can result in governmental resistance or delays in the drug development process, as effort is spent organising and making sense of the data.

Sponsors can structure their raw data more efficiently using CDISC data standards, which are universally recognised and essential for successful data submissions.

Implementing Controlled Terminology is another technique to create clarity (CT). CT is an evolving dictionary of recognised terms that are used to standardise data collected across studies into a single value for computerised data processing and submission.

CT offers data a clear context and eliminates uncertainty in result evaluation.

Pharmacokinetic CDISC Data Standards

Pharmacokinetic (PK) data is an essential subset of clinical trial data inside CDISC. CDISC data management with PK data is a very specialised area.

Understanding the distinctions between the sources and types of PK data acquired during a trial, as well as how to merge those different data sources in the correct format to create a dataset suitable for PK studies, is crucial.

PK and CDISC collaborate to produce a simple and easy-to-understand clinical trial submission package.

CDISC has three key data standards:

SEND for nonclinical data, SDTM for clinical data, and ADaM for analysis ready data, as previously mentioned.

Clinical and bioanalytical data must be reconciled in the PK domains for SDTM and ADaM. Specialized domains are established to highlight the link between bioanalytical data and estimated PK parameters.

CDISC Domains

Domains are used to organise SEND, SDTM, and ADaM data. A domain is a collection of linked observations on a specific topic collected for all human or animal subjects in a clinical or nonclinical study.

Clinical PK Domain Definitions:

Pharmacokinetic concentrations (PC) domain, pharmacokinetic parameters (PP) domain, and related records (RELREC) domain are all relevant PK domains for SEND and SDTM.

The analysis dataset of pharmacokinetic concentrations (ADPC) and the analysis dataset of pharmacokinetic parameters (ADPP), which are used for PK analyses, are the key PK domains for ADaM.

PC: Data obtained for analytes (typically study medications and/or their metabolites) in tissue (e.g., serum or plasma) and fluid concentrations as a function of time before and after dosing the research drug.

PP: PC data in a standardised format describing the PK parameters of the time-concentration curve (e.g., area under the curve, maximum concentration, time of maximum observed concentration sampled during a dosing interval).

RELREC: Data that relates the specific PK concentrations in the PC dataset to the PP dataset’s corresponding PK parameters.

ADPC: Analyze ready data collected for analyte concentrations in tissue and fluid as a function of time. This dataset may contain information not found in the SDTM PC domain, such as elapsed time calculations, analysis flagging, and imputations of values below the quantification lower limit.

ADPP: Analysis ready data for PC data that describes the characteristics of the time-concentration curve. This dataset may include flags for values to be utilised in further analysis, such as tables, listings, figures, or bioequivalence/bioavailability assessments, in addition to the SDTM PP dataset.

Nonclinical PK Domain Definitions:

The pool definitions (POOLDEF) and supplemental qualifiers for pharmacokinetic concentration (SUPPPC), as well as the PC and PP domains outlined above under the clinical PK domains, are all important domains for SEND.

POOLDEF: Data utilised in a pooled profile for analysis to combine and identify individual animals.

SUPPPC: Supplementary dataset that contains extra qualifiers not captured by PC variables.

SEND:SEND stands for “Standard for Nonclinical Data Exchange.” All nonclinical data is organised, structured, and formatted according to SEND.

Based on the format and metadata provided by the SDTM, the SEND Implementation Guide (SEND-IG) includes predefined areas and samples of nonclinical (animal) data.

Single-dose toxicity, repeat dosage toxicology, and carcinogenicity studies are all supported by the current SEND-IG version 3.1.1.

SEND also covers respiratory and cardiovascular testing in safety pharmacology investigations. Data collection for immunogenicity specimen assessment is currently in the works.

SDTM: “Study Data Tabulation Model” is what SDTM stands for. SDTM is the most extensively used CDISC standard. SDTM establishes a common standard for constructing and structuring data sets for particular clinical studies.

The SDTM Implementation Guide (SDTM-IG) provides a standardised, pre-defined collection of domains for clinical data input, each based on the SDTM’s structure and metadata.

SDTM data is unprocessed data that frequently requires additional manipulation before it is ready for analysis.

ADaM: “Analysis Data Model” is what ADaM stands for. ADaM can alternatively be thought of as “analysis ready” data. The way data is displayed is the key distinction between ADaM and SDTM standards.

SDTM is a standard for collecting and mapping data from raw sources, whereas ADaM is a standard for creating analysis-ready data, which frequently uses SDTM data as a source. The FDA can readily repeat analyses using ADaM databases.

Who Belongs to CDISC and Why?

CDISC’s membership covers a diverse spectrum of clinical research organisations, including:

  • Clinical research organizations
  • Government agencies
  • Technology service providers
  • Biotech firms
  • Academic institutions
  • Pharmaceutical companies
  • Non-profit organizations
  • Healthcare providers

These individuals are all motivated by the desire to maximise the effect of clinical research results.

CDISC data standards aid understanding and interpretation of clinical data.

Being a member of CDISC has a number of advantages, including access to a variety of tools, workshops, and training courses designed to help clinical researchers better understand and execute CDISC’s data management standards.

BMS Provides Update on Evaluating Opdivo Plus Yervoy for Urothelial Carcinoma

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BMS Provides Update on Evaluating Opdivo Plus Yervoy for Urothelial Carcinoma

May 16, 2022: “Bristol Myers Squibb announced the Phase 3 CheckMate -901 trial, comparing Opdivo (nivolumab) plus Yervoy (ipilimumab) to standard-of-care chemotherapy as a first-line treatment for patients with untreated unresectable or metastatic urothelial carcinoma, did not meet the primary endpoint of overall survival (OS) in patients whose tumor cells express PD-L1 ≥1% at final analysis.

The company remains blinded to the data, and an independent Data Monitoring Committee recommended that the trial continue to assess other primary and secondary endpoints.

No new safety signals were observed at the time of the analysis.

“Despite some progress in recent years, metastatic urothelial carcinoma remains a difficult disease to address, with a limited number of treatment options that can extend patients’ lives,” said Dana Walker, M.D., M.S.C.E., vice president, development program lead, genitourinary cancers, Bristol Myers Squibb.

“Opdivo plus Yervoy has demonstrated durable, long-term survival improvements in several challenging-to-treat advanced cancers, and we are disappointed that the final analysis of CheckMate -901 did not show this same benefit in urothelial carcinoma patients whose tumor cells express PD-L1 ≥1%.

We remain committed to advancing research in urothelial carcinoma, we look forward to seeing data from other parts of the CheckMate -901 trial, and we thank all of the patients, investigators and site personnel involved.”

The CheckMate -901 trial is also assessing Opdivo plus Yervoy in patients with unresectable or metastatic urothelial carcinoma who are ineligible for cisplatin-based chemotherapy.

Additionally, a sub-study of CheckMate -901 with pivotal intent is evaluating Opdivo in combination with chemotherapy versus chemotherapy alone in patients who are eligible for cisplatin-based chemotherapy.

The CheckMate -901 primary study and sub-study are ongoing, and the company will report results for these additional components of the study when available.

Opdivo plus Yervoy-based combinations have shown significant improvements in OS in six Phase 3 clinical trials in five tumors to date: non-small cell lung cancer, metastatic melanoma, advanced renal cell carcinoma, malignant pleural mesothelioma and esophageal squamous cell carcinoma.

In addition, Opdivo has shown clinical benefit in second-line metastatic urothelial carcinoma and adjuvant muscle-invasive urothelial carcinoma.

About CheckMate -901

CheckMate -901 is a Phase 3, randomized, open-label trial evaluating Opdivo in combination with Yervoy (primary study)or Opdivo in combination with chemotherapy (sub-study) compared to standard-of-care chemotherapy alone, in patients with untreated unresectable or metastatic urothelial cancer.

In the primary study, a total of 707 patients were randomized to receive either Opdivo (1 mg/kg) plus Yervoy (3 mg/kg) every three weeks for four cycles, followed by Opdivo (480 mg) every four weeks for a maximum of two years, or chemotherapy (gemcitabine-cisplatin or gemcitabine-carboplatin) every three weeks for six cycles.

The primary endpoints of the primary study are overall survival (OS) in patients who are ineligible for cisplatin-based chemotherapy and OS in patients with tumor cell PD-L1 expression ≥1%.

Key secondary endpoints include OS in all randomized patients, progression-free survival (PFS) and safety outcomes.

A sub-study of CheckMate -901 is evaluating Opdivo in combination with chemotherapy versus chemotherapy alone in patients who are eligible for cisplatin-based chemotherapy.

The OS outcomes for patients whose tumor cells express PD-L1 ≥1% are based on the final efficacy analysis for this endpoint of the CheckMate -901 primary study; the other parts of the study are ongoing.

About Urothelial Carcinoma

Bladder cancer is the 10th most common cancer in the world, with more than 573,000 new cases diagnosed annually. Urothelial carcinoma, which most frequently begins in the cells that line the inside of the bladder, accounts for approximately 90% of bladder cancer cases.

In addition to the bladder, urothelial carcinoma can occur in other parts of the urinary tract, including the ureters and renal pelvis.

The majority of urothelial carcinomas are diagnosed at an early stage, but rates of recurrence and disease progression are high.

Approximately 50% of patients who undergo surgery will experience disease recurrence. Additionally, approximately 20% to 25% of patients with urothelial carcinoma develop metastatic disease.

For patients with metastatic cancer, the prognosis is poor, with a median overall survival of approximately 12 to 14 months when treated with systemic therapy.

The poor durability of responses in the first-line setting presents a major challenge in the treatment of metastatic disease, and there are limited treatment options in the second-line setting for patients with advanced urothelial carcinoma.”

https://news.bms.com/news/corporate-financial/2022/Bristol-Myers-Squibb-Provides-Update-on-CheckMate–901-Trial-Evaluating-Opdivo-nivolumab-Plus-Yervoy-ipilimumab-as-First-Line-Treatment-for-Patients-with-Unresectable-or-Metastatic-Urothelial-Carcinoma/default.aspx

Sanofi’s Sarclisa combination shows positive results in the multiple myeloma patients

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Sanofi’s Sarclisa combination shows positive results in the multiple myeloma patients

May 15, 2022: “Latest results from the Phase 3 IKEMA clinical trial evaluating Sarclisa® (isatuximab) in combination with carfilzomib and dexamethasone (Kd) demonstrated a median progression free survival (mPFS) of 35.7 months (Hazard Ratio HR 0.58; 95% Confidence Interval CI: 25.8 to 44.0; n=179), compared to 19.2 months in patients treated with Kd alone (95% CI: 15.8 to 25.1; n=123), as evaluated by an Independent Review Committee.

These results, presented at the Controversies in Multiple Myeloma World Congress, represent the longest mPFS among studies investigating a proteasome inhibitor backbone in the second-line setting for the treatment of relapsed multiple myeloma (MM).

These data will also be presented at the European Society for Medical Oncology on May 19.

Philippe Moreau, MD
Head of the Department of Hematology, University Hospital of Nantes, France
“The increase in progression free survival, observed consistently across all subgroups, when adding Sarclisa to carfilzomib and dexamethasone is remarkable in patients with relapsed multiple myeloma in a proteasome inhibitor combination. 

Relapse is common in multiple myeloma, creating the need for differentiated second-line treatments that provide patients a longer period of time without disease progression.

This updated analysis reinforces the potential for Sarclisa to become a new standard of care for patients with relapsed multiple myeloma.”

A PFS analysis following the U.S. Food and Drug Administration recommendations on censoring rules, as applied in the approved U.S. prescribing information, showed an mPFS of 41.7 months for Sarclisa added to Kd (Sarclisa combination therapy) compared to 20.8 months in patients treated with Kd alone (HR 0.59; 95% CI: 27.1 to Not Calculable NC).

Time to next treatment for patients treated with Sarclisa combination therapy was 44.9 months (HR 0.55; 95% CI: 31.6 to NC) versus those treated with Kd alone at 25 months (95% CI: 17.9 to 31.3).

Time to next treatment measured the interval from the date of randomization to the date of commencement of the next line of therapy, thereby allowing for measurement of the period of therapeutic benefit.

Peter C. Adamson, MD
Global Head of Oncology Clinical Development and Pediatric Innovation at Sanofi
“To observe progression free survival of more than three years in patients with relapsed multiple myeloma when Sarclisa was added to a proteasome inhibitor backbone of therapy is unprecedented and reinforces our confidence in Sarclisa as a potential best in class anti-CD38 antibody.”

The safety and tolerability of Sarclisa observed in this analysis were consistent with the safety profile of Sarclisa in other clinical trials, with no new safety signals observed.

For the Sarclisa combination therapy and Kd groups, the most common adverse events were infusion related reaction (45.8%, 3.3%), diarrhea (39.5%, 32%), hypertension (37.9%, 35.2%), upper respiratory tract infection (37.3%, 27%), fatigue (31.6%, 20.5%), dyspnoea (30.5%, 22.1%), pneumonia (27.1%, 21.3%), back pain (25.4%, 21.3%), insomnia (25.4%, 24.6%), and bronchitis (24.3%, 12.3%).

Treatment exposure in the Sarclisa combination therapy arm was 30 weeks longer than in the control arm.

Treatment emergent adverse events (TEAEs) of ≥ Grade 3 were reported in 83.6% of patients treated with Sarclisa combination therapy and in 73% of those treated with Kd alone.

Serious TEAEs were higher in the Sarclisa combination therapy arm versus Kd alone (70.1% versus 59.8%). No difference was observed after exposure adjustment.”

https://www.sanofi.com/en/media-room/press-releases/2022/2022-05-15-09-30-00-2443369

FDA Encourages Importation of Safe Infant Formula and Other Flexibilities to Further Increase Availability

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FDA Encourages Importation of Safe Infant Formula and Other Flexibilities to Further Increase Availability

May 16, 2022: “The U.S. FDA is announcing a guidance that outlines increased flexibilities regarding importation of certain infant formula products to further increase the availability of infant formula across the country while protecting the health of infants.

The agency is encouraging infant formula manufacturers worldwide to take advantage of these flexibilities.

“The FDA is leaving no stone unturned to further increase the availability of infant formula.

We are doing everything in our power as part of the all-of-government efforts to ensure there’s adequate product available wherever and whenever parents and caregivers need it,” said FDA Commissioner Robert M. Califf, M.D.

“Today’s action paves the way for companies who don’t normally distribute their infant formula products in the U.S. to do so efficiently and safely.

We are hopeful this call to the global market will be answered and that international businesses will rise to the occasion to assist in bolstering the supply of products that serve as the sole source of nutrition for many infants.

With these flexibilities in place, we anticipate that those products that can quickly meet safety and nutrition standards could hit U.S. stores in a matter of weeks.”

The U.S. normally produces 98% of the infant formula it consumes, with the primary source of imports coming from trading partners in Mexico, Ireland and the Netherlands.

However, given the production and distribution issues that have led to reduced supplies of infant formula in some parts of the country, the FDA has outlined a process by which the agency would not object to the importation of certain infant formula products intended for a foreign market or distribution in the U.S. of products manufactured here for export to foreign countries.

It also may provide flexibilities to those who manufacturer infant formula products domestically for export and may be able to increase further domestically produced product for the U.S. market. 

Companies seeking to take advantage of these flexibilities should submit information for the FDA to quickly evaluate whether the product can be used safely and whether it provides adequate nutrition.

For example, labeling, information on nutritional adequacy and safety testing, and information about facility inspection history.

The agency intends to prioritize submissions for products that can demonstrate the safety and nutritional adequacy and have the largest volume of product available and/or those who can get product onto U.S. shelves the quickest.

The FDA is already in discussions with some manufacturers and suppliers regarding additional supply. 

As part of a number of significant actions the FDA has undertaken since February to increase supply, the agency had already implemented a streamlined process to facilitate the importation of infant formula at U.S. ports of entry so that formula coming from abroad can be dispersed quickly throughout the country.

This work has already resulted in more infant formula coming into the U.S. Imports of infant formula year-to-date are up more than 300% from last year.

The FDA has and will continue to actively work with the U.S. Department of Agriculture, U.K., and European authorities to expedite entry for products made abroad. 

All of this around-the-clock work has already begun to improve supply and availability with most manufacturers, now producing at normal or expanded capacity.

The FDA expects that the measures and steps it is taking with infant formula manufacturers and others will mean more and more supply is on the way or on store shelves moving forward. 

Data from Information Resources Inc. (IRI) indicate that in-stock rates in retail stores are improving and the FDA’s actions are expected to continue to increase product availability.

While some data suppliers have reported lower in-stock rates, the most complete data sets available from IRI are showing nearly 80% in-stock rates at the week ending May 8.

The agency’s best current assessment is that with all of the current actions, including today’s announcement, and the potential for Abbott Nutrition’s Sturgis, Michigan, facility to safely resume production in the near-term, the supply of infant formula will continue to improve over the next couple of months.

In the meantime, the agency is encouraged to see that as of early May the amount of infant formula sold in the U.S. continues to rise. 

It is important to understand that only facilities experienced in and already making essentially complete nutrition products are in the position to produce infant formula products that would not pose significant health risks to consumers.

The agency continues to advise against making infant formulas at home.

Caregivers are encouraged to work with their child’s health care provider for recommendations on changing feeding practices, if needed.

The U.S. Department of Health and Human Services has also released a fact sheet with information to help families find infant formula.

The FDA will continue to dedicate all available resources to help ensure that infant formula products remain available for use in the U.S. and will keep the public informed of progress updates.”

https://www.fda.gov/news-events/press-announcements/fda-encourages-importation-safe-infant-formula-and-other-flexibilities-further-increase-availability

FDA Authorizes First COVID-19 Test Available without a Prescription That Also Detects Flu and RSV

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FDA Authorizes First COVID-19 Test Available without a Prescription That Also Detects Flu and RSV

May 16, 2022: “The U.S. FDA authorized the Labcorp Seasonal Respiratory Virus RT-PCR DTC Test for use without a prescription by individuals with symptoms of respiratory viral infection consistent with COVID-19.

This product is the first direct-to-consumer (non-prescription) multi-analyte COVID-19 test authorized by FDA and allows an individual to self-collect a nasal swab sample at home and then send that sample to Labcorp for testing.

The test can identify and differentiate multiple respiratory viruses at the same time, detecting influenza A and B, commonly known as the flu, respiratory syncytial virus, commonly known as RSV, along with SARS-CoV-2, the virus that causes COVID-19.

Results are delivered through an online portal, with follow-up from a health care provider for positive or invalid test results.

“While the FDA has now authorized many COVID-19 tests without a prescription, this is the first test authorized for flu and RSV, along with COVID-19, where an individual can self-identify their need for a test, order it, collect their sample and send it to the lab for testing, without consulting a health care professional,” said Jeff Shuren, M.D., J.D., director of FDA’s Center for Devices and Radiological Health.

“The rapid advances being made in consumer access to diagnostic tests, including the ability to collect your sample at home for flu and RSV without a prescription, brings us one step closer to tests for these viruses that could be performed entirely at home.”

This home sample collection kit can be purchased online or in a store without a prescription.

The samples can be self-collected by individuals ages 18 years and older, self-collected by individuals 14 years and older with adult supervision, or collected with adult assistance for individuals 2 years and older.

This will enable consumers to more easily determine whether they may be infected with COVID-19, flu, or RSV, which can aid in determining if self-isolation (quarantine) is appropriate and to assist with health care decisions after discussion with a health care professional.”

https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-covid-19-test-available-without-prescription-also

First time an albuterol/budesonide fixed-dose combination rescue medication has been shown to reduce severe exacerbations

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First time an albuterol/budesonide fixed-dose combination rescue medication has been shown to reduce severe exacerbations

May 15, 2022: “Full results from the positive MANDALA Phase III trial showed that PT027 (albuterol/budesonide) at two different strengths of budesonide, an inhaled corticosteroid (ICS), used as an as-needed rescue medicine, demonstrated a statistically significant reduction in the risk of a severe exacerbation versus albuterol rescue in patients with moderate to severe asthma.

PT027 is a potential first-in-class inhaled, fixed-dose combination rescue medication containing albuterol, a short-acting beta2-agonist (SABA), and budesonide in the US. It is being developed by AstraZeneca and Avillion.

Globally, more than 176 million asthma attacks are experienced each year.

Compared with albuterol rescue, PT027 at the 180mcg albuterol/160mcg budesonide dose reduced the risk of a severe exacerbation by 27% (p<0.001) in adults and adolescents.

In the trial, patients were randomised to receive PT027 or albuterol rescue, on top of their usually prescribed maintenance ICS, with or without additional controller medicines.

In secondary endpoints, PT027 (180mcg albuterol/160mcg budesonide) demonstrated a 33% reduction in mean annualised total systemic corticosteroid exposure (p=0.002) and a 24% reduction in annualised severe exacerbation rate (p=0.008).

A numerically higher odds of patients experiencing an improvement in symptom control and quality of life was also observed after 24 weeks of treatment with PT027 compared to albuterol rescue.

Adverse events (AEs) were similar across the treatment groups in the trial and consistent with the known safety profiles of the individual components, with the most common AEs including nasopharyngitis and headache.

Bradley E. Chipps, Past President of the American College of Allergy, Asthma & Immunology and Medical Director of Capital Allergy & Respiratory Disease Center in Sacramento, US, said:

“The MANDALA Phase III trial results demonstrated that PT027, a novel fixed-dose combination of albuterol/budesonide used as-needed, provided additional anti-inflammatory treatment in response to patient symptoms, which led to a reduced risk of severe exacerbations compared with albuterol alone.

These data further strengthen the growing body of evidence around the value of as-needed anti-inflammatory treatment in asthma and support PT027’s potential to transform the current rescue treatment approach.”

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said: “Asthma is an inflammatory, variable disease and patients are at risk of experiencing a severe exacerbation regardless of disease severity and adherence to treatment.

The results from these Phase III trials support the clinical benefit of PT027, an albuterol/budesonide rescue inhaler, which has the potential to be a first-in-class treatment approach that can prevent asthma attacks over and above their current maintenance therapies.”

In the MANDALA trial, PT027 at a lower budesonide dose (180mcg albuterol/80mcg budesonide), also demonstrated a statistically significant reduction of 17% in the risk of severe exacerbation versus albuterol rescue (p=0.041), when used as an as-needed rescue medicine in adults, adolescents, and children aged 4–11 years.

The results were published in the New England Journal of Medicine and will be presented at the American Thoracic Society (ATS) 2022 International Conference.1,2,4

Also being presented at the ATS International Conference this week are the positive DENALI Phase III trial results.

In this trial, PT027 demonstrated a statistically significant improvement in lung function measured by forced expiratory volume in one second (FEV1), compared to the individual components albuterol and budesonide, and compared to placebo in patients with mild to moderate asthma aged 12 years or older.

Onset of action and duration of effect were similar for PT027 and albuterol. The safety and tolerability of PT027 in DENALI was consistent with the known profiles of the components.”

https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2022/pt027-significantly-reduced-the-risk-of-a-severe-exacerbation-compared-to-albuterol-in-patients-with-asthma.html

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