FDA Action Alert: Alvotech, Otsuka and More

 After a quiet week, the FDA is now set to decide on a Humira biosimilar and hold an Adcomm meeting for an Alzheimer’s agitation treatment. Also on its calendar for April are decision dates for two vaccine hopefuls.

Read below for more details.

Alvotech’s Biosimilar for AbbVie’s Humira Awaits FDA Decision

Iceland-based Alvotech is seeking regulatory approval for AVT02, a biosimilar to AbbVie’s therapeutic antibody Humira (adalimumab), which is indicated for rheumatoid arthritis, Crohn’s disease, ulcerative colitis and plaque psoriasis, among other conditions.

AVT02’s Biosimilar User Fee Amendment action date is on April 13.

AVT02 is a monoclonal antibody that has been approved as a Humira biosimilar in the E.U., Canada and Australia, among other territories. The treatment is also already being marketed in many of these countries.

The FDA first accepted AVT02’s Biologics License Application in November 2020, but due to a legal tussle between AbbVie and Alvotech, decided to defer action.

Seeking to break AbbVie’s monopoly on the arthritis market, Alvotech filed a lawsuit against the American company in December 2021. AbbVie retaliated with over 60 patent claims. The two reached a settlement in March 2022 for an undisclosed amount.

The FDA reconsidered Alvotech’s case in February 2022. In December of the same year the regulator handed Alvotech a Complete Response Letter stating the approval for the investigational biosimilar is contingent on successful and satisfactory inspection of the company’s manufacturing facility in Iceland.

In its application, Alvotech touted data showing that AVT02 was interchangeable with Humira, leading to comparable levels of clinical efficacy, immunogenicity and safety in treated patients. Alvotech will market AVT02 with its exclusive partner, Teva Pharmaceuticals.

Adcomm Convenes to Discuss Pill for Alzheimer’s Agitation

On April 14, the FDA’s Psychopharmacologic Drugs Advisory Committee will hold a joint meeting with the Peripheral and Central Nervous System Drugs Advisory Committee to discuss Otsuka Pharmaceutical Company’s supplemental New Drug Application (sNDA) for Rexulti (brexpiprazole) tablets.

Otsuka hopes to expand Rexulti’s label to include agitation in patients with Alzheimer’s disease.

In July 2022, Rexulti cleared a Phase III trial and elicited significant improvements in the Cohen-Mansfield Agitation Inventory, a validated caregiver-rated questionnaire to assess agitation, as compared with placebo. Otsuka planned to present these results to the FDA for an sNDA submission in late 2022.

Data from three more Phase III studies, released in December 2022, additionally highlighted the therapeutic potential of Rexulti in this indication.

Rexulti was first approved by the FDA in 2015 for schizophrenia and as an adjunctive therapy for major depressive disorder. In January 2022, the drug’s indication was expanded to allow for the treatment of schizophrenia in teenagers aged 13 to 17 years. Rexulti was discovered by Otsuka and is being co-developed with Lundbeck.

Pfizer to Add New Serotypes to its Pneumococcal Conjugate Vaccine

The FDA is also expected to decide this month on Pfizer’s supplemental Biologics License Application (sBLA) for its 20-valent pneumococcal conjugate vaccine candidate against Streptococcus pneumoniae, though no specific date has been given yet.

The FDA accepted Pfizer’s sBLA in January and gave it the Priority Review designation, which cuts the review period by four months.

Pfizer’s candidate includes the 13 serotypes covered by its approved vaccine Prevnar 13, along with seven new serotypes which are known to cause invasive pneumococcal disease globally and are associated with high case-fatality rates, complications and antibiotic resistance.

These 20 strains are also covered by Pfizer’s Prevnar 20, a vaccine for active immunization against pneumonia for patients aged 18 years or older. The sBLA hopes to expand this coverage to children from 6 weeks through 17 years of age.

Data from the Phase II and Phase III pediatric programs for the 20-valent vaccine candidate supported the sBLA application and collectively demonstrate a favorable efficacy, immunogenicity and safety profile.

If approved, Pfizer’s vaccine would have the broadest serotype coverage of any pneumococcal conjugate vaccines in babies and children.

Emergent’s Anthrax Vaccine Nears Verdict

The FDA is expected to release its verdict regarding Emergent Biosolutions’ anthrax vaccine candidate AV7909 in April, though no specific date has been set.

In its BLA, which the FDA accepted in June 2022, Emergent proposed AV7909 for post-exposure prophylaxis after confirmed or suspected exposure to Bacillus anthracis. The candidate is being evaluated for adults aged 18 through 65 years and is to be given with recommended antibacterial agents.

Emergent supported its rolling BLA with data from a pivotal Phase III clinical trial, which assessed the immunogenicity and safety of a two-dose regimen of AV7909, along with its lot consistency. Data from a Phase II study, showing that the vaccine candidate did not interfere with antibacterial drugs for anthrax, was also included in its BLA package. Emergent completed its rolling submission in April 2022.

The development of AV7909 was supported by the Biomedical Advanced Research and Development Authority.

https://www.biospace.com/article/fda-action-alert-alvotech-otsuka-and-more/

Gene Editing Therapeutics Could Hit the Market in 2023

 Currently, there are no gene editing–based treatments on the market, but the technology continues its march toward potential FDA approval, with several products in mid- and late-stage trials. As these programs mature, 2023 could be a pivotal year for companies in the space. Here are some highlights to look forward to as the year progresses.

CRISPR Therapeutics/Vertex Pharmaceuticals

Just this month, collaborators CRISPR Therapeutics and Vertex Pharmaceuticals completed the submission of a rolling Biologics License Application (BLA) to the FDA for their product, exa-cel, as a potential treatment for sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT).

Exa-cel is a CRISPR/Cas9 ex vivo treatment designed to increase levels of fetal hemoglobin in red blood cells. Fetal hemoglobin carries oxygen more efficiently than adult hemoglobin, which is defective in SCD and TDT. Exa-cel is currently undergoing two Phase III trials, CLIMB-111 and CLIMB-121, as well as an ongoing long-term follow-up study, CLIMB-131.

As such, exa-cel will be perceived as a viable alternative to existing treatments, which do not address the direct cause of the disease. For SCD, current treatments include narcotics, chemotherapy, vitamins and blood transfusions; for TDT, the only management option available is blood transfusions every two to four weeks.

If priority review is granted by the FDA within 60 days, the agency could approve the treatment by the end of this year.

Intellia Therapeutics

In March 2023, Intellia Therapeutics received a Regenerative Medicine Advanced Therapy (RMAT) designation from the FDA for NTLA-2002, an in vivo CRISPR-based treatment for hereditary angioedema (HAE). As a CRISPR-based investigational therapy designed to inactivate kallikrein B1, a pro-inflammatory glycoprotein, NTLA-2002 aims to prevent heart swelling attacks in HAE. Phase II trials are currently screening patients outside the U.S.

Established by the 21st Century Cures Act, the RMAT designation is important because Intellia gets access to early interactions with the FDA, accelerated approval support and priority review of NTLA-2002’s BLA. Having previously earned an Orphan Drug designation, NTLA-2002 is sure to be on the radar for regulators and investors this year.

In addition, Intellia is preparing an IND application submission for NTLA-2001 for mid-2023. Designed as an in vivo intravenous treatment for transthyretin (ATTR) amyloidosis, NTLA-2001 is undergoing Phase I trials with more data expected in 2023. Additional variations of ATTR amyloidosis such as ATTR amyloidosis with cardiomyopathy (ATTR-CM) and ATTR amyloidosis with polyneuropathy (ATTRv-PN) are also being investigated, with an ATTR-CM trial ready to be initiated by the end of 2023 and a Phase III ATTRv-PN trial currently being discussed with regulators.

Editas Medicine

Editas Medicine has undergone some internal restructuring in Q1 2023, with strategic reprioritization focusing on hemoglobinopathies and in vivo gene editing. A competitor to CRISPR Therapeutics, the company is currently working on EDIT-301 for SCD and TDT as well. Unlike CRISPR’s product, EDIT-301 uses AsCas12a to edit the genome instead of Cas9. AsCas12a only requires a single RNA molecule while Cas9 requires two RNA molecules.

However, Editas is currently behind others in the space as it initiates parallel patient dosing for SCD in the Phase I/II RUBY trial and doses the first patient for TDT in the Phase I/II EDITHAL trial. Updates for RUBY are expected by mid-2023 and data from EDITHAL will be available by the end of 2023.

Beam Therapeutics

Beam Therapeutics’ specialty is in base editing, and the company intends to use its CRISPR-based technology to edit point mutations. Beam’s most advanced pipeline product is BEAM-10, which is in Phase I/II BEACON trials. BEAM-101 serves as an ex vivo treatment for SCD and beta thalassemia via activation of fetal hemoglobin. With the expansion phase expected to initiate later in 2023, data from BEACON is slated to be available in 2024.

In addition, Beam has been working in collaboration with Apellis Pharmaceuticals since 2021 to find gene editing–based treatments for complement-driven diseases. While research in complement pathways is ongoing between the two companies, the data remains undisclosed.

With multiple companies focusing intently on getting gene editing to the market, the technology is increasingly moving into the realm of reality for patients in need of life-altering treatments. While there is no doubt that the state of gene editing–based treatments has changed over the past decade, FDA approval is seldomly the end of the road for new drugs. As other issues such as market access and pricing continue to influence the debate around gene editing’s role in medicine, there is much to watch in the gene editing space.

https://www.biospace.com/article/gene-editing-therapeutics-could-hit-the-market-in-2023/

AbbVie, J&J Pull Two Accelerated Approvals for Imbruvica

 AbbVie and Johnson & Johnson will withdraw the accelerated approvals for Imbruvica (ibrutinib) in mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL), the companies announced Thursday.

The voluntary withdrawals follow disappointing results from Phase III confirmatory studies, which the FDA deemed insufficient to support full approval for Imbruvica in these indications. Imbruvica’s other indications will not be affected.

Developed and commercialized by J&J’s Janssen and AbbVie’s Pharmacyclics, Imbruvica won accelerated approval for MCL in November 2013. To keep it on the market, the companies ran the Phase III SHINE trial, a randomized, double-blinded, placebo-controlled confirmatory trial that enrolled 523 participants with newly diagnosed diseases.

In June 2022, the pharma partners released preliminary results from SHINE, showing that the once-daily oral Imbruvica, in combination with bendamustine-rituximab and rituximab maintenance, significantly improved progression-free survival (PFS) in MCL patients.

However, the investigational regimen was not significantly better than the placebo regarding overall survival and complete response.

The companies couldn’t validate the efficacy of Imbruvica in MZL, for which it earned accelerated approval in January 2017.

In the confirmatory Phase III SELENE trial, a randomized, double-blinded and placebo-controlled study, Imbruvica fell short of its primary endpoint of PFS in patients with relapsed or refractory MZL, according to a press release from J&J.

Efficacy data from these two studies was insufficient to push the FDA to convert Imbruvica’s accelerated approval to full approval in these indications.

Imbruvica is a BTK inhibitor that suppresses the hyperactive proliferation of B cells in blood cancers. The drug will remain approved for chronic lymphocytic leukemia (CLL), Waldenström’s Macroglobulinemia, small lymphocytic lymphoma and chronic graft-versus-host disease.

Opening the Doors for Competitors

A date has yet to be set for the withdrawal of Imbruvica in MCL and MZL, but once that happens, BeiGene’s Brukinsa (zanubrutinib) will become the only BTK inhibitor available in the U.S. for MZL, for which it won accelerated approval in September 2021.

In December 2022, results from the Phase III ALPINE study showed BeiGene’s bet reduced the risk of disease progression or death by 35% relative to Imbruvica.

After two years of follow-up, PFS was 78.4% in Brukinsa-treated patients, as opposed to 65.9% in Imbruvica comparators. In January 2023, the FDA approved Brukinsa for CLL.

As for MCL, AstraZeneca and Eli Lilly are looking to fill the void that Imbruvica will leave. The former’s Calquence (acalabrutinib) was approved in October 2017 for patients with at least one prior line of therapy. Meanwhile, the latter’s Jaypirca (pirtobrutinib) became the first approved reversible BTK inhibitor in January 2023 when it won the FDA’s nod for late-line treatment. Brukinsa is also approved for MCL.

https://www.biospace.com/article/abbvie-j-and-j-pull-two-accelerated-approvals-for-imbruvica/

Moderna Surges On A Key Win For Its Merck-Partnered Cancer Vaccine In Europe

 Moderna (MRNA) stock climbed Monday after European regulators granted its Merck (MRK)-partnered personalized cancer vaccine a key designation.

Under the prime scheme designation, the European Medicines Agency gives early feedback on test results to speed up the development and evaluation of medicines that may significantly improve patients' lives. In this case, Moderna and Merck are testing their cancer vaccine in combination with Merck's Keytruda in patients who've had their melanoma surgically removed.

"There is a high unmet need for therapies in melanoma, as it can be a life-threatening condition where available therapies may not be sufficiently effective in a significant proportion of patients," Moderna's president Stephen Hoge said in a written statement.

https://www.investors.com/news/technology/moderna-stock-jumps-on-european-designation-for-cancer-vaccine/

Cerner Enviza Collaborates with FDA to Develop Innovative AI Tools

 FDA's Sentinel Innovation Center chose Cerner Enviza and John Snow Labs for electronic health record and natural language processing expertise

 Cerner Enviza, an Oracle company, along with John Snow Labs, are now helping support the U.S. Food and Drug Administration's drug safety Sentinel Initiative. By developing artificial intelligence (AI) tools aimed at extracting critical information from clinical notes within electronic health records (EHR), Oracle and John Snow will aid the FDA in better understanding the effects of medicines on large populations. Looking at the asthma drug, montelukast, and its possibility of mental health side effects, this two-year project will demonstrate how the use of machine learning and natural language processing (NLP) technology with unstructured data may help fill gaps in knowledge.

https://finance.yahoo.com/news/cerner-enviza-collaborates-fda-develop-130000706.html

Rallybio started at Outperform by Wedbush

 Target $17

https://finviz.com/quote.ashx?t=RLYB&p=d

Catholic archdiocese accuses Walter Reed of stifling religious rights with ‘cease and desist’ order

 The Catholic Archdiocese for the Military Services is accusing Walter Reed National Military Medical Center of denying Catholic service members and veterans their right to practice their religion after it canceled a contract for pastoral care and issued a “cease and desist” order to a community of Catholic priests just days before Holy Week.

The Catholic archdiocese says in a statement that Walter Reed issued the order against Holy Name College Friary, a Franciscan community of priests and brothers that has served at the center for nearly 20 years.

Instead, it says the contract for Catholic Pastoral Care was terminated at the end of March, just as Holy Week was about to begin.

Walter Reed replaced the contract with a secular defense contracting firm that the archdiocese says will not be able to provide the adequate care needed.

The archdiocese condemned the move as an encroachment upon the right of free exercise of religion under the First Amendment and said its requests to have the ministry reinstated through Easter have not received a response. 

“It is incomprehensible that essential pastoral care is taken away from the sick and the aged when it was so readily available,” Archbishop Timothy Broglio said in a statement.

“This is a classic case where the adage ‘If it is not broken, do not fix it’ applies. I fear that giving a contract to the lowest bidder overlooked the fact that the bidder cannot provide the necessary service,” he said. “I earnestly hope that this disdain for the sick will be remedied at once and their First Amendment rights will be respected.”

While the Archdiocese acknowledged that the chaplain’s office said Catholic care is being provided during Holy Week, it said that without Catholic priests, service members and veterans are being denied their right to practice their religion. Certain central Catholic practices – such as the celebration of the Mass and the administration of Confession – can only be carried out by an ordained Catholic priest.

In a statement on Saturday, Walter Reed said the center is a “welcoming and healing environment that honors and supports a full range of religious, spiritual, and cultural needs.” 

“Tomorrow, Catholic Easter Services will be provided to those who wish to attend. Services will include a celebration of Mass and the administration of Confession by an ordained Catholic Priest,” the statement said. “For many years, a Catholic ordained priest has been on staff at WRNMMC providing religious sacraments to service members, veterans and their loved ones. There has also been a pastoral care contract in place to supplement those services provided.”

“Currently a review of the pastoral care contract is under review to ensure it adequately supports the religious needs of our patients and beneficiaries,” the statement said. “Although at this time the Franciscan Diocese will not be hosting services on Sunday parishioners of the Diocese while patients at our facilities may still seek their services.”

The AMS was created by St. Pope John Paul II to provide the Church’s services to veterans and service members in the US and overseas.

The archdiocese, which does not have geographical boundaries, is responsible for the care of 1.8 million Catholics across the globe. 

Walter Reed was most recently in the headlines after Sen. John Fetterman, D-Pa., checked into the center on Feb 15 for clinical depression.

He was released at the end of March, and his office said that he is now in remission after his treatment.

https://nypost.com/2023/04/09/catholic-archdiocese-accuses-walter-reed-of-stifling-religious-rights-with-cease-and-desist-order/