The Judiciary Committee’s top Democrat wants everyone to know that surging Big Apple crime is only an illusion manufactured by the party’s political enemies.
Manhattan Congressman Jerry Nadler said he will come out swinging in defense of Manhattan District Attorney Alvin Bragg during the panel’s Monday hearing in New York.
The hearing will focus on the victims of Bragg’s soft-on-crime policies.
“We will show the essentially fraudulent nature of what [committee chair] Jim Jordan and company are claiming about the crime rates in New York and compared to other cities, including Republican-led cities,” Nadler told The Post.
“And we will talk about how this whole hearing is part of Jim Jordan and the Republicans’ general attempts to obstruct justice and to attack the DA in Manhattan and to obstruct justice in the Trump case,” he added, referring to the president’s indictment in Manhattan last month.
The GOP-controlled committee will set the tone of the proceedings with four announced witnesses, while Democrats will only be able to call one, Nadler said. Democrats have so far not announced who they will invite to speak.
City crime statistics belie Nadler’s rosy assessment. Overall violent crime surged in Manhattan South by 34% and Manhattan North by 14.5% in 2022 — Bragg’s first year in office — compared to 2021.
“I dare Jerry Nadler to ask me or [crime victims] to our faces … and tell us why the lives that are being destroyed here in New York City don’t matter [just] because it’s happening elsewhere,” said Jennifer Harrison, a victims-rights advocate who has been called by Republicans to testify at the Monday hearing.
https://nypost.com/2023/04/15/democrats-to-participate-in-ny-judiciary-committee-hearing/
Commercial launch of DAYBUE offers Rett syndrome community the first and only approved therapy for Rett syndrome, a rare, neurodevelopmental disorder, which affects 6,000 to 9,000 patients in the U.S.
Preclinical data supports targeting ITK as a new approach for cancer immunotherapy
Novel mechanism of action modulates T cell differentiation and enhances the immune system via Th1 skewing, increased T cell cytolytic capacity and reduction of T cell exhaustion
Enrollment continues in Phase 1/1b clinical trial of CPI-818 for the treatment of refractory T cell lymphoma, including use of minimum absolute lymphocyte count (ALC) predictive biomarker for patient selection
Preclinical data describes a novel EGFR-sparing, brain-penetrant ErbB2 inhibitor active against key oncogenic ErbB2 mutations
In vivo characterization shows a novel, selective, reversible FGFR2 inhibitor has potency against molecular brake mutations and potential advantages over covalent approaches
APEX Part 2 underway in AdvSM patients at once-daily 150 mg optimized dose of bezuclastinib
April is Parkinson’s Awareness Month, and with new approaches to treating Parkinson’s disease in the pipeline, 2023 is poised to be a pivotal year for this space.
First, a handful of new formulations of the traditional levodopa/carbidopa drugs are nearing the market. The new formulations are designed to improve treatment outcomes, in particular by reducing the severity of symptoms associated with “off” periods with periodic dosing.
And hot on their heels are several new therapeutic entities, mostly in Phase II trials, that build upon existing mechanisms of action or hit entirely novel targets.
Old Drugs, New Formulations
The Levodopa/carbidopa combination has long been considered the gold standard for treating Parkinson’s disease. Approved by the FDA in 1975, the drug duo is administered together because carbidopa reduces the amount of levodopa needed to achieve the desired therapeutic effect within the brain.
When initially marketed as an immediate-release combination tablet, the first formulation, known as Sinemet, had to be administered multiple times a day, with precise timing needed to optimize effects. This led to adherence issues and complications such as potential motor fluctuations. Companies then developed longer-lasting oral formulations such as Rytary capsules, but even these led to cycles of “on” and “off” periods, where patients only intermittently experienced well-controlled symptoms.
The move to other routes of administration has been driven by several factors. The gastrointestinal system can break down levodopa before the it can reach the brain for therapeutic activity, and previous oral formulations sought to fight this effect by administering higher doses. While bypassing the gastrointestinal system leads to better safety and efficacy outcomes, the FDA is treading cautiously because subcutaneous formulations of levodopa/carbidopa have not yet been approved.
In March 2023, the FDA declined to approve AbbVie’s subcutaneously administered formulation, ABBV-951, to treat motor fluctuations in Parkinson’s disease. AbbVie’s formulation contains foscarbidopa and foslevodopa, prodrugs designed to activate after administration to the body. In Phase III trials, foslevodopa/foscarbidopa led to increases in “on” time without dyskinesia and significantly reduced “off” time compared to standard-of-care treatment. Although AbbVie’s data contained no safety or efficacy issues, the FDA said it needed more data on the subcutaneous pump device to proceed.
Meanwhile, Mitsubishi Tanabe Pharma Corporation reported positive Phase III trial results in January 2023 for its subcutaneous liquid formulation, ND0612. Although slightly behind AbbVie, Mitsubishi’s collaboration with NeuroDerm uses a continuous subcutaneous infusion of levodopa/carbidopa, which showed improved control over Parkinson’s disease symptoms when combined with supplemental oral levodopa/carbidopa, compared to traditional oral levodopa/carbidopa alone.
Refining the Capsule
In terms of extended-release oral formulations, Amneal Pharmaceuticals submitted its levodopa/carbidopa capsule formulation to the FDA in November 2022. Known as IPX203, Amneal’s product has a unique mixture of immediate-release granules and extended-release beads to extend “on” periods of symptom control and decrease “off” periods. While the immediate-release granules contain carbidopa and levodopa, the extended-release beads only contain levodopa and are enterically coated to prevent stomach acid from affecting the beads. Amneal is scheduled to hear back from the FDA on June 30, 2023.
Multiple Paths to Treatment
While new formulations of levodopa/carbidopa are further along in the development process, companies continue to look at other pharmacologic targets to treat Parkinson’s disease. While some investigators such as Denali Therapeutics and Biogen are focused on LRRK2 inhibitors, others are trying to repurpose existing agents such as ambroxol, a mucolytic approved in the EU to fight respiratory disease by clearing mucus secretions.
In December 2022, Denali and Biogen launched a Phase III trial called LIGHTHOUSE to investigate the use of its LRRK2 inhibitor, BIIB122, also known as DNL151. The Phase IIb LUMA trial was still at the dosing phase as of February 2023. As a first-in-class small molecule, BIIB122 is hypothesized to function by decreasing LRRK2 kinase activity to reduce lysosomal impairment in Parkinson’s patients.
As for ambroxol, a Phase III trial will be launched in early 2023 by the University College of London to assess the drug’s use in Parkinson’s disease. Data from the Phase II AiM-PD study, reported in January 2020, showed ambroxol was able to cross the blood-brain barrier, increase GCase activity and reduce alpha-synuclein levels. Because GCase activity is lower in patients with GBA1 mutations and Parkinson’s disease, scientists hope Phase III trials of ambroxol will demonstrate clinical efficacy.
Because ambroxol's Phase III data may not arrive until 2027, and Denali and Biogen's Phase III data not expected to be finalized until 2031, it is likely that newer formulations of levodopa/carbidopa will be marketed first. But as more compelling treatments make their way toward the market, the coming years could be pivotal for Parkinson’s disease research.
https://www.biospace.com/article/reformulated-new-takes-on-parkinson-s-disease-treatments/
The 2023 American Association for Cancer Research (AACR) Annual Meeting kicked off over the weekend, featuring advances in the treatment of several cancer types.
Here are some notable presentations.
Roche’s Tecentriq-Avastin Combo in Adjuvant Liver Cancer
Interim results from Roche subsidiary Genentech’s Phase III IMbrave050 study showed the combination of Tecentriq (atezolizumab) and Avastin (bevacizumab) significantly improved recurrence-free survival (RFS) in adjuvant hepatocellular carcinoma (HCC), as compared with active surveillance.
IMbrave050 enrolled 668 patients who were deemed to be at a high risk of recurrence following surgery. After a median of 17.4 months, treatment with Genentech’s antibody combo reduced the risk of recurrence or death by 28%.
Overall survival data and those for other secondary endpoints were not yet mature at the time of the interim analysis, Pierce Chow, lead study author and senior consultant surgeon at the National Cancer Centre Singapore, said in a press interview.
There is a lack of proven and effective adjuvant treatments for HCC, Chow said, adding that patients who undergo resection or ablation typically have poor survival and often see their disease recur. Results from IMbrave050 help address this urgent need, he said.
According to a story from Fierce Pharma, there were 27 deaths in the Tecentriq-Avastin arm, two of which were directly attributed to the study treatment. Twenty patients in the active surveillance group died.
Serious adverse events occurred in 24.1% of patients treated with Tecentriq-Avastin, as opposed to 10.3% in active surveillance comparators.
The Tecentriq-Avastin combo is approved for use in HCC patients with unresectable or metastatic disease who have not previously received systemic therapy.
Moderna and Merck’s High-Risk Melanoma Combo
In the Phase IIb KEYNOTE-942/mRNA-4157-P201 trial, Moderna’s individualized mRNA vaccine combined with Merck’s Keytruda (pembrolizumab), a PD-1 blocker, boosted recurrence-free survival in patients with resected stage III/IV melanoma.
The mRNA vaccine, an individualized neoantigen therapy, works by priming the patient’s immune system to launch a potent anti-tumor response specific to their cancer’s mutation signature. Compared with Keytruda alone, the combination led to a 44% drop in the risk of recurrence or death. Over 12 months of observation, the RFS rate was 83.4%, which dropped slightly to 78.6% by 18 months.
In an exploratory subgroup analysis of patients with high and low tumor mutational burden, the use of the mRNA vaccine reduced the risk of recurrence or death by 35% and 41%, respectively.
As for safety, the observed adverse events were largely consistent with what had been previously recorded. Common toxicities included fatigue, injection-site pain and chills.
These data point to the potential of combining an individualized vaccine with PD-1 blockage in high-risk melanoma, Kyle Holen, senior vice president and head of development, therapeutics and oncology at Moderna, said in a statement. Moderna looks forward to beginning a Phase III trial soon, he said.
Beyond melanoma, Moderna also plans to study this candidate in lung cancer, Holen said.
AstraZeneca’s Imfinzi in Late-Stage NSCLC
In a planned interim analysis of the Phase III AEGEAN study, AstraZeneca’s Imfinzi (durvalumab) plus neoadjuvant chemotherapy, followed by Imfinzi on its own, significantly improved event-free survival (EFS) in patients with early-stage non-small cell lung cancer (NSCLC), as compared with neoadjuvant chemotherapy alone.
The Imfinzi-based regimen cut the risk of recurrence, progression or death by 32%.
Pathologic complete response (pCR), defined as having no viable tumor after neoadjuvant treatment, was a key secondary endpoint of AEGEAN. The Imfinzi regimen led to a 17.2% pCR rate, as opposed to 4.3% after neoadjuvant chemotherapy alone.
AEGEAN’s results underline the importance of diagnosing NSCLC and initiating treatment earlier, when patients are most likely to be cured, Susan Galbraith, executive vice president of oncology R&D at AstraZeneca, said in a statement.
AstraZeneca will discuss these data with the regulatory bodies, Galbraith said.
The AEGEAN study consisted of 802 NSCLC patients who were given Imfinzi at a fixed dose of 1,500 mg. Those with tumor mutations in the EGFR and ALK genes were excluded from the study.
AEGEAN found no new safety signals in either the neoadjuvant or adjuvant settings.
Affimed’s Mid-Stage Lymphoma Study
Final data from the Phase II REDIRECT study showed that Affimed’s AFM13 was effective for the treatment of heavily pretreated, advanced relapsed or refractory peripheral T Cell Lymphoma (PTCL).
Affimed’s candidate induced a 32.4% objective response rate (ORR) and a 10.2% complete response rate (CRR) in the study’s intention-to-treat population. In the subgroup of patients with angioimmunoblastic T cell lymphoma, a common PTCL subtype, AFM13 elicited ORR and CRR values of 53.3% and 26.7%, respectively.
AFM13’s effects endured for a median of 2.3 months, and treated patients showed a median progression-free survival of 3.5 months. Overall survival was 13.8 months.
AFM13 is an investigational, first-in-class innate cell engager that works by activating innate immune players including natural killer cells and macrophages to attack CD30-positive hematologic cancer cells. It is Affimed’s most advanced innate cell engager.
REDIRECT is a multicenter, registration-directed trial enrolling 108 patients who received 200-mg intravenous infusions of AFM13.
Affimed reported an adverse event profile that was consistent with what had previously been reported. Common treatment-emergent toxicities included infusion-related reactions, neutropenia and pyrexia. There were no side effects that led to death.
https://www.biospace.com/article/aacr-weekend-roundup-roche-astrazeneca-moderna-and-affimed/
