Takeda’s ADZYNMA Approved by FDA as the First and Only Recombinant ADAMTS13 Enzyme Replacement Therapy for the Treatment of Congenital Thrombotic Thrombocytopenic Purpura

Takeda has received FDA approval for ADZYNMA (ADAMTS13, recombinant-krhn) for both prophylactic and on-demand treatment in adults and pediatric patients diagnosed with congenital thrombotic thrombocytopenic purpura (cTTP). This marks a significant milestone as ADZYNMA is the first and only recombinant ADAMTS13 (rADAMTS13) protein sanctioned by the FDA. It addresses an unmet medical need by replacing the deficient ADAMTS13 enzyme in individuals with cTTP.

“People grappling with cTTP confront severe and potentially life-threatening health hurdles. Until now, there has been a notable absence of approved treatments tailored specifically for this condition,” remarked Julie Kim, President of the U.S. Business Unit and U.S. Country Head at Takeda. “Our commitment to assisting patients with limited or no treatment alternatives is evident in our ongoing pursuit of innovative solutions for rare diseases—a commitment we’ve upheld for over 70 years as pioneers in hematology. Today marks a significant milestone as we proudly contribute to the rare disease community by introducing ADZYNMA, the first FDA-approved therapeutic option tailored for individuals affected by cTTP.”

cTTP is an ultra-rare, chronic blood clotting disorder caused by a deficiency in the ADAMTS13 enzyme. It is associated with acute events and debilitating chronic symptoms or thrombotic thrombocytopenic purpura (TTP) manifestations, which can include thrombocytopenia, microangiopathic hemolytic anemia, headache, and abdominal pain. When left untreated, acute TTP events have a mortality rate of >90%.

The FDA’s green light for ADZYNMA was substantiated by a comprehensive examination of efficacy, pharmacokinetic, safety, and tolerability data. This scrutiny drew from the outcomes of the inaugural randomized, controlled, open-label, crossover Phase III trial in cTTP, coupled with insights from the subsequent continuation trial. Throughout the Phase III trial, participants were administered 40 IU/kg ADZYNMA intravenously or plasma-based therapy bi-weekly or weekly, determined by the enrollment regimen, during months 1-6 (period 1). Subsequently, a crossover to the alternative treatment occurred during months 7-12 (period 2), followed by all patients receiving ADZYNMA during months 13-18 (period 3).

AskBio Presents Preliminary Data from Phase I Trial of Gene Therapy for Congestive Heart Failure (CHF) at the 2023 American Heart Association Scientific Sessions

Asklepios BioPharmaceutical, Inc., a subsidiary of Bayer AG operating independently, shared initial findings from the Phase 1 trial of AB-1002 (NAN-101) during the American Heart Association Scientific Sessions in Philadelphia. The trial explores the potential of AB-1002 for treating patients with congestive heart failure (CHF). The trial aimed to assess the safety and early efficacy of AB-1002 gene therapy in patients diagnosed with NYHA Class III Heart Failure, commonly referred to as advanced heart failure. AB-1002, an AAV vector with targeted action on protein phosphatase inhibitor-1, a molecule associated with heart failure, was rationally designed for this purpose.

In the realm of congestive heart failure, the early positive outcomes observed in patients with advanced heart failure are a beacon of hope for a sub-population in dire need of treatment options. According to Litsa G. Kranias, Ph.D., Hanna Chair of Cardiology at the University of Cincinnati and US Coordinator for Cure-PLaN, these encouraging results pave the way for exploring gene therapy’s potential in addressing this devastating disease. With heart failure being a leading cause of morbidity and mortality in westernized countries, the prospect of gene therapy represents a significant stride towards altering the course of this ailment in the future.

AB-1002, administered as a single dose, led to significant enhancements in key efficacy parameters:

  • In Cohort 1, where six patients were enrolled, three individuals who completed the 12-month follow-up displayed notable improvements in left ventricular ejection fraction (LVEF), NYHA Functional Class (NYHA FC), Minnesota Living with Heart Failure Questionnaire (MLHFQ), cardiopulmonary exercise test (VO2 max), and 6-minute walk test (6MWT) at 12 months post-administration. The remaining three patients in Cohort 1 are still within the initial 3 months following the injection.
  • For Cohort 2, consisting of five patients, two exhibited substantial improvements in MLHFQ and NYHA FC, and all four patients (100%) demonstrated significant enhancements in LVEF at the 12-month mark compared to baseline. Meaningful changes from baseline were defined as NYHA FC, ≥1 point; LVEF, ≥5%; MLHFQ, ≥10 points; VO2 max, ≥1.5 mL/kg/min; 6MWT, 30 meters.

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has issued a favorable opinion endorsing aflibercept 8 mg for extended treatment intervals in two prevalent retinal eye conditions: neovascular (wet) age-related macular degeneration (nAMD) and diabetic macular edema (DME). This recommendation encompasses injections of aflibercept 8 mg at extended treatment intervals of up to every 4 months, following 3 initial monthly doses. In cases with stable visual outcomes, consideration may be given to treatment intervals of up to 5 months. Aflibercept 8 mg, once approved, will stand as the sole sanctioned drug offering extended treatment intervals of up to 5 months, based on findings from clinical trials, for patients with nAMD and DME.

The CHMP recommendation stems from encouraging findings in the PULSAR clinical trial for neovascular age-related macular degeneration (nAMD) and the PHOTON trial for diabetic macular edema (DME). In both trials, aflibercept 8 mg demonstrated non-inferior changes in best-corrected visual acuity (BCVA) compared to Eylea (aflibercept 2 mg) at week 48, with dosing regimens of 12 or 16 weeks.

Recent clinical trials involving aflibercept 8 mg have showcased prolonged vision improvements, extended treatment intervals, effective fluid control, and a safety profile comparable to Eylea 2 mg. The sustained disease control achieved is a significant breakthrough, offering lasting relief to patients and addressing capacity challenges at eye clinics, said Prof. Paolo Lanzetta, Chairman of the Department of Ophthalmology at the University of Udine.

Bayer and Regeneron are collaboratively developing Aflibercept 8 mg. Exclusive rights to Eylea (aflibercept 2 mg) and aflibercept 8 mg in the United States are held by Regeneron, while outside the United States, Bayer holds exclusive marketing rights, with both companies sharing profits equally from Eylea (aflibercept 2 mg) sales.

FDA Grants Orphan Drug Designation to MAIA Biotechnology for THIO as a Treatment for Glioblastoma

On November 10, 2023, MAIA Biotechnology, Inc. (NYSE American: MAIA) announced that the U.S. Food and Drug Administration (FDA) has bestowed Orphan Drug Designation upon their primary product, THIO, an agent targeting cancer telomeres, for treating glioblastoma. This marks the third orphan drug designation for THIO, following its previous designations for hepatocellular carcinoma (HCC) and small cell lung cancer (SCLC) in 2022. The Phase 2 trial of THIO, known as THIO-101, continues to enroll participants, assessing the drug’s potential in treating advanced non-small cell lung cancer (NSCLC). Notably, THIO stands as the sole direct telomere-targeting agent presently undergoing clinical development.

THIO (6-thio-dG or 6-thio-2’-deoxyguanosine) represents a pioneering telomere-targeting agent undergoing clinical development to explore its efficacy in Non-Small Cell Lung Cancer (NSCLC). Telomeres, coupled with the enzyme telomerase, hold pivotal significance in cancer cell survival and their resistance to current therapies. Through the modified nucleotide 6-thio-2’-deoxyguanosine (THIO), a cascade of telomerase-dependent telomeric DNA modifications, DNA damage responses, and selective cancer cell demise is initiated. This process leads to the accumulation of THIO-damaged telomeric fragments within cytosolic micronuclei, triggering both innate (cGAS/STING) and adaptive (T-cell) immune responses.

In advanced in vivo cancer models, the sequential administration of THIO followed by PD-(L)1 inhibitors has resulted in substantial and enduring tumor regression. This occurs by inducing cancer type–specific immune memory. THIO is currently being developed as a treatment option for NSCLC patients beyond the standard-of-care regimen involving existing checkpoint inhibitors, serving as a secondary or subsequent line of therapy.

“We are pleased to receive a third orphan drug designation for THIO, further highlighting FDA’s recognition of THIO’s potential in the treatment of multiple cancer indications, including rare ones such as glioblastoma,” said Vlad Vitoc, M.D., MAIA’s Chairman and Chief Executive Officer. “Each year, globally, more than 300,000 people are diagnosed with brain tumors, of which, 25,000 are in the United States. Glioblastoma represents the majority of these cases in the U.S., with 15,000 new patients diagnosed and more than 10,000 deaths yearly, making it an orphan indication. Given this prevalence there is significant room for growth in the $2.2 billion glioblastoma market, which is expected to reach $3.2 billion globally in the next three years. We consider this ODD an important milestone for our development strategy and for glioblastoma patients who could benefit from a potentially revolutionary therapy.”

“In the data presented to the FDA, THIO successfully penetrated the blood brain barrier (BBB) in syngeneic and humanized mouse models of telomerase-expressing brain cancers. Treatment with THIO resulted in potent anticancer activity and significant expansion of the animal lifespan for several difficult to treat cell lines and xenograft mouse models,” added Sergei Gryaznov, Ph.D., MAIA’s Chief Scientific Officer. “These results stem from THIO’s remarkable mechanism of action and its BBB penetrating property that allows for direct targeting of brain tumors in vivo and potentially in glioblastoma patients.”

THIO-101 represents a multicenter, open-label Phase 2 clinical trial dedicated to dose finding. This trial marks the pioneering attempt to appraise THIO’s effectiveness against tumors in tandem with PD-(L)1 inhibition. It aims to validate the theory that administering low doses of THIO prior to an anti-PD1 agent will bolster and prolong the immune response in individuals with advanced NSCLC. These are patients who either didn’t respond initially or developed resistance and progressed after receiving a first-line treatment regimen involving another checkpoint inhibitor. The trial’s structure focuses on two primary objectives: first, to assess the safety and tolerability of THIO as an anticancer compound and an immune activator for priming, and second, to gauge THIO’s clinical efficacy by utilizing Overall Response Rate (ORR) as the primary clinical endpoint.

Glioblastoma presents a formidable burden within the realm of neuro-oncology, characterized by its aggressive nature and limited treatment options. Its complexity arises from its infiltrative growth, making complete surgical removal challenging, and its resistance to standard therapies like chemotherapy and radiation. 

Pharma companies such as MAIA Biotechnology, among others, have intensified their efforts, focusing on innovative approaches such as immunotherapies, targeted therapies, and precision medicine to combat glioblastoma’s treatment challenges. They’re delving into personalized treatments, leveraging genetic profiling to tailor therapies specific to individual patient profiles, aiming to enhance efficacy and minimize adverse effects. Moreover, ongoing clinical trials exploring novel drug combinations and therapeutic techniques offer promise in reshaping the treatment landscape for this aggressive brain cancer.

First Patient Dosed in Phase III ProstACT GLOBAL Study of Antibody-based Prostate Cancer Therapy Candidate, TLX591

On November 12, 2023, Telix Pharmaceuticals Limited announced the dosing of the first patient in its Phase III ProstACT GLOBAL study involving TLX591, an investigational therapy targeting the prostate-specific membrane antigen (PSMA) with a radio-antibody drug conjugate (rADC) approach. TLX591 comprises a high-specificity PSMA-targeting antibody, a chelator linker, and a cytotoxic lutetium (177Lu) payload. This approach utilizing a PSMA-targeted monoclonal antibody (mAb) presents distinct targeting and pharmacological characteristics compared to small molecules targeting anti-PSMA.

ProstACT GLOBAL (ClinicalTrials.gov ID: NCT04876651) represents the pioneering Phase III trial assessing TLX591 in adult patients dealing with PSMA-positive metastatic castrate-resistant prostate cancer (mCRPC). This study administers TLX591 alongside the Standard of Care (SoC), encompassing androgen receptor inhibition or taxanes, in contrast to the sole use of SoC. This distinctive integration with the ongoing real-world Standard of Care sets ProstACT GLOBAL apart from other studies on PSMA and underscores Telix’s ongoing drive for innovation in prostate cancer treatment while prioritizing improved patient outcomes.

Thus far, 242 patients have undergone treatment across eight Phase I and II investigations involving TLX591. Among these studies is Telix’s ProstACT SELECT study (ClinicalTrials.gov ID: NCT04786847), which affirmed the clinical reliability of Telix’s optimized fractionated dosing and the product’s safety profile. Previously published data from a Phase II (single-arm) study revealed a 42.3-month overall survival (OS) and a satisfactory safety profile when TLX591 was administered using a fractionated dosing regimen alongside docetaxel chemotherapy. Notably, in contrast to other radioligand therapies, prolonged monitoring of patients receiving TLX591 has shown no significant acute or delayed nephrotoxicity, attributed to the agent’s hepatic clearance.

Initial findings from the recently concluded ProstACT SELECT study revealed robust binding of PSMA to tumors and efficient radiation delivery to bone, nodal, and visceral metastases. Importantly, this process mitigated concerns regarding uptake and toxicity in the kidneys, salivary glands, and lacrimal glands. Such distinct biodistribution sets this approach apart from small molecule diagnostic and therapeutic PSMA agents, where uptake might extend beyond cancerous tissue. Furthermore, the SELECT outcomes underscore the clinical advantage of a brief, uncomplicated treatment schedule involving two doses administered 14 days apart. Simultaneously, these results highlight the prolonged retention, internalization, and potential therapeutic advantages of the 177Lu-labeled PSMA-antibody targeting method.

Nat Lenzo, MD, GenesisCare Group Clinical Director Theranostics and Principal Investigator on the ProstACT GLOBAL study commented, “Recent studies, including ProstACT SELECT, have further advanced the development of this antibody-based PSMA therapy for prostate cancer patients. We have been encouraged with the safety profile, tolerability and early efficacy observed in our previous and ongoing studies, in particular for symptom control. It’s an important step forward for patients to see this investigational therapy enter a Phase III study.”

Dr Colin Hayward, Group Chief Medical Officer of Telix said, “Dosing a first patient in the ProstACT GLOBAL study is a significant milestone for Telix and will help build on an already extensive data set for this product candidate. The current TLX591 experience underlines the potential benefits of an antibody-based approach in combination with real world standards of care, including physician choice of ARPI[5] or taxane. As we take this potential first-in-class rADC candidate into a large, mid-stage patient population for the first time, we would like to thank Professor Lenzo and his clinical team, as well as the patients who will contribute to the study.”

ProstACT GLOBAL extends the groundwork laid by earlier Phase I and II trials involving TLX591, notably ProstACT SELECT. This multinational, multicenter, forward-looking Phase III study is structured as a randomized, controlled, open-label investigation, aiming to verify the advantages and potential risks for patients receiving TLX591 alongside Standard of Care (SoC) versus SoC alone. The overarching goal of ProstACT GLOBAL is to enroll approximately 400 patients, marking a significant step, with the initial dose administered successfully at GenesisCare’s facility located at the St John of God Hospital Murdoch campus in Australia.

Pending regulatory approvals, the study aims to broaden its reach globally, encompassing Europe and the United States. Telix anticipates filing its investigational new drug (IND) application with the US Food and Drug Administration (FDA) in Q4 2023, maintaining its scheduled course. The US segment of the study is also set to include a preliminary phase to connect manufacturing data to a newly implemented commercial-scale process. An interim analysis is projected following the enrollment of the initial 120 patients.

Prostate cancer imposes a substantial burden globally, affecting countless lives and challenging treatment paradigms due to its diverse nature. Pharma companies such as Telix Pharmaceuticals, among others, are addressing Prostate cancer by innovating precision therapies, exploring novel treatment modalities, and conducting extensive clinical trials to enhance treatment outcomes and elevate the standard of care for those impacted by this prevalent disease.

FDA Grants Orphan Designation for Lipella’s LP-310 Drug Candidate for Oral Graft-versus-Host Disease

Lipella Pharmaceuticals Inc. (Nasdaq: LIPO) revealed on November 10, 2023, that its drug candidate, LP-310, formulated to address oral Graft-versus-Host Disease (GvHD), has secured “Orphan Drug Designation” from the U.S. Food and Drug Administration (FDA). LP-310, an asset in Lipella’s clinical stage pipeline, aims to target inflammatory conditions within the oral cavity, encompassing oral lichen planus and oral GvHD among its intended indications.

LP-310, a proprietary oral rinse formulation containing liposomal tacrolimus, stands as Lipella’s prime drug candidate derived from LP-10. Lipella has recently obtained FDA clearance for a Phase 2a clinical trial, aiming to assess the safety and effectiveness of LP-310 in individuals suffering from symptomatic oral lichen planus. Notably, this condition lacks an FDA-approved treatment and significantly affects the quality of life for those affected.

The FDA previously granted Orphan Drug Designation to Lipella’s LP-10, marking LP-310 as the second among Lipella’s primary product candidates to secure this recognition. 

Dr. Jonathan Kaufman, Ph.D., Chief Executive Officer of Lipella, said, “We are very pleased to have received Orphan Drug Designation for LP-310 in oral GvHD. This designation is an example of the way we build value, pursuing all available resources that can de-risk and accelerate our clinical research programs. Our collaborative practice with the FDA is critical to our ability to increase the value of all of our clinical assets. We look forward to advancing this drug as a potential treatment for this painful complication of chronic GvHD.”

Dr. Michael Chancellor, Chief Medical Officer at Lipella, said, “GvHD occurs when donor immune cells attack the recipient’s body tissues after an allogeneic tissue or bone marrow transplant. GvHD affects approximately 30,000 Americans and oral GvHD contributes significantly to morbidity in cancer survivors. Morbidity of oral GvHD encompasses significant oral pain and discomfort, making it difficult for patients to eat, drink and speak. In addition, the risk of oral cavity infection, fibrosis and even oral cancer increases. Oral GvHD affects patients’ quality of life and is a great unmet need in cancer survivors.”

Graft-Versus-Host Disease emerges when transplanted bone marrow or stem cells from a donor attack a response against the recipient’s body, typically post-treatment for leukemia, lymphoma, or related blood cancers. Acute GvHD primarily impacts the skin, liver, and gastrointestinal tract, while the chronic form affects various organs, including the skin, mouth, eyes, lungs, stomach, bowel, and liver. Notably, oral lichen planus can manifest singularly as a symptom of chronic GvHD. Managing Graft-versus-Host Disease poses a substantial hurdle, often affecting multiple organs and impeding patients’ quality of life. To address this challenge, pharmaceutical firms are exploring novel approaches, seeking therapies that modulate immune responses while minimizing adverse effects.