On April 16, 2024 Astrazeneca reported updated exploratory results from the TOPAZ-1 Phase III trial showed IMFINZI (durvalumab) in combination with standard-of-care chemotherapy demonstrated a clinically meaningful long-term overall survival (OS) benefit at three years for patients with advanced biliary tract cancer (BTC) (Press release, AstraZeneca, APR 16, 2024, View Source [SID1234642119]).

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These results from TOPAZ-1, which are the longest survival follow-up ever reported for a global, randomized Phase III trial in this setting, will be presented on April 18 at the 2024 Cholangiocarcinoma Foundation Conference in Salt Lake City, Utah.

At more than three years (median follow-up of 41.3 months), results showed IMFINZI plus chemotherapy reduced the risk of death by 26% versus chemotherapy alone (based on a hazard ratio [HR] of 0.74; 95% confidence interval [CI], 0.63-0.87). The median OS was 12.9 months for IMFINZI plus chemotherapy versus 11.3 months for chemotherapy alone. More than twice as many patients on the IMFINZI-based regimen were alive at three years versus chemotherapy alone (14.6% versus 6.9%).

The TOPAZ-1 trial met the primary endpoint of OS in October 2021 at a planned interim analysis, showing that the combination reduced the risk of death by 20% versus chemotherapy alone (based on a HR of 0.80; 95% CI, 0.66-0.97; 2-sided p=0.021 at a statistical significance threshold of 0.03).

Do-Youn Oh, MD, PhD, Professor, Division of Medical Oncology, Department of Internal Medicine at Seoul National University Hospital and Seoul National University College of Medicine, and principal investigator in the trial, said: "The latest data from TOPAZ-1 show that twice as many patients with advanced biliary tract cancer were still alive at three years with durvalumab and chemotherapy, an especially meaningful advance in a setting where historically the prognosis has been poor. These results reinforce the long-term benefit of this immunotherapy-based combination as a standard of care for patients with this devastating disease."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "TOPAZ-1 raised the bar for the treatment of advanced biliary tract cancer, showing a remarkable survival benefit for IMFINZI added to chemotherapy with a well-tolerated regimen. These data represent the longest survival follow-up reported for immunotherapy in this setting, and the three-year landmark survival improvement underscores our commitment to improving long-term outcomes in gastrointestinal cancers."

Stacie Lindsey, CEO, Cholangiocarcinoma Foundation said: "AstraZeneca’s longer survival data in advanced biliary tract cancer represents a meaningful milestone in that we are seeing three-year survival data for the first time for these patients. The data spurs hope that research will continue to improve outcomes for patients living with these challenging and rare cancers."

Summary of updated survival results: TOPAZ-1i

OSi,ii

IMFINZI+ chemotherapy

(n=341)

Chemotherapy

(n=344)

Median OS (95% CI in months)

12.9

(11.6-14.1)

11.3

(10.1-12.5)

HR (95% CI)iii

0.74 (0.63-0.87)

OS rate at 36 months (95% CI) (%)iv

14.6

(11.0-18.6)

6.9

(4.5-10.0)

i. 26 months of additional follow-up (data cut-off: 23 October 2023) after the primary analysis, with 89% overall OS event maturity

ii. At data cut-off for this analysis, median (95% CI) follow-up time in all patients calculated using reverse Kaplan-Meier technique was 42.9 (39.8-44.3) months for IMFINZI plus chemotherapy and 41.8 (36.7-46.2) months for chemotherapy

iii. HR and 95% CI calculated using Cox proportional hazards model

iv. OS rates calculated using Kaplan-Meier technique

IMFINZI plus chemotherapy continued to be well-tolerated, with no new safety signals observed with longer follow-up. Results showed 15.4% of patients experienced treatment-related serious adverse events with IMFINZI plus chemotherapy versus 17.3% with chemotherapy alone.

IMPORTANT SAFETY INFORMATION

There are no contraindications for IMFINZI (durvalumab).

Immune-Mediated Adverse Reactions

Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment or after discontinuation. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue IMFINZI depending on severity. See USPI Dosing and Administration for specific details. In general, if IMFINZI requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

IMFINZI can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients who did not receive recent prior radiation, the incidence of immune-mediated pneumonitis was 2.4% (34/1414), including fatal (<0.1%), and Grade 3-4 (0.4%) adverse reactions. In patients who received recent prior radiation, the incidence of pneumonitis (including radiation pneumonitis) in patients with unresectable Stage III NSCLC following definitive chemoradiation within 42 days prior to initiation of IMFINZI in PACIFIC was 18.3% (87/475) in patients receiving IMFINZI and 12.8% (30/234) in patients receiving placebo. Of the patients who received IMFINZI (475), 1.1% were fatal and 2.7% were Grade 3 adverse reactions. The frequency and severity of immune-mediated pneumonitis in patients who did not receive definitive chemoradiation prior to IMFINZI were similar in patients who received IMFINZI as a single agent or with ES-SCLC or BTC when given in combination with chemotherapy.

Immune-Mediated Colitis

IMFINZI can cause immune-mediated colitis that is frequently associated with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 2% (37/1889) of patients receiving IMFINZI, including Grade 4 (<0.1%) and Grade 3 (0.4%) adverse reactions.

Immune-Mediated Hepatitis

IMFINZI can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 2.8% (52/1889) of patients receiving IMFINZI, including fatal (0.2%), Grade 4 (0.3%) and Grade 3 (1.4%) adverse reactions.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency: IMFINZI can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Immune-mediated adrenal insufficiency occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.
Hypophysitis: IMFINZI can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. Grade 3 hypophysitis/hypopituitarism occurred in <0.1% (1/1889) of patients who received IMFINZI.
Thyroid Disorders: IMFINZI can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated.
Thyroiditis: Immune-mediated thyroiditis occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.
Hyperthyroidism: Immune-mediated hyperthyroidism occurred in 2.1% (39/1889) of patients receiving IMFINZI.
Hypothyroidism: Immune-mediated hypothyroidism occurred in 8.3% (156/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.
Type 1 Diabetes Mellitus, which can present with diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Grade 3 immune-mediated Type 1 diabetes mellitus occurred in <0.1% (1/1889) of patients receiving IMFINZI.
Immune-Mediated Nephritis with Renal Dysfunction

IMFINZI can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.5% (10/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.

Immune-Mediated Dermatology Reactions

IMFINZI can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Immune-mediated rash or dermatitis occurred in 1.8% (34/1889) of patients receiving IMFINZI, including Grade 3 (0.4%) adverse reactions.

Other Immune-Mediated Adverse Reactions

The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMFINZI or were reported with the use of other PD-1/PD-L1 blocking antibodies.

Cardiac/vascular: Myocarditis, pericarditis, vasculitis.
Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.
Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.
Gastrointestinal: Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis.
Musculoskeletal and connective tissue disorders: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic.
Endocrine: Hypoparathyroidism.
Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection.
Infusion-Related Reactions

IMFINZI can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue IMFINZI based on the severity. See USPI Dosing and Administration for specific details. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses. Infusion-related reactions occurred in 2.2% (42/1889) of patients receiving IMFINZI, including Grade 3 (0.3%) adverse reactions.

Complications of Allogeneic HSCT after IMFINZI

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/L-1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/L-1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/L-1 blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. In females of reproductive potential, verify pregnancy status prior to initiating IMFINZI and advise them to use effective contraception during treatment with IMFINZI and for 3 months after the last dose of IMFINZI.

Lactation

There is no information regarding the presence of IMFINZI in human milk; however, because of the potential for adverse reactions in breastfed infants from IMFINZI, advise women not to breastfeed during treatment and for 3 months after the last dose.

Adverse Reactions

In patients with locally advanced or metastatic BTC in the TOPAZ-1 study receiving IMFINZI (n=338), the most common adverse reactions (occurring in ≥20% of patients) were fatigue (42%), nausea (40%), constipation (32%), decreased appetite (26%), abdominal pain (24%), rash (23%), and pyrexia (20%).
In patients with locally advanced or metastatic BTC in the TOPAZ-1 study receiving IMFINZI (n=338), discontinuation due to adverse reactions occurred in 6% of the patients receiving IMFINZI plus chemotherapy. Serious adverse reactions occurred in 47% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 2% of patients were cholangitis (7%), pyrexia (3.8%), anemia (3.6%), sepsis (3.3%) and acute kidney injury (2.4%). Fatal adverse reactions occurred in 3.6% of patients receiving IMFINZI plus chemotherapy. These include ischemic or hemorrhagic stroke (4 patients), sepsis (2 patients), and upper gastrointestinal hemorrhage (2 patients).
The safety and effectiveness of IMFINZI have not been established in pediatric patients.

Indication:

IMFINZI, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC).

Please see Full Prescribing Information including Medication Guide for IMFINZI.

Notes

Biliary tract cancer

Biliary tract cancer (BTC) is a group of rare and aggressive gastrointestinal (GI) cancers that form in the cells of the bile ducts (cholangiocarcinoma), gallbladder or ampulla of Vater (where the bile duct and pancreatic duct connect to the small intestine).1,2 Approximately 50,000 people in the US, Europe and Japan and about 210,000 people worldwide are diagnosed with BTC each year.3-5 These patients historically have a poor prognosis, with approximately 5% to 15% of patients with BTC surviving five years. For patients with metastatic disease, the five-year survival rate drops to less than 5%.6

Cholangiocarcinoma is more common in China and Thailand and is on the rise in Western countries.1,7 Gallbladder cancer is more common in certain regions of South America, India and Japan.8

Early-stage BTC affecting the bile ducts and gallbladder often presents without clear symptoms and most new cases of BTC are therefore diagnosed at an advanced stage, when treatment options are limited and the prognosis is poor.7-9

TOPAZ-1

TOPAZ-1 is a randomized, double-blind, placebo controlled, multicenter, global Phase III trial of IMFINZI in combination with chemotherapy (gemcitabine plus cisplatin) versus placebo in combination with chemotherapy as a 1st-line treatment in 685 adult patients with unresectable, locally advanced or metastatic BTC including intrahepatic and extrahepatic cholangiocarcinoma, and gallbladder cancer. Patients with ampullary carcinoma were excluded.

The primary endpoint is overall survival and key secondary endpoints included progression-free survival, objective response rate and safety. The trial was conducted in 105 centers across 17 countries including in the US, Europe, South America and several countries in Asia including South Korea, Thailand, Japan and China.

IMFINZI (durvalumab)

IMFINZI (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics and releasing the inhibition of immune responses.

In addition to its indications in unresectable, Stage III NSCLC and ES-SCLC, IMFINZI is currently approved in a number of countries in combination with a short course of tremelimumab-actl and chemotherapy for the treatment of metastatic NSCLC.

IMFINZI is also approved in a number of countries in combination with chemotherapy in locally advanced or metastatic biliary tract cancer and in combination with tremelimumab-actl in unresectable hepatocellular carcinoma (HCC). IMFINZI is also approved as a monotherapy in unresectable HCC in Japan and the EU and in previously treated patients with advanced bladder cancer in a small number of countries.

Since the first approval in May 2017, more than 220,000 patients have been treated with IMFINZI. As part of a broad development program, IMFINZI is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, breast cancer, several gastrointestinal cancers and other solid tumors.

On April 16, 2024 Asher Biotherapeutics, a biotechnology company developing precisely-targeted immunotherapies for cancer, autoimmune, and infectious diseases, reported the closing of a Series C financing, which raised $55 million (Press release, Asher Biotherapeutics, APR 16, 2024, View Source [SID1234642118]). The financing was led by RA Capital Management, and included new investors AstraZeneca (LSE/STO/Nasdaq: AZN) and Bristol Myers Squibb, along with existing investors Janus Henderson Investors, Third Rock Ventures, Wellington Management and Boxer Capital and other undisclosed institutional investors.

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"We are delighted to have the continued support of RA Capital, and excited to add two top biopharmaceutical companies and experts in oncology to our investor syndicate," said Craig Gibbs, Ph.D., Chief Executive Officer of Asher Bio. "We are committed to delivering a new class of highly selective cis-targeted immunotherapies for cancer, which are designed to activate only the desired immune cell type to potentially maximize efficacy and limit off-target toxicities. We are pleased to have investors with deep and hands-on expertise in the cytokine space recognizing our early clinical data and our differentiated approach. This Series C financing generated robust demand and positions us well to continue AB248’s clinical development to generate tumor response data from monotherapy expansion cohorts, as well as data from dose escalation and expansion in combination with a PD-1 checkpoint inhibitor."

Asher Bio plans to use the proceeds from this financing to advance the clinical development of its lead program, AB248, a novel CD8+ T cell selective IL-2, generated by fusing a reduced potency IL-2 mutein to an anti-CD8β antibody. AB248 is currently being investigated in a Phase 1a/1b study, which is evaluating AB248 as a monotherapy and in combination with KEYTRUDA (pembrolizumab), in patients with recurrent locally advanced or metastatic solid tumors, including melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (SCCHN), previously treated with a PD1 or PD-L1 checkpoint inhibitor.

AB248 was specifically engineered to selectively and potently activate CD8+ T-cells, while avoiding natural killer (NK) cells, which can act as a pharmacological sink and contribute to toxicity, and regulatory T (Treg) cells, which are immunosuppressive. Initial pharmacokinetic and pharmacodynamic data from the ongoing Phase 1a/1b clinical trial support AB248’s proof of mechanism and activity with a highly differentiated clinical profile. Early data shows potent and selective CD8+ T cell activation without substantial changes to Treg and NK cell numbers and initial evidence of anti-tumor activity, with a generally well-tolerated safety profile.

"Asher’s groundbreaking cis-targeting platform offers a highly differentiated approach to immunotherapy, with the potential to overcome the limitations of other immune-based treatments by maximizing efficacy and limiting off-target toxicities," said Jake Simson, RA Capital Management. "The company has produced promising preclinical and early clinical data to date and we are excited to continue to support Asher as they further advance their lead program in the clinic."

KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

On April 16, 2024 Ferring Pharmaceuticals reported start up of new studies in the United States (U.S.) for three new ADSTILADRIN in BLadder cancEr (ABLE) clinical trials in patients with non-muscle invasive bladder cancer (NMIBC) with plans to expand select clinical trials outside of the U.S. later this year (Press release, Ferring Pharmaceuticals, APR 16, 2024, View Source [SID1234642117]). ADSTILADRIN was approved by the U.S. Food and Drug Administration (FDA) in December 2022 for adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumors.

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"ADSTILADRIN is the foundation of Ferring’s leadership mission in the uro-oncology therapeutic category and our ambition is for it to become the new standard of care and the backbone therapy for patients across the NMIBC disease spectrum," said Bipin Dalmia, Senior Vice President, Global Head, Uro-Oncology Franchise, Ferring Pharmaceuticals. "Embarking on a broad research and geographic expansion program is yet another demonstration of our commitment to the uro-oncology community, together with our significant manufacturing investments that recently enabled full availability of ADSTILADRIN to every appropriate U.S. patient who needs it."

The addition of three new ABLE clinical trials to the existing multi-year ADSTILADRIN studies program will expand the body of evidence for the intravesical non-replicating gene therapy:

ABLE-22: A Phase 2, randomized, multi-center, open label clinical study to evaluate the safety and efficacy of ADSTILADRIN alone or in combination with chemotherapy (gemcitabine and docetaxel) or immunotherapy (pembrolizumab) in adult patients with high-grade BCG-unresponsive NMIBC.
ABLE-32: A Phase 3b randomized, controlled clinical study to evaluate the safety and efficacy of ADSTILADRIN versus observation in patients with intermediate-risk NMIBC.
ABLE-42: A Phase 4, multi-center, open-label clinical study to evaluate the efficacy of retreatment with ADSTILADRIN in previously-treated patients with high-grade BCG-unresponsive NMIBC with CIS with or without papillary tumors who had not responded to the product at the first three-month assessment.
"ADSTILADRIN is an established monotherapy treatment option for patients with BCG-unresponsive NMIBC disease, an area where patients’ treatment options have been severely limited for decades," said Pierre-Yves Berclaz, M.D., Ph.D., Executive Vice President and Chief Science and Medical Officer, Ferring Pharmaceuticals. "These new trials underscore Ferring’s commitment to create solutions for patients by enlarging the body of evidence for this novel nonreplicating gene therapy."

The ADSTILADRIN clinical trial program includes two additional studies, the first being ABLE–41, a U.S. Real-World Evidence (RWE) Study announced in September 2023 and the second being a bridging study in Japan. The ABLE-22, ABLE-32 and ABLE-42 clinical trials announced today are yet another milestone for this comprehensive research program.

Additional ongoing studies in the ADSTILADRIN clinical trial program include:

ABLE-41 (NCT06026332): An ongoing, non-interventional RWE study following NMIBC patients aged 18 years or older with high-risk, BCG-unresponsive NMIBC who are being treated with ADSTILADRIN in a clinical setting and had not previously received this therapy in a clinical trial. The study is exploring early utilization, experiences, and outcomes of ADSTILADRIN in the routine care setting in these patients. The first patient was enrolled in September 2023.
Japan Phase 3B Study (000381): Single arm bridging study of high grade, BCG-unresponsive NMIBC patients.
Healthcare providers in the U.S. can learn more about the ADSTILADRIN clinical trial program by calling 1-888-FERRING (888-337-7464) and selecting option number one or emailing [email protected].

About ADSTILADRIN

ADSTILADRIN (nadofaragene firadenovec-vncg) is the first and only FDA-approved intravesical non-replicating gene-therapy for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors. It is a non-replicating adenovirus vector-based therapy containing the gene interferon alfa-2b, administered locally as a monotherapy by catheter directly into the bladder once every three months. The vector enters the cells of the bladder wall, releasing the active gene and causing the bladder’s cell walls to secrete high quantities of interferon alfa-2b protein, a naturally-occurring protein the body uses to fight cancer. This approach essentially turns the bladder wall cells into interferon microfactories, enhancing the body’s own natural defenses against the cancer.

ADSTILADRIN has been studied in a clinical trial program that includes 157 patients with high-grade, BCG-unresponsive NMIBC who had been treated with adequate BCG previously and did not see benefit from additional BCG treatment (full inclusion criteria published on clinicaltrials.gov: NCT02773849).1

About Non-Muscle Invasive Bladder Cancer (NMIBC)

NMIBC is a form of bladder cancer which is present in the superficial layer of the bladder and has not invaded deeper into the bladder or spread to other parts of the body.2 In the United States, bladder cancer is the seventh most common cancer, fourth among men3-4, and it is estimated that there will be approximately 83,190 new cases of bladder cancer in the U.S. in 2024.5 Historically, 75% of bladder cancer presents as NMIBC.6 In patients with high-risk NMIBC, intravesical BCG remains the first-line standard-of-care. However, more than 50% of patients who receive initial treatment with BCG will experience disease recurrence and progression within one year, with many developing BCG-unresponsive disease.5 Current treatment options for BCG-unresponsive patients are very limited, and National Comprehensive Cancer Network (NCCN) guidelines recommend cystectomy (partial or complete removal of the bladder).7

INDICATION

ADSTILADRIN is a non-replicating adenoviral vector-based gene therapy indicated for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS: ADSTILADRIN is contraindicated in patients with prior hypersensitivity reactions to interferon alfa or to any component of the product.

WARNINGS AND PRECAUTIONS:

Risk with delayed cystectomy: Delaying cystectomy in patients with BCG-unresponsive CIS could lead to development of muscle invasive or metastatic bladder cancer, which can be lethal. If patients with CIS do not have a complete response to treatment after 3 months or if CIS recurs, consider cystectomy.
Risk of disseminated adenovirus infection: Persons who are immunocompromised or immunodeficient may be at risk for disseminated infection from ADSTILADRIN due to low levels of replication-competent adenovirus. Avoid ADSTILADRIN exposure to immunocompromised or immunodeficient individuals.
DOSAGE AND ADMINISTRATION: Administer ADSTILADRIN by intravesical instillation only. ADSTILADRIN is not for intravenous use, topical use, or oral administration.

USE IN SPECIFIC POPULATIONS: Advise females of reproductive potential to use effective contraception during ADSTILADRIN treatment and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during ADSTILADRIN treatment and for 3 months after the last dose.

ADVERSE REACTIONS: The most common (>10%) adverse reactions, including laboratory abnormalities (>15%), were glucose increased, instillation site discharge, triglycerides increased, fatigue, bladder spasm, micturition (urination urgency), creatinine increased, hematuria (blood in urine), phosphate decreased, chills, pyrexia (fever), and dysuria (painful urination).

You are encouraged to report negative side effects of prescription drugs to FDA. Visit www.FDA.gov/medwatch or call 1-800-332-1088. You may also contact Ferring Pharmaceuticals at 1-888-FERRING.

Please click to see the full Prescribing Information.

On April 16, 2024 Calidi Biotherapeutics, Inc. (NYSE American: CLDI or "Calidi"), a clinical-stage biotechnology company developing a new generation of targeted immunotherapies, reported the pricing of its "reasonable best efforts" public offering of 15,197,500 shares of common stock (or pre-funded warrants in lieu thereof) and accompanying Series A Common Warrants, Series B Unit Warrants, with each unit consisting of one share of common stock and a Series B-1 Common Warrant and Series C Unit Warrants, with each unit consisting of one share of common stock and a Series C-1 Common Warrant (or common stock equivalents in lieu thereof) at an effective combined price of $0.40 per share and common warrants for aggregate gross proceeds of approximately $6.1 million, before deducting placement agent fees and other offering expenses (Press release, Calidi Biotherapeutics, APR 16, 2024, View Source [SID1234642116]). The common warrants will have an exercise price of $0.60 per share, and the Series A Common Warrants, Series B Unit Warrant and Series C Unit Warrant will be exercisable immediately. The common warrants will expire in five years (with respect to the Series A Common Warrant, the Series B-1, Warrant and the Series C-1 Common Warrant), twelve months (with respect to the Series B common warrants) and four months (with respect to the Series C common warrants) from the issuance date.

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The closing of the offering is expected to occur on or about April 18, 2024, subject to the satisfaction of customary closing conditions. The Company currently intends to use a portion of the net proceeds of this offering for working capital and general corporate purposes, and pre-clinical and clinical trials subject to the actual amount of proceeds received.

Ladenburg Thalmann & Co. Inc. is acting as sole placement agent in connection with the offering.

The securities described above are being offered pursuant to a registration statement on Form S-1 (File No. 333-276741) previously filed with the Securities and Exchange Commission (SEC) which became effective on April 15, 2024. The offering is being made only by means of a prospectus forming part of the effective registration statement. Copies of the preliminary prospectus and, when available, copies of the final prospectus, relating to the offering may be obtained on the SEC’s website located at View Source Electronic copies of the final prospectus relating to the offering may be obtained, when available, from Ladenburg Thalmann & Co. Inc., 640 Fifth Avenue, 4th Floor, New York, New York 10019, or by telephone at (212) 409-2000, or by email at [email protected].

This press release shall not constitute an offer to sell or the solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation, or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or other jurisdiction.

On April 16, 2024 SCG Cell Therapy (SCG) and the Agency for Science, Technology and Research (A*STAR) reported the launch joint laboratories for cellular immunotherapies (Press release, SCG Cell Therapy, APR 16, 2024, View Source [SID1234642115]). This collaboration, at a combined funding of close to S$30 million supported under Singapore’s Research, Innovation and Enterprise 2025 Plan (RIE2025), aims to advance the development of induced pluripotent stem cell (iPSC) technology to produce novel cell therapies that meet Good Manufacturing Practice (GMP) standards. The collaboration will also establish a talent development programme to train the next generation of experts in this field, in accordance with current GMP and regulatory requirements.

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The research and application of new technologies are essential for addressing growing healthcare needs and maintaining long-term sustainability. However, turning laboratory innovations into practical clinical solutions poses significant challenges. These often involve developing manufacturing processes, validating analytical methods, and implementing automation and digitalisation to guarantee the stability and scalability of products.

The joint laboratories, established at SCG’s GMP facility and A*STAR’s research facility, leverage SCG’s and A*STAR’s proprietary technologies to develop scalable GMP-grade iPSC and therapeutic products. SCG contributes its specialised, automated cell therapy manufacturing technologies, while A*STAR brings its unique monoclonal antibody assets, iPSC banks, and expertise in process scaling and analytics.

This collaboration bridges the expertise between public sector research and development (R&D) and industry, consolidating resources from SCG Cell Therapy and A*STAR’s Bioprocessing Technology Institute (BTI) and Institute of Molecular and Cell Biology (IMCB) to advance innovative R&D towards GMP manufacturing. Additionally, it immerses researchers in the rigorously controlled GMP environment, facilitating the progression from research to clinical application.

"Cellular immunotherapies herald a new era of regenerative medicine, offering hope for patients with cancers and other serious illnesses. As a key player in T cell receptor (TCR) T cell therapeutics, SCG has developed in-house cGMP manufacturing capabilities to supply high-quality cell therapy products to patients. Through this first-of-its-kind joint collaboration with A*STAR, we bring together A*STAR’s advanced iPSC technology and bioprocessing capabilities with our expertise in GMP cell therapy manufacturing and clinical development, furthering our mission to provide affordable off-the-shelf cell therapy treatment options to patients", said Christy Ma, Chief Strategy Officer of SCG Cell Therapy.

"The discovery of iPSCs has revolutionised regenerative medicine, offering the potential for standardised, off-the-shelf cell therapies. Through this collaboration with SCG Cell Therapy, we aim to accelerate the translation of iPSC research into clinically viable therapies and strengthen Singapore’s position as a global leader in cell therapy innovation. By leveraging our complementary expertise and resources, the joint labs will not only advance iPSC technology for scalable, GMP-compliant cell therapy production but also serve as a platform for nurturing the next generation of talent in this transformative field," said Prof Koh Boon Tong, Executive Director, A*STAR’s BTI.

About iPSC

Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from adult cells. The iPSC technology was pioneered by Shinya Yamanaka’s lab in Kyoto, Japan, who showed in 2006 that the introduction of four specific genes encoding transcription factors could convert adult cells into pluripotent stem cells. He was awarded the 2012 Nobel Prize along with Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent". Pluripotent stem cells hold great promise in the field of regenerative medicine. Because they can propagate indefinitely, as well as give rise to every other cell type in the body (such as neurons, heart, pancreatic and liver cells), they represent a single source of cells that could be used to replace those lost to damage or disease.