On May 1, 2023 Akari Therapeutics, Plc (Nasdaq: AKTX), a late-stage biotechnology company developing advanced therapies for autoimmune and inflammatory diseases, reported financial results and highlights for the full year ended December 31, 2022, as well as recent company updates (Press release, Akari Therapeutics, MAY 1, 2023, View Source [SID1234630750]). Akari’s lead asset is investigational nomacopan, a novel bispecific inhibitor of both complement C5 and leukotriene B4 (LTB4). Nomacopan is currently in a Phase 3 clinical trial for pediatric hematopoietic stem cell transplant-related thrombotic microangiopathy (HSCT-TMA). Long-acting PAS-nomacopan is in pre-clinical development as a potential treatment for geographic atrophy (GA).

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"Nomacopan’s distinctive dual mechanism of action against two key proinflammatory mediators, C5 and LTB4, we believe has blockbuster potential with the versatility to take the complement inhibitor category to the next level across multiple rare diseases and mass markets," said Rachelle Jacques, Akari President and CEO. "During the last twelve months, Akari has made significant progress in realizing the promise of this novel asset by advancing to the registrational part of the Phase 3 clinical trials in pediatric HSCT-TMA and toward a regulatory filing for PAS-nomacopan to begin clinical trials in GA in the first half of 2024."

Full Year 2022 Highlights and Recent Updates
Phase 3 clinical trials of nomacopan in pediatric hematopoietic stem cell transplant-related thrombotic microangiopathy (HSCT-TMA)

Thrombotic microangiopathy (TMA) is a rare complication that can occur following a stem-cell transplant in adults or children; blood clots that develop in small blood vessels and capillaries can lead to multi-organ failure and death
There are no approved therapies to treat HSCT-TMA; across adults and children with severe HSCT-TMA, the mortality rate is estimated to be 80%
Complement activity is known to be implicated in moderate-to-severe HSCT-TMA with sC5b-9 and CH50 identified as key markers of disease; LTB4, which is also inhibited by nomacopan, may also be implicated by causing uncontrolled functioning of certain immune cells (such as neutrophils) that may lead to inflammation, tissue damage, and development of thrombosis
Akari accelerated the Phase 3 clinical trial of nomacopan for treatment of pediatric HSCT-TMA toward the portion of the study that is designed to generate the safety and efficacy data needed to support potential regulatory filings for marketing approval; enrollment in the pivotal portion is expected to begin by the end of 2023
In November 2022, the FDA granted the Rare Pediatric Disease Designation to nomacopan for the treatment of pediatric HSCT-TMA
The FDA Rare Pediatric Disease Designation is a recognition of the significant need that exists for approved treatments in rare pediatric diseases and is intended to encourage development of these treatments; the designation is an important addition to the Orphan Drug and Fast Track designations previously granted by the FDA for nomacopan in pediatric HSCT-TMA
With the Rare Pediatric Disease Designation, a sponsor who receives an approval of a new drug application (NDA) or biologics license application (BLA) is eligible for a Priority Review Voucher (PRV) to either redeem for priority review of a subsequent marketing application for a different product or sell to a third party
In the past year, other companies sold PRVs to third parties for prices ranging from $95 million to $110 million
A case study of the first patient to complete treatment in the Phase 3 clinical study of nomacopan in pediatric HSCT-TMA was presented as a late-breaker at the Transplantation & Cellular Therapy Tandem Meetings on February 16 and as a poster presentation at the European Society for Blood and Marrow Transplantation (EBMT) 49th Annual Meeting on April 23.
A 6-year-old male patient with severe HSCT-TMA was enrolled in the Phase 3 Part A clinical trial, and began treatment with a single age- and weight-based ablating dose of nomacopan followed by maintenance dosing for 21 days
Pharmacodynamic data demonstrated that the patient’s sC5b-9 had normalized and CH50 was reduced by >95% within the first 24-48 hours after initiating treatment
Treatment continued for 46 days until the patient’s urine protein creatinine ratio was corrected for ≥28 days; gut pathology and thrombocytopenia were resolved
The patient was discharged from the hospital and no adverse events related to nomacopan were experienced during the treatment period
Akari added a new pipeline program that will develop nomacopan for HSCT-TMA in adults
The adult HSCT-TMA population is >10 times the size of the pediatric population
There are no approved therapies for the treatment of adult HSCT-TMA
Study enrollment for the adult program is expected in 2024
Pre-clinical development of long-acting PAS-nomacopan for geographic atrophy (GA) which is estimated to affect the vision of approximately one million people in the U.S. alone

GA is a chronic progressive degeneration of the macula in the aging eye leading to lesions on the outer retina that can cause irreversible vision loss
There is currently one FDA-approved therapy for treatment of GA and one filed with the FDA, both are complement inhibitors; treatments are administered to patients through monthly or every-other-month needle injections into the eye (intravitreal injections/IVTs)
Frequent needle injections into the eye are a source of fear, discomfort, disruption for patients and has been shown to decrease patient compliance with optimal dosing regimens
Long-acting PAS-nomacopan has the potential to deliver efficacy benefits of complement inhibition using a fraction of the annual doses/injections of approved and late-stage complement-only inhibitors for GA
Sight-threatening choroidal neovascularization (CNV) is a safety risk associated with currently approved and late-stage complement-only inhibitors used for the treatment of GA; CNV is typically treated chronically with anti-VEGF intravitreal injections
CNV is an overdevelopment of blood vessels and leakage in the retina that can significantly damage sight; LTB4 can cause the overexpression of VEGF-A, which can stimulate overproduction of the cells that form the inner layer of blood vessels, leading to CNV
The dual mechanism of PAS-nomacopan may offer the well-understood benefits of intravitreally-administered complement C5 inhibition in slowing the progression of GA lesions, while also providing LTB4 inhibition that also has the potential to help prevent VEGF-A overexpression, reducing the likelihood of CNV and the need for chronic IVT injection or therapies to control CNV
During the past year, Akari significantly advanced the pre-clinical development of long-acting PAS-nomacopan as a potential treatment for GA; the program is on track to submit an Investigational New Drug (IND) application to the FDA in the first half of 2024 for clinical trials
Chemical Manufacturing and Controls (CMC)

U.K, and Poland regulatory authorities –Medicines & Healthcare products Regulatory Agency (MHRA) and Office for Registration of Medicinal Products, Medical Devices and Biocidal Products (URPL) have approved the use of a new, approximately 5X higher-yielding manufacturing process (compared to the previous process) in the pivotal Phase 3 clinical trial of nomacopan in pediatric HSCT-TMA
Patents/Intellectual Property (IP)

A composition of matter patent application was filed on long-acting PAS-nomacopan versions, which, if granted, provides patent protection until 2042
Akari continues to secure IP for lead asset nomacopan in pipeline programs beyond current priority programs in preparation for future development by the company, licensing or partnering
In April 2023, the European Patent Office granted a patent for nomacopan in the treatment of autoimmune blistering diseases (including bullous pemphigoid)
Management Team

• The Akari management team was expanded with industry veterans John Neylan, M.D., Executive Vice President and Chief Medical Officer, and Melissa Bradford Klug, Chief Operating Officer

Full Year 2022 Financial Results

At December 31, 2022, the Company had cash of approximately $13.2 million, compared to cash of approximately $9.4 million at December 31, 2021
Since the beginning of 2022, Akari entered into agreements with Paulson Investment Company, LLC as well as A.G.P./ Alliance Global Partners to serve as placement agents in connection with a total of three registered direct offerings for total gross proceeds of approximately $27.7 million
Research and development expenses for full year 2022 were approximately $9.6 million, as compared to approximately $9.1 million for full year 2021. The change was the net impact of multiple factors. The Company’s research and development expenses increased due to the receipt of a lower tax credit in 2022 as compared to 2021 and increased maintenance and renewal costs for our patents. These increases were partially offset by decreases in staffing costs and decreases in clinical trial costs resulting from the Company’s decision to close the BP trial in August 2022.

General and administrative expenses for full year 2022 were approximately $13.5 million, as compared to approximately $8.1 million for full year 2021. The increase was due to several factors including hiring of a new CEO and COO, severance paid to our departing CEO, issuance costs from our September 2022 registered direct offering, and external costs for consulting personnel, investor relations and corporate communications.
For full year 2022, total other income was approximately $5.3 million as compared to total other expense of approximately $0.2 million for full year 2021. The change was primarily attributed to the classification of our warrants, issued as part of the September 2022 offering, which are accounted for as liabilities and subject to revaluation at each reporting period.
Net loss for the full year 2022 was approximately $17.8 million, as compared to net loss of approximately $17.4 million for full year 2021

On May 1, 2023 Immutep Limited (ASX: IMM; NASDAQ: IMMP), a clinical-stage biotechnology company developing novel LAG-3 immunotherapiesfor cancer and autoimmune disease, reported that it has received regulatory approval from the Paul-Ehrlich-Institut ("PEI"), German Federal Institute for Vaccines and Biomedicines, to initiate INSIGHT-005, an investigator-initiated, open-label Phase I trial evaluating the safety and efficacy of eftilagimod alpha ("efti") in combination with BAVENCIO (avelumab) in up to 30 patients with metastatic urothelial carcinoma (Press release, Immutep, MAY 1, 2023, View Source [SID1234630710]).

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Urothelial carcinoma is the most common type of bladder cancer. For 2023, it is estimated there will be 82,290 new cases of bladder cancer and 16,710 deaths in the US alone. 1 Patients not eligible for platinum-based chemotherapy or progressing during or after platinum-based chemotherapy represent an area of high unmet need and will be enrolled in the trial.

"We are excited to get this important trial underway. In addition to possibly bringing a new chemo-free treatment option to patients with advanced urothelial cancer, we hope to further build upon the encouraging clinical data we have seen to date combining efti and avelumab in other challenging cancers. Efti’s unique activation of antigen-presenting cells to fight cancer has shown a benefit with avelumab, and we believe this dual IO-IO approach has broad potential to drive superior clinical outcomes across a variety of indications, including bladder cancer where avelumab monotherapy has regulatory approval," said Immutep CEO, Marc Voigt.

BAVENCIO is a checkpoint inhibitor owned by Merck KGaA, Darmstadt, Germany, that works by targeting and blocking a protein called PD-L1 on the surface of cancer cells and certain immune cells, activating the cells to find and kill cancer cells. It is approved as a monotherapy for first-line maintenance treatment for adult patients with advanced urothelial carcinoma that has not progressed with first-line platinum-containing chemotherapy in more than 60 countries around the world.

Efti, a soluble LAG-3 protein and novel MHC Class II agonist, was previously evaluated in combination with BAVENCIO in patients with advanced solid tumours in the INSIGHT-004 Phase I trial. Encouragingly, deep and durable responses were achieved in patients with low or negative PD-L1 expression as well as immunooncology insensitive tumours.

INSIGHT-005 will be conducted by the Institute of Clinical Cancer Research IKF at Krankenhaus Nordwest in Frankfurt as part of the investigator-initiated INSIGHT platform for studies investigating efti in different combination treatments and routes of administration. INSIGHT currently consists of 5 different arms from stratums A to E (INSIGHT-005 is Stratum E). 1 US National Cancer Institute: View Source About Eftilagimod

Alpha (Efti) Efti is Immutep’s proprietary soluble LAG-3 protein and MHC Class II agonist that stimulates both innate and adaptive immunity for the treatment of cancer. As a first-in-class antigen presenting cell (APC) activator, efti binds to MHC (major histocompatibility complex) Class II molecules on APC leading to activation and proliferation of CD8+ cytotoxic T cells, CD4+ helper T cells, dendritic cells, NK cells, and monocytes. It also upregulates the expression of key biological molecules like IFN-ƴ and CXCL10 that further boost the immune system’s ability to fight cancer.

Efti is under evaluation for a variety of solid tumours including non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), and metastatic breast cancer. Its favourable safety profile enables various combinations, including with anti-PD-[L]1 immunotherapy and/or chemotherapy. Efti has received Fast Track Designation in 1st line HNSCC and in 1st line NSCLC from the United States Food and Drug Administration (FDA).

On April 30, 2023 Pulse Biosciences, Inc. (the "Company") reported to have entered into a Securities Purchase Agreement (the "Purchase Agreement") with Robert W. Duggan ("Investor"), the Company’s Executive Chairman of the Board of Directors and majority stockholder of the Company (Filing, 8-K, Pulse Biosciences, APR 30, 2023, View Source [SID1234630781]). Pursuant to the Purchase Agreement, the Company agreed to issue and sell to the Investor 10,022,937 shares of the Company’s common stock, par value $0.001 per share, in a private placement (the "Private Placement"), at a price per share of $6.51 (the "Shares"), a greater than 1% premium over the last closing price on NASDAQ of $6.44 per share on Friday, April 28, 2023.

The Shares will be paid for through the cancellation of $65 million aggregate principal amount, together with all accrued and unpaid interest outstanding, pursuant to that certain Loan Agreement (the "Loan Agreement"), dated as of September 20, 2022, as amended on March 17, 2023 by that certain First Amendment to Loan Agreement (the "Amendment"), by and between the Company and the Investor, as previously disclosed on a Current Report on Form 8-K filed with the Securities and Exchange Commission (the "SEC") on September 23, 2022 and March 21, 2023, respectively. At the time of Mr. Duggan’s original loan to the Company in September 2022, the Company’s stock was trading under $1.50 per share. Upon closing of the Private Placement and satisfaction of the outstanding debt, the Loan Agreement will terminate, without early termination fees or penalties being owed by the Company, and no additional amounts will be owed to the Investor under the Loan Agreement.

The foregoing description of the Purchase Agreement does not purport to be complete and is qualified in its entirety by reference to the full text of the Purchase Agreement, which is filed as Exhibit 10.1 to this Current Report on Form 8-K and incorporated herein by this reference.

The representations, warranties and covenants contained in the Purchase Agreement were made solely for the benefit of the parties to the Purchase Agreement and may be subject to limitations agreed upon by the contracting parties. Accordingly, the Purchase Agreement is incorporated herein by reference only to provide investors with information regarding the terms of the Purchase Agreement and not to provide investors with any other factual information regarding the Company or its business, and should be read in conjunction with the disclosures in the Company’s periodic reports and other filings with the U.S. Securities and Exchange Commission.

The Investor, who is already the majority holder of the Company, will have a beneficial ownership interest in the Company of approximately 69%, after the closing of the Private Placement.

Termination of a Material Definitive Agreement.

The description of the termination of the Loan Agreement set forth in Item 1.01 of this Current Report on Form 8-K is incorporated by reference into this Item 1.02 in its entirety. The terms of the Loan Agreement and the Amendment were previously disclosed in a Current Report on Form 8-K filed with the SEC on September 23, 2022 and March 21, 2023, respectively, which disclosures are incorporated herein by this reference.

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On May 1, 2023 Telix Pharmaceuticals Limited (ASX: TLX, Telix, the Company) reported additional positive results from its completed pivotal Phase III ZIRCON study of TLX250-CDx (89Zr-DFO-girentuximab) in clear cell renal cell carcinoma (ccRCC) (ClinicalTrials.gov Identifier: NCT03849118) (Press release, Telix Pharmaceuticals, APR 30, 2023, View Source [SID1234630712]).

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The results were featured in a late-breaking oral presentation delivered on Sunday, 30 April 2023 (CST) by Associate Professor Brian Shuch, MD, Director, Kidney Cancer Program, UCLA Institute of Urologic Oncology (Los Angeles, California) and a principal investigator in the Phase III ZIRCON study, at the American Urological Association’s (AUA) Annual Meeting in Chicago.

New data presented demonstrates the high value of TLX250-CDx PET/CT imaging in detecting ccRCC, with secondary analysis confirming utility and effectiveness in very small renal masses, which are prevalent and present a significant diagnostic challenge.

In very small renal lesions (≤2cm, a secondary endpoint), sensitivity was 84% for all three readers, with specificity 92.3% to 100%. This reinforces the accuracy of this investigational diagnostic imaging agent across all analyses, with previously presented data showing an overall sensitivity and specificity of 86% and 87%, respectively.1,2

Dr Colin Hayward, Chief Medical Officer at Telix stated, "The excellent sensitivity and specificity for small lesions considerably expands the clinical utility and potentially the commercial opportunity for TLX250-CDx. We expect that the ability to diagnose even very small lesions as ccRCC will be an important factor in driving market adoption, subject to product approval."

Associate Professor Brian Shuch, MD commented, "It is a great pleasure to be showcasing new data from Telix’s Phase III ZIRCON study at AUA, the largest gathering of urologists in the world. We now have analyses on the outcome for very small renal masses, where the data set still shows outstanding sensitivity and specificity, far exceeding confirmatory trial success targets. This data is meaningful for surgeons to help them improve management by aiding risk stratification, selecting appropriate patients for treatment or in those where further imaging/biopsy could be indicated."

Telix is in the process of implementing an expanded access program in the United States and establishing named patient programs for TLX250-CDx in Europe.

On April 30, 2023 The Janssen Pharmaceutical Companies of Johnson & Johnson reported the first results from the open-label Phase 2 SunRISe-1 study evaluating the efficacy and safety of TAR-200 monotherapy (a novel investigational intravesical drug delivery system) and cetrelimab monotherapy (an investigational anti-PD-1 monoclonal antibody administered intravenously) in patients with Bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer (HR-NMIBC), who are ineligible for, or decline, radical cystectomy (Press release, Johnson & Johnson, APR 30, 2023, View Source;pd-1-antibody-cetrelimab-in-patients-with-bacillus-calmette-guerin-unresponsive-non-muscle-invasive-bladder-cancer-301811583.html [SID1234630711]). The study demonstrated that 72.7 percent of patients treated with TAR-200 alone (95 percent confidence interval [CI] 49.8-89.3) and 38.1 percent of patients treated with cetrelimab alone (CI 18.1-61.6) achieved the primary endpoint of a complete response (CR). These data were featured today in a Late Breaker Podium Presentation Session (Abstract #LBA02-03) at the American Urological Association Annual Meeting (AUA).

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"We continue to see significant unmet need among high-risk patients with non-muscle-invasive bladder cancer, who often experience negative outcomes and poor quality of life with existing standard of care treatments, such as radical cystectomy," said Siamak Daneshmand*, M.D., Professor of Urology, Director of Urologic Oncology at the Norris Comprehensive Cancer Center, Keck School of Medicine of University of Southern California and SunRISe-1 study principal investigator. "As a clinician, my ultimate treatment goal is to achieve deep and durable responses in these patients. It is encouraging to see an improvement among those treated with TAR-200 alone, as well as cetrelimab alone, and we look forward to reporting on results from the study cohort that is evaluating these two treatments in combination in the future."

HR-NMIBC includes lesions confined to the bladder mucosa and has a higher likelihood of local recurrence and distant progression to other parts of the body.1 HR-NMIBC is typically treated with BCG – a type of intravesical immunotherapy – as the standard of care. BCG involves injecting a weakened form of tuberculosis bacteria into the bladder, stimulating the immune system to attack the cancer cells; however, approximately one-third of HR-NMIBC patients will not respond to the treatment. For BCG-unresponsive patients, there is an anti-PD-1 monoclonal antibody as an alternate, approved treatment option.2,3,4 NMIBC represents some 70 percent of newly diagnosed bladder cancer cases, of which 10 percent are carcinoma in situ (CIS), early cancer cells confined within the innermost layer of the bladder lining; 50 percent of all cases of CIS will progress to muscle-invasive bladder cancer (MIBC) within 5 years if left untreated.5,6

TAR-200 is a novel investigational intravesical drug delivery system designed to provide sustained local release of gemcitabine into the bladder urine. Cetrelimab is an investigational anti-PD-1 monoclonal antibody administered intravenously. The SunRISe-1 study evaluated patients with histologically confirmed CIS, with or without concomitant high-grade Ta (CIS) or T1 (CIS cases with higher risk of progressing to MIBC) papillary disease, a type of NMIBC. Patients were randomized to one of three cohorts: treatment with TAR-200 in combination with cetrelimab (Cohort 1 [C1]), TAR-200 alone (Cohort 2 [C2]) or cetrelimab alone (Cohort 3 [C3]). C2 and C3 results were reported at AUA with C1 results to be reported at a future date. The primary endpoint of CR at any time was determined by cystoscopy, central cytology, and central pathology (Weeks 24 and 48). Secondary endpoints included duration of response (DOR), overall survival (OS), pharmacokinetics, quality of life, safety, and tolerability.

Preliminary results of the SunRISe-1 study included 23 evaluable patients in C2 and 24 evaluable patients in C3. After median follow-up of 10.6 months, 15 of 16 responses in C2 are still ongoing; median DOR was not reached. Additionally, six of the patients in C2 maintained their response beyond 12 months and none of the complete responders had documented recurrence or progression.

The initial findings from SunRISe-1 showed low rates of grade three or higher adverse events (AEs) and a limited number of treatment discontinuations due to adverse events were observed with TAR-200. The most common AEs were pollakiuria (34.8 percent), micturition urgency (34.8 percent), dysuria (26.1 percent), and noninfective cystitis (21.7 percent) in C2; pruritus (20.8 percent) and diarrhea (20.8 percent) occurred in patients in C3. Seven patients in C2 (30.4 percent) and two patients in C3 (8.3 percent) had AEs that were grade three or higher.

"Our ambition is to improve the lives of patients living with non-muscle and muscle-invasive bladder cancers and redefine the treatment of this disease in the future," said Christopher Cutie, M.D., Vice President, Disease Area Leader, Bladder Cancer, Janssen Research & Development, LLC. "With the innovative TAR-200 intravesical drug delivery system, we are committed to advancing bladder cancer treatment across the spectrum of this disease, and we look forward to providing further updates from our robust SunRISe clinical program."

Bladder cancer is the sixth most common cancer in the United States, with more than 80,000 patients diagnosed annually, and is the tenth most common cancer worldwide, with more than 600,000 patients diagnosed each year.6,7 Bladder cancer occurs when cells in the bladder tissue grow uncontrollably, often forming a tumor that can then spread to other parts of the body if left untreated. Non-muscle-invasive bladder cancers are limited to the urothelium, the innermost layer of the bladder, and may be less aggressive than muscle-invasive bladder cancer, a type of cancer that arises from the muscular layer of the bladder or has grown beyond the urothelium and is more likely to spread to other parts of the body.8

About SunRISe-1
SunRISe-1 (NCT04640623) is a Phase 2 randomized, parallel-assignment, open-label clinical study evaluating the safety and efficacy of TAR-200 in combination with cetrelimab, TAR-200 alone, or cetrelimab alone for BCG-unresponsive HR-NMIBC CIS patients who are ineligible for, or decline, radical cystectomy. Participants are randomized to one of three cohorts: treatment with TAR-200 in combination with cetrelimab (C1), TAR-200 alone (C2), or cetrelimab alone (C3). The primary endpoint is CR rate at any time point. Secondary endpoints include DOR, OS, pharmacokinetics, quality of life, safety, and tolerability.

About TAR-200
TAR-200 is an investigational drug delivery system, enabling controlled release of gemcitabine into the bladder, increasing dwell time and local drug exposure. The safety and efficacy of TAR-200 are being evaluated in Phase 2 and Phase 3 studies in patients with muscle-invasive bladder cancer in SunRISe-2 and SunRISe-4 and NMIBC in SunRISe-1 and SunRISe-3.

About Cetrelimab
Administered intravenously, cetrelimab is an investigational programmed cell death receptor-1 (PD-1) monoclonal antibody being studied to treat bladder cancer, prostate cancer, melanoma, and multiple myeloma as part of a combination treatment. Cetrelimab is also being evaluated in multiple other combination regimens across the Janssen Oncology portfolio.

About High-risk Non-Muscle-Invasive Bladder Cancer
High-risk non-muscle-invasive bladder cancer (HR-NMIBC) is a type of non-invasive bladder cancer that is more likely to recur or spread beyond the lining of the bladder, called the urothelium, and progress to invasive bladder cancer compared to low-risk NMIBC. HR-NMIBC makes up 15-44 percent of patients with NMIBC and is characterized by a high-grade, large tumor size, presence of multiple tumors, and CIS. Radical cystectomy is currently recommended for NMIBC patients who fail BCG therapy, with over 90 percent cancer-specific survival if performed before muscle-invasive progression. Given that NMIBC typically affects older patients, many may be unwilling or unfit to undergo radical cystectomy. The high rates of recurrence and progression can pose significant morbidity and distress for these patients.