On April 29, 2024 AstraZeneca reported that Truqap (capivasertib) in combination with Faslodex (fulvestrant) has been recommended for approval in the European Union (EU) for the treatment of adult patients with estrogen receptor (ER)-positive, HER2‑negative locally advanced or metastatic breast cancer with one or more PIK3CA, AKT1, or PTEN-alterations following recurrence or progression on or after an endocrine-based regimen (Press release, AstraZeneca, APR 29, 2024, View Source [SID1234642406]).

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The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) based its positive opinion on the results from the CAPItello-291 Phase III trial published in The New England Journal of Medicine.1

In the trial, Truqap in combination with Faslodex reduced the risk of disease progression or death by 50% versus Faslodex alone in patients with tumours harbouring PI3K, AKT or PTEN alterations (based on hazard ratio of 0.50, 95% confidence interval 0.38-0.65; p=<0.001; median progression-free survival (PFS) 7.3 versus 3.1 months).1

In Europe, breast cancer remains the leading cause of cancer death, with more than 140,000 deaths in 2022 and more than 550,000 new patients diagnosed in the same year.2 HR-positive breast cancer (expressing estrogen or progesterone receptors, or both), is the most common subtype of breast cancer with 70% of tumours considered HR-positive and HER2-low or HER2-negative.3 More than 97% of HR-positive breast cancer tumours are ER-positive.4,5 Collectively, mutations in PIK3CA, AKT1 and alterations in PTEN occur frequently, affecting approximately 50% of patients with advanced HR-positive breast cancer.6-8 HR-positive breast cancer progression is often driven by estrogen receptors, and endocrine therapies that target ER-driven disease are widely used as 1st-line treatment in the advanced setting, and often paired with CDK4/6 inhibitors.9-11 However, resistance to these therapies develops in many patients with advanced disease, and alternative approaches are needed to extend the effectiveness of endocrine-based therapies.10

Mafalda Oliveira, MD, PhD, Senior Consultant at the Department of Medical Oncology, Vall d’Hebron University Hospital, and Senior Clinical Investigator of the Vall d’Hebron Institute of Oncology’s (VHIO) Breast Cancer Group in Barcelona, Spain, said: "There is an urgent need to extend the effectiveness of widely used endocrine therapies in patients with advanced ER-positive breast cancer to delay disease progression or resistance. With this combination demonstrating a fifty per cent reduction in disease progression or death in patients with tumours harbouring PIK3CA, AKT1, or PTEN-alterations in the CAPItello-291 trial, this positive recommendation marks an important step in providing a much-needed new treatment option for approximately half of patients in this setting with these specific tumour biomarkers."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "Today’s news reinforces the practice-changing potential of Truqap in combination with Faslodex to extend the effectiveness of endocrine-based treatment approaches for patients who experience tumour progression on, or resistance to widely used endocrine-based therapies. This recommendation recognises the high unmet need in this biomarker-specific patient population, and if approved, patients in Europe with this specific type of disease may be able to benefit from this first-in-class treatment option."

In the CAPItello-291 trial, the safety profile of Truqap plus Faslodex was similar to that observed in previous trials evaluating this combination.1

Regulatory applications are currently under review in China and several other countries, and similar indications for Truqap in combination with Faslodex are already approved in Japan, the US and several other countries based on results from the CAPItello-291 trial.

Notes

HR-positive breast cancer
In Europe, breast cancer remains the leading cause of cancer death, with more than 140,000 deaths in 2022 and more than 550,000 new patients diagnosed in the same year.2

HR-positive breast cancer (expressing estrogen or progesterone receptors, or both), is the most common subtype of breast cancer with 70% of tumours considered HR-positive and HER2-low or HER2-negative.3

HR-positive breast cancer progression is often driven by estrogen receptors, and endocrine therapies that target ER-driven disease are widely used as 1st-line treatment in the advanced setting, and often paired with CDK4/6 inhibitors.9-11 However, resistance to CDK4/6 inhibitors and current endocrine therapies develops in many patients with advanced disease.10 Once this occurs, treatment options are limited – with chemotherapy being the current standard of care – and survival rates are low with approximately 35% of patients anticipated to live beyond five years after diagnosis.3,10,12

The optimisation of endocrine therapy and overcoming resistance to enable patients to continue benefiting from these treatments, as well as identifying new therapies for those who are less likely to benefit, are active areas of focus for breast cancer research.

CAPItello-291
CAPItello-291 is a Phase III, double-blind, randomised trial evaluating the efficacy of Truqap in combination with Faslodex versus placebo plus Faslodex for the treatment of locally advanced (inoperable) or metastatic HR-positive (ER-positive and ER-positive, progesterone receptor-positive), HER2-low or negative (immunohistochemistry (IHC) 0 or 1+, or IHC 2+/in-situ hybridisation (ISH)-negative) breast cancer.

The global trial enrolled 708 adult patients with histologically confirmed HR-positive, HER2-low or negative breast cancer whose disease has recurred or progressed during or after aromatase inhibitor therapy, with or without a CDK4/6 inhibitor, and up to one line of chemotherapy for advanced disease. The trial has dual primary endpoints of PFS in the overall patient population and in a population of patients whose tumours have qualifying alterations in the PI3K/AKT pathway (PIK3CA, AKT1 or PTEN genes). In the trial, approximately 40% of tumours had these alterations and approximately 70% of patients received a prior CDK4/6 inhibitor.

Truqap
Truqap is a first-in-class, potent, adenosine triphosphate (ATP)-competitive inhibitor of all three AKT isoforms (AKT1/2/3). Truqap 400mg is administered twice daily according to an intermittent dosing schedule of four days on and three days off. This was chosen in early phase trials based on tolerability and the degree of target inhibition.

Truqap is approved in Japan, the US and several other countries for the treatment of adult patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer with one or more biomarker alterations (PIK3CA, AKT1 or PTEN) following recurrence or progression on or after an endocrine-based regimen based on the results from the CAPItello-291 trial.

Truqap is currently being evaluated in Phase III trials for the treatment of multiple subtypes of breast cancer and in other tumour types in combination with established treatments. The ongoing clinical research programme is focused on tumours reliant on signalling via the PI3K/AKT pathway, and in tumours harbouring biomarker alterations in this pathway.

Truqap was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited).

Faslodex
Faslodex is an endocrine therapy indicated for the treatment of estrogen receptor-positive, locally advanced or metastatic breast cancer in postmenopausal women not previously treated with endocrine therapy, or with disease relapse on or after adjuvant anti-estrogen therapy, or disease progression on anti-estrogen therapy.

In the US, EU and Japan, Faslodex is also approved in combination with CDK4/6 inhibitors for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer, whose cancer has progressed after endocrine medicine. Faslodex represents a hormonal treatment approach that helps to slow tumour growth by blocking and degrading the estrogen receptor – a key driver of disease progression.

Faslodex is approved as monotherapy or in combination with medicines from various drug classes including CDK4/6, PI3K and AKT inhibitors for the treatment of patients with HR-positive advanced breast cancer and is being evaluated in combination with medicines from other drug classes.

On April 29, 2024 Immutep Limited (ASX: IMM; NASDAQ: IMMP) ("Immutep" or "the Company"), a clinical-stage biotechnology company developing novel LAG-3 immunotherapies for cancer and autoimmune disease, reported an update on the ongoing development of its product candidates, eftilagimod alpha (efti) and IMP761 for the quarter ended 31 March 2024 (Q3 FY24) (Press release, Immutep, APR 29, 2024, View Source [SID1234642403]).

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EFTI DEVELOPMENT PROGRAM FOR CANCER

TACTI-002 (KEYNOTE-PN798) – Phase II clinical trial in 1L NSCLC The TACTI-002 trial is ongoing with Immutep continuing to follow patients with 1L NSCLC (Part A) where, encouragingly, a median Overall Survival has not yet been reached in patients with high PD-L1 expression (TPS ≥50%). As previously reported at ESMO (Free ESMO Whitepaper) 2023, excellent median Overall Survival rates were seen across all levels of PD-L1 expression, including in patients expressing any PD-L1 (patients with a Tumor Proportion Score [TPS] of >1%) and patients with low PD-L1 expression (TPS 1-49%), with 35.5 months and 23.4 months reported respectively. Immutep has previously reported final data from Parts B and C of the TACTI-002 trial.

TACTI-003 (KEYNOTE-PNC34) – Phase IIb clinical trial in 1L HNSCC The TACTI-003 multicenter Phase IIb trial evaluating efti in combination with MSD’s anti-PD-1 therapy KEYTRUDA (pembrolizumab) is ongoing with a total of 171 first line head and neck squamous cell carcinoma (1L HNSCC) patients enrolled. Cohort A evaluating efti in combination with KEYTRUDA as compared to KEYTRUDA monotherapy (randomised) involves 138 patients with PD-L1 positive (Combined Positive Score [CPS] ≥1) tumours and Cohort B (non-randomised) includes 33 patients with PD-L1 negative tumours.

Subsequent to quarter end Immutep announced positive preliminary topline results from Cohort B. The investigational immuno-oncology combination demonstrates an overall response rate (ORR) of 26.9% and disease control rate (DCR) of 57.7% in 26 evaluable patients whose tumours do not express PD-L1 (CPS<1), according to RECIST 1.1, which compares favourably to historical controls.

The final number of evaluable patients in Cohort B is expected to be higher and additional data, including complete response rate, is expected to be released together with Cohort A data. Data collection, cleaning, and analysis continue for TACTI-003, and the Company expects to report the primary endpoint (overall response rate according to RECIST1.1) from Cohorts A & B in H1 CY2024.

TACTI-004 – Phase III registrational trial in 1L NSCLC Immutep continued to advance the necessary preparations for the Phase III TACTI-004 trial in first line nonsmall cell lung cancer (1L NSCLC) during the quarter. Productive interactions with regulatory agencies as well as with other stakeholders and potential partners are ongoing. Immutep expects to announce the trial design for TACTI-004 in H1 CY2024.

AIPAC-003 – Integrated Phase II/III trial in MBC Immutep announced the first clinical data from the 90mg dosing of efti, the highest dose ever administered to patients, from patients participating in the safety lead-in of the AIPAC-003 trial in metastatic breast cancer (MBC). Data from the six patients in the safety lead-in showed the 90mg dose of efti in combination with paclitaxel is safe and well tolerated. The initial efficacy data was also encouraging, with a 50% overall response rate, including one patient reporting a complete response (complete disappearance of all lesions), and a 100% disease control rate. The trial has proceeded to the randomised Phase II portion of study consisting of up to 58 evaluable patients who will receive 30mg efti or 90mg efti to determine the optimal biological dose of efti in combination with paclitaxel. Currently, 34 patients have been dosed in the randomised part. Further updates from AIPAC-003 will be provided in CY2024.

INSIGHT-003 – Phase I in non-squamous 1L NSCLC The investigator-initiated INSIGHT-003 trial continued to enrol patients throughout the quarter, with 38 out of a total of 50 patients enrolled and safely dosed across six sites in Germany. INSIGHT-003 evaluates a triple combination therapy consisting of efti and an approved standard of care combination of chemotherapy (carboplatin and pemetrexed) and anti-PD-1 therapy (pembrolizumab) in patients as first line treatment in non-squamous NSCLC adenocarcinomas.

INSIGHT-005 – Phase I trial in Urothelial Carcinoma The first patient in the investigator-initiated INSIGHT-005 trial was enrolled and safely dosed, as announced in January 2024. The study is evaluating efti and the anti-PD-L1 therapy BAVENCIO (avelumab) in up to 30 patients with metastatic urothelial cancer and is jointly funded with Merck KGaA, Darmstadt, Germany.

EFTISARC-NEO – Phase II Trial in Soft Tissue Sarcoma The investigator-initiated EFTISARC-NEO trial is ongoing with 14 patients now enrolled and safely dosed. The study evaluates efti in combination with pembrolizumab and radiotherapy in up to 40 soft tissue sarcoma (STS) patients in the neoadjuvant (prior to surgery) setting.

IMP761 DEVELOPMENT PROGRAM FOR AUTOIMMUNE DISEASE

IMP761 is the Company’s proprietary preclinical candidate and world’s first LAG-3 agonist that aims to treat the underlying cause of multiple autoimmune diseases. Throughout the quarter, Immutep progressed its preclinical development and IND-enabling toxicology studies for IMP761 to evaluate the safety and toxicity of its product candidate before entering first-in-human trials. Subsequent to quarter end, Immutep entered into an agreement with the Centre for Human Drug Research (CHDR), a world-class institute in Leiden, the Netherlands specializing in cutting-edge early-stage clinical drug research, to perform a first-in-human clinical study of IMP761, which it expects to begin mid-CY2024.

GLAXOSMITHKLINE (GSK)-IMP731 (GSK2831781)

As detailed in Immutep’s half year report in February 2024, Immutep received from GSK a written notice of termination of its exclusive License and Research Collaboration Agreement with GSK entered into in 2010 for the development of GSK2831781, a LAG-3 depleting antibody derived from Immutep’s IMP731 antibody, targeting autoimmune disease, with an effective termination date of 30 May 2024. The Company expects no material impact on the financial statements due to the termination.

CORPORATE & FINANCIAL SUMMARY

Board Appointment

In February 2024, Anne Anderson was appointed as an independent non-executive director of Immutep Limited. Ms Anderson has extensive board and leadership experience serving Australian and international companies and brings considerable capability across capital markets, risk management and governance to Immutep’s Board.

Cash Flow Summary

During the quarter, Immutep continued to fund the advancement of its clinical trial programs for efti and preclinical program for IMP761 to create value for shareholders. The Company is well funded with a strong cash and cash equivalent balance as at 31 March 2024 of approximately $95.4 million, giving it an expected cash reach into early CY2026.

Cash receipts from customers in Q3 FY24 were $14k, compared to $38k in Q2 FY24. The net cash used in G&A activities in the quarter was $0.7 million, compared to $0.8 million in Q2 FY24. Payments of $310k to Related Parties (detailed in Item 6 of the Appendix 4C) comprises Non-Executive Directors’ fees and Executive Directors’ remuneration.

The net cash used in R&D activities in the quarter was $6.9 million, which is consistent with Q2 FY24. Payment for staff costs was $2.0 million in the quarter compared to $2.2 million last quarter.

Total net cash outflows used in operating activities in the quarter was $9.0 million compared to $5.5 million in Q2 FY24. This difference was mainly due to the receipt of $3.8 million in R&D tax grants in Q2 FY24.

A copy of the Appendix 4C-Quarterly Cash Flow Report for the quarter is attached.

On April 26, 2024 Biodexa Pharmaceuticals PLC, (Nasdaq: BDRX), an acquisition-focused clinical stage biopharmaceutical company developing a pipeline of innovative products for the treatment of diseases with unmet medical needs, reported it entered into a definitive agreement with Rapamycin Holdings Inc. (d/b/a Emtora Biosciences) ("Emtora") for the rights to eRapa under an exclusive, worldwide license (with the ability to grant sublicenses) to develop, manufacture, commercialize and otherwise advance the clinical potential of eRapa.

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Stephen Stamp, CEO and CFO of Biodexa said, "Acquiring a Phase 3 ready asset, particularly one supported by $17 million of non-dilutive grant funding, significantly advances Biodexa’s oncology pipeline and adds numerous valuation catalysts for our stakeholders. We are delighted to be working with the Emtora team which has excelled in bringing eRapa close to the end of Phase 2 in Non-muscle Invasive Bladder Cancer and to the beginning of a Phase 3 trial in FAP, a devastating disease for which there is currently no approved pharmacological agent for altering its progression. Left untreated, it almost always leads to incredibly invasive surgery and a major deterioration in the quality of life."

Stephen Dufilho, Executive Chairman of Emtora added, "The transaction with Biodexa is the culmination of a decade-long effort to advance our potentially game-changing eRapa to a registrational Phase 3 trial – and ultimately to patients in need. Our story began in San Antonio – where eRapa was originally invented at the University of Texas and funded in part by grants from the Cancer Prevention Research Institute of Texas. We thank the scientists, clinicians, investors and biotech executives that supported our efforts to reach this important milestone. We look forward to working with the Biodexa team as we embark upon this next chapter."

About eRapa
eRapa is a proprietary oral tablet formulation of rapamycin, also known as sirolimus. Rapamycin is an mTOR (mammalian Target Of Rapamycin) inhibitor. mTOR has been shown to have a significant role in the signalling pathway that regulates cellular metabolism, growth and proliferation and is activated during tumorgenesis1. Rapamycin is approved in the US for organ rejection in renal transplantation as Rapamune(Pfizer). Through the use of nanotechnology and pH sensitive polymers, eRapa is designed to address the poor bioavailability, variable pharmacokinetics and toxicity generally associated with the currently available forms of rapamycin. eRapa is protected by a number of issued patents which extend through 2035, with other pending applications potentially providing further protection beyond 2035.

eRapa in FAP
FAP is characterized as a proliferation of polyps in the colon and/or rectum, usually occurring in mid-teens. There is no approved therapeutic option for treating FAP patients, for whom active surveillance and surgical resection of the colon and/or rectum remain the standard of care. If untreated, FAP typically leads to cancer of the colon and/or rectum. There is a significant hereditary component to FAP with a reported incidence of one in 5,000 to 10,000 in the US2 and one in 11,300 to 37,600 in Europe3. eRapa has received Orphan Designation in the US with plans to seek such designation in Europe. Importantly, mTOR has been shown to be over-expressed in FAP polyps – thereby underscoring the rationale for using a potent and safe mTOR inhibitor like eRapa to treat FAP.

Emtora is currently completing an open-label, multi-center Phase 2 study in 30 patients with confirmed FAP with the primary endpoints of safety and tolerability, and percentage change in polyp burden after six months of treatment with eRapa. The Phase 2 study was partially funded by a $3.0 million grant from CPRIT.

The results of the Phase 2 study will be presented at two leading scientific conferences in Q2 24. Following a positive end of Phase 2 meeting with the FDA and, Emtora plans to initiate a Phase 3 multi-center, double-blind, placebo-controlled study in FAP. The Phase 3 study, which is expected to be registrational, plans to recruit approximately 140 patients across thirty or more sites, with a primary endpoint being time to a progression free survival event (the occurrence of which is related to the reduction in polyp burden studied in the earlier Phase 2 trial). The study is expected to recruit over 15 months and is supported by a further non-dilutive grant of $17.0 million from CPRIT.

eRapa in Non-Muscle Invasive Bladder Cancer
Non-muscle Invasive Bladder Cancer ("NMIBC") refers to tumors found in the tissue that lines the inner surface of the bladder. The most common treatment is transurethral resection of the bladder tumor followed by intravesical Bacillus Calmette-Guerin ("BCG") with chemotherapy depending upon assessment of risk of recurrence. NMIBC is the fourth most common cancer in men with an incidence of 10.1 per 100,000 and 2.5 per 100,000 in women4.

Emtora’s ongoing multi-center, double-blind, placebo-controlled Phase 2 study in NMIBC is expected to enroll up to 166 patients with primary endpoints of safety/tolerability and relapse free survival after 12 months of treatment. The Phase 2 study, which is supported by a $3.0 million non-dilutive grant from the National Cancer Institute, part of the National Institutes of Health, is expected to read out in Q2 ’25.

Other Potential Indications for eRapa
A number of rare/orphan gastro-intestinal diseases (other than FAP) have been identified that share the strong scientific rationale (relating to mTOR inhibition) and support the potential utility of eRapa in FAP. Biodexa intends to evaluate such opportunities over the coming months, including by leveraging low-cost, investigator-sponsored trials to produce initial proof of concept data.

The License Transaction
The transaction terms include the issuance to Emtora of 378,163 of the Company’s American Depository Shares (representing 5% of the Company’s issued and outstanding ordinary shares on a fully-diluted basis (including in-the-money warrants)) at close. In addition, the Company may pay up to $41.5 million in sales milestones within the first six months of the first commercial sale of a first-approved indication of eRapa in major markets, with decreasing milestones for subsequent approvals for additional indications. The Company is also obligated to pay single digit tiered royalties on net sales of eRapa in addition to meeting Emtora’s legacy royalty obligations and paying Emtora a certain (stage-dependent) percentage of income derived from sublicensing and partnering of eRapa.

Ladenburg Thalmann & Co. Inc. acted as financial advisor to BioDexa in connection with this transaction.

The Cancer Prevention and Research Institute of Texas
To date, CPRIT has awarded $2.9 billion in grants to Texas research institutions and organizations through its academic research, prevention and product development research programs. CPRIT has recruited 237 distinguished researchers, supported the establishment, expansion or relocation of 43 companies to Texas and generated over $5.7 billion in additional public and private investment. CPRIT funding has advanced scientific and clinical knowledge and provided 7.4 million life-saving cancer prevention and early detection services reaching Texans from all 254 counties. On November 5, 2019, Texas voters overwhelmingly approved a constitutional amendment to provide an additional $3 billion to CPRIT for a total $6 billion investment in cancer research and prevention. Learn more at View Source

(Press release, Biodexa Pharmaceuticals, APR 26, 2024, View Source [SID1234673477])

On April 26, 2024 Disruptive Pharma reported the company raises 27 million SEK to conduct clinical study on its improved sorafenib product DPH001 and to nominate second product candidate (Press release, Disruptive Pharma, APR 26, 2024, View Source [SID1234649946]). The company also reported we now have sufficient funds to advanced our innovative first product DPH001 through clinical proof-of-concept and nominating a second product candidate within the next 12 months, thus transforming Disruptive Pharma from a research company into a clinical stage pharmaceutical company. I want to extend a warm thank you to all long-term shareholders and new investors for your trust." comments Peter Åsberg, CEO of Disruptive Pharma.

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On April 26, 2024 Sihuan Pharmaceutical reported its annual report for year 2023 (Presentation, Sihuan Pharmaceutical, APR 26, 2024, View Source [SID1234644740]).

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