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Alpha1H: A Unique Bladder Cancer Therapeutic, Acting with Great Precision

Periodic Reporting for period 2 - HAMLET-BC (Alpha1H: A Unique Bladder Cancer Therapeutic, Acting with Great Precision)

Reporting period: 2021-06-01 to 2022-11-30

Novel cancer treatments should ideally combine efficacy with selectivity. Tissue toxicity and side-effects are still the norm, however. Although new, targeted therapies act with greater precision, the notion of tumour-specific cell death is justly regarded with skepticism. The Swedish company Hamlet Pharma provides new cancer treatments based on a new molecular approach for targeting and killing tumour cells with greater precision. Its proprietary drug complex, HAMLET (‘Human Alpha-lactalbumin Made LEthal to Tumour cells’) represents a ground-breaking discovery, killing >40 different types of tumour cells. The synthetic peptide based drug candidate Alpha1H offers a therapeutic solution with high tumour-killing capacity, high target specificity and no demonstrated toxicity. As such, it has the potential to revolutionize cancer treatment. Hamlet Pharma is now advancing the synthetic drug candidate Alpha1H along the clinical development pipeline as anti-cancer therapeutic for early stage bladder cancer.

HAMLET is a ground-breaking innovation that has the potential to revolutionize cancer treatment.
HAMLET goes beyond current cancer-specific therapies in the following aspects: HAMLET and its family members Alpha1H and BAMLET represent a novel class of biologicals with high tumour-killing capacity and high degree of specificity
• HAMLET was discovered in human breast milk and consists of the human milk protein alpha-lactalbumin in a complex with oleic acid that has been structurally characterized in great detail (Nature Com, 2021).
• The second-generation drug product of HAMLET, called ‘Alpha1H’, is synthetically produced at drug quality (GMP-compliant) in large quantities;
• The first results of the clinical placebo-controlled Phase I/II clinical studies in 40 NMIBC patients show astonishing and significant anti-cancer effects of Alpha1H (1.7mM) without any drug-related side effects.
• The dose-escalation study of 8.5mM and 17 mM of Alpha1H show clear evidence of a dose-dependent effect, with increased tumor response but still low toxicity.

The company is focusing on bladder cancer given the high clinical need for more effective and safe treatment options. Bladder cancer has the highest recurrence rates (70%) and treatment costs per patient among all cancer types (total costs in Europe: >€4.9 billion). Current NMIBC treatments (surgery, chemotherapy, immunotherapy) are suboptimal: they have significant side effects and limited efficacy, resulting in a high tumor recurrence rate (70%).

Alpha1H is important showcase the impact the HAMLET concept on cancer treatment. Generated revenues will be reinvested into development of HAMLET for other cancer indications. In the HAMLET-BC project, Hamlet Pharma has advanced Alpha1H along the clinical development pipeline as an anti-cancer therapeutic for early stage bladder cancer. Recent successful outcomes include the placebo-controlled Phase I/II clinical trial, proving data to show that Alpha1H acts with high efficacy without any detectable toxicity. With the EIC Accelerator funding, Hamlet Pharma has finalized the Phase I/II clinical safety and efficacy studies and advance development of Alpha1H towards a Phase III trial, including dose-finding studies.

The investigational product, Alpha1H, which is a second‐generation product of HAMLET, is formed by a synthetic peptide corresponding to the alpha1 domain of α‐lactalbumin in complex with oleic acid. Alpha1H reproduces important cellular responses of HAMLET and the tumoricidal activity both in preclinical and clinical settings.
The Hamlet Pharma team is highly competent, equipped with unique research and development competence. The company is headed by a strong Board of Directors and run by an executive management team, bringing leading scientific, clinical, legal, and commercial expertise in drug development to the company. Through a connected network of senior consultants in specific areas, Hamlet Pharma is run with high efficiency and minimal cost; covering the operational capacity to successfully turn all ‘wheels’ in the drug development process.

The main results achieved so far can be summarized as follows:
• Molecular properties and mode of action of HAMLET and Alpha1H are established.
• Successful large-scale production of Alpa1H in GMP-certified manufacturing process with a new production partner.
• Proven preclinical therapeutic efficacy of Alpha1H and improvement of therapeutic efficacy of other cancer drugs like Mitomycin C and Epirubicin, which are widely used.
• Successful completion of the Phase I/II study of Alpha1H in bladder cancer patients. The study revealed highly significant differences between the Alpha1H treated patients and the placebo group. Treatment was also shown to be safe, as no drug-related side effects were observed (Publication in Nature Communication 2021).
• Successful outcomes of the dose-escalation study of Alpha1H in bladder cancer patients, which is an extension of the Phase I/II trial. Initial data analysis revealed a dramatic increase in the tumor response to Alpha1H, measured both as shedding of tumor fragments into the urine and as changes in remaining tumor tissue.
• Discussions are ongoing with the regulatory authorities in Europe and the USA.
• Project valuation and Health Technology assessment present the company in a very positive light.
HAMLET and its second-generation version Alpha1H will offer a highly promising alternative to the current standard of care in cancer medicine, including surgery, radio- and chemotherapy, which place a significant burden on the individual patient and on society as a whole. For example, there is a high unmet medical need for novel therapies as current NMIBC treatment approaches have limitations. Current standard of care in NMIBC includes Transurethral resection of the bladder tumour (TURBT), a surgery by which tumour cells are cut away from the bladder lining. TURBT is followed by intra-vesicular injections, drug delivery via catheter into the bladder, of chemotherapeutics (with Mitomycin C or Epirubicin) or with Bacillus Calmette Guérin (BCG) for maintenance and recurrence prevention. Even if TURBT completely removes the tumour, tumour recurrence rates are high (50%). As a consequence, typically several TURBTs are performed. Multiple TURBT therapies may result in scarring of the bladder, leading to side-effects as frequent urination or even incontinence. Mitomycin C and BCG are generally given also post-surgery to reduce the risk of recurrence.

Alpha1H goes far beyond the current state-of-the-art. The discovery of HAMLET identified a new type of cancer-killing molecule, which has not previously been described. It is highly specific for tumour tissues and targets the tumour directly via its unique mode of action by attacking conserved cancer cell membrane constituents and multiple intracellular targets and triggering cell death. It has a direct selective apoptotic effect on tumour tissues resulting in a reduction in tumor number and tumour size, while not affecting adjacent healthy bladder tissue, as demonstrated in preclinical studies and the outcomes of the Phase I/II and dose-escalation trial, performed by Hamlet Pharma. Moreover, unlike most available therapies, Alpha1H can be used as both prophylactic and therapeutic agent in early stages of cancer. Based on these unique benefits, Alpha1H will add an entirely new dimension to the treatment of cancer.
High resolution imaging of the uptake of α1H by a Tumor Cell. By real-time confocal microscopy techn