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

Periodic Reporting for period 1 - HAMLET-BC (Alpha1H: A Unique Bladder Cancer Therapeutic, Acting with Great Precision)

Reporting period: 2020-06-01 to 2021-05-31

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 scepticism.
The Swedish company Hamlet Pharma provides new cancer treatments based on a peptide-based molecular approach for targeting and killing tumour cells with greater precision. Its proprietary drug complex, HAMLET (‘Human Alpha-lactalbumin Made LEthal to Tumour cells’) is derived from the human breast milk protein, alpha-lactalbumin, and represents a ground-breaking therapeutic solution with high tumour-killing capacity, high target specificity, killing >40 different types of tumour cells and no demonstrated toxicity. As such, it has the potential to revolutionize cancer treatment. Hamlet Pharma is now advancing HAMLET and the synthetic drug candidate Alpha1H along the clinical development pipeline as anti-cancer therapeutic for early stage bladder cancer.
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 tumour recurrence rate (70%).
We have discovered an entirely new concept for cancer therapy: the anti-cancer therapeutic HAMLET (‘Human Alpha-lactalbumin Made LEthal to Tumour cells’). 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 is derived from the human breast milk protein, alpha-lactalbumin, and represents a novel class of biologicals with high tumour-killing capacity and high degree of specificity;
- 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 without any drug-related side effects.
Alpha1H will be an important showcase of the impact HAMLET will have on cancer treatment. Generated revenues will be reinvested into development of HAMLET for other cancer indications.

In the HAMLET-BC project, Hamlet Pharma will advance Alpha1H along the clinical development pipeline as anti-cancer therapeutic for early stage bladder cancer. Recent successful outcomes include initial Phase I/II clinical trial data, proving that Alpha1H acts with high efficacy without any detectable toxicity. With the EIC Accelerator funding, Hamlet Pharma will finalise Phase I/II clinical safety and efficacy studies and advance development of Alpha1H towards a Phase III trial.
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.
- Large scale production of Alpa1H in GMP-certified manufacturing process has been set up 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 for chemotherapy.
- 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 accepted in Nature Communication for June 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.
- The combination study has been initiated, combining Alpha1H with a currently used chemotherapeutic agent, Epirubicin.
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 clinical 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 derived from human breast milk 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 in tumour areas resulting in tumour size reduction, while not affecting adjacent healthy bladder tissue, as demonstrated in preclinical studies and the outcomes of the Phase I/II 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.