Development plan, achievements

  • Development plan, milestones Alpha1H

The discovery of HAMLET defines a new class of cancer drugs with broad effects against cancers of different origin and a high degree of selectivity. Our aim is to prove the efficacy of HAMLET therapy and to develop drugs that kill tumour cells with greater precision than most current drugs.

Hamlet Pharma Ltd. is making great progress and preparations to start the first clinical trial in patients with bladder cancer are rapidly moving forward. In this newsletter, we briefly summarise recent advances and present an overview of the clinical study protocol that will be used. Drug development often takes many years, due to complex development and approval processes. Based on our extensive prior experience, the drug candidate Alpha1H has passed a number of important milestones in a relatively short time and with moderate cost.

We have rapidly and successfully developed important technologies that now are available for the start of the clinical trial. These include

  1. The second generation drug candidate Alpha1H

Detailed molecular studies have allowed us to make a map of the protein and to identify domains responsible for the effect on tumor cells. Based on the science, we have developed a new synthetic drug candidate Alpha1H, which is the business end of HAMLET and kills tumor cells with similar efficacy.

The peptide can be synthesized in large amounts and activated by the addition of the lipid, just like HAMLET. We can now guarantee the supply of material needed to initiate placebo-controlled clinical trials.

  1. GMP production

Clinical studies require large quantities of the drug candidate, produced in accordance with GMP, as well as documentation, according to the guidelines of the European authorities and the American FDA. The first manufacturing batch, also called “engineering batch”, has been analysed with positive results.

Hamlet Pharma has successfully established large-scale production of the active compound Alpha1H with full GMP standards. The peptide-based technology has added precision, reduced the complexity of the GMP approval process and lowered production costs. In addition, the patent life of the peptide complexes lasts until 2031. The peptide production technology will also make it possible for the company to explore additional clinical indications and out-licensing of selected therapeutic areas.

  1. Therapeutic effects in animal models

In animal studies local HAMLET treatment limited the progression of brain tumors, colon cancer and bladder cancer, suggesting that HAMLET could be used to prevent tumor development in genetically susceptible individualsUsing the engineering batch of the synthetic Alpha1H complex, we have also shown that Alpha1H reproduces the therapeutic activity of HAMLET, against bladder cancer, in a murine model.

  1. Toxicology and safety studies

A central goal of cancer therapy is to achieve selectivity for the tumor and minimal toxicity for healthy tissues. Tissue toxicity and side effects are still the norm, however, and even though new, targeted therapies act with greater precision, the notion of tumor specific mechanisms of cell death is justly regarded with scepticism.

Yet, Alpha1H and HAMLET have not shown toxicity for healthy cells or tissues, in animal models or clinical studies. We are performing toxicity studies to exclude any unwanted effects of Alpha1H.

  1. Regulatory process

We have drafted key documents needed to initiate clinical trials, including the

Investigator’s brochure, Clinical trial protocol and Ethical application forms.

  1. Clinical trial protocol

The safety and efficacy of Hamlet Pharma’s drug candidate Alpha1H will be investigated in patients with bladder cancer. Clinical studies have shown that HAMLET is active against bladder cancer, as local HAMLET injections caused shedding of tumour cells into the urine. HAMLET altered the morphologic appearance of the tumour and triggered cell death in tumour tissue. The healthy adjacent tissue was left untouched, and the patients did not report any toxic side effects.

We will conduct a single centre, randomised, double-blind trial in patients with non-muscle invasive bladder cancer. The trial will compare Alpha1H to placebo and will determine the safety and efficacy of Alpha1H by measuring outcomes such as tumour size and cell death. The trial will enrol patients consecutively until the designated number is reached.

Hamlet pharma's clinical protocol

  1. Clinical trial organization

The clinical trial will be conducted at a leading European centre for bladder cancer studies, in compliance with European regulatory requirements. The investigator has prepared the clinical trial protocol jointly with Hamlet Pharma, as well as the study design and documentation for the ethics application. The subjects will receive six intra-vesical instillations of Alpha1H or placebo.

The trial will be monitored by a well-respected Contract Research Organization (CRO), in accordance with applicable guidelines. The CRO will ensure that the study meets both European and US FDA quality standards. In addition, they will be responsible for Data Management, Statistics and Pharmacovigilance.

  1. Evaluation

The study is designed to collect data on safety (pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of Alpha1H and to evaluate the efficacy of Alpha1H as a cancer drug. The study will use cell shedding after instillations of Alpha1H as a biomarker of cancer cells death. The change in tumour size will be an important measure of effect, together with molecular end points.

Why clinical trials matter?

The strategic goal of Hamlet Pharma is to develop novel cancer treatments for patients who currently lack therapeutic options. Conducting clinical trials is crucial to reach primary goals such as evaluating the therapeutic window for HAMLET in bladder cancer. We also aim to gain new insights that facilitate the drug development for Alpha1H and the diversification of our activities to include other indications.

Cancer and its complications contribute to patient suffering and costs for society. Identifying new treatments and more cost-effective surveillance strategies is essential.  In addition, there is a need for new approaches to preventing cancer, thereby reducing the number of patients, the burden of disease for individuals and society and minimizing the clinical and economic consequences.

HAMLET has been found to kill > 40 types of cancer cells, and Hamlet Pharma is exploring HAMLET’s potent capabilities against different cancer indications through clinical trials and collaborations, aiming towards licensing agreements with experienced partners.

Cancer worldwide

  • More than 14 million new cancer cases that occur each year with an estimated mortality of about 8.2 million worldwide1. The number of new cancer cases will rise to 25 million within the next two decades.
  • Cancer is the second leading cause of death globally and was responsible for 8.8 million deaths in 2015. Nearly 1 in 6 deaths is due to cancer2.

Cancer in Sweden

  • 90,000 persons in Sweden are diagnosed with cancer annually.
  • One person gets cancer every 10 minutes.
  • Based on IHE estimations from the Swedish Cancer Society, the number of new cancer cases is expected to increase from around 89,000 in 2013 to about 165,000 in 2040, which corresponds to an increase of 86 percent. 3
    • Costs of cancer

      • The economic impact of cancer is significant and is increasing. The total annual economic cost of cancer in 2010 was estimated at approximately US$ 1.16 trillion 4.
      • In the US, total cancer costs were estimated at $206.3B in 2006, with estimated productivity losses of $17.9B for cancer-related morbidity and $110.2B for cancer-related mortality 5.

Cost of cancer in Sweden

The total socioeconomic costs of cancer in 2013 amounted to SEK 36 billion. Based on the prognosis for the number of people with cancer, the socioeconomic costs of cancer could increase to SEK 44 billion by 2020, with a predicted further increase to over SEK 68 billion by 2040, assuming the 2013 price level.

The cost increase would correspond to a 90 percent increase in socio-economic costs by the year 2040. In comparison, the Swedish population is expected to grow to almost 12 million according to Statistics Sweden’s forecasts, or just over 20 percent 3.

Bladder cancer cost

  • Today, about 80,000 new cases of bladder cancer are expected to be diagnosed in 2017 in the US alone. while, 430,000 new Bladder cancer cases were diagnosed in 2012 worldwide 6
  • In the world, bladder cancer is the ninth most common cancer form and the sixth most common cancer in Sweden 7. The number of newly diagnosed cases of bladder cancer in Sweden is more than 3000 per year.

In addition, the lifetime treatment costs per patient is very high, due to frequent recurrences and a need for invasive monitoring.  Depending on the country, the lifetime cost per patient ranges from $96,000 to $202,000 8. BC has the highest per patient treatment costs, and the 5th highest overall cost. In the US alone, it was estimated at $3.4B annually with $2.9B in direct treatment-related costs, in 2006 9. A further increase occurred in 2012, when an estimated $4.1 billion was spent to treat bladder cancer 10. The diagnosis and care of bladder cancer thus represents a significant financial burden for patients and society, worldwide.

Given the aging population and the continued technological advances likely to occur over the next decade, such as new urinary markers for bladder cancer, improved endoscopy, and the evolving role of minimally invasive surgery, managing patients with bladder cancer will likely become even more costly than it is today. Thus, there will be growing pressure to contain costs and more efficiently manage care and societal resources.

References

  1. WHO. Who. http://www.who.int. [Online] February 2017. http://www.who.int/mediacentre/factsheets/fs297/en/.
  2. WILD, Edited by BERNARD W. STEWART and CHRISTOPHER P. World cancer report 2014. Lyon : International Agency for Research on Cancer, 2014.
  3. A Lundqvist, E Andersson, K Carlsson. KOSTNADER FÖR CANCER I SVERIGE IDAG OCH ÅR 2040. s.l. : IHE – Institutet för Hälso- och Sjukvårdsekonomi.
  4. 4. World health organisation . Cancer prevention and control in the context of an integrated approach. l. : World health organisation , 2016.
  5. American Cancer Society. American Cancer Society Cancer facts & figures. www.cancer.org. [Online] http://www.cancer.org/downloads/STT/CAFF2007PWSecured.pdf.
  6. J. Ferlay, I. Soerjomataram, R. Dikshit, S. Eser, C. Mathers, M. Rebelo, D.M. Parkin, D. Forman, F. Bray. Cancer incidence and mortality worldwide. s.l. : International Journal of Cancer doi:10.1002/ijc.29210, 2014.
  7. Cancer fonden. cancerfonden.se. [Online] 2017. https://www.cancerfonden.se.
  8. The health economics of bladder cancer: a comprehensive review of the published literature. Botteman MF, Pashos CL, Redaelli A et al. s.l. : Pharmacoeconomics 21:1315–1330. , Vols. doi:10.2165/00019053-200321180-00003.
  9. Estimating health care costs related to cancer treatment from SEER-Medicare data. Brown ML, Riley GF, Schussler N et al. s.l. : Med Care 40:IV-104–IV-117. , 2002, Vols. doi:10.1097/00005650-200208001-00014.
  10. Cancer Prevalence and Cost of Care Projections. Cancer Prevalence and Cost of Care Projections. [Online] https://costprojections.cancer.gov/graph.php.

Operativt fokus

  • Focus on cancer treatment –”an unmet medical need ‘’

a very large and still growing market and As demonstrated in the ‘Who gets cancer’ page the need for a cancer drug with no or low toxicity is an essential part for the advancement in healthcare. HAMLET does not damage or attack healthy cells and has not shown toxicity to healthy tissues in animal models or in clinical trials (Generally Regarded As Safe). Alpha1H

as a synthetic component of the HAMLET molecule is instead attacking only tumor tissues with a high degree of selectivity. Alpha1H as a cancer second- generation drug has so far demonstrated high efficacy in clinical studies and animal models.

  • Multi-indication research portfolio provides diversification

HAMLET kills more than 40 different types of cancer cells in vitro. HAMLET can become a new cancer drug and has a therapeutic effect against bladder cancer, colon cancer, cervical cancer, brain tumors and / or other forms of cancer.

  • Genuine research and pharmaceutical skills

The discovery of HAMLET Identity is a new type of cancer-inducing molecule, which had not previously been described. Further analyses of the second-generation drug Alpha1H were able to reveal unexpected discoveries and to create new knowledge about the conditions for life and health.

  • Hamlet Pharma will be conducting as scheduled phase I/II studies with Alpha1H on bladder cancer, one of the difficult and common cancer. The study aim to provide a solid base in the development process of Alpha1H into a registered drug, which may require cooperation with major pharmaceutical companies.
  • Strong competence international network

Hamlet Pharma has a strong board with experience in cancer research and drug development at the national and international level. The company is supported by a strong network of advisors/consultants in matters concerning legal and regulatory issues, immaterial rights, toxicology, clinical study organisation, auditing and finance.  Through scientific collaborations, the company engages the best national and international expertise in the field.

  • Solid financial position and fully funded bladder cancer study (Phase I / II)

Hamlet Pharma’s current financial situation shows a budget excess which guarantees reaching the final results of the bladder cancer study. This includes capital requirements for large-scale production, carrying out toxicology studies and Phase I/II study in bladder cancer with Alpha1H.

  • Strong and continuously updated patent portfolio

Intellectual property rights include more than 35 patents for the manufacturing and use of HAMLET as well as the second-generation drug Alpha1H of the HAMLET molecule. Patents have been granted in the United States, Europe, Asia and Australia and are valid until 2031.

A brief summary of the latest financial report, Q3 2016/2017

Note: Future clinical studies in different indications or countries are excluded

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