Hamlet Biopharma

An innovative pharmaceutical company with a wide and robust portfolio of
projects for the treatment of cancer and infections.

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Cancer

A central goal of cancer therapy is to selectively target the tumor and
minimize toxicity for healthy tissue. Hamlet Biopharma is developing new
therapeutic solutions for targeting and killing tumor cells with greater
precision. Alpha1H is one of Hamlet Biopharma's main drug candidates. Alpha1H
is a synthetically manufactured peptide in complex with oleic acid and an
efficient anti-tumor drug candidate for the treatment of bladder cancer and
brain tumors.

Bladder cancer

(Non-Muscle Invasive Bladder Cancer)
Problem: lack of effective bladder cancer therapeutics, in particular for
early-stage bladder cancer
Bladder cancer is the fifth most common cancer in the European Union(EU) and
has thehighest recurrence rate of all cancer indications. Each year, around
500,000 patients worldwide are diagnosed with bladder cancer, and this number
is rising. Worldwide, bladder cancer results in around 165,000 deaths each
year. The high mortality of bladder cancer is mainly caused by the lack of
effective therapies andthe high recurrence rate (~70%). Moreover, bladder
cancer places a significant burden on the health care system with high
healthcare expenses.In fact, it accounts for the highest treatment cost per
patient in the cancer area. The total costs associated with bladder cancer
treatment in the EU amount to €4.9 billion (2012), of which €2.9 billion are
direct treatment costs. These data clearly demonstrate the significance of
bladder cancer as a health care problem.
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Figure: Illustration of the societal impact of bladder cancer. Source:
bladdercancer.org.au

Bladder cancer is classified into three different clinical stages:

• Non-muscle invasive bladder cancer (NMIBC): Stages Ta, T1 and Tis
• Locally invasive bladder cancer: Stages T2 and T3
• Metastatic bladder cancer (spreading to other parts of the body): Stage T4

At diagnosis, around 70% of the diagnosed bladder cancers are classified as
NMIBC,corresponding to 1.6 million patients currently suffering from NMIBC in
the EU. The main challenge in NMIBC management is to prevent progression
towards metastatic bladder cancer. At present, however,all available treatment
options for NMIBC are suboptimal due to a lack of efficiency and significant
side-effects. To prevent progression towards muscle invasion, and thus
metastatic bladder cancer, radical removal of the bladder (`cystectomy') is
often the only treatment option, which is a drastic surgical procedure,
significantly impairing the patient's quality of life. In view of the high
risk of tumor recurrence and the limited treatment options, there is an urgent
need for novel NMIBC treatments that combine efficacy and selectivity for the
targeted tumor, without causing side-effects.

Our solution: Alpha1H, a novel biological anti-cancer drug that acts with
great selectivity

Hamlet BioPharma chose bladder cancer (NMIBC) as the first indication because
previous studies with HAMLET had shown clear effects on this particular form
of cancer. As the entire HAMLET molecule is difficult to manufacture, the
synthetic peptide drug Alpha1H was developed for clinical trials. Alpha1H has
powerful positive effects in animal cancer models and the clinical study
program has been able to be designed with high precision thanks to the
extensive research. In preparation for the clinical studies, Alpha1H has been
analyzed for toxicity by an external CRO and toxicity has not been detected.

Clinical studies with Alpha1H in bladder cancer patients
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Successful placebo-controlled Phase I/II trial published in Nature
Communications
A randomized, placebo-controlled study of Alpha1H was carried out by a medical
team at the University Hospital in Prague in collaboration with Hamlet Pharma
with good results. Patients did not experience more side effects caused by
Alpha1H than those treated with placebo. The treatment had clear effects on
the tumors, which decreased significantly in size. Cells and pieces of the
tumors were detached from the tumor and released into the urine, where large
amounts of cells that had taken up the drug were seen by microscopy. The
tumors also showed signs of apoptosis, which is a form of cell death with low
toxicity. Advanced molecular analyzes also showed interesting and specific
responses in tumors treated with Alpha1H, inhibiting the expression of a large
number of different cancer genes. Reaching these clinical and molecular
effects is an important milestone.

Read the paper published in Nature
Communications. (https://hamletbiopharma.com/wp
-content/uploads/2022/11/Nature_Bladder-cancer_2021_s41467-021-23748-y.pdf)

The clinical study was extended with a dose-escalation part.

The effects of Alpha1H increased with the higher dose, reducing the tumor
size, increasing tumor cell shedding and tumor cell death by apoptosis.

Strong anti-tumor effects detected in Alpha1H-treated patients, for a
combination of clinical and molecular endpoints
The combined data analysis from the two clinical study parts has now been
completed, including extensive laboratory analyses of patient samples. The
results, which have been submitted for publication, are summarized below.

1. Reduction in tumor size

Treatment resulted in a complete or partial response in 82% of the tumors
treated with 8.5 mM and in 45% treated with 1.7 mM of Alpha1H.

2. Changes in the tumor

• Treatment resulted in tumor fragmentation and release of fragments and

cells into the urine. This effect increased markedly with the higher dose of
Alpha1H.

• The tumor cells died by apoptosis, after taking up Alpha1H.
• Tissues left in the patient after treatment had lost their tumor

characteristics and become more "healthy-like", as shown by gene expression
analysis.

Extended treatment with Alpha1H - ongoing study
The positive effects on the tumor and the absence of significant side effects
compared to placebo, now make it possible to add a second round of treatment
after the patients have undergone the first treatment according to the
original protocol in the current study.

The goal of prolonging the treatment is to optimize the effect on the tumor by
introducing repeated treatment, which better corresponds to the future
clinical reality. The treatment will be tested in a small number of patients
and will not delay the regulatory process.

The FDA has approved Hamlet BioPharma's application for an IND

Hamlet BioPharma has recently announced that the U.S. Food and Drug
Administration (FDA) has cleared the Investigational New Drug (IND)
application for Alpha1H, a highly selective synthetic peptide for treatment of
non-muscle invasive bladder (NMIBC).  Hamlet BioPharma is proceeding with the
clinical trialto optimize the design of further clinical trialsindialogue
withthe FDA.

Clinical use of Alpha1H

Overall, an effective neoadjuvant therapy could significantly enhance
treatment approaches, improving outcomes and quality of life for patients with
this condition. A novel neoadjuvant therapy holds the promise of improving the
standard of care for multiple reasons.

• First, it could lead to an enhanced tumor response to subsequent

treatment, facilitating more effective surgical removal.

• Second, this approach might reduce the recurrence rate by targeting

residual cancer cells that could otherwise lead to tumor regrowth post
-surgery.

• Third, by down-staging tumors, the therapy could limit the extent of

cancer spread into deeper layers of the bladder wall, potentially enabling
less invasive surgical interventions.

The investigational drug, Alpha1H, has the potential to be an effective
neoadjuvant therapy for several key reasons

• There is limited or even no toxicity associated with the administration of

Alpha1H; nonclinical studies of Alpha1H all found no evidence of symptoms or
signs or effects on body weight or organ weights, gross pathology or
histopathology.

• An ongoing clinical trial evaluating the safety and efficacy of Alpha1H in

Adult Patients with Non-Muscle Invasive Bladder Cancer Awaiting Transurethral
Surgery (Study HP002-001), has found that Alpha1H is safe and well tolerated
in this patient population

Bladder cancer market trends
Bladder cancer is the fourth most common malignancy in the United States and
the fifth in Europe, with a prevalence of approximately 1/4000 (Antoni, S et
al, 2016). Each year, approximately 500,000 patients worldwide are diagnosed
with bladder cancer, and this number is increasing (Globocan WHO, 2012).
Worldwide, bladder cancer results in approximately 165,000 deaths each year.
In addition, bladder cancer has the highest recurrence rate of all cancer
indications (EUCAN, Bladder cancer statistics, 2012; NIH Cancer Stat Facts:
Bladder cancer 2015) as more than 80% recur after complete surgical removal of
the first tumor and 15% progress to muscle invasive disease (Van Rhijn, B.W,
et al., 2009).
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Commercialization of Alpha1H will initially focus on the bladder cancer
market, which is estimated by GlobalData to be worth SEK 6.8 billion in 2018
in the 7 largest markets (USA, France, Germany, Italy Spain, UK and Japan).

In 2018, the US accounted for approximately 60% of bladder cancer drug sales
in these 7 countries, while the 5 largest markets of the EU and Japan
contributed 35% and 6% respectively. It is expected that the bladder cancer
market will grow with an annual growth rate (CAGR) of 24% and thus reach a
market equivalent to SEK 57 billion in 2028. In 2028, the USA is expected to
account for 62% of the market, while the 5 largest countries within the EU and
Japan will account for 30% and approximately 9% respectively.

For Non-Muscle Invasive Bladder Cancer (NMIBC), where Alpha1H currently has
its focus, the market is expected to increase significantly. About 70% of
diagnosed bladder cancer cases are NMIBC, which corresponds to about 1.6
million patients annually in the EU. Bladder cancer is also the most expensive
form of cancer in the United States (NIH Cancer Stat Facts: Bladder cancer
2015).

Summary
Hamlet BioPharma's investigational new drug Alpha1H has a huge potential as a
general cancer therapeutic, with future impact on the treatment of cancer.
Alpha1H directly taps into thegrowing bladder cancer therapeutics
market(estimated value in 2025: €1B) characterized by high need for new more
effective and safe treatment options.

Hamlet BioPharma AB (publ) is listed on the Spotlight Stock Market and
publishes all regulatory information through press releases available on the
website.

[Email [Website
icon] (info@hamletbiopharma.com) icon] (https://hamletbi
opharma.com/)

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