Drug Test

TESTING SM001 (Tigerase)

The benefit aspects for patients participating in our present clinical study include free test drug product as well as complex diagnostic procedures not included into the routine clinical practice which are also free under the present protocol to the study subjects. During the study, patients will be closely supervised by the hospital’s medical personnel participating in the study and will be able to obtain more complete information on their health condition. The potential benefit for the patients may include effect of SM001 on pulmonary sarcoidosis.

SarcoMed USA Study Vision by Brian Davies, M.D. CEO

Formed in 2017, SarcomedUSA, Inc. “Sarcomed” is led by experienced biotech entrepreneurs with strong drug development backgrounds and respected expert clinical advisors. Below is our vision to share with you:

Sarcoidosis is a rare disease that results in an abnormal collection of inflammatory cells that form aggregates in the lung, skin and lymph nodes.

There are fewer than 200,000 cases in the U.S. per year.
Treatments can help manage the condition but no known cure.
Sarcoidosis can occur at any age, but often occurs between the ages of 20 and 60 years.
Women are slightly more likely to develop the disease.
People of African descent and those of Northern European descent have a higher incidence of sarcoidosis.
African Americans are more likely to have involvement of other organs along with the lungs.
If someone in your family has had sarcoidosis, you are more likely to develop the disease.

SM001 also helps to break up mucous in Cystic Fibrosis patients.

SM001 is a recombinant human DNase I with superior activity in breaking down extracellular DNA.

Originally developed for Cystic Fibrosis to be resistant to actin inhibition, while maintaining enzymatic activity.
Licensed from a Biotech company with extensive drug discovery and development experience including an FDA approved drug and large Pharma collaborations.
SM001 exhibits kinetic properties compared to Dornase alfa (“Pulmozyme”).
Phase 3 human study was completed in Russia demonstrated a safe drug with low absorption and antibody formation.

SM001’s mechanism of action in sarcoidosis.

Microbial DNA [mDNA] along with Amyloid-like protein aggregates and bacterial biofilms are found in sarcoidosis tissues.
[mDNA] and Serum amyloid A (SAA) aggregates cause an inflammatory response mediated by TLR2 and TLR9.
Microbial DNA stimulates the potent TLR9 release of cytokines which are critical to sarcoidosis inflammation.
SM001 reduces the biofilms and amyloid complex by a breakdown of mDNA reducing fragments from entering the cell for TLR9 stimulation.

Murine sarcoidosis model study.

Propionibacterium acnes (P. acnes) is the one of the microorganisms isolated from sarcoid lesions.
P. acnes [protein & adjuvant] trigger a cellular immune response in sarcoid patients and induces pulmonary granulomas in sensitized mice.
The heat-killed P. acnes is employed 28 days before therapy to ensure that the inflammation in the lung of a sarcoidosis like condition is fully established prior to the initiation of therapy.
In the company’s study there were 8 animals in the control group (PBS) and 8 animals in the test group (rDNAse1)
Inflammatory markers are measured in the control and test mice then compared after four weeks of therapy [day 56].
Significant decrease in all treated BALF cell cytokines/chemokines: g-CSF, INF-γ, IL-1β, IL-4, IL-6, IL-17, IP-10, MIP-1β, and MIP2 (p value range 0.003 to 0.05).
Significant decrease in BALF leucocyte content in the lungs (p=0.007); total neutrophil content (p≤0.0001) neutrophil-leukocyte ratio (p=0.003).

SM001 development status.

Questions covering full development plans for SM001 (CMC, Toxicology, Clinical, and Regulatory), have been reviewed.
Term sheet with licensing partner has been executed, and development plan has been established, including a clinical synopsis for the planned Proof of concept study in Kazakhstan.
Advisory board has been established and we are in discussions to partner with The Foundation for Sarcoidosis Research to leverage their clinical site network.
A phase 2/3 study is planned for an open label, 20-30 patient study of inhalation SM001 in Patients with Pulmonary Sarcoidosis is starting in Kazakhstan.
The endpoints are safety in this population of Sarcoidosis patients and a look at the reduction of steroids used in these patients over a six (6) month period.

Comparison to Cystic Fibrosis (CF) shows substantial market potential for Sarcoidosis.

Pulmozyme® was approved in 1994 for Cystic Fibrosis [70,000 patients worldwide] and all patents expired by 2015.
Reported sales of $755M in 2018 and $746M in 2017.
~ 1.2M sarcoid patients worldwide, 50% of sarcoidosis patients require systemic therapy corticosteroids and ~ 30% exhibit chronic progressive disease.

Sarcomed plans to raise $12-20 million in a Series A offering for use in the tech transfer and approval studies in the United States.

NAME AND DESCRIPTION OF THE STUDY DRUG PRODUCTS

Name: SM001 (Tigerase)
INN: Dornase alfa
Pharmacotherapeutic group: Drugs used for cough and cold; expectorants, except combinations with antitussives; mucolytics
ATC code: R05CB13
Registration status: Registered in Kazakhstan, reg. number РК-ЛС-5№025257
Manufacturer: AO Generium, Russian Federation
Marketing Authorization holder: OOO Generium-Next, Russian Federation
Sponsor of the study: SarcoMedUSA, Inc., USA
Pharmaceutical form: Inhalation solution
Strength: 2.5 mg/2.5 ml
Composition:
Active ingredient: dornase alfa (each 2.5 ml ampoule contains 2.5 mg of dornase alfa (1.0 mg/ml)). 1 mg of dornase alfa is 1000 U.
Inactive components: sodium chloride, calcium chloride dihydrate, water for injection.
Description: Transparent colorless or yellowish solution
Storage conditions: Protected from light, at a temperature from 2 to 8 °C. Do not freeze.

PACKAGING AND LABELING:

2.5 mg / 2.5 ml of inhalation solution in polymer ampoules. 6 polymer ampoules in a light-proof bag. A sealed light-proof bag together with a leaflet in a pack of cardboard. To control the first opening, the side valves of the pack are fixed with self-adhesive labels.

As per the Appendix No. 13 to the Rules of Good Manufacturing Practice of EAEU, labeling of the test drug packs will contain the following information (or space for entering the respective information):
• Information on the clinical site, name, patronymic and surname of the Principal Investigator, name, address and phone number of the Sponsor.
• Name of the study drug, pharmaceutical form, method of administration, quantity in a pack, strength, batch number.
• Study code.
• A reference to the instruction for medical use or leaet or another explanatory document intended for the clinical study subject or the person who is administering the drug.
• Storage conditions, shelf life.
• Note For clinical studies only».
• Visit number (if applicable).

METHOD OF ADMINISTRATION AND DOSING REGIMEN IN THIS STUDY

Mode of administration and dosage scheme:
Study drug will be inhaled once a day (2.5 mg) for the first 7 days, using jet nebulizer while the patient is seated in an upright position. The patients will be instructed to inhale SM001 (Tigerase) at the same time of day during the study, except for study visit days at the clinical sites when they will be administered SM001 (Tigerase) on site. After the initial week if there are no issues the dosing will be increased to twice daily of 2.5 mg to be administered using jet nebulizer at the same times each day for a total 24 weeks.

Stopping Criteria for Dose Escalation
Upon completion of Day 7, assessments for single 2.5 mg dose of SM001 (Tigerase) should be made before increasing the dose to twice daily. AEs registered during treatment will be considered intolerable if they meet any of the following criteria:

• Serious adverse events (SAEs) if related to the study drug,
• Clinically signicant broncho-constrictive episode in the opinion of the investigator, and absolute decrease from baseline in the FEV1 predicted value by ≥20% (to be confirmed by a repeat spirometry approximately 4 hours later),
• Treatment emergent AEs related to Laboratory and ECG parameters at Grade 3 or higher according to the National Cancer Institute’s common toxicity criteria (NCI CTCAE, v.5.0), or
• All other treatment emergent AEs at Grade 3 or higher according to the NCI CTCAE.

If at least 1 intolerable AE is reported for a patient in the first week, the further treatment dose for this patient should be considered on a case-by-case basis by the Investigator and approved by the Sponsor and Medical Monitor. Intolerable AEs during weeks 2-24 will be reviewed by the investigator, medical monitor and sponsor medical monitor to assess dose moving forward. Dose escalation to the next dose of Tigerase 2.5 mg twice daily will not occur if two or more patients develop intolerable AEs that are considered drug related and clinically relevant after review by investigator, medical monitor and sponsor medical monitor, as defined above.

In the event any of the stopping criteria for dose escalation are met, the study will continue with once daily regimen following review by the Sponsor Medical Monitor and Medical Monitor.

The Medical Monitor or designee may request to discuss the treatment with the Investigator, before any further patients are dosed.

Dose adjustment
If a patient does not tolerate twice daily regimen (according to the opinion of the investigator AEs are dose related), the patient may have dose reduced to once a day and continue study protocol.

If under the judgement of the treating physicians there may be a temporary halt and reinstitution of the SM001 (Tigerase) treatment if considered appropriate.

Since the test drug SM001 (Tigerase) is already approved in Kazakhstan, full information on clinical data and pharmacological properties of this drug is available in Summary of Product Characteristics (SmPC) at the State Register of medicinal products and medical devices of the Republic of Kazakhstan: http://register.ndda.kz/category/search_prep)

REFERENCE DRUG PRODUCT (R)

Not applicable. This study is a non-comparative.

RESULTS OF NONCLINICAL AND CLINICAL STUDIES

RISK-TO-BENEFIT RATIO FOR PATIENTS

Known risks
The risks related to use of the drug product, risks related to the study procedures as well as risks defined by the experimental nature of the study refer to the risks accepted by the study subject due to participation in the present study.

Risks related to the use of test product SM001 (Tigerase)
The test drug SM001 (Tigerase) is approved in Kazakhstan and its safety profile is described in the SmPC of Tigerase (AO Generium). The onset and
development of the following adverse reactions is possible while using this drug (according to the SmPC of Tigerase):
Adverse reactions attributed to dornase alfa are rare (<1/1000). In most cases, the adverse reactions are mild and transient in nature and do not require alterations in the dosing.

The following is a summary of adverse reactions reported during clinical trials, as well as in the post-marketing period in patients with cystic fibrosis
(in accordance with the system organ classes and the WHO classification of frequency):

System organ class	Rare (≥1/10000 but <1/1000)
Eye disorders	Conjunctivitis
Gastrointestinal disorders	Dyspepsia
Respiratory, thoracic and mediastinal disorders	Voice alteration, dyspnea, pharyngitis, laryngitis, rhinitis (all of non-infectious nature), respiratory tract infections, including those caused by Pseudomonas, increased bronchial mucous
Skin and subcutaneous tissue disorders	Rash, urticaria
General disorders and administration site conditions	Chest pain (pleuritic/non-cardiac), pyrexia, headache
Investigations	Decrease of respiratory function parameters

In clinical trials, few patients experienced adverse events resulting in permanent discontinuation from dornase alfa treatment, and the discontinuation rate was observed to be similar between placebo (2%) and dornase alfa (3%).

Antibodies to dornase alpha were found in less than 5% of the patients, but they did not belong to the IgE class in any of them. Improvement in lung function was noted even after the appearance of antibodies to dornase alpha.

In a clinical study in 50 patients treated with Tigerase, no statistically significant differences were found as compared to the reference drug in the frequency of IgG and IgM antibodies formation; antibodies belonging to the IgE class were not detected similarly to the reference drug. Additional safety measures are provided by the Protocol for the safety of patients during selection of the study subjects. The protocol provides continuous medical monitoring of patients including registration and evaluation of adverse events which allows to minimize the risk for patients while participating in this study.

If known adverse reactions to the drug product develop, the Investigator will take appropriate measures. In addition, unknown and unexpected side reactions to the drug products used in the study are probable. In this study SM001 (Tigerase) at a dose of 2.5 mg will be inhaled once daily during the first week and twice daily for the remaining 23 weeks. The study drug is approved for twice daily use without interruptions. Favorable safety profile of once and twice daily regimen during 24 weeks was shown in patients with cystic fbrosis (Fuchs 1994), please refer to Section 2.5 for details. It is assumed that treatment regimen in this study will be characterized by a low probability of adverse reactions. However, patients will be closely monitored and in case of safety issues dosage alterations may be implemented (Section 2.5).

Based on the above, it can be concluded that for patients of the active treatment group, the benefits of participating in the study exceed the possible risks.

Risks related to performance of diagnostic procedures Risks related to performance of diagnostic study procedures do not outweigh the risks for the routine medical practice.

Other risks
Other risks accepted by patients due to participation in the clinical study are defined by the experimental nature of the study, because its precise result is unknown.

Based on the above, it may be concluded that benefit from the participation of patients in the present clinical study outweighs the risk accepted by patients of both groups which characterizes benefit-to-risk ratio as ethically acceptable.

Description and justification of method of administration, strength and dosage regimen of the drug products

According to the legislative and regulatory basis, the study will be conducted using the test product provided by the Sponsor.
Evaluation of safety and preliminary ecacy of SM001 (Tigerase) in pulmonary sarcoidosis patients on chronic steroid use is expected within the study.
Patients who meet the eligibility criteria for the study will be administered the study drug:

• Daily administration of SM001 (Tigerase) for 24 weeks.

Study drug will be inhaled once a day (2.5 mg) for the first 7 days, using jet nebulizer while the patient is seated in an upright position. The patients will be instructed to inhale SM001 (Tigerase) at the same time of day during the study, except for study visit days at the clinical sites when they will be administered SM001 (Tigerase) on site. After the initial week if there are no issues the dosing will be increased to twice daily of 2.5 mg to be administered using jet nebulizer at the same times each day for a total 24 weeks.

SM001 (Tigerase) is a biosimilar of original dornase alfa Pulmozyme. Currently, SM001 or Tigerase is approved in Kazakhstan [reg. number РК-ЛС-5№ 025257] in adults and children aged >5 years with FVC ≥40% of predicted for symptomatic treatment of cystic brosis in combination with standard therapy. Patients should use the drug daily without interruption. SM001 (Tigerase) at a dose of 2.5 mg is approved for once daily use in all patients and twice daily use in some patients >21 years of age. The data suggest that the eects of Pulmozyme on respiratory tract infections in older cystic fibrosis patients (>21 years) may be smaller than in younger patients, therefore twice daily dosing may be benecial for such patients. The age limit of 21 years for twice daily use is due to ecacy reasons, meanwhile safety prole of both once and twice daily regimens has shown to be favorable.

STOPPING CRITERIA FOR DOSE ESCALATION

Upon completion of Day 7, assessments for single 2.5 mg dose of SM001 (Tigerase) should be made before increasing the dose to twice daily. AEs registered during treatment will be considered intolerable if they meet any of the following criteria:

• Serious adverse events (SAEs) if related to the study drug,
• Clinically significant broncho-constrictive episode in the opinion of the investigator, and absolute decrease from baseline in the FEV1 predicted
value by ≥20% (to be conrmed by a repeat spirometry approximately 4 hours later),
• Treatment emergent AEs related to Laboratory and ECG parameters at Grade 3 or higher according to the National Cancer Institute’s common
toxicity criteria (NCI CTCAE, v.5.0), or
• All other treatment emergent AEs at Grade 3 or higher according to the NCI CTCAE.

If at least 1 intolerable AE is reported for a patient in the rst week, the further treatment dose for this patient should be considered on a case-by-case
basis by the Investigator and approved by the Sponsor and Medical Monitor. Intolerable AEs during weeks 2-24 will be reviewed by the investigator, medical monitor and sponsor medical monitor to assess dose moving forward.
Dose escalation to the next dose of Tigerase 2.5 mg twice daily will not occur if two or more patients develop intolerable AEs that are considered drug related and clinically relevant after review by investigator, medical monitor and sponsor medical monitor, as defined above.
In the event any of the stopping criteria for dose escalation are met, the study will continue with once daily regimen following review by the Sponsor Medical Monitor and Medical Monitor.
The Medical Monitor or designee may request to discuss the treatment with the Investigator, before any further patients are dosed.
Dose adjustment
If a patient does not tolerate twice daily regimen (according to the opinion of the investigator AEs are dose related), the patient may have dose reduced
to once a day and continue study protocol.
If under the judgement of the treating physicians there may be a temporary halt and reinstitution of the SM001 (Tigerase) treatment if considered appropriate.

STUDY QUALITY STATEMENT

The study will be performed as per the Protocol, strictly as per the Constitution of the Republic of Kazakhstan, International Conference of Harmonisation – Good Clinical Practice (ICH-GCP) Guidelines, ethical principles of the Declaration of Helsinki developed by the World Medical Association as of 1964 in the latest edition, Decision of the Council of the Eurasian Economic Commission dated 03.11.2016 No. 79 “On approval of Good Clinical Practice of the Eurasian Economic Union”, Decision of the Council of the Eurasian Economic Commission dated 03.11.2016 No. 89 “On approval of Rules of conducting studies of biological medicinal products of the Eurasian Economic Union”; as well as per the applicable requirements of the legislation of the Republic of Kazakhstan, including the Order of the Ministry of Health of the Republic of Kazakhstan dated
December 11, 2020 No. KR DSM-248/2020 “On approval of the rules for conducting clinical trials of medicines and medical devices, clinical and laboratory tests of medical devices for diagnostics outside a living organism (in vitro) and requirements for clinical bases and the provision of public service on a permission to conduct a clinical study and (or) testing of pharmacological and medicinal products, medical devices”, the Code of the Republic of Kazakhstan dated July 7, 2020 No. 360-VI ZRK “About the health of the people and the healthcare system”, order of the Minister of Healthcare of the Republic of Kazakhstan dated February 4, 2021 No. KR DSM-15 “On the approval of good pharmaceutical practices”.

DESCRIPTION OF THE STUDY POPULATION

The criteria of selection into the study are scientifically justified and were carefully thought in order to ensure safety of patients and reliability of results of the present study. The study is planned to include patients with diagnosed symptomatic and/or active pulmonary sarcoidosis receiving steroids aged from 18 to 70 years old. This will allow, within the framework of a clinical study, to obtain data close to real clinical practice, and will allow an assessment of safety and preliminary efficacy of the studied therapy.

The study is planned to include not more than 30 patients with diagnosed pulmonary sarcoidosis receiving steroids, of which at least 20 patients meeting the study inclusion criteria and having no non-inclusion criteria are approved to administer the study drug.

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