Exhibit 10.1


 


APPENDIX TO THE AGREEMENT DATE JULY 07, 2019


 


Signed at October 23, 2022


 


	Between:	Rambam Med-Tech Ltd Reg. no. 514496587
	 	By Roee Atlas – CEO 
	 	(So Called: “Med- Tech”) 
	 	 
	AND Between:	Raphael Pharmaceutical Ltd Reg. no. 516054400
	 	By Shlomo Pilo –CEO  
	 	(So Called: “Raphael”)


 


WHEREAS, the parties signed research agreement
on July 7, 2019 (So called: “the Primary Agreement”); 


 


WHEREAS, Med-Tech had signed on December
31, 2020 an appendix to the Primary Agreement in which its extent the primary agreement for an extra of four years in terms & conditions
as will set up between the parties;


 


WHEREAS, the parties will set up, herein,
the terms & conditions for the extension of two years out of the four in this appendix;


 


WHEREAS, the description plan & the
objectives of the new research development will be set forth herein;


 


Now, THEREFORE, in consideration of the
promises & mutual covenants set forth herein, the parties agrees as follows:


 


		A.	Description of the Research Development:



 


Development of a novel patentable formulation
based on combination of purified cannabinoid and Cannabinoid Receptor’s antagonist to treat rheumatoid
diseases


 


		B.	Research plan:



 


Scientific background


 


Rheumatoid diseases are characterized by progressive
chronic inflammation of the musculoskeletal system afflicting primarily the joints but can lead to systemic comorbidities like pulmonary
diseases or vasculitis. Chronic inflammation results in cartilage and bone damage, which in the course of deterioration can lead to disability
of the affected patient (Smolen, Aletaha, & McInnes, 2016).


 


Rheumatoid diseases have a great individual and
societal burden. Pain and musculoskeletal deficits lead to a progressive decline in physical activity and quality of life and carry the
risk of cumulative comorbidity. Medical costs for treatment as well as the reduction in work capacity and the decreased societal participation
of patients with RA have a major socioeconomic effect on society (Cross et al., 2014).


 






     


     


    

 


Therapy
of rheumatoid diseases is challenging not only because of the progressive nature of the disease but also because of the side effects
of the current treatments available (Nawaz, Ali, Rehman, & Aslam, 2020). Moreover, available treatment options cannot reverse rheumatoid
diseases. Thus, therapy efforts are followed in two directions: i) preventive medicine (starting treatment before clinical manifestation)
and ii) development of new drugs that treat rheumatoid diseases. Three classes of drugs are available today; i) disease-modifying anti-rheumatic
drugs (DMARDs), which target TNF, the IL-6 receptor and stimulate the depletion of T and B cells diminishing the progression
of the structural damage (Singh et al., 2016; Smolen et al., 2014), ii) non-steroidal anti-inflammatory drugs (NSAIDS), which improve
the physical function by reducing pain and stiffness but do not modify the disease (Nawaz et al., 2020) and iii) glucocorticosteroids,
which have a rapid symptomatic and disease-modifying effect (Kirwan, 1995).


 


Prolonged use of glucocorticoids and DMARDs has
serious long-term adverse effect (Szostak, Machaj, Rosik, & Pawlik, 2020; Yasir, Goyal, Bansal, & Sonthalia, 2020). Moreover,
biological DMARDs have an increased risk of serious infections by tuberculosis and herpes zoster virus as well as the risk to develop
melanoma (Ramiro et al., 2014). This exemplifies the need for novel treatment approaches and safe therapeutics. One of them might be the
usage of medical cannabis taking advantage of its pain-reducing and immune-modulating features.


 


Cannabis and cannabinoids


 


Cannabis is the most widely used illicit drug
in the world. It is not a single substance but refers to a compilation of > 550 different chemical constituents accumulated in
the cannabis plant, among them ≈ 150 psychoactive and non-psychoactive cannabinoids and > 400 non-cannabinoids. The
cannabis plant belongs to the family Cannabaceae. Two different forms are distinguished; cannabis with high levels of the psychoactive
tetrahydrocannabinoids (THC) is referred to as marijuana and cannabis with high levels of non-psychoactive cannabinoids and low levels
of THC is referred to as hemp (Baron, 2015). Two main THC compounds are pharmacologically active, 8-THC and 9-THC.
The main non-psychoactive but pharmacologically active cannabinoids are cannabinol (CBN), cannabidiol (CBD) or cannabigerol (CBG) (Figure
1) as well as non-cannabinoids like flavonoids, terpenes and fatty acids (Andre, Hausman, & Guerriero, 2016; Gould, 2015).


 






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Figure 1: Cannabinoids in the cannabis plant


 


List and number of phytocannabinoids found in the
cannabis plant.


 


Cannabis and cannabinoids occur in several forms; as they occur in
the cannabis plant or as isolates and synthetic or semi-synthetic produced substances.


 


Natural cannabinoids


 


Medical cannabis is available as the whole plant
in the form of dried flowers or as extracts thereof. Drying and heating allows gradual decarboxylation of the cannabinoid acid precursors
into the proper neutral forms, i.e. cannabidiol acid (CBDA) converts to cannabidiol (CBD) or tetrahydrocannabinol acid (THCA) converts
to tetrahydrocannabinol (THC) (de Meijer et al., 2003). Physiologic effects of non-cannabinoids that are also found in the leaves and
flowers are not yet entirely known (Sarzi-Puttini, Batticciotto, et al., 2019).


 


Synthetic and semi-synthetic cannabinoids


 


Many off the shelf products are available, of
which three cannabis products received approval for medicinal use. These are nabiximol which consists of natural THC and CBD extracts,
dronabinol which is plant-derived but chemically modified after extraction and nabilone is synthetically produced (Häuser, Petzke,
& Fitzcharles, 2018; Mücke, Phillips, Radbruch, Petzke, & Häuser, 2018).


 


Nabiximols, better known under the tradename Sativex®,
is a botanical mouth spray that received approval in the UK in 2010 for the alleviation of MS-symptoms like spasticity, pain and overactive
bladder. Its main ingredients are THC and CBD at similar dosage (Häuser et al., 2018; Mücke et al., 2018; Sarzi-Puttini, Batticciotto,
et al., 2019).


 






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Dronabinol (Marinol) contains mainly THC and is
a partial agonist of the cannabinoid receptors CB1 in the nervous system and CB2 in the periphery that activates appetite, mood, cognition,
memory and perception. Dronabinol received FDA-approval for the United States in 1985 for treatment of anorexia in AIDS patients and for
the prevention of chemotherapy-induced nausea and vomiting (CINV). Adverse effects include drowsiness, fatigue, dizziness, conjunctivitis,
paranoia and abnormal thinking and euphoria as well as gastrointestinal problems like nausea, vomiting, abdominal pain and diarrhea (Häuser
et al., 2018; Mücke et al., 2018). Lack of randomized controlled trials (RCTs) makes a recommendation for usage of dronabinol as
a third-line treatment for CINV difficult (Sarzi-Puttini, Batticciotto, et al., 2019). Dronabinol in the form of an oral tablet is known
under the trade name namisol. It has high bioavailability and a long shelf life and is indicated for Multiple Sclerosis (MS), chronic
pain and behavioral disturbances in dement patients (Häuser et al., 2018; Sarzi-Puttini, Batticciotto, et al., 2019).


 


Nabilone with the main ingredient THC is approved
and sold under the brand name Cesamet in Canada, Mexico, the UK and the USA as an anti-emetic and adjunctive analgesic for neuropathic
pain, CINV and treatment for anorexia in AIDS patients. Its main usage today is as adjunct medicine for chronic pain management. However,
ambiguous results from case studies and clinical trials on benefits of nabilone for fibromyalgia and MS were published so that recommendations
for usage cannot be given (Häuser et al., 2018; Reekie, Scott, & Kassiou, 2017; Sarzi-Puttini, Batticciotto, et al., 2019).


 


Signaling pathways and the importance of
cannabinoid receptors for signal transduction


 


Cannabinoids mediate their biological and therapeutic
effects through cannabinoid receptors (Mackie, 2008; Paland et al., 2021; T. H. Smith, Sim-Selley,
& Selley, 2010). At least two members of the G-protein coupled receptor family (GPCRs),
cannabinoid receptors 1 (CB1R) and 2 (CB2R), were identified. G-proteins act as adaptors that link GPCRs to other signaling and
regulatory proteins to operate or modulate intracellular signaling pathways. Other G-protein
coupled receptors such as GPR55 and GPR18 and transient receptor potential channels such as TRPV2, TRPA1, or TRPM8 are involved in cannabinoid
signaling (Rosenbaum, Rasmussen, & Kobilka, 2009).


 


CB1R is highly expressed
on neural cells in the central nervous system (CNS), and is found in particularly high levels in the neocortex, hippocampus, basal ganglia,
cerebellum and brainstem (Marsicano & Kuner, 2008). Low expression levels are observed in the peripheral nervous system. The CB1R
binds the main active ingredient of marijuana, Δ9-THC, and mediates most of the CNS effects of THC (Zimmer, Zimmer, Hohmann,
Herkenham, & Bonner, 1999).


 


CB2R is present at high
levels in cells of the immune system and commonly associated with the regulation of immune function. Furthermore, a functionally relevant
expression of CB2R was also found in the brain (Salort, Álvaro-Bartolomé, & García-Sevilla, 2017). In the CNS,
CB2R expression is associated with inflammation and it is primarily localized to microglia, resident macrophages of the CNS (Palazuelos
et al., 2009).


 






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The fact
that both CB1 and CB2 receptors have been found on immune cells suggests that cannabinoids play an important role in the regulation of
the immune system. It has been shown to exert anti-inflammatory activities in various in vivo and in vitro experimental
models. Several studies showed that cannabinoids downregulate cytokine and chemokine production
and, in some models, upregulate T-regulatory cells as a mechanism to suppress inflammatory responses (Berdyshev, 2000; Paland et al.,
2021).


 


Cannabinoids
can inhibit cell proliferation through various mechanisms. They block cell cycle progression at the G1/S phase via CB1R and at
the G2/M phase via CB2R activation by inhibiting Akt and ERK signaling. CB1R activation inhibits the FAK/SRC/RhoA pathway leading to inhibition
of cell migration. Cell migration blockade is also achieved by CB2R activation through the inhibition of COX-2 and ERK signaling, which
is important to suppress inflammatory response (Kisková, Mungenast, Suváková, Jäger, & Thalhammer, 2019).


 


		C.	Research Objectives



 


The overall objective of this study is to identify
a novel cannabinoid based patentable formulation to treat Rheumatoid diseases. Specifically, to
investigate combination of purified cannabinoids with cannabis receptors antagonists to downregulate inflammation related to Rheumatoid
diseases. We propose to base our study on data derived from Dr. Igal Louria-Hayon studies (Helsinki # 0442-20-RMB) on the evaluation of
the immune regulation properties of cannabinoids on the immune system and the data derived from the cannabinoids receptors study (Helsinki
# 0331-20-RMB). We will analyze the activation of cannabinoid receptors on mouse models and will study the role of cannabinoid receptors
antagonists as a potential to develop a novel patentable formulation to treat Rheumatoid Arthritis.


 


Specific
aims:


 


		1.	Identify the potential of purified
specific cannabinoid on Rheumatoid Arthritis in a mouse model



 


		2.	Identify Cannabinoid Receptors
antagonist with a potential to downregulate immune cells activities, in human derived cells and mouse model.



 


		3.	Formulate a combination of
purified cannabinoid and Cannabinoid receptors antagonist which will demonstrate synergistic effect to downregulate inflammation related
to Rheumatoid Arthritis.



 


We suggest that our strategy to combine
purified cannabinoid together with cannabinoid receptor’s antagonists, will allow us to develop a novel formulation for Rheumatoid
Arthritis treatment.


 






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		D.	Cost of the New research Development:



 


Raphael will sponsored the new research development
as follows:


 


2 years Budget
(cost including overhead):


 


Pre-Clinical lab research
cost $700,000 USD + V.A.T.


 


Mouse model for systemic
inflammation: 120,000 USD + VAT.


 


Mouse model for Rheumatoid
Arthritis: 140,000 USD + VAT.


 


Total cost: 800,000
+ 160,000 (overhead) + VAT.


 


		●	The
principal investigator is authorized to decide on changes in the budget of each category and the duration of the research in related
to the needs of the study.



 


Payment Schedule:


 


Raphael Pharmaceutical will pay to Rambam MedTech



 


1st payment: 100,000$ + 20,000$
overhead on May 2023 (Mouse Model). 


 


2nd payment: 291,667$ + 58,333$
overhead on December 2023 (Research year I). 


 


3rd payment: 116,667$ + 23,333$
overhead on May 2024 (Mouse Model). 


 


3rd payment: 291,667$+ 58,333$ overhead
$ December 2024 (Research Year II).


 


All payments should be added VAT


 


Payment will be in NIS according to the Bank of
Israel exchange rate on the day of payment.


 






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IN WITNESS WHEREOF, each party has caused this
Appendix to be executed by its duly authorized representative as of the effective date: 


 


	Rambam Med-Tech Ltd	 	Raphael Pharmaceutical Ltd 
	 	 	 
	By:	 /s/ Roee Atlas	 	By:	 /s/ Shlomo Pilo
	Name: 	 Roee Atlas	 	Name: 	 Shlomo Pilo
	Title:	 CEO	 	Title:	 CEO 
	Date: 	23.10.22	 	Date:	 24.10.22


 


	Principal Investigator	 
	 	 
	By:	/s/ Igal Louria- Hayon 	 
	Name: 	Igal Louria- Hayon 	 
	Title: 	Scientific Director Medical Cannabis Research and Innovation Center Rambam health care Campus.  	 
	Date:	23.10.2022 	 


 


 





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