Aranda Pharma – a new treatment option for acne
Topical treatments are the cornerstone in acne management, yet there are mainly oral anti-androgens on the market with side effects. Aranda Pharma’s ADA-308 aims to be the first non-steroidal anti-androgen for topical treatment of acne.
Please note that "The Company’s extraordinary general meeting on November 17, 2021 approved an option program which may issue a maximum of 1 300 000 stock options entitling to the subscription of a maximum of 1 300 000 of the Company’s common shares. In addition, the extraordinary general meeting authorised the Board of Directors to decide on issuance of these option rights. These stock options may be offered to the personnel, key persons, managers, advisors, subcontractors and members of the Board of Directors of the Company and its group companies." As these options have not been issued yet, they are not counted into the fully diluted shares.
Topical treatments are the cornerstone in acne treatment. Androgens induce overproduction of sebum and are known drug target in acne yet there are mainly systemic anti-androgens on the market with side effects restricting their use. Aranda Pharma’s anti-androgen aims to be the first-in-class* topical anti-androgen for the treatment of acne.
*non-steroidal, pure anti-androgen
Aranda Pharma is an innovative Finnish pharmaceutical company developing a novel treatment option for acne. The treatment is based on Aranda Pharma’s proprietary anti-androgen ADA-308, which is the result of extensive research and development done at Aranda Pharma and which aims to be the first-in-class topical anti-androgen for the treatment of acne.
Aranda Pharma is raising up to EUR 1.05 million in equity for finalizing the preclinical development of ADA-308 and designing clinical studies. Thereafter ADA-308 is ready to move on into clinical studies on patients. Our goal is to seek a global development partner for clinical development and commercialization of the ADA-308 product. The partnering deal provides investors an opportunity to exit in one transaction or stepwise. Aranda Pharma’s active investors and the management team will participate in the funding round with total investments of EUR 400,000.00. In addition to equity investments, the company will apply for a research & development loan from Business Finland to finance part of the research.
Aranda Pharma was founded in 2015 by key persons behind a Finnish anti-androgen invention.
ADA-308 is an androgen receptor antagonist, so called anti-androgen, which inhibits androgen activity in the target tissue. Androgens play an essential role in the manifestation of many diseases. In acne they boost excess oil secretion resulting in greasy skin.
ADA-308 has its roots in prostate cancer research conducted by Aranda Pharma since 2015. ADA-308 was a very potent anti-androgen in various prostate cancer research models, but due to changes in the clinical practise commercialization of the program in prostate cancer became particularly challenging and Aranda Pharma decided to explore its potential as topical treatment for acne. In preliminary experiments, ADA-308 proved to be an effective and well-tolerated anti-androgen when applied topically, i.e., directly to the skin, making it an ideal drug candidate for acne treatment. This led to a strategic decision to focus the development of ADA-308 on acne. Acne, as the first target indication, has lower risk compared to, for example, oncology targets due to a faster and lower-cost clinical development phase (please refer to Initial target indication).
To date Aranda Pharma has invested approx. EUR 3 million for the R&D of ADA-308.
Why invest in Aranda Pharma?
- Acne is a novel target indication for Aranda Pharma; thus, the valuation of the Company is investor-friendly providing an attractive potential for returns given the low development costs and short development time of locally acting skin treatments compared to many other types of drugs such as cancer drugs.
- Acne is an economically and commercially interesting target for drug development. It is a common skin disorder and there is a significant medical need for new acne medication. Very few new therapies have entered the market in the past decade. In 2020 USD 8.6 billion was spent on drug treatment for acne. The market is growing fast and is anticipated to reach USD 13.1 billion by 2027. Peak sales for locally acting anti-androgen have been estimated to be over 400 million USD.
- Over 80% of people between ages 12-24 experience at least mild acne. Acne has a major impact on a young person’s body image and self-esteem and untreated acne can lead to permanent damage called acne scars. Acne patients are treatment compliant and highly willing to pay for effective treatment.
- Clinical development in acne is short in duration with low cost compared to many other indications providing quick return of investments.
- Aranda Pharma’s proprietary ADA-308 is a novel, promising, anti-androgen suitable for topical treatment of acne. It combines the good tolerability of topical treatments with efficacy of anti-androgens. ADA-308 has proven to be efficacious in various research models measuring the anti-androgen activity. ADA-308 has a strong IP protection until 2033 with possibility to extend that until 2043 with new patent filings.
- Topical treatments are the first and most widely used treatment option for acne due to minor side effects, but more efficacy is needed for the treatment. Though anti-androgens' acne symptoms relieving effect is undisputed, there are mainly oral anti-androgens on the market which are not suitable for everyone due to side effects. Thus, there is a significant unmet medical need for anti-androgens that act topically through skin, like the one in development by Aranda Pharma. Due to the prevalence of acne, there is a significant market potential for an efficient acne medication that is applied topically on the skin.
- Aranda Pharma’s goal is to develop ADA-308 until the end of preclinical studies at which point it is ready to move on into clinical studies on patients. Partnering efforts for identifying the commercialization partner can be initiated at this point. Alternatively, Aranda may advance ADA-308 into early clinical studies and demonstrate the preliminary safety and efficacy on acne patients (clinical proof-of-concept) which is the major value inflection point in the drug development.
- Aranda Pharma has a highly experienced and well-connected team, a cost-efficient business model, and an international collaborator and service-provider network.
What is the role of androgens in acne and how does anti-androgens work?
Sex hormones are steroid hormones that regulate the development and maintenance of female and male characteristics and sexuality. Sex hormones can be divided into male sex hormones, or androgens, and female sex hormones, or estrogens. Despite the names both men and women produce both types of sex hormones, the biological gender defining the prevalent sex hormone. The biosynthesis of hormones is strictly regulated and changes in hormone balance may lead to problems.
Testosterone is the major androgen. In puberty testosterone production increases for both boys and girls. Testosterone regulates the activity of sebaceous gland and increases oiliness of skin which explains why acne is so prevalent during teenage years. While hormone levels in the male body stabilize after puberty they continue to fluctuate in the female body. As a result, many women suffer from hormonal acne which is triggered by changes in hormone levels during the menstrual cycle.
Androgens need androgen receptors to mediate biological effects. When androgen binds to an androgen receptor it triggers a cascade of events, leading to the activation of androgen-regulated genes, which for example results in the activation of sebocytes and subsequent sebum excretion on the skin. An androgen receptor antagonist is a compound, which competes with androgens on binding to an androgen receptor. Once bound to the receptor, it inhibits its activation thus preventing androgens exerting their biological action (Figure 1). As these compounds counteract androgen activity, they are also called anti-androgens.
As androgens are needed to maintain male characteristics and sexuality, oral anti-androgens have numerous side effects in men such as breast tenderness and gynecomastia, loss of libido and erectile dysfunction. Thus, it is particularly important that anti-androgen used as topical acne treatment acts locally on the skin and does not enter the blood stream.
Figure 1. Mechanism of action for ADA-308. Androgen binding to androgen receptor, AR, triggers AR nuclear translocation and AR mediated signalling (on the right). When ADA-308 binds to androgen receptor, androgen cannot bind to receptor and AR activity is inhibited (on the left).
What is ADA-308?
ADA-308 is a novel androgen receptor antagonist, or so-called anti-androgen, invented in Finland. It is a synthetically produced small molecule with a non-steroidal structure. Steroidal anti-androgen is an anti-androgen with steroidal chemical structure meaning that it resembles testosterone. Because steroids are structurally remarkably like each other, steroidal anti-androgens can bind to other hormone receptors and may affect their function. ADA-308 is specific for androgen receptor which means it is a pure androgen receptor antagonist. Hundreds of different small molecules have been studied in the ADA-308 research program and one has been selected for further development due to its optimal efficacy and safety profile.
What makes ADA-308 unique?
Androgen induced overproduction of sebum plays a vital role in the pathogenesis of acne thus, the symptom relieving effect by anti-androgens for acne is undisputed. The oral anti-androgens are, however, not suitable for men due to their anti-androgenic side effects. Combined oral contraceptive pills are used to treat acne among female patients due to their anti-androgenic beneficial impact for skin. They often result in good, long-lasting, responses to acne but they are not suitable for everyone, and the therapeutic response is slow as it takes 3-6 months before improvements can be seen. In August 2020 Cassiopea announced that the United States Food and Drug Administration (FDA) has approved Winlevi, 1% cream (clascoterone) for the treatment of acne (please refer to Competition). This makes Winlevi the first-in-class topical acne treatment targeting androgen receptor.
ADA-308 is an efficient, non-steroidal, pure anti-androgen
Winlevi (clascoterone) has a steroidal structure. According to Prescribing Information it is an androgen receptor inhibitor with an unknown mechanism of action to acne. Due to its steroidal structure, it is non-selective and able to bind to other hormone receptors as well. ADA-308 is non-steroidal and specific for androgen receptor, thus its mechanism of action is well understood in acne. In preclinical efficacy models determining androgen receptor inhibition potential ADA-308 is as efficient as non-steroidal Xtandi (enzalutamide) used in treatment of prostate cancer.
ADA-308 is suitable for topical application to skin
ADA-308 is applied to skin as a cream or gel. According to preliminary formulation studies ADA-308 readily dissolves in various excipients used in topical formulations to prepare creams or gels. It was very stable and did not degrade upon storage. In preclinical models the drug concentration on the skin was more 100 times that in the plasma upon topical application meaning that ADA-308 penetrates the skin but does not enter the circulation.
ADA-308 does not have systemic anti-androgenic side effects and is thus suitable for both men and women
When ADA-308 is applied topically to the skin its concentration in the plasma is extremely low meaning that it acts locally only at the site of application while orally taken anti-androgens affect the whole body. In preclinical models there have been no signs of anti-androgenic effects in androgen-sensitive organs like prostate or seminal vesicle upon topical application of ADA-308. This is particularly important for the plans to use ADA-308 as acne medication for both genders.
ADA-308 is well tolerated
Many topical medications for acne are skin irritating. In the preclinical studies ADA-308 is very well tolerated and non-skin irritating. Winlevi has been shown to be well tolerated and demonstrated an excellent safety profile in acne patients (Hebert et al 2020). However, in preclinical models Winlevi application caused skin atrophy (thinning), whereas skin treated with ADA-308 was intact.
Topical vitamin A derivatives, or retinoids, are an efficient but skin irritating treatment option for acne. Skin irritation can however be minimized by lowering the retinoid dose. Skin irritation is the major reason for discontinuation of retinoid treatment.
None of the combination medication products for acne have anti-androgen as an active ingredient
There are plenty of topical combination medication products for acne but none of them has anti-androgen as an active ingredient. Aranda Pharma is exploring the opportunity to develop a combination medication product in which ADA-308 is combined to another active ingredient used in acne treatment such as retinoid.
Vår affärs- och marknadssituation
Aranda Pharma is a preclinical stage pharmaceutical development company
Aranda Pharma focuses on the early phases of drug development. Aranda Pharma invents, researches, and develops promising drug candidates until they are ready to move on into clinical trials on patients. Research and development costs are multiplied when moving from preclinical to clinical development. As the drug candidate advances in the development process the risk for failure diminishes and its value increases. Global pharmaceutical companies have reduced their own preclinical research and look for promising early phase drug candidates from companies like Aranda Pharma. Aranda Pharma plans to initiate partnering discussions at the end of the preclinical phase and to sign a collaboration or licensing agreement with a global pharmaceutical company before initiating the early clinical studies or alternatively after completing phase 1-2 of clinical studies. In acne the cost for demonstrating preliminary efficacy and safety in patients is low, approx. EUR 2 million, thus Aranda Pharma considers taking the ADA-308 program through the early clinical phase before looking for a partner.
Development process for pharmaceuticals
Before a drug is ready for the market it has gone through a rigorous and expensive development process with many uncertainties along the journey. It all starts with selecting the target of the drug. A target is a gene or protein with a biological action that is anticipated to have therapeutic utility. At Aranda Pharma, the target is an androgen receptor. Thereafter medicinal chemists design and produce vast number of small molecules whose activity to affect the target, as well as safety, tolerability and other drug-like properties are screened in a test system. Testing for the best drug candidate is continued until after several designing, optimization, and testing cycles, the most efficacious, safe, and well-tolerated drug candidate is selected for further development. Once this so-called preclinical research phase is completed, the drug development process is strictly controlled, and all drug candidates go through a similar process which ensures that only efficacious and safe drugs with true unmet medical need reach the market.
Before a new drug can be tested on patients it must go through a specific panel of preclinical studies to obtain preliminary data about efficacy, safety, and pharmacokinetics (absorption, distribution, metabolism, and excretion). These studies are done in a test tube, cell culture or on an animal model. The data obtained is utilized to design the study plan, dose, and dosing schedule for the First-in-Man clinical studies. The research results are reported to medicinal agencies in the US (Food and Drug Administration, FDA) or Europe (European Medicines Agency, EMA) and a permission to start clinical trials is applied. The application for clinical trials in the US is called IND (Investigational New Drug) (Investigational New Drug Application) and the application for clinical trials to be conducted in the Europe is called CTA (Clinical Trial Application). Some of the preclinical data form the basis for specific information in the drug’s Prescribing Information leaflet (including effects during pregnancy and lactation, pharmacodynamics as well as preclinical safety data).
Clinical development can be divided into three phases which regardless of target indication follow the same pattern. The number of patients needed for trials and study costs increase as the drug moves further in the clinical development.
The first clinical studies are typically carried out in a few dozen healthy volunteers. The primary goal is to study safety - get an idea of safe dose levels and the drugs behaviour in the body as well as determine a dosing schedule for further phases.
The second phase is testing on patients and aims at evaluating the efficacy of the drug and gathering further safety information. Typically, less than a hundred patients are enough to run phase 2 studies. Topical acne medications like Aranda Pharma’s ADA-308 can be studied in a so-called split-face model meaning that only the other side of the face is treated, and the other one is left untreated serving as a control for the treatment. By using this model less patients are needed for phase 2 studies.
The third phase is the most expensive and time-consuming during the whole development process. It aims at determining the efficacy and safety in comparison with the best current treatment. The study is typically conducted as a multi-centre trial involving tens to hundreds of hospitals and clinics all over the world and more than a thousand patients. If the study is successful and the drug proves to be more efficacious and/or safer than the current treatment, a market authorization application is submitted.
Aranda Pharma’s ADA-308 is at the end of preclinical research and moves into preclinical development in early 2022 (please refer to Development plan).
Aranda Pharma’s business model
Aranda Pharma utilizes a cost-effective, semi-virtual, business model in which research & development activities are outsourced to professional contract research organizations and consultants are used in activities requiring special expertise such as designing regulatory studies.
Aranda Pharma’s goal is to finalize the preclinical development of ADA-308 in the next 12-15 months. Thereafter ADA-308 is ready to move on into clinical studies on patients. Our goal is to find a global development partner for clinical development and commercialization of the ADA-308 product. The buyer or collaborator will be a global biotech or pharmaceutical company.
This revenue model is typical for R&D-intensive companies for which high R&D investments are compensated once the R&D project has been successfully commercialized. The commercialization may be through trade sale, exclusive licensing deal giving rights to the partner, or a merger with a listed company. In a typical partnering deal, an upfront payment is paid upon signing the deal. The upfront payment for preclinical phase dermatology assets is approx. EUR 10 million. Development and regulatory milestone payments will be paid upon achieving development milestones, and royalties, in case the drug enters the market. Typical milestone payments are in the range of tens of millions of euros per milestone and royalties are typically 5-10% of sales. The commercialization of ADA-308 would provide an exit opportunity for investors in either a onetime transaction or stepwise depending on the deal type.
Examples of partnering deals in acne and in a related indication
- AstraZeneca discovered a drug candidate with a novel mechanism of action suitable for topical treatment of acne. The candidate, DMVT-503, reduces sebum production by inhibiting DGAT1 enzyme involved in triglyceride synthesis. The program was in the preclinical phase and licensed out since the indication did not fit in the AZ’s focus areas. Swiss Roivant Sciences entered into an exclusive licensing agreement with AstraZeneca in September 2017 with the aim of developing and commercializing DMVT-503. Under the agreement Roivant acquired intellectual property and research and development materials in exchange for the following: upfront payment of USD 2 million, up to USD 13.5 million in potential development milestone payments, up to USD 45 million in potential regulatory milestones, up to USD 25 million upon the achievement of certain commercial milestones and tiered royalties. The total deal value was USD 85.5 million plus royalties. In December 2018 DMVT-503 program was transferred to Dermavant, a subsidiary of Roivant.
- Korean JW Pharmaceutical (JWP) discovered a novel oral drug candidate for atopic dermatitis. The candidate, JW1601, is a histamine H4 receptor antagonist, which acts by blocking the activation and migration of the immune cells that cause atopic dermatitis. In August 2018 LEO Pharma signed a global licensing agreement for JW1601 (excluding Korea) with JWP. JWP will receive USD 17 million as an upfront fee and milestone payments up to USD 385 million as well as a two-digit royalty based on net sales. At the time of the deal JWP was planning to submit IND for phase 1 clinical trial within the same year.
Initial target indication
Due to its mechanism of action Aranda Pharma’s ADA-308 is suitable for all diseases in which androgens play a role. There are many advantages in selecting acne as the initial target indication. Androgens have a vital role in the pathogenesis of acne, but the therapeutic options are restricted to oral anti-androgens. The first topical anti-androgen for the treatment of acne, Winlevi (clascoterone), was approved in the US in August 2020 which means that competition is low. Since acne is a common disease there are many patients available for clinical trials and the recruitment process for the trials is fast which shortens the overall clinical development time. Topical treatments are the golden standard in the treatment of acne and the safety regulations are lighter when the treatment acts locally with no fear for systemic side effects. The treatment response for topical therapies is often visible in a few months, thus the clinical data is available in a short time. The clinical evaluation of the treatment response is based on visual assessment of lesion counts and their inflammatory status (inflammatory vs. non-inflammatory), thus the trial set-up does not require expensive examination methods or special equipment.
It is possible to extend the ADA-308 to other diseases such as androgenetic alopecia, a generic form of hair loss among both men and women, in which androgens play a role.
Acne is a common skin disorder affecting 10 % of the global population and over 80 % of people at some point of their life. While it mostly affects teenagers it is a chronic disease continuing in adulthood for some. Typical features of acne include whiteheads, blackheads (comedones), and pimples (papules or pustules). Acne primarily affects facial skin, but the neck and upper body are also affected for some patients. Severe acne may lead to permanent skin damage and scarring. Acne can have a significant impact on a patient’s quality of life and self-esteem and may lead to depression and social withdrawal.
Acne is a multi-factorial disease, in which excess sebum production is one of the contributing factors. It affects pilosebaceous units in the skin (Figure 2) and develops when pores are blocked, inflamed, and swollen. The pathogenesis of acne involves four main pathways, all of which are targets of medical intervention: 1) excess sebum production, 2) abnormal follicular keratinization leading to blocking of pores, 3) microbial colonization, and 4) inflammation.
Figure 2. The four main pathways in the pathogenesis of acne and their medical interventions. Androgen-driven excess sebum production can be counteracted by anti-androgens. Vitamin A derivatives, retinoids normalize skin shedding and thus inhibit obstruction of pores. Antibiotics and antiseptics, like benzoyl peroxide kill bacteria and reduce inflammation.
Acne can be divided into three clinical subtypes, which all have their own treatment recommendations. Comedonal acne is characterized by black- and whiteheads (comedones) and there is little if any inflammation, thus it is also called non-inflammatory acne. Comedones may also be present in pustulo papular acne, the inflammatory acne, which is characterized by small red pumps, papules or pus containing pustules. The most severe form of acne is so called cystic acne, which is characterized by tender or painful pus-filled cysts and large bumps. (Salava, Duodecim 2017).
Treatment of acne
The treatment options for acne can be divided into systemic therapies and topical treatments (creams, gels, and lotions). They can be further classified as: vitamin A derivatives i.e., retinoids, antibiotics, hormonal therapies, and various medications containing antibacterial ingredients (salicylic acid, azelaic acid, benzoyl peroxide). Due to the multifactorial nature of acne, it is common to combine various treatments and/or use combination medications that combine two acne-fighting ingredients.
Typical acne treatments are:
- Topical treatment
- Systemic antibiotics (always combined to topical treatment)
- Combined oral contraceptive pill
Topical treatment of acne
Topical treatment is usually the first treatment option in acne. It is suitable for the treatment of mild to moderate acne. Treatment options include topical retinoids, topical antibiotics, azelaic acid or benzoyl peroxide. There are also topical combination medications that combine a retinoid to benzoyl peroxide or antimicrobial to retinoid or benzoyl peroxide. It is not uncommon that topical treatment irritates the skin especially in the beginning of the treatment, which in some cases leads to treatment discontinuation. Typically, the treatment response takes a few weeks to develop which means that topical treatment requires commitment and patience. To boost the therapeutics response topical treatment can be combined to systemic antibiotics.
Treating acne with antibiotics
Antibiotic tablets (oral antibiotics) are usually used in combination with a topical treatment to treat moderate to severe pustule papular acne. Antibiotics are not suitable for long term treatment due to side effects. Oral or topical antibiotics should not be used alone but always in combination with topical or systemic retinoid, benzoyl peroxide, azelaic acid or a combination medication. Frequent antibiotic use is associated with development of antibiotic resistant bacterial strains.
Combined oral contraceptive pills in acne treatment
Women benefit from the use of combined oral contraceptive pills due to their anti-androgenic effects on acne. The therapeutic response is often good and long-lasting but takes 3-6 months to develop. Not all women want to, or can, use hormonal contraception and contraceptive pills are not suitable e.g., for those planning pregnancy.
Oral hormonal therapies in the treatment of acne
Spironolactone was originally developed as a diuretic for the treatment of high blood pressure and fluid build-up. It is a steroidal mineralocorticoid receptor antagonist. Due to its steroidal structure it also binds to other receptors including androgen receptor. Based on its anti-androgenic activity it is used off-label for acne treatment. Since it is taken orally it is only suitable for women.
Isotretinoin in acne treatment
Isotretinoin is an oral vitamin A derivative, a retinoid. It is indicated for the treatment of severe acne. It is the most efficacious treatment option for acne, but it is also associated with numerous side effects. Thus, lipids and liver enzymes need to be monitored during the treatment. Since isotretinoin is a strong teratogen there are strict controls associated with its use on female patients. Women in child-bearing age must show a negative pregnancy test result before initiation of the treatment and commit to using two forms of effective contraception during the treatment. Further, some patients experience strong mood alterations and even suicidal ideation during the isotretinoin treatment.
The global acne medication market was valued at USD 8.6 billion and is anticipated to grow to USD 13.1 billion by 2027 (Global Market Insights). Although 55% of acne medication are over the counter (OTC) drugs, the prescription medication market is valued at USD 4.6 billion. Retinoids dominate the market with approx. 30% market share. Topical treatments are more popular than oral treatments with 65% market share. Furthermore, there is a growing trend towards various combination medications from monotherapies.
Hormonal therapies are an underrepresented treatment option in acne due to the anti-androgenic side effects of oral anti-androgens restricting their use to female patients. The therapeutic effect of anti-androgen is non-debatable, which is underlined by using combined oral contraceptive pills in the treatment of acne and off-label use of oral anti-androgens. Topical anti-androgen will be a much-needed novel treatment option for acne.
Winlevi (clascoterone) is the first FDA-approved topical anti-androgen for the treatment of acne. It is a 1% cream which is applied to the affected area twice per day (in the morning and evening). It has been approved to treat all acne patients 12 years of age or older. Notably, due to extremely low systemic exposure, it is indicated for the treatment of acne in both men and women. Winlevi is well tolerated and there has been no major safety concerns in its clinical use thus far. It differs structurally from ADA-308. Winlevi as a steroid bind to other hormonal receptors, whereas ADA-308 is specific for the androgen receptor. The lack of side effects in clinical use are likely due to rapid systemic metabolism of clascoterone to corticosteroid (hormone) lacking anti-androgenic effects. In preclinical studies clascoterone induced epidermal atrophy i.e., skin thinning in rats and minipigs. Clascoterone in a different formulation (Breezula) is currently under investigation for the treatment of hair loss (androgenetic alopecia) among both men and women (please refer to Hair loss, competition).
Chinese Kintor Pharmaceutical Ltd is developing a topical anti-androgen for hair loss and acne. The drug substance is called pyrilutamide and it is non-steroidal in structure like ADA-308. It is currently in phase 2 clinical trials for hair loss and in phase 1 clinical trials for acne.
Future target indication
Hair loss (androgenic alopecia)
Androgenetic alopecia or hereditary hair loss is the most generic form of hair loss among both men and women. It is more common among men, starts earlier, and may lead to complete hair loss, or balding. For men hair is typically lost in a well-defined, M-shaped pattern beginning above both temples and expanding to the crown, thus it is also called “male pattern baldness.” For women hair loss has a different pattern as it begins with gradual thinning from the part line towards the sites and is called “female pattern hair loss.”
The hair growth cycle can be divided into three phases; the growth phase, or anagen, lasts 2-6 years. During this phase, the hair grows in length. The transition phase, or catagen, lasts 2-3 weeks during which the hair follicle regenerates. The resting phase, or telogen, lasts 2-3 months and ends when the hair is lost, and a new hair growth cycle begins. For both genders hair loss is initiated when the balance in the hair growth cycle moves towards the resting phase and the growth phase is so short that the hair does not reach the scalp surface. Also, the hair follicle shrinks and produces shorter and thinner strands of hair.
As the name implies androgens have a role in androgenetic alopecia, or hair loss. The human hair follicle is extremely sensitive to dihydrotestosterone, DHT, which is an androgen. It is made from testosterone via enzyme 5-alpha-reductase catalysed reaction in both men and women. DHT is primarily active in the tissue where it is formed. DHT formed in the scalp contributes to hair loss. DHT binds to the androgen receptor in hair follicles and triggers miniaturizing of the follicles impairing hair growth. Individuals with hair loss typically have elevated 5-alpha-reductase levels in the scalp, increased DHT or increased number of androgen receptors. Hair follicles becoming sensitized to lower DHT concentrations has been thought to be one of the contributing factors to hair loss.
Treating hair loss
Male hair loss can be treated with oral 5-alpha-reductase blockers such as finasteride (Propecia) (dutasteride, off-label). They prevent the conversion of testosterone to DHT. Low finasteride concentrations are used in the treatment of hair loss to reduce anti-androgenic side effects. Topical minoxidil (Rogaine) can be used in both men and women to treat hair loss. It dilates small blood vessels (vasodilator) and was originally developed as an oral medication for the treatment of high blood pressure. The hair growth stimulating and hair loss slowing side effects led to expanding its indication for the treatment of hair loss.
The activity of DHT in the hair follicles is mediated via androgen receptors, thus androgen receptor antagonists have a vital role in the pathophysiology of hair loss. Like acne, oral anti-androgens cannot be used to treat men due to their anti-androgenic side effects. Thus, there is a need for topical treatments acting locally in the scalp with no or low systemic exposure. Clascoterone (Breezula, 5-7.5% lotion) is currently in phase 2 clinical trials for the treatment on androgenetic alopecia among men and women. According to the preliminary results clascoterone was able to slow down the hair loss especially for male patients whereas only a subgroup of female patients, those under 30 years of age, benefitted from the treatment. Chinese Kintor Pharmaceuticals has an androgen receptor antagonist, pyrilutamide, in phase 2 clinical trials for the treatment of hair loss. The one who makes it to the market first will be the first topical anti-androgen for the treatment of the hair loss.
Aranda Pharma’s goal is to finalize the preclinical development of ADA-308 within the next 12-15 months (Figure 3). Aranda Pharma’s ADA-308 has gone through extensive preclinical testing in various research models to confirm preliminary efficacy and safety as well as other drug-like properties and suitability as topical treatment for acne. The following research material generated in the prostate cancer program can be utilized in the acne program, receptor biology, pharmacokinetics, and safety margins. Aranda Pharma has nominated a so-called lead molecule which advances to final confirmatory studies before initiation of preclinical studies.
Before initiating preclinical studies Aranda wants to make sure that the most efficacious and safe molecule will be advanced to these expensive studies. The lead molecule will advance into pharmaceutical development in which a clinically relevant formulation (cream or gel) will be developed, and its pharmacokinetic properties and preliminary safety will be studied. These studies cost approx. EUR 100,000 – 150,000 and the data support preclinical studies and aid in their design.
Preclinical studies aim at conducting studies that fulfil safety regulations set by regulatory authorities for a new drug for submitting the clinical trial application. The studies will be conducted to meet both US (FDA) and/or European (EMA) regulations. The clinical trial application consists of; 1) animal pharmacology and toxicology studies, 2) manufacturing information for the drug substance 3) clinical trial plan. 1) Preclinical safety pharmacology and toxicology studies confirm the safety for initial testing in humans and determine safety margins to be used in calculating the starting dose for the First-in-Man study. These studies cost approx. EUR 500,000. 2) Information pertaining to the manufacturing process, composition, and stability of the drug substance as well quality controls used for the manufacturing process will be reported in the application. The initial drug batches to supply for the first clinical trials will be manufactured as a part of the application process. The costs for this so-called CMC part (Chemistry, Manufacturing and Control) including upscaling and manufacturing costs for the first clinical batches are approx. EUR 500,000. 3) Clinical trial plan includes detailed protocols for proposed clinical studies (number of patients, inclusion, and exclusion criteria, efficacy, and safety endpoints) as well as information about participating centres, qualifications of clinical investigators and informed consent forms. The clinical trial plan as well as meetings with regulatory authorities during the application process costs approx. EUR 200,000.
- Aranda Pharma will build a Scientific Advisory Board, SAB, consisting of clinicians, specializing in dermatology, and clinical trial experts. SAB expertise will be utilized in clinical trial design. If the drug development process moves forward as planned the first clinical studies in acne could be initiated in 2023. These studies can be conducted in Finland.
- Aranda Pharma will strengthen the team by hiring a Project Manager to coordinate pharmacological and preclinical development.
- Aranda Pharma continues the search for potential commercialization partners. To this end Aranda participates in partnering events in Europe and the US as well as presents the ADA-308 program to global pharmaceutical companies.
- Aranda Pharma considers expanding the target indication to hair loss. Expansion would be a cost-effective way to increase the Company’s value, as preclinical and clinical trial data generated in the acne program will streamline the clinical trial application process in hair loss.
Figure 3. Development path for ADA-308 in acne. Expanding the target indication to hair loss is possible with additional funding. Indication expansion is tempting as regulatory procedure is lighter when safety data in patients has accumulated from the first indication.
Aranda Pharma has strong IP protection for ADA-308 through patents and data protection
- ADA-308 compounds have global patent protection until 2033. The patent has been granted in 29 countries and the examination process is additionally ongoing in 3 countries. The patent protection covers all major markets in Europe, Asia, and South- and North America.
- Aranda Pharma will file a new patent application in 2022. This will extend the patent protection until 2043.
- Aranda Pharma is the sole owner of the patents and patent applications.
- In addition, ADA-308 is expected to be entitled to 10 years of data exclusivity in Europe and 12 years in the US after obtaining market authorization.
Aranda Pharma has a highly experienced and internationally well-connected team. The operative team has been involved in the development of the ADA-308 program since its inception. Aranda Pharma’s core team is small, and the specific expertise needed is purchased from top experts in the field via consulting agreements. Thus, many of the team members are not directly employed by Aranda Pharma. This has many advantages. Firstly, it is cost-effective as the required expertise can be acquired on a need basis. Secondly, the need for a specific consultant is short-term and thus, employing an in-house expert is inefficient. Finally, this allows Aranda Pharma to pick the experts with specific knowledge and experience from a larger pool of talent.
Founder and CEO
As one of the founders of Aranda Pharma Anu Muona has been involved in the ADA-308 project since its inception. Anu holds a PhD in Molecular Biology and has made an academic career in collagen research and neurodegenerative diseases. Anu has more than 10 years of experience in preclinical drug development in small molecules for various target indications.https://www.linkedin.com/in/anu-muona-1b93658/
Founder, Board member and advisor / COO, Helsinki Innovation Services
Milla Koistinaho is a serial entrepreneur who has co-founded three biotech companies in Finland including Aranda Pharma. Milla has more than 20 years of experience in preclinical drug development and commercialization of life science invention via licensing or IP sales. Milla holds a PhD and is an adjunct professor in Neurobiology and has made an academic career in research of neurodegenerative diseases. Milla is well connected in the life science sector both nationally and internationally.https://www.linkedin.com/in/milla-koistinaho-b88b637/
Chairman of the Board and advisor / CFO, Rappta Therapeutics Ltd
Chairman of the Board Mikko Mannerkoski has more than 20 years of experience in investment banking and growth companies. For the past 10 years Mikko has been involved in biotech companies in both Finland and the US as a founder, shareholder, and executive. Mikko has vast experience in creating and executing value-creating strategies for growth companies in the life science sector. Mikko holds a MSc in technology from the Helsinki University of Technology and an MBA in finance from the Helsinki School of Economics.https://www.linkedin.com/in/mikko-mannerkoski-476b2b1/
Board member and advisor / Head of Business Development, Rappta Therapeutics Ltd
Erkki Tenhunen is a serial entrepreneur who has co-founded several biotech and MedTech companies in Finland including Contral Pharma which was later listed on the Helsinki Stock Exchange and acquired by a US company. Erkki has more than 25 years of experience in business development in high tech companies as well as commercialization of drug development and MedTech projects.
Clinical advisor / Specialist in dermatology and allergology, HUS
Alexander Salava is a specialist in dermatology and allergology at HUS and a clinical advisor at Aranda Pharma. Alexander holds a doctorate in philosophy and medicine (MD – PhD.) and has over 15 years of experience in dermatology and acne treatment. Alexander is the author of several clinical practise guidelines for acne and dermatology
Non-clinical and clinical advisor / Executive Director, Translational Sciences, Syneos Health Ltd.
Michel Rivier is an executive director at Syneos Health Ltd. And a non-clinical and clinical advisor at Aranda Pharma. Michel has over 25 years of experience in drug development covering all aspects of development ranging from research to preclinical and clinical development up to registration and life cycle management. Before transferring to Syneos Michel worked at Galderma, a global pharmaceutical company focused on the development of dermatology products, for 23 years. Michel holds a PhD. In Molecular and Cellular Pharmacology.https://www.linkedin.com/in/michel-rivier/?originalSubdomain=fr
Non-clinical and clinical advisor / Executive Director, Translational Sciences & Virtual Incubator, Syneos Health Ltd.
Ronan Bouer is an executive director at Syneos Health Ltd. And a non-clinical and clinical advisor at Aranda Pharma. Ronan has over 20 years of experience in drug development focusing on the preclinical development and strategic assessment of clinical candidates. Before transferring to Syneos Ronan worked at Galderma, a company focused on dermatology, for 16 years. Ronan holds a PhD in Pharmacology and an executive MBA from Aix-Marseille University, France.https://www.linkedin.com/in/ronan-bouër-53422418/
Non-clinical and clinical advisor / Director, Project Management, Syneos Health Ltd.
Cécile Cousin is a Project Management Director at Syneos Health Ltd. And a non-clinical and clinical advisor at Aranda Pharma. Cécile has over 25 years of pharmaceutical industry experience of which she spent 20 years at Galderma being responsible of the company’s patent portfolio. Cécile holds an MSc in Industrial Pharmacy.
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Investing in the funding round involves risks, some of which may be significant. The description of the risks below is based on the information available at the date of this pitch document and estimates made based on this information, and therefore the description of the risks is not necessarily exhaustive.
The materialization of one or more risks may have a significant adverse effect on the Company's business, financial condition, and prospects as well as on the value of shares. As a result of the materialization of one or more risks, investors who have invested in the funding round could lose their investment partly or fully.
Investment risks include:
The company’s product is at a development stage and the Company may fail to reach profitability
Aranda Pharma focuses on the early stage of drug development. Aranda Pharma has not yet commercialized any projects or products. Hence Aranda Pharma currently has no revenue. Operations have been financed through equity investments and research & development loans from Business Finland. To generate revenue and become profitable Aranda Pharma must succeed in the development and commercialization of ADA-308. Failure to do so may have an adverse effect on the Company’s business and share value.
Pharmaceutical development is a lengthy and expensive process with a lot of uncertainties
Before obtaining marketing approval a pharmaceutical product goes through time-consuming, complex, and costly preclinical and clinical studies, whose outcome is inherently uncertain. As only humans can get acne the conclusive proof of ADA-308 efficacy can only be obtained in the clinical studies on patients. Failures and setbacks in the development of ADA-308, such as disappointing preclinical study results in safety or delays in regulatory approval processes, may have an adverse effect on the Company’s business and share value.
The Company may fail to receive financing needed for further development under favourable terms or at all
The funding will be used to finalize the preclinical development of ADA-308. The drug candidate may not be attractive enough for commercialization without preliminary clinical proof-of-concept for efficacy and safety on acne patients. The clinical development of ADA-308 requires a substantial amount of funding. Further development depends on Aranda Pharma’s ability to raise more funding as equity investments, loans, or grants. Failure to obtain sufficient funding under favourable terms may have an adverse effect on the Company’s business and share value.
Company may fail in making partnership agreements or collaboration does not work
Aranda Pharma’s business strategy is to negotiate a partnering agreement with an international pharmaceutical company for the global rights of ADA-308 at the end of the preclinical phase or after the first clinical studies. Aranda Pharma cannot guarantee that such agreements will be obtained with good terms or at all or that the collaboration works in practise. Should Aranda Pharma fail in negotiating a partnering deal, or in case the collaboration does not work, it may have an adverse effect on the Company’s business or share value.
Company may be unsuccessful in protecting or enforcing its intellectual property rights
Aranda Pharma’s commercial success depends partially on its ability to protect and maintain the intellectual property rights for ADA-308. Aranda Pharma has already obtained a global patent protection for ADA-308 in the major territories. If Aranda Pharma fails in the future patent protection or enforcing its intellectual property rights, it may have an adverse effect on the Company’s business or share value.
Decisions by regulatory authorities and changes in laws and regulations may have an adverse impact on the Company’s business
Aranda Pharma operates in a heavily regulated industry. The laws, regulations, and regulatory practises applicable to Aranda may change. Changes in the rules, regulations and decisions by the regulatory authorities may have an adverse effect on the Company’s business and share value.
The Company’s business depends on its ability identify, recruit, and retain professionals in the pharmaceutical industry
Aranda Pharma’s ability to succeed in the highly competitive, global, pharmaceutical business depends on its ability to attract and retain experienced managers, scientific- and medical personnel as well as consultants. The loss of a key employee or consultant may have an adverse effect on the Company’s business and share value
Competitive products or treatments options may have negative impact in Aranda Pharma’s prospectus
Should Aranda Pharma’s competitors develop drugs or therapies with similar or better results or with lower prices, it may have an adverse effect on the Company’s business or share value.