SPG Therapeutics, Inc.

Topical Androgen Receptor Degradation for the Treatment of Hormonally Mediated Hair and Skin Conditions

Zory Shaposhnik, PhD CEO 818-800-6891 [email protected]

1  PCOS afflicts up to 10% of women in their reproductive years.1  PCOS is mediated by elevated androgen (“male hormones”)

 Alopecia, hirsutism, and acne, the primary dermatological symptoms of PCOS, are prevalent, yet treatment options are limited to a generic oral anti-androgen that frequently fails, is not well tolerated or can cause birth defects.

Source: 1. https://www.healthywomen.org/condition/polycystic-ovary-syndrome

SPG Therapeutics, Inc. 2  Spironolactone is a generic blood pressure drug with off-target anti-androgen activity.  It can be effective in hirsutism, acne, hair loss and hidradenitis suppurativa if taken at 5x-10x the on-label 20mg dose.  Key Opinion Leaders: Women greatly prefer an effective topical anti-androgen.  Why? Better efficacy with fewer side effects.

 Our Solution: The “super spironolactone” SPG-3.

SPG Therapeutics, Inc. 3 $500 Million + Peak Sales Opportunity Per Indication

Alopecia Hirsutism $4.6-13B3 $2.3-5.3B2 Acne

$4.9-7.4B1

Hidradenitis $1B+ Suppurativa Source: 1. IQVIA, NPA and NDTI Data 2. https://www.grandviewresearch.com/industry-analysis/acne-drugs-market 3. https://www.marketresearchfuture.com/reports/hirsutism-treatment-market-3857

SPG Therapeutics, Inc. 4 Genetic/Pharmacological Data: Humans insensitive to androgens have virtually none of these dermatological problems.

We are developing novel compounds termed Androgen Receptor Eliminators (AREs) to topically block and degrade the AR in skin and hair using a novel mechanism of action.

Targeting the AR will prevent the progression of hidradenitis, androgenetic alopecia, reverse hirsutism and acne without the side effects of oral anti- androgens.

http://www.carcinogenesis.com/articles/2011/10/1/images/JCarcinog_2011_10_1_20_83937_f2.jpg SPG Therapeutics, Inc. 5  Lead novel asset (SPG-3) identified, patent filed internationally (US 16/608,748) and developed by SPG Therapeutics.

 SPG-3 shows androgen receptor inhibition in human skin cell assays superior to spironolactone, the current standard of care for hormonal dermatology conditions.

 Preclinical studies indicate SPG-3 can be stably formulated, demonstrates high skin retention, good tolerability and in vivo activity in an androgen driven skin model.

SPG Therapeutics, Inc. 6 Keratinocyte AR Reporter Gene Assay in Primary Human Keratinocytes

24-hr Treatment 72-hr Treatment Max. Target Compound Max. Target IC (M) IC (M) IC (M) IC (M) Inhibition 50 90 Inhibition 50 90

Spiron. No S-curve No S-curve 65% 4.51 x 10-6 1.66 x 10-5 85%

-6 -6 -6 93% SPG-3 3.68 x 10 6.96 x 10 91% 2.57 x 10 5.68 x 10-6*

24hr treatment: 91% target inhibition in skin cells for SPG-3.

72hr treatment: SPG-3 is 3x more potent compared to spironolactone.

Cell viability exceeded 97% post SPG-3 treatment. *p<0.05 vs. spironolactone Source: Report SR6917

7 SPG-3 Is Well Tolerated Topically, Hits Target in Skin in a 21 Day Hamster Sebum Model 21 Day Topical Syrian Hamster Ear Sebaceous Gland Study

% Dermal Gland Size #of Glands Group (n) Oil-Red-O (mM2/section) Per Section Pos. Area

Vehicle (1) 39% 8062 59 0.025% Tretinoin (3) 19 ± 4.0% 5575 ± 1607 52 ± 8.8 0.06% SPG-1/Spiron. 31 ± 5.7% 8580± 2419 40 ± 5.5 (3)

0.1% SPG-3 (3) 28 ± 10% 6978 ± 2362 36 ± 8.3

Data expressed as ave.+/- SD. SPG-3 is safe: No negative health effects were noted w/BID dosing

SPG-3 is effective: Hits target in vivo in the skin.

Reductions in lipid content (10%), gland size (19%) and glands per section (10%) observed.

SPG Therapeutics, Inc. 8 SPG-3 Fits Into An Ideal Product Profile For the Treatment of Hormonally Mediated Hair And Skin Indications Related to HS and PCOS Description Analog of spironolactone that triggers the degradation of the androgen receptor. Medical Need PCOS/HS is treated with oral spironolactone off-label. Causes irregular cycles, headaches, breast tenderness and fetal harm.

Competitive Strong patent protection, unique mechanism, exquisite skin retention, Advantage 2-3 day target inhibition. Low risk profile and wider usage by both sexes. Indications Dermatological issues associated with hidradenitis suppurativa (HS) and Usage and polycystic ovary disease: inflammation, hirsutism, acne and alopecia. Dosage and Daily application to the face and/or the scalp. Administration Clinical SPG-3 effectively penetrates the skin/scalp to trigger cellular AR Pharmacology clearance in a well-tolerated formulation. Toxicology Safety studies in two species to allow for 2-3 month clinical trials and chronic use. Clinical Controlled 2-3 month Phase I/2 trials of 40 woman age 18-49 with Studies hirsutism or HS. 9 Confidential, SPG Therapeutics, Inc. SPG-3 Vellus hair covers the face. It is thin, unpigmented and virtually invisible from a distance. Androgens promote the conversion of facial vellus hair to undesirable terminal hair associated with hirsutism.

Confidential, SPG Therapeutics, Inc. 10 Obtain Clinical Proof-Of-Concept (POC) In Females With Hirsutism; Exit After Phase 1 Planned  Key opinion leaders have indicated that a rapid path for us to obtain POC with SPG-3 is to focus on treating hirsutism in woman.

 Hirsutism trial design is established and non-invasive.

 Focus on hirsutism simplifies recruitment and increases probability of success. Once clinical POC is obtained in hirsutism, pivot to an exit, strategic partnership and/or funding for new indications.

 Increased valuation via pipeline expansion into scalp hair loss in males, HS and acne in both sexes is possible pending clinical proof-of-concept in hirsutism.

SPG Therapeutics, Inc. 11 Vast Opportunities Exist to Treat Hidradenitis Suppurativa (HS) Topically with SPG-3

 HS is virtually incurable, inflammatory skin condition of skin folds affecting an estimated 1% of the population.  Spironolactone can stabilize mild-moderate HS.  ~½ of HS female HS patients can’t take oral spironolactone.  ~½ who do take it benefit.  No approved topical for HS.

12  Mild/moderate HS:  Payers: $1B+ Humira sales Undertreated/undiagnosed. in moderate to severe HS.  Approved: Humira (4xRA Orphan. dose) or surgery, which often is not curative.  Solution: Target mild/moderate HS to  HS specialists want to see a reduce payer costs/arrest topical anti-androgen progression. treatment like SPG-3 to dramatically expand the use  KOL: Streamlined 8 week P1 of anti-androgens in this study. disease.  Endpoints: Stabilize. Reduce flares.

SPG Therapeutics, Inc. 13 Age Rate

The Norwood Scale of Hair Loss

Medical hair restoration is a $1B+ market in North America for men and women.

14 Balding scalp: Follicles of various thickness can be seen. Overall number of follicles is unchanged.

Balding Scalp: AR and DHT are about 2X higher levels in balding scalp vs. non- balding scalp.

15 Proposed Development Strategy and Timelines

2021 2022 2023

IND enabling IND Phase 1: Exit/ Out- Nonclinical Hormonal Derm. licensing development Study Facial Indications

SPG-003 Female Dermatology (Face/Hirsutism)

SPG-003 Female HS/Female Dermatology Inflammatory (Body/Hidradenitis Suppurativa) Derm. Study

SPG-003 Male POC in Male Dermatology Androgenetic (Scalp) Alopecia

SPG Therapeutics, Inc. 16 Three Year Budget To Exit

Cost Estimated Timeline Activity (millions USD) Q3,2020 Incorporation, Fund Raising 0.15

Q4, 2020 Formulation Development 0.15

Q1, 2021 GMP material manufacturing 0.7

Q4, 2020-Q3, 2021 IND Enabling Nonclinical 2.0 Development Q4, 2021 IND Submission 0.2 Q1, 2022-Q4 2022 Phase 1(Safety/POC Hirsutism) 1.0

G&A 0.5 Total Investment Needed 4.7

$500,000 seed round was self-funded.

SPG Therapeutics, Inc. 17 Generic drugs of limited Hidradenitis No topical drug for HS Suppurativa efficacy with poor patient Surgery/Humira

compliance are approved. Androgen Receptor Eliminators (ARE)

Hormonal Androgenetic Surgery/minoxidil/ Acne Alopecia finasteride

Hirsutism Spiron./Winlevi

Devices/Vaniqa $500 Million + Peak Sales Opportunity Per Indication

18  2013 HHS statistics, women between the ages of 18 and 45 make up 36% of the US population.

 7 million and 12 million women are potential candidates for topical SPG-3 to treat hirsutism alone.  10% of those patients: 1 million estimated annual US prescriptions for SPG-3.  Market supports peak annual sales in excess of $500M and does not take into account additional off-label prescriptions or use in HS.

5 Year SPG-3 Revenue Projection 600

400

200 $ MILLIONS$ 0 1 2 3 4 5 Revenue EBITDA

SPG Therapeutics, Inc. 19 COMPARABLE EXITS

Future Upfront Payments Company Product Stage Acquirer/Event Neuvolution ROR gamma inhibitor for 11M EUR 172M EUR+ (2016) skin inflammation Preclinical Almirall/License

Small molecule for Allergan: option for ??? ??? Pelage (2019) alopecia Preclinical 100% stake multi- million ??? Stemson (2019) Alopecia cell therapy Preclinical Allergan/Partnership 2 topical nucleic acids for $25M up to $725M Exicure (2019) alopecia Preclinical Allergan/Partnership JAK 1/3 inhibitor for $8M $90M Rigel (2015) alopecia Preclinical Aclaris $210M DP2 receptor inhibitor for (est.) N/A Kythera (2015) alopecia Phase 1 Allergan

SPG Therapeutics, Inc. 20  CEO/CSO: Zory Shaposhnik, PhD Former Research Program Leader at Kythera Biopharmaceuticals. Contributed to approval for Kybella®, a first-in-class drug for submental fat reduction and developed a first-in-class clinical-stage treatment for androgenetic alopecia (ATX-105).

 IP/Patent Consultant: Richard Hake, PhD/JD Former Chief Patent Counsel, Kythera Biopharmaceuticals. Over 15 years of experience in biotechnology IP management and business development for Elan, Chugai, and P&G.

 Clinical/Regulatory Consultant: Ken Washenik, MD/PhD Bosley Medical Group Medical Director. Former CEO of Aderans Research, a regenerative medicine biotechnology company focused on androgenetic alopecia. Former director of the Dermatopharmacology Unit at the New York University School of Medicine.

 Product Development Consultant: Vern Leibman, MS/MBA Former COO of Aderans Research, a regenerative medicine biotechnology company focused on androgenetic alopecia. Previously VP of R&D and C.R. Bard.

 Medicinal Chemistry/Operations Consultant: Pascal Druzgala, PhD Co-founder and former CSO of ARYx. Senior VP of R&D of Armethon.

SPG Therapeutics, Inc. 21 SPG Therapeutics, Inc.

Disruptive Biology Exceptional Results

SPG Therapeutics, Inc. 22 23 Analog In vivo tox. Formulation development study 24 Androgen Androgen

Androgen Androgen Receptor

Androgen Androgen Receptor Receptor

SPG-ARE ● DHT (androgen) is added to MDA-kb2 cells or primary human keratinocytes.

● DHT binds to the androgen receptor.

● The DHT-receptor complex activates the luciferase gene leading to light production.

● Molecules that interfere with AR signaling are identified by a quantifiable reduction in light signal.

● The compounds are applied to the cells for 24 hrs. Light emission is then measured.

25  Focus on modifying two existing generic drugs (SPG-1/Spiron., SPG-2/Ketoconazole) with known AR antagonist activity.

 Both drugs have documented competitive AR antagonist activity but neither triggers AR protein degradation or is available in a topical formulation.

 SPG-3 and SPG-5, proprietary analogs of these drugs have shown superior activity to their parent compounds using cell based and in vivo assays of AR activity.

26 * *

SPG-1 lead: Max inhibition= 40% vs. 90% for SPG-3 SPG-2 lead: Max inhibition= 40% vs. 80% for SPG-5 *P<0.05 vs. lead compound 27 * *

SPG-1 lead: Max AR Reduction= 35% vs. 71% for SPG-3 SPG-2 lead: Max AR Reduction= 10% vs. 54% for SPG-5 *P<0.05 vs. lead compound

28 MDA-kb2 Cell AR Report Assay Using 0.1nM DHT Maximum Compound IC (M) IC (M) 50 90 Inhibition SPG-001 — — 0% SPG-003 7.89 x 10-7 2.71 x 10-6 95% Cyproterone — — 24% acetate * p-value < 0.05 (T-test) compared to respective control. Cells were treated for 24 hrs with 0.1nM DHT vs. 1nM DHT in prior experiments to better model female skin hormone levels prior to checking on AR activity. Reporter gene expression was still induced 12-fold. AR antagonists SPG-1 and cyproterone showed little to no activity under these conditions. In contrast, SPG-3’s IC50 was 789nM and its IC90 was 2.71uM. Data suggests that SPG-3 is superior to SPG-1 (Spiron.) when hormone levels are more female-like. Additional studies are planned.

Source: Report SR9134

29 Keratinocyte AR Reporter Gene Assay in Primary Human Keratinocytes

24-hr Treatment 72-hr Treatment Maximum Compound Maximum IC (M) IC (M) IC (M) IC (M) Inhibition 50 90 Inhibition 50 90

SPG-1 No S-curve No S-curve 65% 4.51 x 10-6 1.66 x 10-5 85%

-6 -6 -6 93% SPG-3 3.68 x 10 6.96 x 10 91% 2.57 x 10 5.68 x 10-6* SPG-1 lead @24hr treatment: Max AR Reduction= 65% vs. 91% for SPG-3

SPG-1 lead@ 72hr treatment: AR reduction IC90=16.6mM vs. 5.68mM for SPG-3

Cell viability exceeded 97% post SPG-3 treatment. *p<0.05 vs. lead compound Source: Report SR6917

30 Primary Human Keratinocyte AR Reporter Gene Washout Assay Washout Period Niclosamide (0.5 µM) SPG-001 (7.0 µM) SPG-003 (7.0 µM) 0 days 90 ± 0.2%* 67 ± 1.1%* 89 ± 1.0%* 2 days 70 ± 0.9%* 40 ± 2.5%* 64 ± 0.3%* 3 days 58 ± 2.6%* 24 ± 2.3%* 48 ± 2.4%* •p-value < 0.05 (T-test) compared to respective controls. (Veh. vs. SPG-1; SPG-1 vs. SPG-3) •Niclosamide is a positive control. Cells are treated 24 hours prior to washout. AR activity is then checked. SPG-3 retains 54% of max. AR inhibition 3 days post-washout. SPG-1 only retains 35% of max. AR inhibition at this time point.

SPG-3 AR inhibition is sustained in absolute terms to >48% for up to 3 days post-washout on human skin cells.

Source: Report SR6917

31 Human Skin FDC Penetration Assay Donor 1 Donor 2 Assay Run 1 Run 2 Run 1 Run 2 Receptor – 8 hr 0.133 µM 0.086 µM 0.0424 µM 0.035 µM Epidermis/Dermis – 8 hr 89.1 µM 45.1 µM 117.1 µM 67.1 µM SPG-3 formulations FDC Assays: 1% SPG-3 in 30% denatured alcohol, 49% IPM and 20% Transcutol was added to human skin in an FDC assay. 0.1% SPG-3 in EtOH/IPM/PG/Glycerol (90/5/3/2) was added to hamster skin.

An average of 80uM SPG-3 was retained in human epidermis/dermis. An average of 140uM SPG-3 was retained in hamster epidermis/dermis. No SPG-3 was detected in the receptor fluid.

Formulated SPG-3 was stable for 21 days at 4C and room temperature. Formulated SPG-3 was also stable when incubated with mouse skin homogenates for 24 hours at 32C. Source: Report P2017022501R1, P2018042702R2, P2018021516R3

32 21 Day Topical Syrian Hamster Ear Sebaceous Gland Study

% Dermal Gland Size #of Glands Group (n) Oil-Red-O (mM2/section) Per Section Pos. Area

Vehicle (1) 39% 8062 59 0.025% Tretinoin (3) 19 ± 4.0% 5575 ± 1607 52 ± 8.8 0.06% SPG-1/Spiron. 31 ± 5.7% 8580± 2419 40 ± 5.5 (3)

0.1% SPG-3 (3) 28 ± 10% 6978 ± 2362 36 ± 8.3 Data expressed as ave.+/- SD. SPG-1 and SPG-3 in EtOH/IPM/PG/Glycerol (90/5/3/2) were applied to ears BID for 21 days. No negative health effects were noted. Sections were stained for lipid content and gland size. Reductions in lipid content (10%), gland size (19%) and number of glands per section (10%) were noted in SPG-3 vs. spiron. treated skin sections.

33  SPG-3 and SPG-5 are analogs of approved, generic dermatological drugs with no currently available topical formulations.

 SPG-3 and SPG-5 show superior AR antagonist activity by targeted reduction in AR protein levels in primary human keratinocytes.

 Preliminary studies indicate SPG-3 can be formulated into a topical formulation with good tolerability and in vivo activity in a 21 day hamster ear sebum model.

34