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Item 7.01. Regulation FD Disclosure.
On October 12, 2021, Protara Therapeutics, Inc. (the “Company”) issued a press release entitled “Protara Therapeutics Announces FDA Clearance of Investigational New Drug Application for TARA-002 for the Treatment of Non-Muscle Invasive Bladder Cancer,” a copy of which is attached hereto as Exhibit 99.1 to this Current Report on Form 8-K.
The information in this Item 7.01, including Exhibit 99.1, is being furnished pursuant to Item 7.01 of Form 8-K and shall not be deemed “filed” for purposes of Section 18 of the Securities Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall the information be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended or the Exchange Act, whether made before or after the date hereof, except as shall be expressly set forth by specific reference in any such filing.
Item 8.01. Other Events.
On October 12, 2021, the Company made available a Corporate Presentation on the Investor Relations page of the Company’s website, which will be used at investor and other meetings. A copy of the Corporate Presentation is attached hereto as Exhibit 99.2 to this Current Report on Form 8-K and is incorporated herein by reference. The Company does not undertake to update this presentation.
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Item 9.01. Financial Statements and Exhibits.
(d) Exhibits
| Exhibit No. | Description | |
| 99.1 | Press Release dated October 12, 2021, issued by the Registrant. | |
| 99.2 | Protara Therapeutics, Inc. Corporate Presentation, October 2021. | |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document) |
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SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| PROTARA THERAPEUTICS, INC. | ||
| Date: October 12, 2021 | By: | /s/ Blaine Davis |
| Blaine Davis | ||
| Chief Financial Officer | ||
3
Exhibit 99.1
Protara
Therapeutics Announces FDA Clearance of Investigational New Drug Application for
TARA-002 for the Treatment of Non-Muscle Invasive Bladder
Cancer
-- Company Plans to Initiate Phase 1 Study of TARA-002 by Year-End --
-- IND Application Included Submission of Confirmatory Large-Scale
GMP Comparability Data --
New York, October 12, 2021 – Protara Therapeutics, Inc. (Nasdaq: TARA), a clinical-stage company developing transformative therapies for the treatment of cancer and rare diseases, today announced the U.S. Food and Drug Administration (FDA) has cleared the Company’s Investigational New Drug (IND) application for TARA-002, an investigational cell-based therapy being developed for the treatment of non-muscle invasive bladder cancer (NMIBC). Protara expects to initiate a Phase 1 clinical trial of TARA-002 in adults with high-grade NMIBC by the end of 2021.
“We are thrilled to have reached this important milestone and look forward to quickly initiating our Phase 1 study in patients with NMIBC,” said Jesse Shefferman, Chief Executive Officer of Protara Therapeutics. “There is an urgent need for new treatments for NMIBC. We are seeing significant increases in recurrence and disease progression, as well as an escalating number of patients requiring cystectomies. Supported by the strength of the existing clinical data in NMIBC for OK-432, the originator therapy for TARA-002, we believe this treatment represents a promising new option for NMIBC patients.”
The Phase 1 dose-finding, open-label trial will evaluate TARA-002 in treatment-naïve and treatment-experienced NMIBC patients with high-grade carcinoma in situ (CIS) and high-grade papillary tumors (Ta). In the initial dose escalation phase of the trial, patients will receive six weekly intravesical doses of TARA-002. The primary objective of the trial is to evaluate the safety, tolerability and preliminary signs of anti-tumor activity of TARA-002, with the goal of establishing a maximum tolerated dose and recommended dose for a future Phase 2 clinical trial.
TARA-002 is manufactured from the same cell bank as OK-432, an approved therapy in Japan and Taiwan for multiple oncologic indications. In 2020, Protara successfully demonstrated initial manufacturing comparability between TARA-002 and OK-432. The confirmatory, GMP-scale comparability data for TARA-002 in relation to OK-432 have been completed and were reviewed by FDA as part of the clearance of the IND.
About TARA-002
TARA-002 is an investigational cell therapy in development for the treatment of non-muscle invasive bladder cancer and lymphatic malformations (LMs) for which it has been granted Rare Pediatric Disease Designation by the U.S. Food and Drug Administration. TARA-002 was developed from the same master cell bank of genetically distinct group A Streptococcus pyogenes as OK-432, a broad immunopotentiator marketed as Picibanil® in Japan and Taiwan by Chugai Pharmaceutical Co., Ltd. Protara has successfully demonstrated manufacturing comparability between TARA-002 and OK-432.
When TARA-002 is administered, it is hypothesized that innate and adaptive immune cells within the cyst or tumor are activated and produce a strong immune cascade. Neutrophils, monocytes and lymphocytes infiltrate the abnormal cells and various cytokines, including interleukins IL-6, IL-8, IL-12, interferon-gamma (IFN-γ)-, tumor necrosis factor-alpha (TNF-α), and vascular endothelial growth factor (VEGF) are secreted by immune cells to induce a strong local inflammatory reaction and destroy the abnormal cells.
About Non-Muscle Invasive Bladder Cancer
Bladder cancer is the 6th most common cancer in the United States, with NMIBC representing approximately 80% of bladder cancer diagnoses. Approximately 65,000 patients are diagnosed with NMIBC in the United States each year. NMIBC is cancer found in the tissue that lines the inner surface of the bladder that has not spread into the bladder muscle.
About Protara Therapeutics, Inc.
Protara is committed to identifying and advancing transformative therapies for people with cancer and rare diseases with limited treatment options. Protara’s portfolio includes its lead program, TARA-002, an investigational cell-based therapy being developed for the treatment of non-muscle invasive bladder cancer and lymphatic malformations, and IV Choline Chloride, an investigational phospholipid substrate replacement therapy for the treatment of intestinal failure-associated liver disease. For more information, visit www.protaratx.com.
Forward-Looking Statements
Statements contained in this press release regarding matters that are not historical facts are “forward looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Protara may, in some cases, use terms such as “predicts,” “believes,” “potential,” “proposed,” “continue,” “designed,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “will,” “should” or other words or expressions referencing future events, conditions or circumstances that convey uncertainty of future events or outcomes to identify these forward-looking statements. Such forward-looking statements include but are not limited to, statements regarding Protara’s intentions, beliefs, projections, outlook, analyses or current expectations concerning, among other things, Protara’s business strategy, including its development plans for its product candidates and plans regarding the timing or outcome of existing or future non-clinical studies and clinical trials, and statements regarding the anticipated safety or efficacy of Protara’s product candidates. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Factors that contribute to the uncertain nature of the forward-looking statements include: risks and uncertainties associated with: Protara’s development programs, including the initiation and completion of non-clinical studies and clinical trials and the timing of required filings with the FDA and other regulatory agencies; the impact of the COVID-19 pandemic on Protara’s business and the global economy; general market conditions; changes in the competitive landscape; changes in Protara’s strategic and commercial plans; Protara’s ability to obtain sufficient financing to fund its strategic plans and commercialization efforts; having to use cash in ways or on timing other than expected; the impact of market volatility on cash reserves; and the risks and uncertainties associated with Protara’s business and financial condition in general, including the risks and uncertainties described more fully under the caption “Risk Factors” and elsewhere in Protara’s filings and reports with the United States Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on management’s assumptions and estimates as of such date. Protara undertakes no obligation to update any forward-looking statements, whether as a result of the receipt of new information, the occurrence of future events or otherwise, except as required by law.
###
Company Contact:
Justine
O’Malley
Protara Therapeutics
Justine.OMalley@protaratx.com
646-817-2836
Exhibit 99.2
Corporate Presentation October 2021
Forward Looking Statements Statements contained in this presentation regarding matters that are not historical facts are "forward looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Protara may, in some cases, use terms such as “predicts,” “believes,” “potential,” “proposed,” “continue,” “designed,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “will,” “should” or other words or expressions referencing future events, conditions or circumstances that convey uncertainty of future events or outcomes to identify these forward - looking statements. Such forward - looking statements include but are not limited to, statements regarding Protara’s intentions, beliefs, projections, outlook, analyses or current expectations concerning, among other things: Protara’s business strategy, Protara’s manufacturing and development plans for its product candidates and related interactions with the FDA, ex - U.S. development plans, Protara’s financial footing, the impact of the COVID - 19 pandemic and related governmental responses on Protara’s business and clinical programs. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward - looking statements. Factors that contribute to the uncertain nature of the forward - looking statements include: risks that Protara’s sales, revenue, expense and other financial guidance may not be as expected, as well as risks and uncertainties associated with: Protara’s development programs, including the initiation and completion of non - clinical studies and clinical trials and the timing of required filings with the FDA and other regulatory agencies; the impact of the COVID - 19 pandemic on Protara’s business, clinical supply chain, clinical trials, and the global economy; general market conditions; changes in the competitive landscape; changes in Protara’s strategic and commercial plans; Protara’s ability to obtain sufficient financing to fund its strategic plans and commercialization efforts; having to use cash in ways or on timing other than expected; the impact of market volatility on cash reserves; the loss of key members of management; and the risks and uncertainties associated with Protara’s business and financial condition in general, including the risks and uncertainties described more fully under the caption "Risk Factors" and elsewhere in Protara's filings and reports with the United States Securities and Exchange Commission. You are cautioned not to place undue reliance on forward - looking statements, which speak only as of the date on which they were made. Protara undertakes no obligation to update any forward - looking statements, whether as a result of the receipt of new information, the occurrence of future events or otherwise, except as required by law. 2
Lead programs: TARA - 002 in Non - Muscle Invasive Bladder Cancer (NMIBC) and Lymphatic Malformations (LMs) • Cell - based immunopotentiator • FDA confirmed initial comparability to Japanese predecessor OK - 432 • NMIBC: Promising existing clinical data in patients and a proven MOA generally similar to current standard of care; Planning to initiate Phase 1 clinical study by year end • LMs: Current standard of care in Japan; completed Phase 2 study in the U.S. with additional clinical study planned; FDA granted Rare Pediatric Disease Designation Other mid - stage development programs provide diversification and additional growth potential • IV Choline in intestinal failure associated liver disease (IFALD): Completed retrospective study evaluating the prevalence of IFALD in patients dependent on parenteral nutrition • Completed End Of Phase 2 dialogue with FDA and aligned on Phase 3 design Company well funded through anticipated key milestones • $145M of cash, cash equivalents and investments as of June 30, 2021 3 Modernizing and Expediting Development of De - Risked Assets
4 Pipeline Addresses Multiple Indications With High Unmet Need *TARA - 002 Granted Rare Pediatric Disease Designation for the treatment of LMs. OK - 432 Granted Orphan Drug Designation by the U.S. FDA for the treatment of LMs, which we believe is applicable under established comparability. **Granted Orphan Drug and Fast Track Designations by the U.S. FDA † Phase 1 PK study to be conducted prior to commencing Phase 3 Phase 3 Phase 2 Phase 1 I N D C l eared IMMUNOLOGY, ONCOLOGY TARA - 002 – Lyophilized, inactivated Group A Streptococcus Lymphatic Malformations (LMs)* Non - Muscle Invasive Bladder Cancer (NMIBC) HEPATOLOGY, GI, METABOLICS IV Choline Chloride for Injection – Phospholipid Substrate Replacement Intestinal Failure Associated Liver Disease (IFALD)** , † OTHER Vonapanitase – Recombinant Human Type 1 Elastase (phase 1 studies completed in fistula patency and PAD)
T A R A - 002 LYOPHILIZED, INACTIVATED GROUP A STREPTOCOCCUS PYOGENES
6 TARA - 002: Cell - Based Immunopotentiator with Significant Potential ▪ TARA - 002 is an investigational, genetically distinct strain of Streptococcus pyogenes that is inactivated while retaining its immune - stimulating properties ▪ TARA - 002 is manufactured under GMP conditions from the same Master Cell Bank as OK - 432 ( 1 ) , which is approved for a number of oncology indications in Japan ▪ OK - 432 has been studied in many different types of cancer and there are close to 2,000 separate publications for OK - 432 listed in PubMed ▪ Protara has successfully demonstrated GMP - scale manufacturing comparability between TARA - 002 and OK - 432, allowing the extensive data generated by OK - 432 to help support TARA - 002* ▪ Protara has worldwide rights ex - Japan & Taiwan for TARA - 002/OK - 432 *Confirmed by FDA Office of Tissues and Advanced Therapies (OTAT) Division as part of NMIBC IND (1) Marketed in Japan and Taiwan as Picibanil ® . Note: Manufacturing modifications reflect manufacturing to U.S. cGMP standards liv e ce lls inactivated
7 TARA - 002: Mechanism of Anti - Tumor / Anti - Cystic Activity Th1 Like Anti - Tumor Cytokine Response (1) Fujimoto T., et al. J Immunol. 1997: 5619. (2) Ryoma Y, et al. Anticancer Res. 2004; 3295 - 3298. (3) Zhao H, et al. Microbiol. Immunol. 1994; 183 - 190. T N F - α I F N - γ Mult i - C y t ok in e I ndu ce r (1)(2)(3) IL - 2 IL - 6 IL - 8 IL - 10 IL - 12 GM - CSF G - CSF Activated immune cells infiltrate the abnormal cells Abnormal cells are destroyed Immune cells detect TARA - 002 and release inflammatory cytokines Abnormal tissue is exposed to TA R A - 002 TARA - 002 (inactivated S t re p . p y o g e n es )
• Lymphangiomas (Lymphatic Malformations) • Gastric cancer combo with chemo (post - operative) • Primary lung cancer combo with chemo • Reduction of ascites in gastrointestinal cancer • Reduction of pleural effusion in lung cancer • Unresponsive head, neck & thyroid cancer OK - 432: Human Efficacy Data in Multiple Indications 8 OK - 432 has been approved (ex - US) or studied in multiple indications 1. Full Prescribing Information. Chugai Pharmaceuticals. 2016 APPROVED INDICATIONS IN JAPAN 1 • Non - Muscle Invasive Bladder Cancer • Ovarian cancer • Malignant mesothelioma • Pancreatic cancer • Esophageal cancer • Oral squamous cell cancer • Hepa to c e ll u l a r c a n c er • Ranula • Thyroglossal cysts • Pleurodesis • Seroma • Symptomatic lymphocele • Auricular hematoma OK - 432 CLINICAL RESEARCH CONDUCTED IN:
TARA - 002 NON - MUSCLE INVASIVE BLADDER CANCER (NMIBC)
10 TARA - 002 in NMIBC: Profile Supports Potential in NMIBC • ~ 150 NMIBC patients tested with OK - 432 demonstrated promising results ( 2 ) • Treatment generally well tolerated • Elicits Th 1 type response inducing multiple cytokines to produce an anti - tumor effect • Mechanistically similar to the current SOC, Bacille Calmette - Guérin (BCG) (1) Market Research Conducted by Protara Therapeutics (2) Study references available by request Note: OK - 432 is not approved for NMIBC Cell - Based Immunopotentiator with Notable Patient Experience MOA Generally Similar to SOC Ma nu fac t u r ing Advantages Promising Existing Clinical Data Modality Familiar with Physicians • MOA with which urologists are familiar and have been using for decades • Intravesical administration is preferred clinical approach among urologists ( 1 ) • State - of - the - art U.S. manufacturing facility • TARA - 002 manufacturing process supported by 40 years of production history of OK - 432
11 Clinical Evidence of OK - 432 Provides Strong Rationale for Development of TARA - 002 in NMIBC Data across multiple investigator - initiated studies in ~150 NMIBC patients treated intravesically shows that OK - 432: Was generally well - tolerated, with safety and tolerability observed across a range of doses Demonstrated treatment effect and lower rates of recurrence vs. control group, including in the randomized, controlled setting
NMIBC Represents the Most Common Form of Bladder Cancer N M I B C pa t ien t s are treated by a urologist Bladder Cancer in the US NMIBC makes up ~80% of all bladder cancer with ~65,000 diagnosed per year in the U.S. a r e ag e 55+ 9 i n 10 4x more likely to be diagnosed i n m en ( 2) High rate of recurrence with 3 - year rate estimated at up t o 80 % ( 3) Significant increase in recurrence, progression & an escalated number of patients needing cystectomies (5) ( 4) (1) National Cancer Institute. SEER Bladder Cancer – Stat Facts . Accessed February 5, 2021. (2) Saginala, K. et al. Med Sci. 2020. (3) Campbell Walsh 11th edition, Elsevier. (4) Anastasiadis et al. Therapeutic Advances in Urology, 2012. (5) Ourfali, S. et. al. European urology focus, 2019. age 55+ 6 th most prevalent c an ce r i n t he U. S. ( 1) ( 1) 12
13 TARA - 002 in NMIBC: Target Patient Population NMIBC is categorized and treated based on risk stratification, determined by combination of tumor grade, stage, size, recurrence history and focality Treatment goal is to prevent: 1. Progression 2. Cystectomy 3. Recurrence 1. National Cancer Institute, SEER Cancer Stat Facts: Bladder Cancer, 2019. 2. Anastasiadis et al. Therapeutic Advances in Urology, 2012. 3. Market Research Conducted by Protara Therapeutics NMIBC, non - muscle invasive bladder cancer. 80 , 000 65 , 000 Patients diagnosed with bladder cancer annually 1 Patients with NMIBC 2 ~30,000 Initial target patient population: Patients with high grade NMIBC who are candidates for immunotherapy 1 - 3
TARA - 002 in NMIBC: Phase 1a/1b Study Design 1 Subjects will receive weekly intravesical doses of TARA - 002 instillation for 6 weeks 2 Defined as not previously treated with or unable to access BCG. 3 Defined as disease present at last cystoscopic evaluation during the dose expansion phase. Definitions: BCG, bacillus Calmette - Guérin; HGCIS, high - grade carcinoma in situ; HGTa, high - grade Ta; KE, Klinische Einheit; MTD, maximum tolerated dose; RP2D, recommended phase 2 dose; TURBT, trans urethral resection of bladder tumor. Phase 1 Phase 1a: Dose Escalation 1 Phase 1b: Expansion Cohort 1 Enroll NMIBC HGCIS or HGTa in pa t i e n t s p r e v io u s ly treated or unable to access BCG (BCG - naïve 2 ) N = 9 – 18 patients 10 KE 20 KE 40 KE 3+3 Dose Es c a l a t i o n De s i g n • Evaluate safety, tolerability and preliminary signs of anti - tumor activity of TARA - 002 and establish MTD and RP2D for Phase 2 study • Further assess safety and preliminary signs of anti - tumor activity of TARA - 002 at the established RP2D Dose finding, open - label study evaluating intravesical TARA - 002 in adults with high - grade NMIBC Enroll RP2D NMIBC HGCIS active disease 3 N = 12 patients* * Subjects enrolled in the dose expansion phase will not include subjects previously enrolled and treated in the dose escalation phase
TARA - 002 LYMPHATIC MALFORMATIONS (LM S )
16 TARA - 002 in LMs Lymphatic Malformations Rare, non - malignant lesions consisting of dilated, lymphatic fluid - filled sacs caused by abnormal development of the lymphatic endothelial system (1) Epidemiology Epidemiology: incidence of lymphatic malformations is ≈1,400 - 1,800 LM cases per year (2) Current Treatment Options Current treatment options include surgical excision with high complication (33%) and recurrence (55%) rates (3) as well as off - label use of sclerosants FDA Granted Pediatric Rare Disease Designation Majority of LMs present at birth (65 - 75%) or by age 3 (80 - 90%) during active lymphatic growth period (3) (1) Brouillard P, et al. J Clin Invest. 2014;124:898 - 904. (2) Internal company estimates (3) Ha J, et al. Curr Ped Rev. 2014;10:238 - 248.
Before A f t e r 17 OK - 432 in LMs: Clear Evidence of Biologic Activity in Patients Before A f t e r Completed Phase 2 study of OK - 432 in U.S. provides evidence of treatment effect with support for strong safety profile Protara Therapeutics data on file
IV CHOLINE CHLORIDE INTESTINAL FAILURE ASSOCIATED LIVER DISEASE (IFALD)
19 IV Choline in IFALD: Late - stage Opportunity for an Unmet Medical Need Clinical History Supporting Choline Substrate Replacement in Patients with IFALD A Phase 2 study demonstrated the clinical potential of choline substrate replacement therapy by reversing certain hallmark pathologies of IFALD 1 Strong Market Opportunity with Potential to Expand Addressable Patients Prevalence of patients on PN 79/million 2 ; recent Medicare diagnosis data suggests ≈ 5,000 IFALD patients 3 Clear Regulatory and Clinical Path Forward Received Orphan Drug and Fast Track Designations from FDA. Positive End of Phase 2 meeting with FDA requesting Phase 1 PK study and Phase 3 trial to complete registrational package An Essential Molecule in Several Metabolic Processes Patients dependent on PN cannot absorb sufficient levels of choline. Data confirms that choline deficient diets results in steatosis and cholestasis. 1 There are currently no approved PN treatments that offer sufficient choline 1. Buchman A, et al. JPEN . 2001;5:260 - 268. 2. Mundi M, et al. ASEPN . 2017;32:799 - 805. 3. Internal Protara market research. IFALD, intestinal failure associated liver disease; IV, intravenous; PK, pharmacokinetic; PN, parenteral nutrition. H 3 C OH H 3 C C H 3 N +
20 IV Choline in IFALD: Prevalence Study Prevalence study to enhance understanding of the patient population DESIGN Retrospective, observational study of patients in both academic & community settings POPULATION Patients dependent on PN for 6 or more months OBJECTIVE • Understand the incidence of cholestasis, a hallmark pathology of IFALD in this patient population • Measuring serum alkaline phosphatase (ALP) levels greater than 1.5 times the upper limit of normal (ULN) as a key marker of cholestasis RESULTS • ~31% of all patients, irrespective of baseline levels, presented with ALP levels greater than 1.5 times the ULN at any given time during 6 to 36 months. • ~28% of all patients had persistent ALP elevations greater than 1.5 times the ULN at 36 months. • At baseline, ~23% of patients presented with ALP levels greater than 1.5 times the ULN with ~76% presenting with greater than 1.5 times the ULN at any given time during 6 to 36 months and ~59% with persistent ALP elevations greater than 1.5 times the ULN at 36 months. • While medical management demonstrated some improvement in ALP levels, it was not sufficient for managing ALP levels over the long term in patients on PN. • Results support further exploration in patient population to determine rates of choline deficiency & steatosis. NEXT STEPS Prospective observational study under way to further characterize the prevalence of choline deficiency, as well as cholestasis and steatosis, in ~300 patients dependent on PN
IV Choline in IFALD : Phase 2 Results 21 CHOLESTASIS IMPROVEMENT: ALL PATIENTS* (1) CLINICALLY MEANINGFUL IMPROVEMENT IN STEATOSIS At Baseline After 24 Weeks * Mi x e d mo d e l for r e p e a t e d m e asur e m en t ( MM R M) m e t h od us ed ǂ A placebo subject was excluded from all analyses due to likely IV contrast - induced imaging abnormalities, confirmed by independent radiologist n=14 ǂ (7 active; 7pbo) (1) Protara Therapeutics re - analysis of patient CRF’s, data on file Improvement in Steatosis and Cholestasis
S u mm ary
Building Momentum in 2021 23 NMIBC: Significant Market Potential 2H’21: File IND with GMP scale confirmatory comparability data • Year - End 2021: Initiate Phase 1 study IV Choline: Late - Stage Pipeline Opportunity • 2H’21: Complete retrospective prevalence study to better characterize the unmet need in IFALD Solid Financial Position • $145M of cash, cash equivalents and investments as of June 30, 2021 • 19.2M Common Share Equivalents:11.2M Common + 8.0M Preferred on as - converted basis as of June 30, 2021 LMs: Rare Disease Opportunity • 2H’21: Update IND with GMP scale confirmatory comparability data • 2H’21: Engage FDA on design of additional clinical study
Corporate Presentation October 2021
Appendix
Current Standard of Care Highlights High Unmet Need for Patients 26 Primary care / PCP Uro l ogist Medical Oncologist I n i t i al P r esen t a t i on Referral & Testing High Grade TURBT Treatment Recurrence R epeat T URBT Present to PCP : • Blood in urine • B ladder irritation Urologist tests : • CT scan • Cytology • C y s to sc opy Diagnose, S tage & Grade Pr esc r ibe BCG I V T r e a t m e n t Transfer to M edical O ncologist • C he ck point inhibitors Cystectomy Bladder Removal I n t r av e si c a l Agents Experimental Agents in Development Under Urologist Care Up to 8/10 r ec u r i n 3 years 1 (1) Campbell Walsh 11th edition, Elsevier.
27 BCG Shortage Causes Significant Impact on Care Shortage has prompted major urological associations to issue guidan c e o n pati e nt m anag eme nt (1) “…remain extremely concerned about this shortage and its effects on the care of bladder cancer patients…” - Joint Statement on BCG Shortage, Feb 2019 “I see patients every week whose treatment decisions are affected by the BCG shortage …sometimes I just recommend moving patients more quickly to cystectomy because we don’t have any better options available. ” - Academic Hospital Urologist Dose rationing and resorting to less desirable treatment options are impacting patient care (2) BCG shortages begin after Sanofi lab is shut down due to mold infractions Sanofi production of B CG r e s um es Merck announces anticipated BCG supply constraints despite expanding capacity 201 2 202 0 201 3 201 4 201 5 2016 2017 Sanofi announces discontinuation of TheraCys BCG; Merck becomes sole US provider of BCG Merck announces shortages of Tice strain of BCG = BCG Shortage 2018 2019 US Urologists are continuing to ration BCG doses and adjust treatment decisions due to shortage Merck announces plans to construct new facility to expand BCG manufacturing. Facility could take 5 - 6 years to construct. (1) AUA/SUO Joint Guideline: Published 2016; Amended 2020 (2) Market Research Conducted by Protara Therapeutics
28 OK - 432 in LMs: Robust Results of Completed Phase 2 Study (1) in U.S. ITT: Observations 6 Months After Enrollment 69% 7 . 5% Immediate Treatment Group (N=110) Delayed Treatment Group Pre - Treatment** (N=40) 69% CLINICAL SUCCESS ǂ IN IMMEDIATE TREATMENT GROUP 6 MONTHS AFTER ENROLLMENT • Patients with radiographically confirmed macrocystic lesions had the greatest chance for clinical success • In those patients with mixed lesions, clinical success was still achieved 84% * CLINICAL SUCCESS ǂ IN PATIENTS WITH MACROCYSTIC LESION TYPES ǂ Clinical Success was defined as complete or substantial response *Reflects data prior to dosing with OK - 432. After dosing, the clinical success rate was 66%, which was not statistically different from the Immediate Treatment Group **Results were analyzed by lesion type across all treatment groups (1) Results based on retrospective analysis of source verified data that included the full dataset of subjects enrolled in the P2 randomized study between January 1998 and August 2005, including data in the published study (Smith et al. 2009) which included subjects enrolled between January 1998 and November 2004. • During this same period, 7.5% of patients in the delayed treatment group experienced spontaneous regression of LM • Treatment: 1 - 4 injections at 8 - week intervals max of 0.2mg/session (2KE) P < 0.0001 62% 28% 0% 22% 32% Macrocystic Lymphangiomas (n=77) Mixed (n=47) Microcystic Lymphangiomas (n=14) Complete or Substantial Response by Radiographically Confirmed Lesion Type** Complete Response Substantial Response 84% 60%
*Results based on retrospective analysis of source verified data that included the full dataset of subjects enrolled in the P2 randomized study between January 1998 and August 2005, including data in the published study (Smith et al. 2009) which included subjects enrolled between January 1998 and November 2004. Safety Profile* ▪ Most common AEs with treatment were local injection site reactions, fever, fatigue, decreased appetite, with resolution within two weeks ▪ Treatment emergent SAEs related to OK - 432: reported in 4.1% of patients, with the most severe events being airway obstruction and facial paralysis due to massive swelling post - injection that required tracheostomy and hospitalization. Both of these events were reported as resolved. ▪ One SAE related to OK - 432 led to discontinuation: Proptosis of the eye ▪ One SAE not related to OK - 432 led to death: Death due to tracheotomy tube obstruction OK - 432 in LMs: Compelling Safety Record 29
IV Choline in IFALD: Informative Clinical History A significant body of supportive evidence across 4 studies 1992 - Oral Lecithin Study (1) n=15 PN patients Lecithin did not achieve physiologic levels ; however did reduce steatosis with moderate ALP* improvement 1994 - IV PK Study (2) n=4 PN patients 1st continuous exposure to IV choline, established safety and 2g dose 1995 - IV Pilot Study (3) n=4 PN patients IV Choline replacement reversed steatosis, improved other measures of hepatobiliary injury 2001 - IV Phase 2 RCT (4) n=15 PN patients 2g dose confirmed, reversal of steatosis, improvement in cholestasis (reduction of ALP*) 1) Buchman A, et al. Gastroenterology. 1992;102:1363 - 1370. 2) Buchman A, et al. Clin Pharmacol Ther. 1994;55:277 - 283. 3) Buchman A, et al. Hepatol. 1995;22:1399 - 1403. 4) Buchman A, et al. JPEN. 2001;5:260 - 268. 30 * ALP=Alkaline phosphatase
IV CHOLINE REPLACEMENT PROOF OF CONCEPT STUDY 1 Study Design Randomized Double - blind Phase 2 Trial Subjects 15 (9 per protocol) Age >16 years old PN Requirement Greater than 80% of all nutrient requirements supplied by PN Randomization 1:1 Usual PN or PN + 2g IV choline/day D u r ati on of Treatment 24 Weeks Visits Weeks 2,4,6,12,16, 20, 24 Follow up Week 34 Dose 2g Choline Chloride QD in PN solution ▪ The IV Choline Chloride replacement POC, randomized study did not have pre - specified endpoints ▪ The primary objective of the study was to determine if IV Choline Chloride substrate replacement would reverse hepatic steatosis and improve liver function in patients receiving long - term PN Randomized, Controlled Study Design & Objective IV Choline in IFALD: Multi - Center Phase 2a POC Study 31 1. Buchman A, et al. JPEN . 2001;5:260 - 268. IFALD, intestinal failure associated liver disease; IV, intravenous ; POC, proof of concept; PN, parenteral nutrition; QD, once a day.