UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): April 21, 2020
APPLIED THERAPEUTICS, INC.
(Exact name of registrant as specified in its charter)
| Delaware | 001-38898 | 81-3405262 | ||
| (State or Other Jurisdiction of Incorporation) |
(Commission File Number) | (I.R.S. Employer Identification No.) |
| 545 5th Avenue, Suite 1400 New York, NY 10017 |
10017 | |
| (Address of Principal Executive Offices) | (Zip Code) |
Registrant’s telephone number, including area code: (212) 220-9226
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
| ¨ | Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
| ¨ | Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) |
| ¨ | Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) |
| ¨ | Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company x
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. x
Securities registered pursuant to Section 12(b) of the Act:
| Title of each class | Trading Symbol(s) | Name of each exchange on which registered | ||
| Common stock | APLT | The Nasdaq Stock Market LLC |
Item 7.01. Regulation FD Disclosure.
On April 21, 2020, Applied Therapeutics, Inc. (the “Company”) issued a press release announcing that the Company will present data from the pivotal ACTION-Galactosemia study via webcast. This data was originally planned for the Society of Inherited Metabolic Diseases (which was cancelled due to Covid-19). The Company’s presentation will be on Tuesday April 21, 2020 at 8:00am ET. A copy of this press release is attached as exhibit 99.1 hereto.
During the webcast, a corporate slide presentation will be presented. A copy of the Company’s presentation slide deck, which will be referenced during the conference, including during the Company’s webcast presentation, is furnished herewith as Exhibit 99.2.
The information provided under this Item (including Exhibits 99.1 and 99.2, attached hereto) shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934 or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, except as expressly set forth by specific reference in such a filing.
Item 8.01. Other Events.
On April 21, 2020, the Company provided the following updates regarding its clinical trials and business operations in light of the ongoing novel coronavirus (Covid-19) pandemic:
| · | The Company has taken steps in line with guidance from the U.S. Centers for Disease Control and Prevention (CDC) and the State of New York to protect the health and safety of its employees and the community. In particular, the Company has implemented a work-from-home policy for all employees and has restricted on-site activities to certain chemical, manufacturing and control (CMC) and clinical trial activities. The Company is continuing to assess the impact of the Covid-19 pandemic to best mitigate risk and continue the operations of its business. | |
| · | The Company is working closely with its clinical sites to monitor the potential impact of the evolving Covid-19 pandemic. The Company remains committed to its clinical programs and development plans. As of now, the Company has not experienced any significant delays to its ongoing or planned clinical trials. Notwithstanding the Company’s current expected timing and milestones, the ability to continue to enroll patients, conduct patient follow-up and provide data readouts as planned may be impacted by the Covid-19 pandemic and is subject to rapid change as events proceed. | |
| · | A COVID-19 Investigational New Drug Application (IND) has been opened with the Food and Drug Administration (FDA) for AT-001, a novel potent Aldose Reductase inhibitor in global Phase 3 development for Diabetic Cardiomyopathy. Multiple AT-001 investigator-initiated trials are currently underway to address acute lung inflammation and cardiomyopathy in critical COVID-19 patients. Several New York City hospitals have initiated Emergency Investigational Drug applications for AT-001 use in critical COVID-19 patients. AT-001 is currently being accessed in these New York City hospitals via “Named Patient” Emergency INDs or Investigator-Initiated Trials, depending on the patient circumstance and hospital institution. Institutions that have initiated trials include Mount Sinai, NYU, and Columbia. Data is being gathered through these studies on the effect of AT-001 therapy in critical COVID-19 patients. Depending on the outcome of such studies, the Company may initiate a limited cost-effective company-sponsored study of AT-001 in critical COVID-19 patients. | |
| · | The Company continues to characterize AT-007’s long-term safety in adult patients for the treatment of Galactosemia and to evaluate a potential pediatric trial. The Company has not experienced any meaningful delays in treatment or evaluations of patients in connection with this study. Many of the activities on the AT-007 program have been converted to home health visits. | |
| · | The Company is also continuing with its Phase 3 registrational trial for AT-001 in diabetic cardiomyopathy and has experienced some delays in patient enrollment for this trial, particularly in study sites associated with hospitals. The Company is taking actions to mitigate the impact of these delays on the timeline for the study, including adding additional study sites globally. |
In addition, in light of recent developments relating to the Covid-19 pandemic, the Company is amending and restating the risk factor titled “Our business may be adversely affected by the recent coronavirus outbreak” previously disclosed in Part I., Item 1A. of its Annual Report on Form 10-K for the fiscal year ended December 31, 2019, filed with the Securities and Exchange Commission on March 13, 2020, as follows:
Our business may be adversely affected by the recent coronavirus outbreak.
In December 2019, a novel strain of coronavirus, referred to as 2019-ncov, Covid-19 coronavirus epidemic, or Covid-19, was reported to have surfaced in Wuhan, China. Covid-19 has since spread globally, including the United States where we have our executive offices and principal operations. Infections and deaths related to Covid-19 have disrupted the United States’ healthcare and healthcare regulatory systems. Such disruptions could divert healthcare resources away from, or materially delay FDA approval with respect to, our clinical trials. It is unknown how long these disruptions could continue. In addition, other known and unknown factors caused by Covid-19 could materially delay our clinical trials, including our ability to recruit and retain patients and principal investigators and site staff who, as healthcare providers, may have heightened exposure to Covid-19. For example, with respect to our trials related to AT-001 for the treatment of Diabetic Cardiomyopathy, we have experienced delays in patient enrollment. Though we have undergone efforts to mitigate such delays, such efforts may not entirely avoid the effects of Covid-19 on our trials. Furthermore, we may experience additional delays in patient enrollment that we may not be able to mitigate. In addition, we have partnered with clinical research organizations, or CROs, to conduct clinical studies in jurisdictions, such as the EU, that have been affected by the spread of Covid-19. There is a possibility that such CROs may become unavailable or that the clinical trials they manage may be delayed due to Covid-19 or containment efforts associated with it. Such events may lead to termination of our relationship with affected CROs, affecting the development and study of our product candidates. Any elongation or de-prioritization of our clinical trials or delay in regulatory review resulting from such disruptions could materially affect the development and study of our product candidates, and increase the costs related to such development.
Government response to Covid-19 may also materially impact our business. Our executive offices and principal operations are located in New York and are currently subject to a statewide stay-at-home order. In addition, many of our potential partners and study participants worldwide are similarly impacted. In response, we have implemented a work-from-home policy for all employees and have restricted on-site activities to certain chemical, manufacturing and control (CMC) and clinical trial activities. However, many of our clinical trials sites and certain of our vendors, including our third-party contract manufactures, currently rely on exemptions from stay-at-home, shelter-in-place or similar orders for certain operations. Any of the applicable exemptions may be curtailed or revoked, which would further adversely impact our business.
In addition, we have in the past and may in the future source equipment and materials from China and other countries affected by Covid-19. If we were to engage with third party manufacturers in such countries in the future, there would be an increased risk of supply interruption, resulting in business/operational disruption. Covid-19’s spread, which has caused a broad impact globally, such as restrictions on travel and quarantine policies put into place by businesses and governments, may materially affect us economically. While the potential long-term economic impact of the Covid-19 pandemic may be difficult to assess or predict, there has already been a significant disruption of the global financial markets and the world economy, including the United States economy. A prolonged recession or market correction resulting from the spread of Covid-19 could materially affect our business and the value of our common stock, and reduce our ability to access capital, which could in the future negatively affect our liquidity.
While it is too early to tell whether Covid-19 will have a material effect on our business over time, we continue to monitor the situation as it unfolds. The extent to which Covid-19 impacts our results will depend on many factors and future developments, including new information about Covid-19 and any new government regulations which may emerge to contain the virus, among others.
This Form 8-K contains “forward-looking statements” that involve substantial risks and uncertainties for purposes of the safe harbor provided by the Private Securities Litigation Reform Act of 1995. Any statements, other than statements of historical fact, included herein regarding strategy, future operations, prospects, plans and objectives of management, including words such as “may,” “will,” “expect,” “anticipate,” “plan,” “intend,” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are forward-looking statements. These include, without limitation, statements regarding (i) the design, scope and results of our clinical trials, (ii) the timing of the initiation and completion of our clinical trials, including that the Company may initiate a limited cost-effective company-sponsored study of AT-001 in critical COVID-19 patients, (iii) the likelihood that data from our clinical trials will support future development of our product candidates, (iv) the likelihood of obtaining regulatory approval of our product candidates and qualifying for any special designations, such as orphan drug designation, (v) our cash runway and the timing of our clinical development plan and (vi) the impact of the COVID-19 pandemic on the timing and progress of our ongoing clinical trials and our business in general. Forward-looking statements in this Form 8-K involve substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by the forward-looking statements, and we, therefore cannot assure you that our plans, intentions, expectations or strategies will be attained or achieved. Such risks and uncertainties include, without limitation, the uncertainties inherent in the initiation, execution and completion of clinical trials, in the timing of availability of trial data, in the results of the clinical trials, in the actions of regulatory agencies, in the commercialization and acceptance of new therapies as well as the impact of the COVID-19 pandemic on these plans and expectations. Factors that may cause actual results to differ from those expressed or implied in the forward-looking statements in this Form 8-K are discussed in our filings with the U.S. Securities and Exchange Commission, including the “Risk Factors” contained therein. Except as otherwise required by law, we disclaim any intention or obligation to update or revise any forward-looking statements, which speak only as of the date they were made, whether as a result of new information, future events or circumstances or otherwise.
Item 9.01. Financial Statements and Exhibits.
(d) Exhibits:
The following exhibits are attached with this current report on Form 8-K:
|
Exhibit |
Description | |
| 99.1 | Press Release, dated April 21, 2020. | |
| 99.2 | Copy of Applied Therapeutics, Inc. slide presentation dated April 2020 | |
SIGNATURE
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.
| APPLIED THERAPEUTICS, INC. | ||
| Dated: April 21, 2020 | By: | /s/ Shoshana Shendelman |
| Name: | Shoshana Shendelman, Ph.D. | |
| Title: | Chief Executive Officer | |
Exhibit 99.1
Applied Therapeutics Announces Full Data and Scientific Presentations from the Pivotal Phase 2 ACTION-Galactosemia Trial
AT-007 demonstrated rapid and sustained reduction in toxic galactitol levels with no accompanying increase in galactose
Positive trend on MRI outcomes, including indirect measures of edema, neuronal health and brain galactitol levels in AT-007-treated patients
40 mg/kg dose of AT-007 was well-tolerated with no drug-related adverse events reported in healthy volunteers; evaluation of 40 mg/kg dose in Galactosemia patients remains ongoing
NEW YORK, April 21, 2020 - Applied Therapeutics, Inc. (Nasdaq: APLT), a clinical-stage biopharmaceutical company developing a pipeline of novel drug candidates against validated molecular targets in indications of high unmet medical need, today announced new data and scientific presentations from the pivotal Phase 2 ACTION-Galactosemia trial. The full study data, originally planned to be presented at the Society for Inherited Metabolic Disorders conference this week, will be available on the company’s website.
| · | Slides from the presentation “Development of AT-007 for the treatment of Galactosemia”, presented by Riccardo Perfetti, MD, PhD, Chief Medical Officer of Applied Therapeutics, will be made available today, April 21, at 8:00 a.m. EDT on the Events page under the Investor Relations section of the Applied Therapeutics website at www.appliedtherapeutics.com. Key data from the presentation are summarized below. |
| · | A Galactosemia Educational Symposium for healthcare providers hosted by Applied Therapeutics will be webcast with a live Q&A moderated by Eva Morava, MD, PhD, Professor of Clinical Genomics, Mayo Clinic, on April 27 at 1:00 p.m. EDT. The live event will be available on the Presentations & Publications section of the Applied Therapeutics website at www.appliedtherapeutics.com. A replay of the call will be available on the Applied Therapeutics website approximately two hours after the completion of the call and will be archived for 30 days. |
The double-blind placebo-controlled ACTION-Galactosemia trial evaluated safety and pharmacokinetics of AT-007, a Central Nervous System (CNS) penetrant Aldose Reductase Inhibitor (ARI) in healthy volunteers, as well as safety, pharmacokinetics, and efficacy biomarkers in adult Galactosemia patients. The key biomarker outcome of the study was reduction in galactitol, an aberrant toxic metabolite of galactose, formed by Aldose Reductase in Galactosemia patients. Accumulation of galactitol causes long-term complications ranging from CNS dysfunction to cataracts.
“We are pleased to share the full results of ACTION-Galactosemia,” said Riccardo Perfetti, MD, PhD, Chief Medical Officer of Applied Therapeutics. “Patients with this devastating disease experience life-long accumulation of galactitol in the CNS and in other tissues, and our data demonstrates rapid and sustained reduction in this toxic metabolite.”
“We remain steadfast in our commitment to bring this treatment to patients as quickly as possible, and understand the urgency to potentially prevent worsening of disease in adults and onset of disease-related complications in children,” said Shoshana Shendelman, PhD, Founder and CEO of Applied Therapeutics. “We look forward to initiating a pediatric study in Q2 and remain on track to submit an NDA later this year.”
Galactitol Reduction
As previously announced, once-daily 20mg/kg AT-007 reduced galactitol levels by approximately 50% in Galactosemia patients. Reduction in galactitol levels was rapid (within 6 days of consecutive AT-007 treatment) and sustained throughout the treatment period of 27 days. Reduction in galactitol from baseline was statistically significant at the 20mg/kg vs placebo (p<0.01). The lower dose tested, 5mg/kg, demonstrated a similar trend in reducing galactitol levels approximately 20% from baseline (p=NS from placebo).
Other Galactose Metabolites
Reduction in galactitol was not accompanied by any increase in galactose. This data confirms that reduction of the toxic metabolite galactitol through Aldose Reductase inhibition does not result in derangement of other metabolites in the galactose pathway as previously demonstrated in animal models of Galactosemia.
MRI/MRS Data
Patients treated with AT-007 (once-daily over 27 days) demonstrated a positive trend in MRI outcomes, specifically on measures of edema and overall neuronal health. AT-007 treated patients demonstrated improvement in ventricular volume, a measure of edema, which has been shown to occur in the brain of Galactosemia patients due to osmotic dysregulation caused by galactitol. Patients treated with AT-007 also demonstrated improvements in N-acetyl-aspartate, a marker of neuronal health. Galactitol was visible on MRI in the brain of all patients at baseline, and a positive trend toward decreased brain galactitol levels in AT-007 treated patients was observed by quantitative MR Spectroscopy (MRS).
40mg/kg Data
As no drug-related adverse events were seen at the once-daily 20mg/kg dose, a once-daily 40mg/kg dose was subsequently studied in healthy volunteers and is ongoing in Galactosemia patients. The 40mg/kg dose was safe and well tolerated. Evaluation of once-daily 40mg/kg AT-007 in Galactosemia patients remains ongoing and this data will be shared when available.
Safety
No drug-related adverse events were reported at any dose of AT-007 in ACTION-Galactosemia. This robust safety data includes all 80 healthy volunteers and 8 adult Galactosemia patients who received active drug during the core study.
Future Development
A 90-day safety extension study for ACTION-Galactosemia is ongoing. The extension study is open to patients from the core study and to new adult Galactosemia patients. A pediatric study with a safety and biomarker design similar to ACTION-Galactosemia is planned to commence in Q2 of this year. Both the extension study and the pediatric study are designed to incorporate primarily home health visits in order to limit travel and risk of exposure to COVID-19. More information on the pediatric study will be shared in coming weeks.
About Applied Therapeutics
Applied Therapeutics is a clinical-stage biopharmaceutical company developing a pipeline of novel drug candidates against validated molecular targets in indications of high unmet medical need. The Company’s lead drug candidate, AT-007, is a novel central nervous system penetrant aldose reductase inhibitor (ARI) for the treatment of Galactosemia, a rare pediatric metabolic disease. The Company initiated a Phase 1/2 clinical trial in June 2019 and read out positive top-line biomarker data in adult Galactosemia patients in January of 2020. The Company is also developing AT-001, a novel potent ARI that is being developed for the treatment of Diabetic Cardiomyopathy, or DbCM, a fatal fibrosis of the heart. The Company initiated a Phase 3 registrational study in DbCM in September 2019. The preclinical pipeline also includes AT-003, an ARI designed to cross through the back of the eye when dosed orally, for the treatment of diabetic retinopathy, expected to advance into a Phase 1 study in 2020, as well as novel dual PI3k inhibitors in preclinical development for orphan oncology indications.
Forward-Looking Statements
This press release contains “forward-looking statements” that involve substantial risks and uncertainties for purposes of the safe harbor provided by the Private Securities Litigation Reform Act of 1995. Any statements, other than statements of historical fact, included in this press release regarding strategy, future operations, prospects, plans and objectives of management, including words such as “may,” “will,” “expect,” “anticipate,” “plan,” “intend,” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are forward-looking statements. These include, without limitation, statements regarding (i) our plan to move quickly towards regulatory filing following our pivotal Phase 2 ACTION-Galactosemia study, while preparing for Galactosemia commercial launch and growing our organization, (ii) the design, scope and results of our clinical trials, (iii) the timing of the initiation and completion of our clinical trials, (iv) the likelihood that data from our clinical trials will support future development of our product candidates, and (v) the likelihood of obtaining regulatory approval of our product candidates and qualifying for any special designations, such as orphan drug designation. Forward-looking statements in this release involve substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by the forward-looking statements, and we, therefore cannot assure you that our plans, intentions, expectations or strategies will be attained or achieved. Such risks and uncertainties include, without limitation, (i) our plans to develop and commercialize our product candidates, (ii) the initiation, timing, progress and results of our current and future preclinical studies and clinical trials and our research and development programs, (iii) our ability to take advantage of expedited regulatory pathways for any of our product candidates, (iv) our estimates regarding expenses, future revenue, capital requirements and needs for additional financing, (v) our ability to successfully acquire or license additional product candidates on reasonable terms, (vi) our ability to maintain and establish collaborations or obtain additional funding, (vii) our ability to obtain regulatory approval of our current and future product candidates, (viii) our expectations regarding the potential market size and the rate and degree of market acceptance of such product candidates, (ix) our ability to fund our working capital requirements and expectations regarding the sufficiency of our capital resources, (x) the implementation of our business model and strategic plans for our business and product candidates, (xi) our intellectual property position and the duration of our patent rights, (xii) developments or disputes concerning our intellectual property or other proprietary rights, (xiii) our expectations regarding government and third-party payor coverage and reimbursement, (xiv) our ability to compete in the markets we serve, (xv) the impact of government laws and regulations and liabilities thereunder, (xvi) developments relating to our competitors and our industry, (xvii) the impact of the COVID-19 pandemic on the timing and progress of our ongoing clinical trials and our business in general and (xviii) other factors that may impact our financial results. In light of the significant uncertainties in these forward-looking statements, you should not rely upon forward-looking statements as predictions of future events. Although we believe that we have a reasonable basis for each forward-looking statement contained in this press release, we cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward-looking statements will be achieved or occur at all. Factors that may cause actual results to differ from those expressed or implied in the forward-looking statements in this press release are discussed in our filings with the U.S. Securities and Exchange Commission, including the “Risk Factors” contained therein. Except as otherwise required by law, we disclaim any intention or obligation to update or revise any forward-looking statements, which speak only as of the date they were made, whether as a result of new information, future events or circumstances or otherwise.
Contacts
Investors:
Maeve Conneighton
(212) 600-1902 or
appliedtherapeutics@argotpartners.com
Media:
Trammy Lai
917.297.5956
media@appliedtherapeutics.com
Exhibit 99.2
ACTION - GALACTOSEMIA: April 2020 Trial Results Development of AT - 007 for the Treatment of Galactosemia Riccardo Perfetti , MD, PhD Chief Medical Officer
Summary: ACTION - Galactosemia Study Results 2 Safety/ PK/ PD • AT - 007 was safe and well - tolerated • PK/PD data supports once - daily oral dosing • AT - 007 is CNS penetrant – important in Galactosemia, which includes significant CNS clinical presentation Efficacy in Galactosemia Patients • AT - 007 induced rapid and sustained reduction in plasma galactitol, an aberrant, toxic metabolite formed in Galactosemia patients • 20mg/kg dosing resulted ~50% reduction in plasma galactitol (p <0.01 vs. placebo) • Positive AT - 007 MRI/MRS impact
Overview of Galactosemia
AT - 007 for Treatment of Galactosemia • Rare genetic metabolic disease caused by inability to break down galactose • Galactose is a natural sugar formed by metabolism of lactose, but is also produced endogenously by the body • In patients with Galactosemia, Aldose Reductase converts galactose to galactitol, an aberrant toxic metabolite • Mandatory newborn screening and initiation of dairy free diet • Dietary restriction prevents fatalities, but does not prevent long term consequences of disease • No approved therapies Pathogenesis of Disease Standard of Care 4
Galactosemia Clinical Presentation • Hepatic and renal failure • Brain swelling (edema; encephalopathy) • Potentially life threatening if not identified and managed immediatel y 5 Acute Newborn • CNS complications • Low IQ/ intellectual impairment • Motor skills • Speech/ language • Learning, behavioral, social impairments • Psychiatric problems (anxiety, depression) • Primary ovarian insufficiency • Cataracts Chronic/ Long - Term
Galactosemia Effects ~2,800 Patients in the US; Potential for Abbreviated Regulatory Approval & Low Burden of Development • ~2,800 living US patients ; ~80 new births per year • Majority of patients are under the age of 40, as newborn screening was adopted in the 1980s and 1990s • Regulatory pathway: • Galactosemia is a “slowly progressive, low prevalence rare disease” disease • Under new FDA guidance, surrogate metabolic biomarkers may be acceptable for demonstration of therapeutic activity • Potential low burden of clinical development 6
Aldose Reductase Activity Causes Toxic Accumulation of Galactitol in Galactosemia Galactose Aldose Reductase Galactitol Toxic Aberrant Metabolite GALK TYPE II GALT Classic Galactosemia Gal - 1 - Phosphate Glu - 1 - Phosphate • Galactosemia results in accumulation of galactose, which becomes an aberrant substrate for AR • AR converts galactose to galactitol, which causes toxic complications in many tissues Sorbitol Dehydrogenase Sorbitol dehydrogenase, the next enzyme in the polyol pathway, can’t reduce galactitol Galactitol Accumulation in Organs & Tissues 7
AT - 007, a CNS - Penetrant Novel Aldose Reductase Inhibitor, Prevents Galactitol Formation and Accumulation Galactose Aldose Reductase Galactitol Toxic Aberrant Metabolite GALK TYPE II GALT Classic Galactosemia Gal - 1 - Phosphate Glu - 1 - Phosphate • Galactosemia results in accumulation of galactose, which becomes an aberrant substrate for AR • AR converts galactose to galactitol, which causes toxic complications in many tissues Sorbitol Dehydrogenase Sorbitol dehydrogenase, the next enzyme in the polyol pathway, can’t reduce galactitol 8 AT - 007
Galactosemia Preclinical Data
0 1 2 3 4 5 6 7 Liver Brain Plasma GALT Deficient Rat Model Closely Mirrors Human Disease 10 Biochemical Effects Tissue Deposition of Galactitol CNS Outcomes 0 1 2 3 4 5 Liver Brain Plasma Galactose pmol Galactitol pmol Wild Type GALT null GALT null WT All GALT null rats display cataracts (caused by galactitol deposition in the eye) vs. none of the WT rats GALT null rats have exponentially higher levels of galactose and galactitol, as well as Gal1p GALT null rats display deficiencies in learning, cognition, and motor skills as measured by rotarod and water maze 0 5 10 15 20 25 30 35 40 45 1 2 3 4 * * Water Maze Latency Time (s) WT GALT null
Cataract Severity Score Dose AT - 007 (mg/kg) 0 0.5 1 1.5 2 0 200 400 600 800 1000 AT - 007 Treatment Corrects All 3 Aspects of Disease in the Galactosemia Rat Model 11 Biochemical Effects Tissue Deposition of Galactitol CNS Outcomes Wild Type GALT null Placebo GALT null (placebo) WT AT - 007 treatment prevented galactitol accumulation in tissues, resulting in absence of cataracts AT - 007 treatment significantly reduced galactitol levels in all tissues without increasing galactose or Gal1p AT - 007 treatment normalized CNS outcomes on both water maze and rotarod Water Maze Latency Time (s) WT GALT null GALT null AT - 007 0 5 10 15 20 25 30 35 40 45 1 2 3 4 GALT null AT - 007 * * GALT null AT - 007 Cataract Quantitation AT - 007 Dose Response 0 5 10 15 20 25 30 35 Liver Brain Plasma 0 5 10 15 20 Liver Brain Plasma Galactose Galactitol pmol pmol
A Closer Look: AT - 007 Significantly Reduces Galactitol Levels in all Target Tissues Without Increasing Galactose or Gal - 1P • AT - 007 treatment from neonatal Day 1 to Day 10 significantly reduced galactitol in liver, brain and plasma • AT - 007 treatment did not increase galactose or Gal1P levels; similar results seen at Day 22 and age 5 months 12 0 5 10 15 20 25 30 35 Liver Brain Plasma Galactose 0 0.2 0.4 0.6 0.8 1 1.2 Liver Brain Gal - 1P Galactitol (Aberrant Toxic Metabolite) 0 2 4 6 8 10 12 14 16 18 20 Liver Brain Plasma WT GALT null placebo GALT null AT-007 pmol pmol pmol
Clinical Program: ACTION - Galactosemia Trial April 2020 Data
Galactosemia Phase 1/2 Registrational Study (ACTION - Galactosemia) Multi - Center Placebo - Controlled Study in Healthy Volunteers & Adult Galactosemia Patients Single Ascending Dose (n=40) 14 Multiple Ascending Dose (n=40, 7 days) 5 mg/kg single dose 5 mg/kg 27 Days Daily Dosing (n=4) Adult Galactosemia Patients Healthy Volunteers 3 Month Extension Galactosemia Endpoints: • Safety • Pharmacokinetics/ Pharmacodynamics • Efficacy Biomarker - Galactitol Placebo Single dose Placebo 27 Days Daily Dosing (n=4) 20 mg/kg Single dose 20mg/kg 27 Days Daily Dosing (n=4) Based on initial topline data from Jan 2020, the study was expanded to include a 40mg/kg dose in healthy volunteers and then Galactosemia patients Healthy Volunteer Endpoints: • Safety • Pharmacokinetics • CNS Penetrance (via CSF sample)
15 • AT - 007 was safe and well tolerated at all doses, including 40mg/kg • No treatment - related discontinuations • Dose - dependent increase in exposure • PK results supportive of once daily oral dosing Healthy Volunteer Data AT - 007 Was Safe and Well Tolerated; PK Supports Once - Daily Dosing
AT - 007 is Brain Penetrant Important in Galactosemia Given CNS Complications 16 AT - 007 CSF concentration (ng/ml) Dose - Dependent Increase in CSF Concentration in Healthy Volunteers (via lumbar puncture) AT - 007 Dose (in mg/kg) 0 10 20 30 40 50 5mg 20mg 40mg
ACTION - Galactosemia Trial Data Adult Galactosemia Patient Baseline Demographics
18 Baseline Demographic and Diagnostic Characteristics (n=11*) Broad Age Range, Multiple Genetic Mutations Represented Subject Age Gender Ethnicity BMI Gene mutation Urine galactitol (mM/urine creatine mol/L) Baseline Plasma galactitol (ng/ml) Baseline GALT enzyme activity (Mmol/h/mg) 2003 - 101 33 M Caucasian 24.3 Q188R/Q188R 208 2630 0 2003 - 102 51 M Caucasian 21.7 Q188R/Q188R 123 2390 0 2003 - 104 19 M Caucasian 21.6 Q188R/Q188R 137 2150 0 2003 - 105 22 F Caucasian 22.7 Q188R/Q188R 255 2860 0 2004 - 001* 37 M Caucasian 21.3 Q188R/Q188R 152 2700 0 2004 - 004 40 M Caucasian 32.7 N314D/ c119 - 116 deletion 102 2500 0 2004 - 005 24 F Caucasian 23.1 Q188R/Q188R 142 2210 0 2002 - 002 19 F Caucasian 23.9 K285N/c119 - 116 deletion 139 2500 0 2004 - 007 19 F Caucasian 21.4 Q188R/Q188R 133 2450 0 2004 - 008 22 M Caucasian 17.4 Q188R/Q188R 130 1930 0 2004 - 009 28 M Caucasian 20.5 Q188R/Q188R 99 2630 0 Summary 28.55 ± 10.5 4F and 7M Caucasian 22.78 ± 3.8 9 Q118R homozygous and 2 compound heterozygous 147.27 ± 45.8 2450 ± 268.7 0 *One placebo patient in cohort 1 crossed over to active for total of n=12
19 Galactosemia Patient Baseline Clinical & Descriptive Characteristics (n=11*) CNS Disorders Psychiatric Disorders Seizures (n=5) Anxiety (n=4) Dementia (n=1) Depression (n=3) Encephalopathy (n=1) ADHD (n=3) Tremor Clinical Characteristics Patient Quality of Life Living with family members or proximity of caregiver (all, n=11) Able to travel only with caregiver (n=9) Unemployed and/or not in school (n=5) Employed (primarily manual employment, unskilled labor n=6) Secondary education (n=2) Descriptive Characteristics Endocrine Disorders Primary ovarian insufficiency (All Females) Short stature (n=1) Gynecomastia (n=1) Osteopenia (n=2) Erectile dysfunction (n=1) Vitamin D deficiency (n=6) Hypothyroidism (n=1) *One placebo patient in cohort 1 crossed over to active for total of n=12
MRI/MRS Baseline Characteristics • Brain morphology changes caused by galactitol - induced osmotic dysregulation • Galactitol was present and quantifiable in the brain of all adult Galactosemia patients (absent in healthy adults) • N - acetyl - aspartate, a marker of neuronal health, was markedly decreased ( - 75%) in all Galactosemia patients
ACTION - Galactosemia Trial Data AT - 007 Pharmacokinetics and Safety Data in Galactosemia Patients
22 Pharmacokinetic Results Support Once Daily Dosing in Galactosemia Patients • Plasma PK parameters of AT - 007 support once daily oral dosing • PK profile in Galactosemia patients was similar to healthy volunteers, suggesting similar drug metabolism and clearance • PK profile suggests no first pass clearance or other PK effects (de - sensitization or induction) Mean AT - 007 Plasma Concentrations at 20mg/kg by Day
SYSTEM ORGAN CLASS PREFERRED TERM NUMBER (%) OF PATIENTS, NUMBER OF EVENTS Placebo N=4 AT - 007 (5 mg/kg) N=4 AT - 007 (20 mg/kg) N=4 Overall N=12* Significance Any Adverse Event 1 (25.0), 3 3 (75.0), 6 2 (50.0), 2 6 (50.0), 11 Not Significant Cardiac Disorders 1 (25.0), 1 0 (0.0), 0 0 (0.0), 0 1 (8.3), 1 Not Significant Tachycardia 1 (25.0), 1 0 (0.0), 0 0 (0.0), 0 1 (8.3), 1 Not Significant Ear and Labyrinth Disorder 0 (0.0), 0 1 (25.0), 1 0 (0.0), 0 1 (8.3), 1 Not Significant Ear discomfort 0 (0.0), 0 1 (25.0), 1 0 (0.0), 0 1 (8.3), 1 Not Significant Gastrointestinal Disorders 1 (25.0), 1 1 (25.0), 1 0 (0.0), 0 2 (16.7), 2 Not Significant Dyspepsia 1 (25.0), 1 0 (0.0), 0 0 (0.0), 0 1 (8.3), 1 Not Significant Abdominal Discomfort 0 (0.0), 0 1 (25.0), 1 0 (0.0), 0 1 (8.3), 1 Not Significant General Disorder and Administration site conditions 1 (25.0), 1 0 (0.0), 0 0 (0.0), 0 1 (8.3), 1 Not Significant Feeling hot 1 (25.0), 1 0 (0.0), 0 0 (0.0), 0 1 (8.3), 1 Not Significant Infections 0 (0.0), 0 2 (50.0) 2 0 (0.0), 0 2 (16.7) 2 Not Significant Upper respiratory tract infection 0 (0.0), 0 2 (50%) 2 0 (0.0), 0 2 (17%) 2 Not Significant Injury/ Procedural Complications 0 (0.0), 0 1 (25.0), 1 0 (0.0), 0 1 (8.3), 1 Not Significant Contusion 0 (0.0), 0 1 (25.0), 1 0 (0.0), 0 1 (8.3), 1 Not Significant Musculoskeletal and Connective Tissue Disorders 0 (0.0), 0 0 (0.0), 0 1 (25.0), 1 1 (8.3), 1 Not Significant Mobility decreased 0 (0.0), 0 0 (0.0), 0 1 (25.0), 1 1 (8.3), 1 Not Significant Psychiatric Disorder 0 (0.0), 0 0 (0.0), 0 1 (25.0), 1 1 (8.3), 1 Not Significant Anxiety 0 (0.0), 0 0 (0.0), 0 1 (25.0), 1 1 (8.3), 1 Not Significant Skin and Subcutaneous Tissue Disorders 0 (0.0), 0 1 (25.0), 1 0 (0.0), 0 1 (8.3), 1 Not Significant Pruritus 0 (0.0), 0 1 (25.0), 1 0 (0.0), 0 1 (8.3), 1 Not Significant 23 Detailed Safety Findings AT - 007 Safe and Well - Tolerated: No Drug - Related Adverse Events
24 Detailed Laboratory Findings No Drug - Related Changes in Hepatic or Renal Function PARAMETER/VISIT Placebo N=4 AT - 007 5 mg/kg N=4 AT - 007 20 mg/kg N=4 Significance ALT (U/L) – Mean (SD) Baseline 21.50 (7.00) 17.75 (9.0) 18.25 (9.07) Not Significant Post - Dosing (Day 32) 23.00 (10.15) 14.5 (8.39) 22.00 (6.38) Not Significant AST (U/L) – Mean (SD) Baseline 22.00 (2.58) 19.25 (6.70) 21.75 (9.43) Not Significant Post - Dosing (Day 32) 21.33 (4.04) 17.25 (7.14) 23.33 (5.51) Not Significant Bilirubin (mg/dL) – Mean (SD) Baseline 0.44 (0.18) 0.51 (0.14) 0..38 (0.19) Not Significant Post - Dosing (Day 32) 0.38 (0.21) 0.44 (0.12) 0.5 (0.28) Not Significant GFR (mL/min/1.73/m 2 ) – Mean (SD) Baseline 116.50 (27.40) 98.75 (12.04) 109.75 (22.65) Not Significant Post – Dosing (Day 32) 108.67 (17.79) 88.50 (3.87) 115.25 (28.30) Not Significant
Safety and PK Summary in Galactosemia Patients Pharmacokinetics • PK supports once - daily dosing • Linear increase in AT - 007 dose - dependent plasma concentration • Similar exposure levels in Galactosemia patients and healthy volunteers Safety • AT - 007 was safe and well - tolerated • N o treatment - related discontinuations • No treatment - related Adverse Events • No treatment - related lab abnormalities 25
ACTION - Galactosemia Trial Data AT - 007 Efficacy Results in Galactosemia Patients
27 -1400 -1200 -1000 -800 -600 -400 -200 0 PBO 5mg/kg 20 mg/kg Plasem Galactitol (ng/ml) Maximum Galactitol Reduction AT - 007 Treatment Significantly Reduced Plasma Galactitol Levels in Adult Galactosemia Patients in a Dose - Dependent Fashion
28 AT - 007 Decreased Galactitol Levels in All Treated Patients Galactitol Reduction Was Rapid and Sustained Reduction in Galactitol at 5mg/kg ~20% Reduction in Galactitol at 20mg/kg ~50% -70.0% -60.0% -50.0% -40.0% -30.0% -20.0% -10.0% 0.0% Baseline DAY 1 DAY 12 DAY 32-34 % Change from BL Maximum Galactitol Reduction % Change from Baseline (AT - 007: 5mg/kg) 101 102 104 105 -70.0% -60.0% -50.0% -40.0% -30.0% -20.0% -10.0% 0.0% Baseline DAY 1 DAY 12 DAY 32-34 % Change from BL Maximum Galactitol Reduction % Change from Baseline (AT - 007: 20mg/kg) 001 007 008 009 Day 12 (6 Days Consecutive) Day 32 (27 Days Consecutive) Day 1 (Single Dose) Baseline Day 12 (6 Days Consecutive) Day 32 (27 Days Consecutive) Day 1 (Single Dose) Baseline
29 AT - 007 Reduction in Galactitol Was Maintained Throughout the 24 - Hour Treatment Period, Supporting Once Daily Dosing 1,000 1,200 1,400 1,600 1,800 2,000 2,200 2,400 2,600 2,800 0HR 0.5HR 1HR 1.5HR 2HR 4HR 6HR 8HR 12HR 24HR Plasma Galactitol (ng/ml) Hours post - dosing on Day 12 Plasma Galactitol on Day 12 (6 Days Consecutive Dosing) Placebo 5mg/kg 20mg/kg 1,000 1,200 1,400 1,600 1,800 2,000 2,200 2,400 2,600 2,800 0HR 0.5HR 1HR 1.5HR 2HR 4HR 6HR 8HR 12HR 24HR Plasma Galactitol (ng/ml) Hours post - dosing on Day 32 Plasma Galactitol on Day 32 (27 Days Consecutive Dosing) Placebo 5mg/kg 20mg/kg Reductions of ~20% at 5mg/kg and ~50% at 20mg/kg were stable throughout the 24 - hour dosing period
30 Treatment with AT - 007 Does Not Increase Galactose Levels Supports Pre - Clinical Data Demonstrating AT - 007 Does Not Cause Derangement of Galactose or Other Galactose Pathway Metabolites 0 100 200 300 400 500 600 700 800 900 1,000 0HR 0.5HR 1HR 1.5HR 2HR 4HR 6HR 8HR 12HR 24HR Plasma Galactose (ng/ml) Hours post - dosing on Day 12 Plasma Galactose Day 12 (6 Days Consecutive Dosing) Placebo 5mg/kg 20mg/kg 0 100 200 300 400 500 600 700 800 900 1,000 0HR 0.5HR 1HR 1.5HR 2HR 4HR 6HR 8HR 12HR 24HR Plasma Galactose (ng/ml) Hours post - dosing on Day 32 Plasma Galactose Day 32 (27 Days Consecutive Dosing) Placebo 5mg/kg 20mg/kg
MRI/MRS Results MRI • AT - 007 treated patients demonstrated a trend towards decreased ventricular volume, a measure of edema (brain swelling) MRS • AT - 007 treated patients (4 out 6)* demonstrated decreased galactitol levels in the brain • AT - 007 treated patients (4 out of 6) demonstrated an improvement in N - acetyl - aspartate (NAA, a marker of neuronal health) *MRI/MRS was limited by inability of some patients to withstand MRI (anxiety) and low - quality scans in others (due to tremor/ movement)
A Closer Look at Seizures 32 Seizures • 5 patients had a history of seizures (generalized onset) • All 5 patients were maintained on antiepileptic medications • 4 patients had < 1 seizure per year • 1 patient had > 1 seizure per month • Due to the low frequency of seizures in the majority of patients, no significant changes in seizure frequency during the ACTION - Galactosemia core study (1 month treatment) could be assessed
ACTION - Galactosemia Trial Data AT - 007 for Treatment of Galactosemia: Future Development Plans
AT - 007 Extension Study: Designed to Confirm Long - Term Safety • 90 Day Safety Extension • Open to those who participated in 28 - day core study and new patients • Placebo - controlled; 3:1 randomization (active to placebo) • Active dose flexible to allow 20mg/kg and potentially 40mg/kg • Safety monitoring & biomarker assessments (as conducted in core study) • Revised to primarily at - home visits (limited to no travel required) to address burden of travel to sites/ impact on families and COVID - 19 concerns • Study remains on track despite COVID - 19 • Will be included in NDA filing 34
Adult European Study Cohort to Recruit GALK - Deficient Patients and Support EU Approval • Primarily designed to recruit GALK deficient patients • More prevalent in Europe, but still extremely rare • Display similar CNS complications to Classic Galactosemia (GALT - deficient) patients • Secondary objective to include European patients to support EU approval • UK site (University College London) • One cohort of patients (~6) planned at UK site, but large pool of patients exists (~70 at single site) • Czech Republic alternative site for GALK deficient patients (given incidence in Romani/ Irish Traveler population) 35
Proposed AT - 007 Pediatric Study (Under Discussion with FDA) 36 Proposed Study Design • 2 - Part Multiple Dose Study • Several age groups investigated • 2 – 6 • 7 – 12 • 13 <18 • Children 2 months – 2 yrs may be added following initial safety data (newborns/ infants) Study Objectives • Safety • Dose determination (via PK/PD) • Efficacy biomarker effects (plasma galactitol) • Exploratory: MRI/MRS effects • Galactitol quantitation • Brain morphometry & cerebral edema • NAA concentration (neuronal health biomarker)
ACTION - Galactosemia Trial Data Summary & Conclusions
Summary: ACTION - Galactosemia Study Results 38 Safety/ PK/ PD • AT - 007 was safe and well - tolerated • PK/PD data supports once - daily oral dosing • AT - 007 is CNS penetrant – important in Galactosemia, which includes significant CNS clinical presentation Efficacy in Galactosemia Patients • AT - 007 induced rapid and sustained reduction in plasma galactitol, an aberrant, toxic metabolite formed in Galactosemia patients • 20mg/kg dosing resulted ~50% reduction in plasma galactitol (p <0.01 vs. placebo) • Positive AT - 007 MRI/MRS impact
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