UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, DC 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): May 3, 2018
Sarepta Therapeutics, Inc.
(Exact name of registrant as specified in its charter)
| Delaware | 001-14895 | 93-0797222 | ||
| (State or other jurisdiction of incorporation) |
(Commission File Number) |
(IRS Employer Identification No.) |
215 First Street
Suite 415
Cambridge, MA 02142
(Address of principal executive offices, including zip code)
(617) 274-4000
(Registrant’s telephone number, including area code)
(Former name or former address, if changed since last report)
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 (see General Instruction A.2. below):
☐ 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 ☐
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. ☐
| Item 7.01. | Regulation FD Disclosure. |
On May 3, 2018, Sarepta Therapeutics, Inc. issued a press release announcing, among other things, that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has rendered a negative trend vote following an oral explanation of the Company’s Marketing Authorization Application (MAA) for eteplirsen. The Company plans to seek a re-examination and request that a Scientific Advisory Group (SAG) be convened to provide expert guidance and insight into different neuromuscular issues, including the validity of the external controls used and the importance of significantly slowing pulmonary decline in patients with Duchenne muscular dystrophy. A copy of the press release is furnished as Exhibit 99.1 and is incorporated herein by reference, including the cautionary statement on forward-looking statements included in the press release regarding the Company’s plan to seek a re-examination and request that a SAG be convened.
At the oral explanation, the Company presented and had a Q&A session with CHMP members per standard meeting protocol. A copy of the presentation is furnished as Exhibit 99.2 and is incorporated herein by reference.
The information in this report furnished pursuant to Item 7.01, including Exhibits 99.1 and 99.2 attached hereto, shall not be deemed “filed” for the purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section. It may only be incorporated by reference in another filing under the Exchange Act or the Securities Act of 1933, as amended, if such subsequent filing specifically references the information furnished pursuant to Item 7.01 of this report.
| Item 9.01 | Financial Statements and Exhibits. |
(d) Exhibits.
| Exhibit Number |
Description | |
| 99.1 | Press release dated May 3, 2018. | |
| 99.2 | Oral Explanation Presentation Slides | |
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.
| Sarepta Therapeutics, Inc. | ||
| By: | /s/ Douglas S. Ingram | |
| Douglas S. Ingram President and Chief Executive Officer | ||
Date: May 3, 2018
Exhibit 99.1
Sarepta Therapeutics Announces First Quarter 2018 Financial Results and Recent Corporate Developments
— First quarter 2017 EXONDYS 51® (eteplirsen) total net revenues of $64.6 million —
— Sarepta signs exclusive partnership and buy-out option with Myonexus Therapeutics; pipeline expands from 16 to 21 programs —
— Company announces date of first R&D day, at which clinical data from gene therapy micro-dystrophin program will be announced —
— Company receives negative trend vote following its CHMP oral explanation; will request re-examination and Scientific Advisory Group to be convened —
CAMBRIDGE, Mass., May 3, 2018 (GLOBE NEWSWIRE) — Sarepta Therapeutics, Inc. (NASDAQ: SRPT), a commercial-stage biopharmaceutical company focused on the discovery and development of precision genetic medicine to treat rare neuromuscular diseases, today reported financial results for the three months ended March 31, 2018.
“In the first quarter, we continued our successful launch of EXONDYS 51 and advanced our pipeline to bring life-enhancing therapies to those suffering from rare disease around the world,” said Doug Ingram, Sarepta’s president and chief executive officer. “We accelerated our gene therapy and RNA platform, and in that regard are excited to announce that our first R&D day will take place on June 19 to showcase the breadth, depth and progress of our pipeline. Significantly, at this event we will report preliminary safety and gene expression data from at least two patients from our micro-dystrophin gene therapy trial underway with Nationwide Children’s Hospital.”
Mr. Ingram continued, “Aligned with our stated goal of leveraging our expertise beyond DMD, we announced today a collaboration with Myonexus Therapeutics for the development of five potentially transformative gene therapies to treat a debilitating set of diseases, all under the umbrella of Limb-girdle muscular
dystrophy. Through this collaboration, we have expanded our pipeline to 21 therapies in development. Our confidence in the Myonexus collaboration comes from the similarities between the Myonexus and Sarepta approaches to gene therapy. Both are seeking to treat rare neuromuscular disease through the AAVrh.74 vector; and both rely upon the unparalleled expertise of Dr. Louise Rodino-Klapac in developing and executing gene therapy constructs. This partnership with Myonexus enables us to expand our efforts beyond DMD while maintaining our unwavering commitment to those suffering from DMD.”
Mr. Ingram concluded, “Unfortunately, in addition to our successes in the first quarter, we also have had a delay in our effort to bring eteplirsen to patients in Europe who could potentially benefit from it. I could not be prouder of our Sarepta team and the team of experts who spoke on behalf of eteplirsen at the CHMP oral explanation last week. The rigorous work that was done to prepare for the hearing only strengthened our resolve that eteplirsen should urgently be made available to those waiting in Europe. Unfortunately, the CHMP’s trend vote was negative. Based on discussions with CHMP representatives, it is our understanding that the CHMP did not conclude that eteplirsen is ineffective for exon 51 amenable patients, but rather that Sarepta has not yet met the regulatory threshold for conditional approval, in part due to the use of external controls as comparators in the studies. Sarepta plans to file for re-examination and will request that a Scientific Advisory Group (SAG), which is made up of DMD and neuromuscular specialists, be convened to provide expert guidance and insight into, among other things, the validity of the external controls used and the importance of slowing pulmonary decline in patients with DMD.”
Financial Results
For the first quarter of 2018, on a GAAP basis, Sarepta reported a net loss of $35.4 million, or $0.55 per basic and diluted share, compared to net income of $84.1 million reported for the same period of 2017, or $1.53 per basic share and $1.50 per diluted share. On a non-GAAP basis, the net loss for the first quarter of 2018 was $17.9 million, or $0.28 per share, compared to a net loss of $31.4 million for the same period of 2017, or $0.57 per share.
Net Revenues
For the three months ended March 31, 2018, the Company recorded net product revenues of $64.6 million, compared to net revenues of $16.3 million for first quarter of 2017. The increase primarily reflects increasing demand for EXONDYS 51 in the U.S.
Cost and Operating Expenses
Cost of sales (excluding amortization of in-licensed rights)
For the three months ended March 31, 2018, cost of sales (excluding amortization of in-licensed rights) was $5.6 million, compared to $0.2 million for the same period of 2017. The increase primarily reflects royalty payments to BioMarin Pharmaceuticals (BioMarin) as a result of the execution of the settlement and license agreements with BioMarin in July 2017 as well as higher inventory costs related to increasing demand for EXONDYS 51 during 2018. Prior to the approval of EXONDYS 51, the Company expensed related manufacturing and material costs as research and development expenses.
Research and development
Research and development expenses were $46.2 million for the first quarter of 2018, compared to $29.1 million for the same period of 2017, an increase of $17.1 million. The increase in research and development expenses primarily reflects the following:
| • | $4.4 million increase in clinical and manufacturing expenses primarily due to increased patient enrollment in the Company’s ongoing clinical trials in golodirsen and casimersen, as well as a ramp-up of manufacturing activities for the Company’s PPMO platform. These increases were partially offset by a ramp-down of clinical trials in eteplirsen primarily because the PROMOVI trial has been fully enrolled; |
| • | $3.2 million increase in collaboration cost sharing with Summit on its utrophin platform; |
| • | $2.7 million increase in compensation and other personnel expenses primarily due to a net increase in headcount; |
| • | $2.4 million increase in professional services primarily due to an expansion of the Company’s research and development pipeline; and |
| • | $1.6 million increase in preclinical expenses primarily due to the continuing ramp-up of toxicology studies in the Company’s PPMO platform as well as golodirsen and casimersen. |
Non-GAAP research and development expenses were $43.3 million for the first quarter of 2018, compared to $26.7 million for the same period of 2017, an increase of $16.6 million.
Selling, general and administration
Selling general and administrative expenses were $43.3 million for the first quarter of 2018, compared to $26.2 million for the same period of 2017, an increase of $17.1 million. The increase in selling, general and administrative expenses primarily reflects the following:
| • | $6.4 million increase in professional services primarily due to continuing global expansion as well as preparation for a potential product launch in the EU should the Company’s Marketing Authorization Application be approved by the European Medicines Agency; |
| • | $5.3 million increase in compensation and other personnel expenses primarily due to a net increase in headcount; and |
| • | $4.6 million increase in stock-based compensation primarily due to the impact of revising the forfeiture rate assumption for officers and Board of Directors as well as an increase in stock price. |
Non-GAAP selling, general and administrative expenses were $33.7 million for the first quarter of 2018, compared to $21.1 million for the same period of 2017, an increase of $12.6 million.
Amortization of in-licensed rights
Amortization of in-licensed rights was $0.2 million during the first quarter of 2018, compared to less than $0.1 million for the same period of 2017. The increase was primarily due to the BioMarin transactions that occurred in July 2017.
Other (loss) Income
Gain from sale of Priority Review Voucher
In connection with the completion of the sale of the Priority Review Voucher (PRV) in March 2017, the Company recorded a gain of $125.0 from sale of the PRV in the first quarter of 2017. There was no similar activity in the first quarter of 2018.
Interest (expense) income and other, net
For the three months ended March 31, 2018 and 2017, the Company recorded $4.5 million interest expense and other, net and $0.3 interest income and other, net, respectively. The period over period unfavorable change primarily reflects the interest expense accrued on the Company’s debt facilities partially offset by interest income from higher balances of cash, cash equivalents and investments.
Cash, Cash Equivalents, Restricted Cash and Investments
The Company had $1.0 billion in cash, cash equivalents, restricted cash and investments as of March 31, 2018 compared to $1.1 billion as of December 31, 2017. The decrease is primarily driven by the use of cash to fund the Company’s ongoing operations during the first quarter of 2018.
Use of Non-GAAP Measures
In addition to the GAAP financial measures set forth in this press release, the Company has included certain non-GAAP measurements. The non-GAAP loss is defined by the Company as GAAP net loss excluding interest expense/(income), income tax expense/(benefit), depreciation and amortization expense, stock-based compensation expense, restructuring expense and other items. Non-GAAP research and development expenses are defined by the Company as GAAP research and development expenses excluding depreciation and amortization expense, stock-based compensation expense, restructuring expense and other items. Non-GAAP selling, general and administrative expenses are defined by the Company as GAAP selling, general and administrative expenses excluding depreciation and amortization expense, stock-based compensation expense, restructuring expense and other items.
1. Interest, tax, depreciation and amortization
Interest income and expense amounts can vary substantially from period to period due to changes in cash and debt balances and interest rates driven by market conditions outside of the Company’s operations. Tax amounts can vary substantially from period to period due to tax adjustments that are not directly related to underlying operating performance. Depreciation expense can vary substantially from period to period as the purchases of property and equipment may vary significantly from period to period and without any direct correlation to the Company’s operating performance. Amortization expense associated with in-licensed rights as well as patent costs are amortized over a period of several years after acquisition or patent application or renewal and generally cannot be changed or influenced by management.
2. Stock-based compensation expenses
Stock-based compensation expenses represent non-cash charges related to equity awards granted by Sarepta. Although these are recurring charges to operations, management believes the measurement of these amounts can vary substantially from period to period and depend significantly on factors that are not a direct consequence of operating performance that is within management’s control. Therefore, management believes that excluding these charges facilitates comparisons of the Company’s operational performance in different periods.
3. Restructuring expenses
The Company believes that adjusting for these items more closely represents the Company’s ongoing operating performance and financial results.
4. Other items
The Company evaluates other items of expense and income on an individual basis. It takes into consideration quantitative and qualitative characteristics of each item, including (a) nature, (b) whether the items relates to the Company’s ongoing business operations, and (c) whether the Company expects the items to continue on a regular basis. These other items include the aforementioned gain from the sale of the Company’s PRV.
The Company uses these non-GAAP measures as key performance measures for the purpose of evaluating operational performance and cash requirements internally. The Company also believes these non-GAAP measures increase comparability of period-to-period results and are useful to investors as they provide a similar basis for evaluating the Company’s performance as is applied by management. These non-GAAP measures are not intended to be considered in isolation or to replace the presentation of the Company’s financial results in accordance with GAAP. Use of the terms non-GAAP research and development expenses, non-GAAP selling, general and administrative expenses, non-GAAP other income adjustments, non-GAAP income tax expense, non-GAAP net loss, and non-GAAP basic and diluted net loss per share may differ from similar measures reported by other companies, which may limit comparability, and are not based on any comprehensive set of accounting rules or principles. All relevant non-GAAP measures are reconciled from their respective GAAP measures in the attached table “Reconciliation of GAAP to Non-GAAP Net Loss.”
First Quarter and Recent Corporate Developments
| • | Golodirsen (SRP-4053): Based on Sarepta’s Type C meeting with the FDA’s Division of Neurology Products to solicit the Division’s guidance on the development pathway for golodirsen, the Company remains on track to complete a rolling NDA submission by year-end 2018, seeking accelerated approval based on an increase in dystrophin protein as a surrogate endpoint. |
| • | Myonexus Therapeutics Partnership: Sarepta and Myonexus Therapeutics entered into a partnership to advance multiple gene therapies for various forms of Limb-girdle muscular dystrophies (LGMDs). The lead program, MYO-101, has generated encouraging pre-clinical safety and efficacy |
| data utilizing the AAVrh.74 vector system, the same vector used in the micro-dystrophin gene therapy program Sarepta is developing with Nationwide Children’s Hospital. A Phase 1/2a study of MYO-101 is scheduled to begin in mid-2018. The companies plan to report on 60-day biopsy data in late-2018 or early 2019. Additionally, Myonexus is advancing MYO-102 for LGMD2D, MYO-103 for LGMD2C, MYO-201 for LGMD2B, and MYO-301 for LGMD2L. Under the terms of the agreement, Sarepta will make an upfront payment of $60 million and additional development-related milestone payments to purchase an exclusive option to acquire Myonexus at a pre-negotiated, fixed price with sales-related contingent payments. If all development-related milestone payments are met, Sarepta will make payments of up to $45 million over an approximately two-year evaluation period. Sarepta has the option to purchase Myonexus at any time, including upon review of proof-of-concept data. |
| • | Sarepta R&D Day (Tuesday, June 19, 2018): Sarepta management, along with several key-opinion leaders, will provide an in-depth look into the Company’s pipeline programs across several modalities, included RNA-targeted therapies, gene therapy and gene editing. Of particular note, we look forward to presenting our micro-dystrophin expression data from at least two patients enrolled in the Phase 1/2a gene therapy clinical trial underway with Drs. Jerry Mendell and Louise Rodino-Klapac of Nationwide Children’s Hospital. To date, the Company has enrolled four patients in this study and no significant adverse events have been reported. In addition, Dr. Rodino-Klapac, who is also chief scientific officer and co-founder of Myonexus, will present data from Myonexus’ entire LGMD program. For all to access, Sarepta’s R&D day will be webcast live under the investor relations section of the Company’s website at: www.sarepta.com and will be archived there following the event for 90 days. |
Conference Call
The Company will be hosting a conference call at 4:30 p.m. Eastern Time, to discuss these financial results and provide a corporate update. The conference call may be accessed by dialing 844-534-7313 for domestic callers and +1-574-990-1451 for international callers. The passcode for the call is 2798939. Please specify to the operator that you would like to join the “Sarepta First Quarter 2018 Earnings Call”. The conference call will be webcast live under the investor relations section of Sarepta’s website at www.sarepta.com and will be archived there following the call for 90 days. Please connect to Sarepta’s website several minutes prior to the start of the broadcast to ensure adequate time for any software download that may be necessary.
About EXONDYS 51
EXONDYS 51 uses Sarepta’s proprietary phosphorodiamidate morpholino oligomer (PMO) chemistry and exon-skipping technology to skip exon 51 of the dystrophin gene. EXONDYS 51 is designed to bind to exon 51 of dystrophin pre-mRNA, resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping. Exon skipping is intended to allow for production of an internally truncated dystrophin protein.
Important Safety Information About EXONDYS 51
Hypersensitivity reactions, including rash and urticaria, pyrexia, flushing, cough, dyspnea, bronchospasm, and hypotension, have occurred in patients who were treated with EXONDYS 51. If a hypersensitivity reaction occurs, institute appropriate medical treatment and consider slowing the infusion or interrupting the EXONDYS 51 therapy.
Adverse reactions in DMD patients (N=8) treated with EXONDYS 51 30 or 50 mg/kg/week by intravenous (IV) infusion with an incidence of at least 25% more than placebo (N=4) (Study 1, 24 weeks) were (EXONDYS 51, placebo): balance disorder (38%, 0%), vomiting (38%, 0%) and contact dermatitis (25%, 0%). The most common adverse reactions were balance disorder and vomiting. Because of the small numbers of patients, these represent crude frequencies that may not reflect the frequencies observed in practice. The 50 mg/kg once weekly dosing regimen of EXONDYS 51 is not recommended.
In the 88 patients who received ³30 mg/kg/week of EXONDYS 51 for up to 208 weeks in clinical studies, the following events were reported in ³10% of patients and occurred more frequently than on the same dose in Study 1: vomiting, contusion, excoriation, arthralgia, rash, catheter site pain, and upper respiratory tract infection.
For further information, please see the full Prescribing Information.
About Sarepta Therapeutics
Sarepta Therapeutics is a commercial-stage biopharmaceutical company focused on the discovery and development of precision genetic medicine to treat rare neuromuscular diseases. The Company is primarily focused on rapidly advancing the development of its potentially disease-modifying DMD drug candidates. For more information, please visit www.sarepta.com.
Forward-Looking Statements
In order to provide Sarepta’s investors with an understanding of its current results and future prospects, this press release contains statements that are forward-looking. Any statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Words such as “believes,” “anticipates,” “plans,” “expects,” “will,” “may,” “intends,” “prepares,” “looks,” “potential,” “possible” and similar expressions are intended to identify forward-looking statements. These forward-looking statements include statements relating to Sarepta’s future operations, financial performance and projections, business plans, priorities and development of product candidates including: Sarepta’s goal of leveraging its expertise beyond DMD; expected milestones, including reporting preliminary safety and gene expression data from at least two patients from our micro-dystrophin gene therapy trial on June 19, 2018, completing a rolling NDA submission for golodirsen by year-end 2018, which seeks accelerated approval based on an increase in dystrophin protein as a surrogate endpoint, initiating a Phase 1/2a study of MYO-101 in mid-2018, and reporting on 60-day biopsy data in late-2018 or early 2019; Sarepta’s collaboration with Myonexus involving five potentially transformative gene therapies to treat LGMD; the partnership with Myonexus enabling Sarepta to expand its efforts beyond DMD while maintaining its unwavering commitment to those suffering from DMD; payments that Sarepta is expected to make under the agreement with Myonexus; and Sarepta’s plan to file for re-examination of its marketing authorization application (MAA) for eteplirsen and to request that a SAG be convened.
These forward-looking statements involve risks and uncertainties, many of which are beyond Sarepta’s control. Actual results could materially differ from those stated or implied by these forward-looking statements as a result of such risks and uncertainties. Known risk factors include the following: we may not be able to meet expectations with respect to EXONDYS 51 sales or attain the net revenues we anticipate, profitability or positive cash-flow from operations; we may not be able to comply with all FDA post-approval commitments and requirements with respect to EXONDYS 51 in a timely manner or at all; we may not be granted a re-examination of our MAA for eteplirsen, a SAG may not be convened, and even if a re-examination and a related SAG are granted, the CHMP may render a negative opinion and we may not be able to obtain regulatory approval for eteplirsen from the European Medicines Agency; our data for golodirsen may not be sufficient for a filing for or obtaining regulatory approval; the expected benefits and
opportunities related to the agreement with Myonexus may not be realized or may take longer to realize than expected due to challenges and uncertainties inherent in product research and development; the partnership with Myonexus may not result in any viable treatments suitable for clinical research or commercialization due to a variety of reasons including the results of future research may not be consistent with past positive results or may fail to meet regulatory approval requirements for the safety and efficacy of product candidates or may never become commercialized products due to other various reasons including any potential future inability of the parties to fulfill their commitments and obligations under the agreement, including any inability by us to fulfill our financial commitments to Myonexus; and even if the agreement results in new commercialized products, we may not achieve any significant revenues from the sale of such products; we may not be able to execute on our business plans, including meeting our expectations with respect to EXONDYS 51 sales, meeting our expected or planned regulatory milestones and timelines, research and clinical development plans, and bringing our product candidates to market, for various reasons including possible limitations of Company financial and other resources, manufacturing limitations that may not be anticipated or resolved for in a timely manner, and regulatory, court or agency decisions, such as decisions by the CHMP on eteplirsen or the United States Patent and Trademark Office with respect to patents that cover our product candidates; and those risks identified under the heading “Risk Factors” in Sarepta’s most recent Annual Report on Form 10-K for the year ended December 31, 2017 and most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) as well as other SEC filings made by the Company which you are encouraged to review.
Any of the foregoing risks could materially and adversely affect the Company’s business, results of operations and the trading price of Sarepta’s common stock. You should not place undue reliance on forward-looking statements. Sarepta does not undertake any obligation to publicly update its forward-looking statements based on events or circumstances after the date hereof, except to the extent required by applicable law or SEC rules.
Internet Posting of Information
We routinely post information that may be important to investors in the ‘For Investors’ section of our website at www.sarepta.com. We encourage investors and potential investors to consult our website regularly for important information about us.
Sarepta Therapeutics, Inc.
Consolidated Statements of Operations
(unaudited, in thousands, except share and per share amounts)
| For the Three Months Ended March 31, |
||||||||
| 2018 | 2017 | |||||||
| Revenues: |
||||||||
| Product, net |
$ | 64,604 | $ | 16,342 | ||||
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| Total revenues |
64,604 | 16,342 | ||||||
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|
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| Costs and expenses: |
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| Cost of sales (excluding amortization of in-licensed rights) |
5,582 | 223 | ||||||
| Research and development |
46,204 | 29,119 | ||||||
| Selling, general and administrative |
43,341 | 26,216 | ||||||
| Amortization of in-licensed rights |
216 | 29 | ||||||
|
|
|
|
|
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| Total costs and expenses |
95,343 | 55,587 | ||||||
|
|
|
|
|
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| Operating loss |
(30,739 | ) | (39,245 | ) | ||||
|
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|
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| Other (loss) income: |
||||||||
| Gain from sale of Priority Review Voucher |
— | 125,000 | ||||||
| Interest (expense) income and other, net |
(4,485 | ) | 335 | |||||
|
|
|
|
|
|||||
| Other (loss) income |
(4,485 | ) | 125,335 | |||||
|
|
|
|
|
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| (Loss) income before income tax expense |
(35,224 | ) | 86,090 | |||||
| Income tax expense |
139 | 2,000 | ||||||
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|
|
|
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| Net (loss) income |
(35,363 | ) | 84,090 | |||||
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|
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| Net (loss) income per share |
||||||||
| Basic (loss) earnings per share |
$ | (0.55 | ) | $ | 1.53 | |||
| Diluted (loss) earnings per share |
$ | (0.55 | ) | $ | 1.50 | |||
| Weighted average number of shares of common stock used in computing: |
||||||||
| Basic (loss) earnings per share |
64,631 | 54,850 | ||||||
| Diluted (loss) earnings per share |
64,631 | 56,012 | ||||||
Sarepta Therapeutics, Inc.
Reconciliation of GAAP Financial Measures to Non-GAAP Financial Measures
(unaudited)
(in thousands, except share and per share amounts)
| Three Months Ended March 31, |
||||||||
| 2018 | 2017 | |||||||
| GAAP net (loss) income |
$ | (35,363 | ) | $ | 84,090 | |||
| Interest expense (income), net |
4,503 | (29 | ) | |||||
| Income tax expense |
139 | 2,000 | ||||||
| Depreciation and amortization expense |
2,252 | 1,637 | ||||||
| Stock-based compensation expense |
10,526 | 5,712 | ||||||
| Restructuring expense |
— | 236 | ||||||
| Gain from sale of Priority Review Voucher |
— | (125,000 | ) | |||||
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|
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| Non-GAAP net loss (1) |
$ | (17,943 | ) | $ | (31,354 | ) | ||
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| Non GAAP net loss per share: |
||||||||
| Basic and diluted |
$ | (0.28 | ) | $ | (0.57 | ) | ||
| Weighted average number of shares of common stock outstanding for computing: |
||||||||
| Basic and diluted |
64,631 | 54,850 | ||||||
| Three Months Ended March 31, |
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| 2018 | 2017 | |||||||
| GAAP research and development expenses |
46,204 | 29,119 | ||||||
| Stock-based compensation expense |
(2,060 | ) | (1,874 | ) | ||||
| Depreciation and amortization expense |
(848 | ) | (512 | ) | ||||
| Restructuring expense |
— | (70 | ) | |||||
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|
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| Non-GAAP research and development expenses (1) |
43,296 | 26,663 | ||||||
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| Three Months Ended March 31, |
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| 2018 | 2017 | |||||||
| GAAP selling, general and administrative expenses |
43,341 | 26,216 | ||||||
| Stock-based compensation expense |
(8,466 | ) | (3,838 | ) | ||||
| Depreciation and amortization expense |
(1,188 | ) | (1,125 | ) | ||||
| Restructuring expense |
— | (166 | ) | |||||
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| Non-GAAP selling, general and administrative expenses (1) |
33,687 | 21,087 | ||||||
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| (1) | Commencing in the first quarter of 2018, the Company has excluded interest expense (income), net, and depreciation and amortization expense from the computation of its non-GAAP financial measures. The Company has revised prior year presentation in the tables above in order to conform to the current year presentation. |
Sarepta Therapeutics, Inc.
Consolidated Balance Sheets
(unaudited, in thousands, except share and per share data)
| As of March 31, 2018 |
As of December 31, 2017 |
|||||||
| Assets |
||||||||
| Current assets: |
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| Cash and cash equivalents |
$ | 557,234 | $ | 599,691 | ||||
| Short-term investments |
491,757 | 479,369 | ||||||
| Accounts receivable |
39,848 | 29,468 | ||||||
| Inventory |
99,375 | 83,605 | ||||||
| Other current assets |
31,203 | 36,511 | ||||||
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| Total current assets |
1,219,417 | 1,228,644 | ||||||
|
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|
|
|
|||||
| Property and equipment, net of accumulated depreciation of $19,817 and $18,022 as of March 31, 2018 and December 31, 2017, respectively |
53,927 | 43,156 | ||||||
| Intangible assets, net of accumulated amortization of $4,659 and $4,145 as of March 31, 2018 and December 31, 2017, respectively |
14,473 | 14,355 | ||||||
| Other assets |
12,466 | 21,809 | ||||||
|
|
|
|
|
|||||
| Total assets |
$ | 1,300,283 | $ | 1,307,964 | ||||
|
|
|
|
|
|||||
| Liabilities and Stockholders’ Equity |
||||||||
| Current liabilities: |
||||||||
| Accounts payable |
$ | 17,379 | $ | 8,467 | ||||
| Accrued expenses |
65,648 | 68,982 | ||||||
| Current portion of long-term debt |
3,446 | 6,175 | ||||||
| Other current liabilities |
4,723 | 4,708 | ||||||
|
|
|
|
|
|||||
| Total current liabilities |
91,196 | 88,332 | ||||||
|
|
|
|
|
|||||
| Long-term debt |
427,365 | 424,876 | ||||||
| Deferred rent and other |
4,962 | 5,539 | ||||||
|
|
|
|
|
|||||
| Total liabilities |
523,523 | 518,747 | ||||||
|
|
|
|
|
|||||
| Stockholders’ equity: |
||||||||
| Preferred stock, $0.0001 par value, 3,333,333 shares authorized; none issued and outstanding |
— | — | ||||||
| Common stock, $0.0001 par value, 99,000,000 shares authorized; 65,493,293 and 64,791,670 issued and outstanding at March 31, 2018 and December 31, 2017, respectively |
7 | 6 | ||||||
| Additional paid-in capital |
2,029,767 | 2,006,598 | ||||||
| Accumulated other comprehensive loss |
(643 | ) | (379 | ) | ||||
| Accumulated deficit |
(1,252,371 | ) | (1,217,008 | ) | ||||
|
|
|
|
|
|||||
| Total stockholders’ equity |
776,760 | 789,217 | ||||||
|
|
|
|
|
|||||
| Total liabilities and stockholders’ equity |
$ | 1,300,283 | $ | 1,307,964 | ||||
|
|
|
|
|
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Source: Sarepta Therapeutics, Inc.
Media and Investors:
Sarepta Therapeutics, Inc.
Ian Estepan, 617-274-4052
iestepan@sarepta.com
or
W2O Group
Brian Reid, 212-257-6725
breid@w2ogroup.com
Eteplirsen AVI BioPharma CHMP Oral Explanation Date: 24 April 2018 Exhibit 99.2 The information presented to the CHMP included clinical efficacy and other data that were excluded from the FDA approved product labeling for EXONDYS 51® (eteplirsen). Sarepta Therapeutics, Inc. makes no recommendation for the use of EXONDYS 51 in any manner inconsistent with its FDA approved product labeling
Attendees Name Position AVI BioPharma Douglas Ingram President & Chief Executive Officer Shamim Ruff, MSc Sr. Vice President, Chief Regulatory Affairs Officer Helen Eliopoulos, MD Executive Director, Regulatory Affairs Diane Frank, PhD Sr. Director, Translational Development Chris Mix, MD VP, Clinical Development Heidi Krenz, MD VP, Pharmacovigilance Alex Meldrum Senior Consultant Regulatory Affairs External Experts Craig M. McDonald, MD Study Chair, CINRG Duchenne Natural History Study; Professor and Chair, Dept. Physical Medicine & Rehabilitation; Director, Neuromuscular Disease Clinics; University of California at Davis School of Medicine Bernard Kinane, MD Chief, Pediatric Pulmonary Unit, Massachusetts General Hospital for Children Ping-Yu Liu, PhD Statistician, Fred Hutchinson Cancer Research Center, Member Emeritus
Proposed Indication for DMD DMD is a rare, fatal disease Result from inability to produce dystrophin Proposed indication is in a subpopulation of DMD Treatment of Duchenne muscular dystrophy (DMD) in ambulatory patients 4 years and older who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping No approved therapy for this population in Europe
What You Will Hear Today Eteplirsen: Induces exon skipping and produces functional dystrophin Consistently slows disease progression Multiple studies and endpoints 115 DMD subjects (~ 28% of the eligible population in Europe) Favorable safety profile and well tolerated Commitment to a confirmatory trial if granted conditional marketing approval Urgent unmet need
Dystrophin Quantification: Proof of Eteplirsen Mechanism of Action Craig M. McDonald, MD Study Chair, CINRG Duchenne Natural History Study Professor and Chair, Dept. Physical Medicine & Rehabilitation Professor of Pediatrics Director, Neuromuscular Disease Clinics University of California at Davis School of Medicine
Goal of Eteplirsen: Production of Functional Truncated Dystrophin Protein The truncated dystrophin proteins produced by eteplirsen are functional and the same proteins produced from conception in Becker muscular dystrophy patients (near normal life expectancy) The goal of eteplirsen is not to produce a Becker phenotype The goal is to slow disease progression by producing low levels of dystrophin (as in exon 44 skip amenable DMD patients)
What Amount of Dystrophin is Clinically Relevant? Low levels of truncated dystrophin are naturally present in exon 44 skip amenable patients with DMD – an experiment in nature Exon 44 skip amenable patients have levels of dystrophin which are similar to those seen with pharmacologic exon skipping (20% by IHC) These levels of dystrophin are associated with a milder phenotype (based on 6MWT, NSAA, and loss of ambulation) 50% of exon 44 skip amenable patients ambulate beyond 20 years
Similar Quantity of Truncated Dystrophin Protein Seen in Both Eteplirsen Treated Patients and Exon 44 Amenable Patients *Untreated Exon 51-amenable EC for Study 201/202 Week 180. †Untreated Exon 44-amenable from Anthony K, et al. Neurology. 2014;83(22):2062-2069. Study 201/202 P<0.001 Exon 51–Amenable Untreated (N=9)* Eteplirsen Treated (N=11) Exon 44–Amenable Untreated (N=5)†
0.08% 0.93% 0.16% 0.44% Week 48 Study 301 Week 180 Study 201/202 P=0.007 P=0.008 Treated (N=12) Baseline (N=12) Treated (N=11) Untreated (N=9) 2.8-fold increase 11.6-fold increase Eteplirsen Produces Dystrophin Which Accumulates Over Time Validated Western Blot
Major Objections Related to Dystrophin Objection Eteplirsen MAA The very modest increase in dystrophin production (mean 0.93% WB of normal dystrophin in study 201/202 and 0.44% in study 301) Clinical relevance of the dystrophin produced is confirmed Levels observed in Study 201/202 are similar to exon 44 skip amenable No increase was detected in a number of patients in both studies, only partially supports the proposed mechanism of action of eteplirsen Western Blot shows a range of response, as expected All evaluated patients (N=36) have demonstrated exon skipping by RT-PCR
8 Year Old Untreated DMD Patient: Typical Attempted Run Steroid Treated Since Age 4; 6MWD = 330 Meters
Review of Clinical Data Helen Eliopoulos MD Executive Director, Regulatory Affairs
Eteplirsen DMD Clinical Program: 3 Trials Contribute to Efficacy Phase 1 Phase 2 Phase 3 Study 33 Single IM Dose N=7 Study 28 IV Dose Ranging N=19 Study 201/202 (4-Year) Age 7-13; N=12 Study 204 (2 Year) Age 7-21; N=24 Study 203 Age 4-6; N=26 Study 301 (2-Year) Age 7-16; N=79 Study 102 Age 0.5-48 mo; N=4
Clinical Efficacy Focuses on Phases of Decline in DMD Standard of Care: Glucocorticoid Use 7 Years 20 Years 13 Years 10 Years Pulmonary Linear Decline (FVC%p) 10-18 years Mechanical Ventilation Early Mortality Ambulatory Decline: ≥7 years (6MWT & NSAA)
Rigorous Identification of Most Appropriate External Controls 12 DMD Registries and Untreated Controls identified Only 3 of 12 prospectively collected ambulatory or pulmonary endpoints Long term data for endpoints Patient level data available for genotyping Registry (Patients) Six Minute Walk Test (6MWT) North Star Ambulatory Assessment (NSAA) Loss of Ambulation (LOA) Forced Vital Capacity %predicted (FVC %p) Italian Telethon (N=96) ü ü ü Leuven NMRC (N=89) ü ü CINRG* (N=397) ü ü *At the time of data collection CINRG had limited longitudinal 6MWT & NSAA data.
Ambulatory Data vs Primary EC Six-Minute Walk Test (6MWT) Loss of Ambulation (LOA) North Star Ambulatory Assessment (NSAA)
Identification of Primary External Control (EC) for Ambulatory Outcomes from Italian Telethon and Leuven Centers Genetically Confirmed Amenable to Exon Skipping Exon 51 Skip Amenable Patients N=185 Italian Telethon and Leuven NMRC Pre-specified Criteria Based on Study 201/202 Corticosteroid treatment ≥ 7 years old N=49 Amenable to Any Exon Skip (includes 8 milder exon 44 skip amenable pts) N=12 “Primary External Control”
Primary EC Comparable to Studies 201/202 & 301 Parameter Primary EC N=12 Study 201/202 N=12 Study 301 N=60 Mean Age (years) 9.5 9.4 9.6 Mean 6MWT (m) 362.8 363.2 376.2 Mean NSAA 22.8 24.9 21.9 Corticosteroid Type Deflazacort 8 (67%) 8 (67%) 17 (28%) Prednisone 4 (33%) 4 (33%) 43 (72%) Key Baseline Characteristics
Primary EC and Study 201/202 Received High Standard of Care Frequency of Physical Therapy (Days/wk or Usage) Primary EC: N=12 (Patients) Study 201/202 N=12 (Patients) 4-6 4 2 2-3 8 3 ≤1 0 5 None 0 2
Study 201/202 vs Primary EC: Individual 6MWT Over 4 Years Δ=147 m* p=0.007 Δ=165 m* p=0.001 ANCOVA with a covariate for Baseline 6MWT. *Δ= Difference in Mean Change from Baseline. Eteplirsen Study 201/202 (N=12) Primary EC (N=12)
Probability of Remaining Ambulatory Kaplan-Meier Estimates for Study 201/202 vs Primary EC Eteplirsen (N=12) Primary External Control (N=12) Year 4 Estimate Study 201/202 = 83% Primary EC = 12% Log-rank p=0.007 BL Year 1 Year 2 Year 3 Year 4 Study 201/202 12 10 10 10 10 Primary EC 12 12 9 6 1 Probability of Remaining Ambulatory (%) 100 90 80 70 60 50 40 30 20 10 0
Eteplirsen Study 201/202 vs Italian Telethon: Slowing of NSAA Directionally Consistent with 6MWT ∆3.4 (p=0.333) ∆ = Difference in mean change from baseline. # NSAA Activity 1 Stand 2 Walk 3 Stand from chair 4/5 Stand on one leg (right/left) 6/7 Climb box step (right/left) 8/9 Descend box step (right/left) 10 Sit from supine 11 Rise from supine (Gower) 12 Lift head from floor 13 Stand on heels 14 Jump 15/16 Hop on one leg (right/left) 17 10 meter run/walk Years
ICH E10 (2.5.4 Validity of Inference from External Controls) Externally Controlled Trials Can be Persuasive: Comparison of Study 201/202 vs Primary EC Disease has a well documented, highly predictable course DMD declines are well characterized for homogenous populations Covariates influencing the outcomes of disease are well characterized Key baseline characteristics comparable (age, 6MWT, steroids) Observational variables are similar SOC comparable (physical therapy, steroids) Study endpoint is objective Loss of ambulation is an objective endpoint Treatment outcome is markedly different Large magnitude of effect over 4 years
Study 301 Interim Analysis of 6MWT and NSAA vs Primary EC: Directionally Favoring Eteplirsen Patients at Year 2 ∆38.8 m (p=0.354) Eteplirsen-Treated (N=60) Primary EC (N=12) Mean (meters, ± SE) Mean Score 6MWT NSAA ∆3.8 (p=0.053) Eteplirsen-Treated (N=60) Italilan Telethon (N=9) For reference: Year 1 Study 301 is N= 51 and Year 2 Study 301 is N=34, Years Years BL 1 2
Pulmonary Data vs CINRG Control: Forced Vital Capacity % Predicted (FVC%p) (% FVC in healthy individuals normalized to age & height)
CINRG Duchenne Natural History Study Global (20 Centres) – 3 in EU (Sweden, Italy and UK) Study Period: 2006 – Present Largest prospective multicenter DMD natural history cohort N= 397 patients with pulmonary data CINRG website. www.cinrgresearch.org/. Accessed March 17, 2018. Registry (# of Patients) FVC%p Italian Telethon (N=96) Leuven NMRC (N=89) CINRG (N=397) ü
Eteplirsen Pulmonary Outcomes Evaluated in 2 Ways Addressing CHMP Feedback Slope Model: FVC%p annual change by age (10 to <18 years) Studies 201/202, 301 & 204 Evaluated eteplirsen effects on patients who are expected to decline Time on Study 201/202: Change of FVC%p over 4 years Statistical analyses were pre-specified prior to accessing CINRG patient level data
Identification of CINRG Comparator for Slope Model Analysis (Ages 10 to < 18 years) Genotyped Exon 51 CINRG Registry Patients N=397 Slope Model Criteria Glucocorticoid Tx FVC%p assessments for ages of 10 to < 18 years N=148 N=20
Slope Model: Ages 10 to <18 yrs vs Exon 51 CINRG EC Annual Change (FVC%p, -SE) P-value vs CINRG < 0.001 0.004 0.017 N/A
Identification of CINRG Comparator for Time on Study 201/202 Over 4 Years Genotyped Exon 51 CINRG Registry Patients N=397 Slope Model Criteria Glucocorticoid Tx FVC%p assessments for ages of 10 to < 18 years N=148 N=20 Time on Study Criteria Glucocorticoid Tx BL Age of 7-13 years BL FVC%p of 84-124% N=67 32 with FVC%p at Year 4 N=9 2 with FVC%p at every year
77.4% 87.5% Time on Study 201/202: Change of FVC%p vs Genotyped CINRG EC (N=67) Patients Aged 7-13 Years Change from Baseline Mean (SE) FVC%p By Year Absolute difference ~10% in FVC%p at Year 4 Years
Clinical Efficacy Has Been Convincingly Demonstrated Major Objections Eteplirsen MAA Evidence from the 24 week placebo control period of Study 201 is weak Short treatment duration of placebo did not enable differentiation of effect Study 201/202 and interim analysis of 301 compared with external control groups is very weak Large magnitude of effect for Study 201/202 Ambulatory data from Study 301 (N=60) are supportive Significant slowing of pulmonary decline in 3 studies (N=74) Long-term, compelling data are essential to elucidate whether eteplirsen has a benefit Study 201/202 shows a consistent temporal pattern over 4 years Gradual accumulation of dystrophin
Eteplirsen Safety Experience is Favorable and Generally Consistent with Pediatric DMD 171 clinical patients* (309 patient-years at ≥30 mg/kg); 106 patients with ≥ 2 years Infusion-related reactions; most commonly mild headache, rash, vomiting 1 SUSAR urticaria, resolved with no recurrence 263 post-marketing patients (~113 patient-years): Safety profile generally similar to clinical trials Infusion-related reactions, including 2 bronchospasm events which resolved No signal for risks observed with drisapersen No hepatotoxicity, renal toxicity, hematologic toxicities, severe cutaneous reactions *Includes all doses and routes of administration.
Benefit Risk of Eteplirsen Craig M. McDonald, MD Study Chair, CINRG Duchenne Natural History Study Professor and Chair, Dept. Physical Medicine & Rehabilitation Professor of Pediatrics Director, Neuromuscular Disease Clinics University of California at Davis School of Medicine
Study 201/202: Eteplirsen Slows Disease Progression Across Multiple Endpoints 6MWT NSAA FVC%p LOA BL 1 2 3 4 BL 1 2 3 4 BL 1 2 3 BL 1 2 3 4 Years Years Years Years
Declining FVC%p Linked to Clinically Meaningful Thresholds and Risk of Death (Based on CINRG Data) Modified from † Mayer, et al. 2017; CINRG Data: McDonald CM, et al. 2018. FVC%p Mean (SEM) PFT Value Age (years) Nocturnal hypoventilation Increased risk of death Clinical Progression Intervention Continuous ventilation 6 8 10 12 14 16 18 20 22 24 26 28 30 0 20 30 40 50 60 80 100 10% reduction in FVC%p impacts risk of hypoventilation Night bi-level ventilation
Eteplirsen Slows the Rate of Pulmonary Decline Across Three Studies P-value vs CINRG < 0.001 0.004 0.017 N/A Annual Change (FVC%p, -SE)
Clinical Experience with Eteplirsen (Prof. McDonald): Three Youngest Patients Treated for > 3 Years 7.5 yrs (Study 203) 8.5 yrs (Study 203) 10 yrs (Study 301)
Questions Shamim Ruff, MSc (Moderator) Sr. Vice President, Chief Regulatory Affairs Officer
Backup Slides Displayed at Oral Explanation Q&A
Study 201/202: Similar Eteplirsen Benefit over Primary Comparator, independent of age of steroid initiation and regimen Parameter Eteplirsen Combined 201/202 Studies (N=12) Primary External Control (amenable to Exon 51 skipping) (N=12) Age at Steroid Start 5.2 6.5 Corticosteroid Type Deflazacort 8 (67%) 8 (67%) Prednisone 4 (33%) 4 (33%) Corticosteroid Regimen Continuous 11 (92%) 8 (67%) Intermittent 1 (8%) 4 (33%) 6MWT (m) difference from Primary EC at Year 4 Primary ANCOVA adjusted for BL 6MWT 165, p<0.001 ANCOVA adjusted for BL 6MWT, Age, Age at Steroid Start 163, p=0.005 MMRM adjusted for BL Age, 6MWT & Corticosteroid Type 154, p<0.001 ANCOVA adjusted for BL 6MWT, Corticosteroid Regimen 157, p=0.003 Slightly younger age of steroid initiation and higher proportion of continuous regimen for eteplirsen Sensitivity analyses adjusting for these covariates showed >150 meters with nominal significance
Δ=147 m* p=0.007 Δ=165 m* p=0.001 6MWT Study 201/202 vs Primary EC: Significant Benefit at Years 3 and 4 ANCOVA with a covariate for Baseline 6MWT. *Δ= Difference in Mean Change from Baseline. Both Groups Overlap at BL & Through Year 1 Mean 6MWT Distance (meters, ± SE)
Primary EC Comparable to CINRG Exon 51 Cohort on LOA CINRG, Exon 51, on steroids (N=37) Primary EC, Exon 51, on steroids (N=12) Probability of Remaining Ambulant 1.00 0.75 0.50 0.25 0.00 Years of Age 0 5 10 15 20 Median age of LOA was 13 years for both groups Kaplan-Meier Survival Estimate Data provided by CINRG and Primary External Control.
Eteplirsen Preserves Ambulation: Comparison to EC and CINRG Exon 51 CINRG, Exon 51, on steroids (N=37) Eteplirsen, Exon 51, on steroids (N=12) Primary EC, Exon 51, on steroids (N=12) Data provided by CINRG and Primary External Control. Years of Age Probability of Remaining Ambulant Kaplan-Meier Survival Estimate 1.00 0.75 0.50 0.25 0.00 0 5 10 15 20 Eteplirsen Median age of LOA not reached Median Age of N=10 ambulant patients at last 6MWT: 14.0 CINRG Median age of LOA was 13.0 95% CI: 11.5-15.0
Proportion of Patients Who Lost Ambulation Was Consistent Between Study 201/202 and 301 *Interim analysis. Only patients who completed full 96 weeks of eteplirsen treatment, with 6MWT were included in denominator (n=35). Proportion of Patients with Loss of Ambulation (%) Proportion of Patients with Loss of Ambulation at 96 Weeks (%) 2/12 5/35* 3/12
Study 201/202 vs Primary EC 6MWT Adjusting for Ability to Rise, Rise Time For 201/202 vs Primary EC, there are only 1-2 patients in each group who were unable to rise independently at Baseline Therefore, an analysis adjusting for ability to rise was not feasible An analysis was conducted adjusting for baseline rise time which resulted in a difference of 180 meters (p=0.001)
Age-Based (10 to <18 years) Slope Model Analysis Confirms that Eteplirsen Attenuates the Rate of Pulmonary Decline Pts # of Tests Study 301 42 184 Exon 51 CINRG 20 88 Pts # of Tests Study 204 20 117 Exon 51 CINRG 20 88 -3.79%/Yr -6.00%/Yr -3.66%/Yr -6.00%/Yr Study 301 Study 204
Study 301: Eteplirsen Benefit over Biomarin Placebo – Pre-specified sensitivity analysis adjusting for steroid type Parameter Study 301 Primary Efficacy (N=59) Biomarin Study 044 Placebo (N=20) Age: Mean Min, Max 9.6 (7, 16) 8.8 (7, 12) 6MWT (m): Mean Min, Max 378 (301, 450) 368 (307, 437) Steroid Type (n, %) DFZ PRD 16 (29%) 43 (71%) 11 (55%) 9 (45%) 6MWT difference from Biomarin Placebo (m) at Year 1 19.9 m (P=0.304)
Contemporary Natural History Data for PFTs (CINRG, n=397) Longitudinal Models in DMD Patients 7 Years and Older Over Time PFT assessment GC use status Change per age in 7 to 9.9 year olds Change per age in 10 to 17.9 year olds Change per age in those 18 and older N (obs) N (indiv) Coefficient (p-value) N (obs) N (indiv) Coefficient (p-value) N (obs) N (indiv) Coefficient (p-value) FVC % predicted Not on GC 63 35 -5.91 (0.002) 358 89 -6.06 (<0.001) 207 55 -2.78 (<0.001) On GC 567 168 -0.69 (0.23) 886 198 -5.44 (<0.001) 309 72 -2.30 (<0.001) % Predicted FVC On GC Not on GC On GC Not on GC On GC Not on GC 150 100 50 0 0 10 20 30 40 Age
CINRG Comparators: Address CHMP Concerns Regarding Variable Literature Dec 2016 April 2017 Nov 2017 CINRG Data*: Linear Decline Ages 10-18 CHMP (Day 180): Requested Pattern over Time for Study 201/202 Dec 2017 Mar 2018 CHMP (Day 120): UDP Age Range of 7-15.5 Too Broad and Pulmonary Literature Varied on Steroids, Age and Genotype Slope Model (10-18 years) CINRG vs. Eteplirsen 201/202, 301 and 204 CINRG Patient Level FVC%p Data (N=397) Pattern Over Time CINRG vs 201/202 *Mayer et al., US Neurology, 2017;13(1):35–41, McDonald et al. Neuromuscular Disorders, 2017; 27(2): S115–S116 Eteplirsen FVC%p vs. Literature 201/202 vs. UDP Patient Level Data (Ages 7-15.5, Partial GC) Submitted Day 180 MAA Submission
Difference in FVC%p annual change favors eteplirsen vs. external controls (Slope Models, Ages 10 - <18 years) Etep. Ctrl 12 20 42 20 20 20 12 148 42 148 20 148 N
Study 201/202: 30 mg/kg and 50 mg/kg Resulted in Similar Dystrophin Response at Week 48 Absolute Values Each bar graph N=6 Week 48
CINRG: Exon 44 vs Exon 51 Skip Amenable LoA Bello et al. Neurology. 2016; 87:4(4)401-9
Longitudinal 6MWD: Exon 44 Skip Amenable vs. Treated/Untreated Exon 51 Exon 44 N=8 Eteplirsen N=12 Untx Exon 51 N=12
Brooke Upper Extremity Functional Grade 1 2 3 4 5 6 Starting with arms at the sides, the patient can abduct the arms in a full circle until they touch above the head. Can raise arms above head only be flexing the elbow or using accessory muscles. Cannot raise arms above head but can raise an 8oz. glass of water to mouth. Can raise hands to mouth but cannot raise an 8oz. glass of water to mouth. Cannot raise hands to mouth but can use hands to hold a pen or pick up small objects from a table. Cannot raise hands to mouth and has no functional use of hands.
FVC is Related to Upper Limb Function in DMD CINRG Duchenne Natural History Study Data; n = 2311 observations. OHR = Overhead Reach Patients with no hand function have very low FVC McDonald et al. Lancet 2017
PUL Assessment Items 1 PUL entry item to define the starting functional level (similar to Brooke score) 4 items: HIGH LEVEL – SHOULDER DIMENSION 9 items: MID LEVEL – ELBOW DIMENSION includes timed items 8 items: DISTAL LEVEL – WRIST and HAND DIMENSION
Study 4658-204 PUL Middle Domain – NON AMBULATORY
Figure 8: Day 180 JRAR Clinical