8-K
PTC THERAPEUTICS, INC. (PTCT)
8-K
2023-07-19
For: 2023-07-19
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April 07, 2026
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): July 19, 2023
PTC THERAPEUTICS, INC.
(Exact Name of Company as Specified in Charter)
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|---|---|---|---|---|
| Delaware | 001-35969 | 04-3416587 | ||
| (State or Other Jurisdiction | | (Commission | | (IRS Employer |
| of Incorporation) | | File Number) | | Identification No.) |
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|---|---|---|
| 100 Corporate Court | | |
| South Plainfield , NJ | | 07080 |
| (Address of Principal Executive Offices) | | (Zip Code) |
Registrant’s telephone number, including area code: (908) 222-7000
Not applicable
(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))
Securities registered pursuant to Section 12(b) of the Act:
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|---|---|---|---|---|
| Title of each class | **** | Trading Symbol(s) | **** | Name of each exchange on which registered |
| Common Stock, $0.001 par value per share | | PTCT | | Nasdaq Global Select Market |
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.
As previously announced, PTC Therapeutics, Inc. (the “Company”) will provide a virtual presentation on phenylketonuria (“PKU”) including discussion of the current therapeutics and commercial landscape with an expert key opinion leader (the “Presentation”) on July 19, 2023 at 12:00 p.m. eastern time. The Company’s corporate presentation slide deck, which includes updated regulatory timelines to be referenced as part of the Presentation, has been posted on the Events and Presentations page under the Investors section of the Company’s website. A copy of the slide deck is also attached to this Current Report on Form 8-K (this “Report”) as Exhibit 99.1 and is incorporated by reference into this Item 7.01.
The information in this Item 7.01 of this Current Report on Form 8-K, including Exhibit 99.1, shall not be deemed “filed” for 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, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such a filing.
Item 8.01. Other Events.
The Presentation includes certain corporate updates including that (i) the Company expects to submit a New Drug Application to the U.S. Food and Drug Administration (“FDA”) for sepiapterin for the treatment of PKU in the fourth quarter of 2023, (ii) the Company expects to submit a biologics license application to the FDA for Upstaza for the treatment of Amino Acid Decarboxylase deficiency in the third quarter of 2023, (iii) the Company expects an opinion from the Committee for Medicinal Products for Human Use in the third quarter of 2023 regarding the Company’s Type II variation submission to the European Medicines Agency to support conversion of the conditional marketing authorization for Translarna for the treatment of nonsense mutation Duchenne muscular dystrophy (“nmDMD”) to a standard marketing authorization and (iv) the Company is preparing to request Type C meetings with the FDA to discuss the potential NDA resubmission for Translarna in the United States, as well as to discuss the potential for an NDA submission for vatiquinone based on the recently released results from its Phase 3 trial of vatiquinone in children and young adults with Friedreich ataxia.
Forward Looking Statements: All statements, other than those of historical fact, contained in this Current Report on Form 8-K, are forward-looking statements, including reporting expectations with respect to regulatory submissions and potential approvals. The Company's actual results, performance or achievements could differ materially from those expressed or implied by forward-looking statements it makes as a result of a variety of risks and uncertainties including those related to: expectations with respect to potential regulatory submissions and commercialization of sepiapterin for PKU; expectations with respect to Upstaza, including any regulatory submissions and potential approvals, commercialization and manufacturing capabilities; the Company’s ability to utilize results from Study 041, a randomized, 18-month, placebo-controlled clinical trial of Translarna for the treatment of nmDMD followed by an 18-month open-label extension, to support a marketing approval for Translarna for the treatment of nmDMD in the United States and a conversion to a standard marketing authorization in the European Economic Area (“EEA”); the Company’s ability to complete Study 041, which is a specific obligation to continued marketing authorization in the EEA; the Company’s ability to utilize results from Study 041, a randomized, 18-month, placebo-controlled clinical trial of Translarna for the treatment of nmDMD followed by an 18-month open-label extension, to support a conversion to a standard marketing authorization in the EEA; and the factors discussed in the “Risk Factors” section of the Company's Annual Report on Form 10-K for the year ended December 31, 2022 as well as any updates to these risk factors filed from time to time in the Company's other filings with the Securities and Exchange Commission. You are urged to carefully consider all such factors. The forward-looking statements contained herein and the exhibits hereto represent the Company's views only as of the date of this Current Report on Form 8-K and the Company does not undertake or plan to update or revise any such forward-looking statements to reflect actual results or changes in plans, prospects, assumptions, estimates or projections, or other circumstances occurring after the date of this Current Report on Form 8-K except as required by law.
Item 9.01. Financial Statements and Exhibits.
(d) Exhibits
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| Exhibit No. | Description | |
| 99.1 | | Corporate Presentation – PKU Deep Dive |
| 104 | | The cover page from this Current Report on Form 8-K, formatted in Inline XBRL |
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.
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| | PTC Therapeutics, Inc. | |
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| Date: July 19, 2023 | By: | /s/ Mark E. Boulding |
| | Name: | Mark E. Boulding |
| | Title: | Executive Vice President and Chief Legal Officer |
Exhibit 99.1
| Patient Living<br>with PKU<br>July 19, 2023<br>PTC Therapeutics<br>PKU Deep Dive |
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| This presentation contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. All statements contained in this presentation, other than<br>statements of historic fact, are forward-looking statements, including statements with respect to (i) 2023 total revenue guidance and (ii) 2023 net product revenue guidance for the DMD franchise,<br>statements with respect to the future expectations, plans and prospects for PTC, including with respect to the expected timing of clinical trials and studies, availability of data, regulatory<br>submissions and responses and other matters, future operations, future financial position, future revenues, projected costs; and the objectives of management. Other forward-looking statements<br>may be identified by the words, "guidance", "plan," "anticipate," "believe," "estimate," "expect," "intend," "may," "target," "potential," "will," "would," "could," "should," "continue," and similar<br>expressions.<br>PTC's actual results, performance or achievements could differ materially from those expressed or implied by forward-looking statements it makes as a result of a variety of risks and uncertainties,<br>including those related to: the outcome of pricing, coverage and reimbursement negotiations with third party payors for PTC's products or product candidates that PTC commercializes or may<br>commercialize in the future; expectations with respect to potential regulatory submissions and commercialization of sepiapterin for phenylketonuria, or PKU, and potential development<br>and regulatory milestone payments that PTC may be obligated to make with regards to sepiapterin; expectations with respect to Upstaza, including any regulatory submissions and potential<br>approvals, commercialization, manufacturing capabilities and the potential financial impact and benefits of its leased biologics manufacturing facility and the potential achievement of development,<br>regulatory and sales milestones and contingent payments that PTC may be obligated to make; PTC's ability to maintain its marketing authorization of Translarna for the treatment of nmDMD in<br>Brazil, Russia, the European Economic Area (EEA) and other regions, including whether the European Medicines Agency (EMA) determines in future annual renewal cycles that the benefit-risk<br>balance of Translarna authorization supports renewal of such authorization; PTC's ability to complete Study 041, which is a specific obligation to continued marketing authorization in the EEA;<br>PTC's ability to utilize results from Study 041, a randomized, 18-month, placebo-controlled clinical trial of Translarna for the treatment of nmDMD followed by an 18- month open-label extension,<br>to support a marketing approval for Translarna for the treatment of nmDMD in the United States and a conversion to a standard marketing authorization in the EEA; expectations with respect to<br>the commercialization of Evrysdi under our SMA collaboration; expectations with respect to the commercialization of Tegsedi and Waylivra; significant business effects, including the effects of<br>industry, market, economic, political or regulatory conditions; changes in tax and other laws, regulations, rates and policies; the eligible patient base and commercial potential of PTC's<br>products and product candidates; PTC's scientific approach and general development progress; PTC's ability to satisfy its obligations under the terms of its lease agreements, including for its<br>leased biologics manufacturing facility; PTC's ability to satisfy its obligations under the terms of the secured credit facility with Blackstone; the sufficiency of PTC's cash resources and its ability to<br>obtain adequate financing in the future for its foreseeable and unforeseeable operating expenses and capital expenditures; and the factors discussed in the "Risk Factors" section of PTC's most<br>recent Annual Report on Form 10-K, as well as any updates to these risk factors filed from time to time in PTC's other filings with the SEC. You are urged to carefully consider all such factors.<br>As with any pharmaceutical under development, there are significant risks in the development, regulatory approval and commercialization of new products. There are no guarantees that any<br>product will receive or maintain regulatory approval in any territory, or prove to be commercially successful, including Translarna, Emflaza, Upstaza, Evrysdi, Tegsedi, Waylivra or sepiapterin.<br>The forward-looking statements contained herein represent PTC's views only as of the date of this presentation and PTC does not undertake or plan to update or revise any such forward-looking<br>statements to reflect actual results or changes in plans, prospects, assumptions, estimates or projections, or other circumstances occurring after the date of this presentation except as required<br>by law.<br>2<br>Forward-Looking Statements<br>PKU Presentation |
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| Matt Klein<br>Chief Executive Officer,<br>PTC Therapeutics<br>Ania Muntau<br>Professor of Pediatrics, Chair,<br>University Children's Hospital,<br>University Medical Center,<br>Hamburg Eppendorf, Germany<br>3<br>Kylie O’Keefe<br>Chief Commercial Officer,<br>PTC Therapeutics<br>PKU Presentation<br>Presenters |
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| Agenda<br>4 PKU Presentation<br>Commercial Landscape for Sepiapterin<br>2 Clinical Practice in PKU<br>3<br>1 Overview of PTC and Sepiapterin |
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| Continued Success Across Our Commercial Portfolio<br>5 PKU Presentation<br>Distributed in<br>50+ countries with<br>continued growth from<br>new patients and<br>geographic expansion<br>First and only<br>corticosteroid for all US<br>DMD patients with<br>growth from new<br>patient starts and<br>favorable access<br>Established market<br>leadership in all major<br>markets with continued<br>growth expected<br>For treatment of hATTR<br>with LATAM patients<br>benefiting through early-access programs<br>For treatment<br>of FCS and FPL, with<br>LATAM patients<br>benefiting through<br>early-access programs<br>First EMA-approved<br>disease-modifying<br>treatment for AADC<br>deficiency for patients<br>18 months and older |
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| Strong Commercial Revenue Guidance for 2023<br>$395 - $435M<br>Other<br>$545 - $565M<br>DMD<br>6 PKU Presentation<br>$940M-$1B |
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| 7 PKU Presentation<br>Substantial Pipeline Progress Expected in H2 2023<br>Translarna FDA<br>Type C Meeting<br>H2<br>Upstaza BLA<br>Submission<br>Q3<br>Vatiquinone FA FDA<br>Type C Meeting<br>H2<br>Sepiapterin NDA<br>Submission<br>Q4<br>Translarna CHMP<br>Type II Variation<br>Opinion<br>Q3<br>Clinical Trials<br>Regulatory<br>Activities* |
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| APHENITY<br>Topline Results<br>8 PKU Presentation |
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| APHENITY Topline Results Demonstrate Clinical<br>and Statistically Significant Benefit<br>Achieved primary endpoint in<br>placebo-controlled portion of<br>study with statistically<br>significant (p<0.0001) blood<br>phenylalanine (Phe) reduction<br>Demonstrated substantial<br>Phe reduction in both the<br>overall primary analysis<br>population (63%) and the<br>subset of classical PKU<br>patients (69%)<br>Achieved Phe reduction<br>sufficient to bring 84% of study<br>patients within US guidelines<br>for Phe reduction <360 µmol/L<br>Well tolerated with no serious<br>adverse events<br>9 PKU Presentation |
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| Sepiapterin Treatment Resulted in Clinically<br>Significant Blood Phe Reduction<br>-70<br>-60<br>-50<br>-40<br>-30<br>-20<br>-10<br>0<br>10<br>Sepiapterin<br>Overall Primary Analysis Population Classical PKU Patients<br>Mean % Blood Phe<br>Reduction<br>Mean % Blood Phe<br>Reduction<br>N=49<br>63% 586<br>464<br>1%<br>N=49<br>-70<br>-60<br>-50<br>-40<br>-30<br>-20<br>-10<br>0<br>10<br>Sepiapterin Placebo<br>N=6<br>69%<br>3%<br>N=9<br>(p<0.0001) (p<0.001)<br>10 PKU Presentation<br>Mean % Blood Phe Reduction<br>Placebo |
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| EU guidelines: ≥12 years of age<br>Vast Majority of Patients Achieved Guidelines<br>Target Blood Phe Levels<br>93%<br>Achieved<br><600µmol/L<br>Blood Phe<br>US guidelines: all ages<br>EU guidelines: <12 years of age<br>84%<br>Achieved<br><360µmol/L<br>Blood Phe<br>11 PKU Presentation |
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| Sepiapterin Part 1 Treatment Effect in Patients<br>Receiving Sapropterin at Study Entry<br>800<br>700<br>600<br>500<br>400<br>300<br>200<br>100<br>0<br>Mean Blood Phe (µmol/L)<br>(N=27 patients)<br>Mean blood Phe on<br>sapropterin (µmol/L)<br>at study entry<br>Mean blood Phe (µmol/L)<br>following 7-day washout<br>Mean blood Phe (µmol/L)<br>on sepiapterin in Part 1<br>48%<br>lower Phe levels<br>following sepiapterin<br>treatment in those<br>patients receiving<br>sapropterin at study<br>entry<br>Guideline<br>Target<br>12 PKU Presentation |
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| 0<br>20<br>40<br>60<br>80<br>100<br>120<br>140<br>M1 W1-W2 (BL)<br>M2 W1-W2<br>M2 W3-W4<br>M3 W5-W6<br>M3 W7-W8<br>M4 W9-W10<br>M4 W11-W12<br>M5 W13-W14<br>M5 W15-W16<br>M6 W17-W18<br>M6 W19-W20<br>M7 W21-W22<br>Initial Phe Tolerance Data in Open-Label Extension Prescribed Phe Consumption (mg/kg/day)<br>Adult recommended<br>Phe intake<br>(N=12) (N=4)<br>0<br>50<br>100<br>150<br>200<br>250<br>300<br>M1 W1-W2 (BL)<br>M1 W3-W4<br>M2 W1-W2<br>M3 W5-W6<br>M4 W9-W10<br>M5 W13-W14<br>M6 W17-W18<br>M7 W21-W22<br>Mean Blood Phe<br>(µmol/L)<br>(N=12) (N=4)<br>Increase in Dietary Phe Intake Blood Phe Levels<br>13 PKU Presentation |
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| Agenda<br>14 PKU Presentation<br>Commercial Landscape for Sepiapterin<br>2 Clinical Practice in PKU<br>3<br>1 Overview of PTC and Sepiapterin |
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| Overview of Phenylketonuria (PKU)<br>1. Blau N, et al. The Lancet. 2010;376:1417-1427. 2. Mitchell JJ, et al. Genet Med. 2011;<br>13:697-707. 3. Hillert, et al. The American Journal of Human Genetics 2020;107,1-17. 15 PKU Presentation<br>Both environment (dietary<br>intake of Phe) and genotype<br>are causal components of PKU<br>PAH genotype may not predict the<br>clinical phenotype or be used to<br>evaluate or treat the disease2<br>Variants in PAH, the gene that<br>encodes PAH, lead to impaired<br>PAH function and cause PKU 1<br>More than 1,000 variants in the human<br>PAH gene have been identified1,3<br>PKU is an inherited, autosomal<br>recessive condition1 |
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| The Role of PAH in Phe Metabolic Pathway<br>Blau N, et al. 2010<br>Phenylalanine Hydroxylating System2<br>GTP<br>GTPCH<br>PTPS<br>SR<br>NAD+<br>DHPR<br>NADH<br>H2O<br>PCD<br>q-dihydrobiopterin<br>4a-hydroxy-BH4<br>Fe+2<br>O2<br>Tyrosine<br>Phenylalanine<br>BH4<br>LIVER PAH<br>PAH catalyzes the first and rate-limiting step in the metabolic pathway<br>of Phe, conversion of Phe to Tyr1<br>BH4 corrects misfolding and early<br>degradation of PAH and by this<br>improves in-vivo PAH enzyme<br>activity2<br>Impaired PAH enzymic function leads<br>to a systemic accumulation of Phe<br>16 PKU Presentation DHPR, dihydropteridine; GTP, guanosine triphosphate; GTPCH, GTP cyclohydrolase; HPA, hyperphenylalaninemia; PAH, phenylalanine hydroxylase; PCD, carbinolamie-4a-dydropterin; Phe, phenylalanine;<br>PTPS, 6-pyruvoyl-tetra-hydopterin synthase. 1. Flydal MI, Martinez A. IUBMB Life. 2013;65:341-349. 2. Blau N, et al. The Lancet. 2010;376:1417-1427. |
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| Elevated Blood Phe Interferes With Normal Production of<br>Neurotransmitters and Leads to PKU<br>17 PKU Presentation<br>Excessive Phe Impact<br>Elevated blood Phe level<br>and accumulation of Phe in<br>the brain is toxic to the central<br>nervous system and impairs<br>neurological functions<br>White matter lesion and<br>reduced myelin production<br>Reduced cerebral glucose<br>metabolism<br>LNAA deficiency due to Phe-mediated competition for LAT1<br>Neurotransmitter deficiency<br>Formation of amyloid-like<br>Phe aggregates<br>Alteration of methylation<br>pattern of a panel of genes<br>Oxidative stress<br>Cardiovascular and renal effects<br>Phe, phenylalanine; PKU, phenylketonuria.<br>van Spronsen FJ, et al. Nat Rev Dis Primers. 2021;7:36. |
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| PKU Severity Is Associated With Higher Blood Phe Levels and<br>Decreasing Phe Tolerance<br>• Patients with PKU are<br>intolerant of dietary<br>intake of the essential<br>amino acid Phe11<br>18 PKU Presentation<br>Blood Phe level<br>Normal Mild HPA Mild/Moderate PKU Severe PKU<br>Dietary Phe<br>tolerance<br>50–110 µmol/L<br>120–600 µmol/L<br>600–1,200 µmol/L<br>>1,200 µmol/L<br>250–300 mg<br>350–400 mg<br>400–600 mg<br>Complete<br>to near-complete loss<br>of PAH function<br>Normal PAH function Partially inhibited PAH function<br>PAH variants<br>associated<br>with loss of<br>PAH function<br>HPA, hyperphenylalaninemia; PAH, phenylalanine hydroxylase; Phe, phenylalanine; PKU, PKU, phenylketonuria. 1 Blau N, et al. The Lancet. 2010;376:1417-1427. |
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| PKU Management Guidelines<br>ACMG (US) TREATMENT GUIDELINES1 EU TREATMENT GUIDELINES 2<br>The treatment of PKU should be initiated as<br>early as possible.<br>No intervention is required if the blood phenylalanine concentration is less<br>than 360 μmol/L. Treatment is recommended up to the age of 12 years if the<br>phenylalanine blood concentration is between 360 μmol/L and 600 μmol/L,<br>and lifelong treatment is recommended if the concentration is more than 600<br>μmol/L.<br>Treatment is lifelong with a goal of maintaining<br>blood phe levels in the range of 120-360<br>µmol/l (2-6 mg/dl) in patients of all ages.<br>Treatment target concentrations are as follows: 120–360 μmol/L for<br>individuals aged 0–12 years and for maternal PKU, and 120–600 μmol/L for<br>non-pregnant individuals older than 12 years.<br>• Guidelines focus on Phe levels that are 10x normal levels<br>19 PKU Presentation 1Vockley, Andersson, Antshel et al, Phenylalanine hydroxylase deficiency: diagnosis and management guideline, Genetics in Medicine, 2014, doi:10-1038/gim.2013.57 and Singh, Rohr, Frazier, etc al, Recommendations for the nutrition<br>management of phenylalanine hydroxylase deficiency, Genetics in Medicine, 2014, doi:10- 1038/gim.2013.179. 2van Wegberg AMJ, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M,<br>Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, van Rijn M, Trefz F, Walter JH, van Spronsen FJ. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017 Oct 12;12(1):162. |
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| Types of<br>Dietary Treatment<br>Barriers to<br>Long-Term Continuation<br>Lifelong Diet Restrictions Remain a Key Requirement for<br>PKU Patients<br>Low-protein diet<br>Phe-free medicinal foods<br>Modified low-protein products<br>Glycomacropeptide<br>High concentration of LNAA<br>Palatability, lack of variety of PKU diet<br>Prohibitive costs of medicinal foods<br>Potential lack of insurance coverage<br>Risk of malnutrition<br>Increased GI issues from microbiome<br>Social barriers<br>20 PKU Presentation LNAA, large neutral amino acid; Phe, phenylalanine, PKU, phenylketonuria.<br>Lowe TB, et al. Orphanet J Rare Dis. 2020;15:266. |
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| Diet Restrictions Alone Result in Suboptimal Outcomes<br>Suboptimal Outcomes in PKU Treated With Dietary Treatment Alone<br>Despite early and<br>continuous<br>management of diet<br>alone, PKU patients<br>may experience<br>cognitive symptoms as<br>well as emotional and<br>behavioral problems<br>Adults<br>• Depressed mood<br>• Generalized anxiety<br>• Phobias<br>• Decreased positive emotions<br>• Social maturity deficit<br>• Social isolation<br>• Low bone density<br>Children and Adolescents<br>• Poor academic performance<br>due to PKU-related suboptimal<br>learning capability<br>• Executive function abnormalities<br>• Reduced processing speeds<br>• Impaired bone formation<br>21 PKU Presentation PKU, phenylketonuria.<br>Enns GM, et al. Mol Genet Metab. 2010;101:99--109. |
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| Two Main Goals of Therapy for PKU Patients<br>22 PKU Presentation<br>Decreased Blood<br>Phe Levels<br>Increased Dietary<br>Protein Intake<br>(Phe Tolerance) |
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| Clinician-Reported Challenges With Two Currently<br>Approved Treatments for PKU<br>23 PKU Presentation<br>Indication: For adult and pediatric patients ≥1 month Indication: Adults who have uncontrolled blood Phe<br>(>600 µmol/L) on existing management<br>Clinician Reported Challenges<br>• Sapropterin has a limited response rate and Phe<br>reduction, both initially and over time<br>• Classical PKU patients receive little to no Phe<br>reduction from sapropterin<br>Clinician Reported Challenges1,2<br>• Palynziq is indicated only for adults<br>• Demonstrated safety issues, including anaphylaxis<br>• Inconvenient injectable administration, and<br>lengthy titration process<br>2PALYNZIQ label (pegvaliase-pqpz) – Accessdata.fda.gov, 3Kramer, J. et al. Mol Genet Metab 2023; 139: 1-9 |
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| Mechanistic Advantages of Sepiapterin Over Sapropterin<br>GI Tract Plasma<br>Co-Factor Therapies<br>Cell Membrane<br>Intracellular (liver, brain, kidney)<br>Synthetic<br>Sepiapterin<br>(PTC923)<br>Rapid Cross-Membrane Active Transport Sepiapterin<br>Sepiapterin reductase<br>Oxidation<br>Synthetic BH4<br>(Kuvan® or<br>sapropterin)<br>BH4<br>BH2<br>Inefficient<br>Cross-Membrane<br>Active Transport<br>Kidney<br>Clearance<br>7.8-Dihydrobiopterin (BH2)<br>Dihydrofolate reductase<br>Tetrahydrobiopterin (BH4)<br>24 PKU Presentation |
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| Additive Effects of Sepiapterin<br>Sepiapterin is actively<br>transported to misfolded<br>variant PAH tetramers inside a<br>cell and converted to BH4 in<br>pharmacologic concentrations<br>25 PKU Presentation<br>SP<br>SP<br>BH4 Sepiapterin (SP)<br>Tetrahydrobiopterin (BH4)<br>Misfolded PAH<br>Functional PAH |
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| Additive Effects of Sepiapterin<br>26 PKU Presentation<br>Sepiapterin and BH4 act as<br>pharmacological chaperones<br>by binding to variant PAH,<br>correcting the conformational<br>structure of the tetramer and<br>promoting metabolism of<br>Phe to Tyr<br>SP<br>Sepiapterin (SP)<br>Tetrahydrobiopterin (BH4)<br>Misfolded PAH<br>Functional PAH |
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| Additive Effects of Sepiapterin<br>27 PKU Presentation<br>SP<br>Sepiapterin (SP)<br>Tetrahydrobiopterin (BH4)<br>Misfolded PAH<br>Functional PAH |
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| Potential for Sepiapterin to Address Majority<br>of PKU Patients<br>Sepiapterin<br>Patient<br>Segments<br>Therapy-Naive<br>Patients Including<br>Classical PKU<br>Patients Who Are<br>Not Well Controlled<br>Patients Who<br>Have Failed on<br>Current Therapies<br>28 PKU Presentation |
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| Unmet Need Remains in PKU That Can Potentially Be<br>Addressed by Sepiapterin<br>Sepiapterin has potential advantages over<br>both sapropterin and Palynziq and can<br>potentially treat a broader range of PKU<br>patients<br>PKU leads to a toxic accumulation of Phe<br>in the brain and must be treated from birth<br>Current therapies are not suitable for all PKU<br>patients, and a large unmet need remains<br>29 PKU Presentation |
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| Agenda<br>30 PKU Presentation<br>Commercial Landscape for Sepiapterin<br>2 Clinical Practice in PKU<br>3<br>1 Overview of PTC and Sepiapterin |
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| Unmet Need<br>in PKU<br>31 PKU Presentation |
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| Large Unmet Need Remains in PKU<br>32<br>of patients are<br>well-controlled<br>on Kuvan<br>Less than<br>patients globally<br>58,000 10%<br>60% poorly<br>controlled<br>40% well<br>controlled<br>Up to<br>70%<br>fail<br>~30%<br>respond<br>PKU Presentation 1. BioMarin first quarter 2021 presentation 1Q 2021. 2. Third party reports prepared for PTC<br>30%<br>therapy naïve<br>including classical<br>PKU<br>70%<br>tried Kuvan |
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| The PKU Patient Journey Begins at Birth and Continues<br>Throughout Life<br>33 PKU Presentation<br>Newborn<br>Screening<br>Geneticist/Pediatric Metabolic<br>Specialist & Dietitian<br>Life-long Protein Restriction,<br>Medical Foods & Formulas<br>Social Isolation, Anxiety,<br>Depression, Fatigue |
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| Key Issues in PKU Management<br>34 PKU Presentation<br>The consequences of lack of<br>effective Phe control can be<br>devastating to the quality of<br>life for these patients and<br>irreversible in terms of<br>intellectual disability<br>A large majority of PKU<br>patients are not well-controlled<br>on any approved treatment or<br>combination of treatments<br>The majority of PKU patients<br>on diet alone do not achieve<br>effective Phe control by early<br>adulthood due to<br>difficulty staying on the<br>unpalatable, expensive foods<br>and medical formulas required |
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| Two Main Goals of Therapy for PKU Patients<br>35 PKU Presentation<br>Decreased Blood<br>Levels Phe<br>Increased Dietary<br>Protein Intake<br>(Phe Tolerance)<br>Decreased Blood<br>Phe Levels |
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| Significant Correlation Between Blood Phe Level and IQ<br>36 PKU Presentation 1 Waisbren et al. Mol Genet Metab (2007) Sep-Oct;92(1-2):63-70<br>Correlations between Phe level<br>and intelligence quotient (IQ)<br>were extracted from 40 studies<br>and confirmed a significant<br>correlation between blood<br>Phe level and IQ1<br>Each 100 µmol/l<br>increase in Phe predicted a<br>1.9 to 4.1<br>point reduction in IQ |
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| Two Main Goals of Therapy for PKU Patients<br>37 PKU Presentation<br>Decreased Blood<br>Levels Phe<br>Dietary Protein<br>Increase<br>(Phe Tolerance)<br>Increased Dietary<br>Protein Intake<br>(Phe Tolerance) |
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| Keeping a Strict Diet Is the Largest Burden and Makes<br>Patients Constantly Feel Frustrated and Extremely Limited<br>38 TRINITY US Qualitative Interviews (N=20 HCPs; N=10 PKU Patients)<br>Patients were asked their current feelings<br>about their dietary restrictions<br>• Patients currently feel limited, frustrated, and<br>anxious regarding their current PKU situation<br>• The inability to eat the same foods as their<br>friends and having limited options at<br>restaurants and school cafeterias heighten<br>these unpleasant emotions<br>• Easing diet restriction is the primary driver<br>for patients to seek more therapeutic options<br>Stressed<br>Limited<br>Frustrated<br>Anxious<br>Disappointed<br>Annoyed Concerned<br>Controlled<br>PKU Presentation |
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| Breakfast<br>§ 2 eggs scrambled with cheese = 18g<br>§ 2 pieces of bacon = 6g<br>§ ½ cup breakfast potatoes = 2.3g<br>Lunch<br>§ turkey wrap = 24g<br>§ Lays potato chips = 2g<br>§ chocolate chip cookie = 1.5g<br>§ Diet Coke = 0g<br>Dinner<br>§ grilled chicken = 55g<br>§ ½ cup broccoli =1.25g<br>§ side salad = 2.2g<br>§ piece of bread with butter = 3g<br>TOTAL PROTEIN = 115.25g<br>Diet for Non PKU Patient<br>39 PKU Presentation<br>Diet for PKU Patient |
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| The Burden of a PKU Diet is Substantial<br>40<br>What is in 5-10g of protein a day?<br>2g of protein 1-2g of protein 6g of protein<br>PKU Presentation<br>Avoid all high<br>protein foods<br>Limited natural protein:<br>under 10g/day<br>Very low protein<br>foods allowed<br>Protein substitute – must be taken at least 3 times daily<br>Special low protein<br>prescription foods<br>Some fruit and veg |
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| Patient<br>Perspective<br>41 PKU Presentation |
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| Patients Want a Treatment That Allows Them to Liberalize Their Diet<br>While Decreasing the Inconveniences of Some Side Effects<br>44<br>Decreasing Importance<br>TRINITY US Qualitative Interviews (N=20 HCPs; N=10 PKU Patients)<br>• Patients mentioned that ease of use<br>includes route of administration,<br>dosing options, and easy storage<br>• Patients are concerned about<br>potential side effects, especially<br>those that are serious and/or<br>persistent<br>• Patients want a treatment that will<br>reduce the Phe levels significantly<br>1. Allow them to eat more protein<br>and liberalize their diet<br>2. Improve their cognitive<br>fog and focus<br>Efficacy Safety Ease of Use<br>PKU Presentation |
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| Physician<br>Perspective<br>45 PKU Presentation |
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| Blood Phe Reduction and Phe Tolerance Are the Most<br>Important Drivers for HCPs<br>48 TRINITY US Qualitative Interviews (N=20 HCPs; N=10 PKU Patients)<br>The goal of PKU treatment is<br>to get patient’s Phe levels into<br>a target range (120-360µM/L)<br>Physicians place high<br>importance on Phe tolerance<br>due to issues with outcomes<br>from diet alone<br>Blood Phe Reduction Phe Tolerance Quality of Life<br>PKU Presentation |
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| 0% 10% 20% 30% 40% 50% 60% 70% 80%<br>Physicians Expect 30%-50% Phe Reduction from Baseline<br>for a First-Line PKU Therapy<br>49<br>Percent Change of Phe<br>Reduction from Baseline<br>Response Rate<br>Minimum Value<br>Ideal Value<br>PKU Presentation TRINITY US Qualitative Interviews (N=20 HCPs; N=10 PKU Patients) (Data on File)<br>APHENITY Topline Results |
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| Commercial<br>Launch Strategy<br>50 PKU Presentation |
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| APHENITY Results Support Potential for<br>Sepiapterin to Address Majority of PKU Segments<br>Therapy-Naive<br>Patients Including<br>Classical PKU<br>Patients Who Are<br>Not Well Controlled<br>Patients Who<br>Have Failed on<br>Current Therapies<br>51<br>Sepiapterin<br>Addressable<br>Population<br>PKU Presentation<br>~15-30% Target PKU Patients |
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| Commercial Pillars for Success Already Established<br>Newborn<br>screening with<br>~58,000 patients<br>worldwide1,2,3<br>Well-known<br>metabolic centers<br>of excellence<br>worldwide<br>Connected and<br>coordinated<br>patient advocacy<br>community<br>Disease pathology<br>well understood<br>and documented<br>52 PKU Presentation 1. NPKUA; https://www.npkua.org/, 2. Shoraka et. Al, Clin Exp Pediatr. 2020; 63(2): 34–43., 3. Borrajo G., Acta Ped Mex. 2012; 33(6): 279-287. |
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| PTC Global Commercial Infrastructure Will<br>Allow for Rapid Worldwide Launch<br>KOL/ Payor<br>Relationships<br>PAG Relationships<br>Patient<br>Support<br>Dedicated<br>Customer Facing<br>Teams<br>EAP/<br>Access &<br>Reimbursement<br>Plug and Play in PKU<br>53 PKU Presentation |
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| Understanding the Cross-Functional Team at PKU Clinics<br>54<br>Patients<br>Dietitian Geneticist<br>Pediatric<br>Metabolic<br>Specialist<br>Nurse Practitioners Endocrinologist<br>Neurologists<br>PKU Presentation |
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| We Have a Deep Understanding of US PKU Treaters<br>and How to Reach Them<br>55<br>For each US HCP we have<br>visibility into:<br>• First/Last Name<br>• Provider taxonomies and demographics<br>• Affiliation Hierarchy<br>• Institutional vs Professional claim types,<br>with differentiation of treatment settings<br>• Line-item charge details for visit types,<br>procedures, and prescriptions<br>• Patient makeup and volume<br>• Professional practice address<br>• Email<br>• NPI number, which is used for one-to-one<br>media targeting and sales call planning<br>Lucid Connected Intelligence Real-World Claims Data<br>~500 HCPs<br>Kuvan Writers<br>Medical<br>Genetics<br>34%<br>NP/PA<br>22%<br>Pediatrics<br>15%<br>Internal<br>Medicine<br>8%<br>Family<br>Medicine<br>8%<br>Other<br>Specialties<br>7%<br>Psychiatry &<br>Neurology<br>6%<br>Treating ~3,000 PKU patients<br>~150 HCPs<br>Palynziq Writers<br>Medical<br>Genetics<br>53%<br>NP/PA<br>27%<br>Pediatrics<br>13%<br>Internal<br>Medicine<br>3%<br>Family<br>Medicine<br>3%<br>Treating ~1,000 PKU patients<br>Overlap exists between KUVAN and PALYNZIQ writers<br>PKU Presentation<br>Other<br>Specialties<br>1%<br>Psychiatry &<br>Neurology<br>0.68% |
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| Initial Areas for New Treatment Consideration<br>Have Been Identified<br>56<br>~60 HCPs<br>Kuvan and/or Palynziq<br>Writers With<br>Lapsed Patients<br>Real-world data reveals a valuable opportunity among clinicians with lapsed Kuvan & Palynziq users<br>Patients per Zip<br>1<br>4<br>Lapsed Kuvan Patients<br>Lapsed Palynziq Patients<br>Prescribing HCPs With Lapsed Patients<br>5 HCPs<br>2 HCPs<br>1 HCPs<br>4 HCPs<br>1 HCPs<br>1 HCPs<br>2 HCPs<br>2 HCPs<br>6 HCPs<br>1 HCPs<br>1 HCPs<br>2 HCPs<br>2 HCPs<br>2 HCPs 3 HCPs 5 HCPs<br>1 HCPs<br>5 HCPs<br>2 HCPs<br>1 HCPs<br>1 HCPs<br>1 HCPs<br>1 HCPs<br>3 HCPs 5 HCPs<br>3 HCPs<br>PKU Presentation Lucid Connected Intelligence Real-World Claims Data |
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| Key Professional Associations & Patient Advocacy Groups<br>Scientific Medical Associations:<br>Dietitian/Nutritionist Associations:<br>Patient Advocacy Groups:<br>57 PKU Presentation |
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| Setting the Launch Strategy for an Effective PKU Treatment<br>That Works for More Patients<br>58<br>• Amplify strong clinical data and MOA<br>• Physician and Patient Education<br>Programs<br>• Leverage advocates<br>• Provide superior patient support<br>• Pricing/reimbursement strategy<br>• Early access programs<br>Build Confidence Establish Differentiation Ensuring Access<br>in the efficacy and<br>safety of sepiapterin at<br>launch<br>through the clinical<br>body of evidence<br>to the broadest range of<br>PKU patients<br>PKU Presentation |
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| APHENITY Results Support Next Steps in the<br>Regulatory Process and Commercial Planning<br>Pre-Submission<br>Meetings<br>Regulatory<br>Submissions<br>Initiate Launch<br>Preparation<br>59 PKU Presentation |
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