8-K
PTC THERAPEUTICS, INC. (PTCT)
8-K
2021-04-15
For: 2021-04-15
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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): April 15, 2021
PTC THERAPEUTICS, INC.
(Exact Name of Company as Specified in Charter)
| | | | | |
|---|---|---|---|---|
| Delaware | 001-35969 | 04-3416587 | ||
| (State or Other Jurisdiction | | (Commission | | (IRS Employer |
| of Incorporation) | | File Number) | | Identification No.) |
| | | |
|---|---|---|
| 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:
| | | | | |
|---|---|---|---|---|
| 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 host a webinar on April 15, 2021 at 9:00 a.m. eastern time. During this webinar, the Company expects to discuss its PTC518 Huntington’s disease program and provide preliminary results from its Phase 1 study of PTC518 in healthy volunteers. A copy of the slide deck that will be presented during the webinar is attached as Exhibit 99.1.
The information in 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. All website addresses given in this Current Report or incorporated herein by reference are for information only and are not intended to be an active link or to incorporate any website information into this Current Report.
Item 9.01. Financial Statements and Exhibits.
(d) Exhibits
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|---|---|---|
| Exhibit No. | Description | |
| 99.1 | | Corporate Presentation – PTC518 Huntington’s Disease Deep Dive Webinar |
| 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. | |
| | | |
| Date: April 15, 2021 | By: | /s/ Emily Hill |
| | Name: | Emily Hill |
| | Title: | Chief Financial Officer |
Exhibit 99.1
| PTC518 Huntington’s<br>Disease Deep Dive<br>April 15th, 2021 |
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| Forward Looking Statements:<br>This presentation contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of<br>1995. All statements contained in this release, other than statements of historic fact, are forward -looking statements, including<br>statements with respect to the future expectations, plans and prospects for PTC, PTC's strategy, including with respect to th e<br>expected timing of clinical trials and studies, availability of data, regulatory submissions and responses and other matters,<br>future operations, future financial position, future revenues, projected costs; and the objectives of management. Other forwa rd-<br>looking statements may be identified by the words "guidance", "plan," "anticipate," "believe," "estimate," "expect," "intend, "<br>"may," "target," "potential," "will," "would," "could," "should," "continue," and similar expressions.<br>PTC's actual results, performance or achievements could differ materially from those expressed or implied by forward -looking<br>statements it makes as a result of a variety of risks and uncertainties, including those related to: the outcome of pricing,<br>coverage and reimbursement negotiations with third party payors for PTC's products or product candidates that PTC<br>commercializes or may commercialize in the future; the enrollment, conduct, and results of ongoing studies under the SMA<br>collaboration and events during, or as a result of, the studies that could delay or prevent further development under the<br>program, including any regulatory submissions and commercialization with respect to Evrysdi; significant business effects,<br>including the effects of industry, market, economic, political or regulatory conditions; changes in tax and other laws,<br>regulations, rates and policies; the eligible patient base and commercial potential of PTC's products and product candidates;<br>PTC's scientific approach and general development progress; and the factors discussed in the "Risk Factors" section of PTC's<br>most 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<br>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<br>commercialization of new products. There are no guarantees that any product will receive or maintain regulatory approval in<br>any territory, or prove to be commercially successful.<br>The forward-looking statements contained herein represent PTC's views only as of the date of this presentation and PTC does<br>not undertake or plan to update or revise any such forward-looking statements to reflect actual results or changes in plans,<br>prospects, assumptions, estimates or projections, or other circumstances occurring after the date of this presentation except as<br>required by law.<br>2 |
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| Diversified Platform Drives Strong Portfolio<br>3<br>Clinical<br>Commercial<br>Research<br>Nonsense<br>Mutation<br>LatAm<br>Commercial Deflazacort<br>Gene<br>Therapy Bio-e Metabolic Oncology<br>US Dystrophin<br>PTC-AADC<br>PTC299 AML<br>PTC596 DIPG<br>PTC596 LMS<br>Vatiquinone<br>ME<br>Vatiquinone<br>FA<br>PTC923 PKU PTC299<br>COVID-19<br>SCA-3 Undisclosed<br>MAP-Tau<br>PTC857<br>GBA-PD<br>PTC518 HD<br>Splicing Virology<br>• AADC, aromatic L-amino acid decarboxylase deficiency; AML; acute myeloid leukemia; COVID-19, coronavirus disease 2019; DIPG, diffuse intrinsic pontine glioma; FA, Friedreich’s ataxia; GBA, glucocerebrosidase; HD, Huntington‘s disease; IRD, inherited retinal dystrophy;<br>LMS, leiomyosarcoma; ME, Mitochondrial Epilepsy; PD, Parkinson’s disease; PKU, phenylketonuria; SCA-3, spinocerebellar ataxia type 3.<br>SCIENTIFIC PLATFORMS and RESEARCH<br>Potential registrational studies<br>Angelman<br>IRDs<br>Cog Disorders<br>FA |
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| PTC518 Huntington’s Disease Deep Dive Agenda<br>4<br>Preclinical Development of PTC518<br>Anu Bhattacharyya,<br>Exec. Director, Biology<br>PTC518<br>Huntington<br>Deep Dive<br>Splicing Platform and<br>Huntington’s Disease<br>Stuart Peltz, CEO<br>PTC518 Phase 1 Study<br>Matthew Klein, CDO |
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| PTC is the Leader in Splicing With 20 Years of Expertise and<br>Proven Track Record<br>5<br>Spinal muscular atrophy<br>Huntington’s disease<br>Exploiting splicing<br>Proprietary<br>systems and<br>specialty<br>libraries<br>Isoform plex<br>HTSpliceseq<br>Many additional targets<br>Databases of<br>Splicing Targets<br>Familial dysautonomia |
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| 6<br>Recognition of Pre-mRNA is Mediated by U-snRNP<br>Complexes U1 and U2<br>5’ Splice<br>Site<br>3’ Splice<br>Site<br>5’ Splice<br>Site<br>3’ Splice<br>Site<br>U1 recognizes<br>the 5’ splice site<br>at each exon<br>U2 recognizes the<br>branch site near<br>the 3’ splice site |
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| FL mRNA<br>Functional<br>SMN protein<br>Targeting Alternative Splicing of SMN2 in SMA by<br>Targeting the U1 Site<br>SMN1<br>6 8 7<br>mRNA 6 8 7<br>6 8 7<br>SMN2<br>6 8 7 6 8<br>CT<br>Truncated<br>unstable<br>SMN protein<br>ESE ESS U1<br>GA<br>U1<br>GA<br>Risdiplam<br>stabilizes U1<br>Functional<br>SMN protein<br>FL mRNA Δ7 mRNA<br>Activation Inhibition<br>7 |
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| The SMN2 5’-Splice Site Presents a Unique Structural<br>Interface for Small Molecule<br>Risdiplam<br>Canonical Duplex SMN2 Exon 7<br>8 |
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| Risdiplam SMN2 Improves the Ability of the 5’-Splice<br>Site to Promote Splicing<br>Risdiplam<br>Canonical Duplex SMN2 Exon 7<br>9 |
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| Risdiplam Increases SMN Protein in Multiple Tissues to<br>Near or Above Heterozygous Levels<br>Brain Peripheral Blood Mononuclear Cells<br>• SMN protein levels in peripheral blood cells correlate to those in brain<br>• Similar increases in SMN observed in spinal cord, muscle, heart, liver, skin<br>0<br>1 0 0<br>2 0 0<br>3 0 0<br>4 0 0<br>5 0 0<br>V ehicle<br>H e te ro z y g o u s (n o<br>d ise a se p h e n o ty p e )<br>* * *<br>* * *<br>* * *<br>S<br>M<br>N<br><br>p<br>r<br>o<br>t<br>e<br>i<br>n<br>%<br><br>i<br>n<br>c<br>r<br>e<br>a<br>s<br>e<br><br><br>S<br>E<br>M<br>2 6 10<br>D o s e (m g /k g )<br>0<br>1 0 0<br>2 0 0<br>3 0 0<br>4 0 0<br>5 0 0<br>V ehicle<br>H e te ro zyg o u s (n o<br>d ise a se p h e n o ty p e )<br>* *<br>* * *<br>* * *<br>S<br>M<br>N<br><br>p<br>r<br>o<br>t<br>e<br>i<br>n<br>%<br><br>i<br>n<br>c<br>r<br>e<br>a<br>s<br>e<br><br><br>S<br>E<br>M<br>2 6 10<br>D o s e (m g /k g )<br>10 Naryshkin et al. Science 2014<br>Oral dosing for 10 days in mild SMA mouse model |
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| 8<br>6<br>4<br>2<br>0<br>SMN Protein (ng/mL)<br>Baseline Week 4<br>Firefish Sunfish =<11yrs Sunfish >11yrs Jewelfish Healthy Volunteers<br>Risdiplam Increases SMN Protein Levels in All SMA<br>Types to the Level in Adult Healthy Subjects<br>Healthy subjects: n=49, age 18-60 years. Patients with SMA: n=84, age 3.3 months to 52 years. FIREFISH part 1 (n=21), SUNFISH part 1 (n=51), JEWELFISH (n=12). Patients on all dose levels of risdiplam have been included<br>SMA, spinal muscular atrophy; SMN, spinal motor neuron.<br>Kletzl H, et al. 23rd International Annual Congress of World Muscle Society; October 2-6, 2018; Mendoza, Argentina.<br>11 |
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| Evrysdi™ Roadmap to Success<br>12<br>Highly<br>selective<br>Orally<br>bioavailable and<br>penetrates blood<br>brain barrier<br>Broad tissue<br>distribution in<br>animal models<br>1:1 ratio<br>between<br>blood and<br>brain<br>Proof of<br>splicing<br>mechanism<br>demonstrated<br>in P1 HV<br>Evrysdi™<br>clinical<br>benefit<br>established |
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| PTC518 Huntington’s Disease Deep Dive Agenda<br>13<br>Preclinical Development of PTC518<br>Anu Bhattacharyya,<br>Exec. Director, Biology<br>PTC518<br>Huntington<br>Deep Dive<br>Splicing Platform and<br>Huntington’s Disease<br>Stuart Peltz, CEO<br>PTC518 Phase 1 Study<br>Matthew Klein, CDO |
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| PTC518 Huntington’s Disease Key Focus Areas<br>14<br>Overview of Huntington’s Disease<br>Different treatment modalities<br>Why is the blood a good marker<br>that correlates with the CNS?<br>Can mHTT in CSF accurately verify<br>target engagement in brain?<br>Huntington’s<br>Disease<br>What evidence supports partial lowering of wild type<br>HTT?<br>What evidence supports partial lowering of mutant<br>HTT? |
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| PTC518 Huntington’s Disease Key Focus Areas<br>15<br>Overview of Huntington’s Disease<br>Different treatment modalities<br>Why is the blood a good marker<br>that correlates with the CNS?<br>Can mHTT in CSF accurately verify<br>target engagement in brain?<br>Huntington’s<br>Disease<br>What evidence supports partial lowering of wild type<br>HTT?<br>What evidence supports partial lowering of mutant<br>HTT? |
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| Huntington’s Disease is a Debilitating Neurodegenerative<br>Disorder with No Available Disease Modifying Treatments<br>Huntington’s Disease<br>• Caused by a monogenic defect; autosomal dominant inheritance<br>• Expansion of CAG trinucleotide repeat in the huntingtin (HTT) gene<br>• Leads to movement, psychiatric and cognitive disorders<br>Current Treatments<br>• No approved disease modifying therapies<br>~135,000<br>Global<br>prevalence |
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| Molecular Basis of Huntington’s Disease is Well<br>Understood<br>Modified from T a b r i z i , S . C e l l . 2019. 17<br>Repeat<br>Count<br>Classification Disease<br>Status<br><28 Normal Unaffected<br>28–35 Intermediate Unaffected<br>36–39 Reduced<br>Penetrance<br>+/- Affected<br>40-above Full Penetrance Affected |
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| 18<br>Globus<br>Pallidus<br>Striatum<br>Cortex<br>Progressive Neuronal Degeneration Occurs Throughout<br>the Brain<br>HD Healthy<br>Goh et al. Aus Psychiatry. 2018 |
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| HTT is Ubiquitously Expressed and Involved in Many<br>Cellular Processes<br>• Predominantly an intra-<br>cellular protein<br>• Required during embryonic<br>development<br>• Ubiquitously expressed<br>throughout development<br>and in all adult tissues<br>U h l é n M e t a l . , S c i e n c e ( 2 0 1 5 ) ; www.proteinatlas.org 19 |
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| PTC518 Huntington’s Disease Key Focus Areas<br>20<br>Overview of Huntington’s Disease<br>What evidence supports partial lowering of wild type<br>HTT?<br>What evidence supports partial lowering of mutant<br>HTT?<br>Different treatment modalities<br>Why is the blood a good marker<br>that correlates with the CNS?<br>Can mHTT in CSF accurately verify<br>target engagement in brain?<br>Huntington’s<br>Disease |
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| 21<br>Toxic gain of function mutation<br>Huntington’s disease<br>Whole brain atrophy<br>HTT protein aggregates<br>Make less HTT<br>Lowering mHTT Expression to Target Root Cause of<br>Pathogenesis |
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| Oral Treatment has Uniform Lowering Across the Key<br>Regions of the Brain<br>22<br>Property Small molecules<br>Delivery Oral<br>CNS lowering Equal across the key<br>areas of the brain<br>Peripheral lowering Yes<br>Reversible Yes |
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| 23<br>Property ASOs<br>Delivery Intrathecal<br>CNS lowering<br>Less reduction in the<br>striatum compared to<br>cortex<br>Peripheral lowering No<br>Reversible Yes<br>Antisense Oligonucleotide Treatment has More Lowering<br>in the Cortex Compared to the Striatum |
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| 24<br>Property RNAi<br>Delivery Striatum/Thalamus<br>CNS lowering<br>Less reduction in the<br>cortex compared to<br>striatum<br>Peripheral lowering No<br>Reversible No<br>Gene Therapy Treatment has More Lowering in the<br>Striatum Compared to the Cortex |
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| PTC518 Drug Development Objectives<br>25<br>What is the<br>Dose?<br>01<br>What is the<br>Exposure?<br>02<br>What is the<br>Level of HTT<br>Reduction?<br>03 |
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| PTC518 Huntington’s Disease Key Focus Areas<br>26<br>Overview of Huntington’s Disease<br>What evidence supports partial lowering of wild type<br>HTT?<br>What evidence supports partial lowering of mutant<br>HTT?<br>Different treatment modalities<br>Why is the blood a good marker<br>that correlates with the CNS?<br>Can mHTT in CSF accurately verify<br>target engagement in brain?<br>Huntington’s<br>Disease |
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| 27 Purves D, Augustine GJ, et al., editors. Sunderland (MA): Sinauer Associates; 2001.<br>Distribution Through the Blood Effectively Targets the<br>Whole Brain |
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| PTC518 Huntington’s Disease Key Focus Areas<br>28<br>Overview of Huntington’s Disease<br>Different treatment modalities<br>Why is the blood a good marker<br>that correlates with the CNS?<br>Can mHTT in CSF accurately verify<br>target engagement in brain?<br>Huntington’s<br>Disease<br>What evidence supports partial lowering of wild type<br>HTT?<br>What evidence supports partial lowering of mutant<br>HTT? |
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| 29<br>In healthy people, the cerebrospinal fluid (CSF):<br>Does<br>• Cushion the brain<br>• Provide immune surveillance<br>• Remove metabolic waste<br>Does not<br>• Interact with most neurons directly<br>• Contain very much protein (35 mg/dL,<br>compared to 7000 mg/dL in serum)<br>The Cerebrospinal Fluid Cushions the Brain<br>Subarachnoid Space<br>with Cerebrospinal<br>Fluid (CSF) |
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| Limitations of CSF HTT Measurement as a<br>Pharmacodynamic Marker for HTT lowering<br>30<br>What We Know Unknowns<br>The origin of CSF mHTT<br>Specific contributions of<br>brain regions to CSF mHTT<br>levels<br>Not enough data to<br>understand a meaningful<br>treatment related change in<br>levels over assay variability<br>Brain mHTT levels >100X<br>CSF mHTT levels<br>Very low levels of CSF<br>mHTT – an ultra sensitive<br>assay (low fM) required for<br>measurement<br>Assay inconsistency and<br>variability<br>Lack of strong correlation<br>between brain and CSF<br>lowering with different<br>modalities |
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| PTC518 Huntington’s Disease Key Focus Areas<br>31<br>Overview of Huntington’s Disease<br>Different treatment modalities<br>Why is the blood a good marker<br>that correlates with the CNS?<br>Can mHTT in CSF accurately verify<br>target engagement in brain?<br>Huntington’s<br>Disease<br>What evidence supports partial lowering of wild type<br>HTT?<br>What evidence supports partial lowering of mutant<br>HTT? |
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| Multiple Models Demonstrate Partial Reduction of Wild<br>Type HTT Is Well Tolerated<br>32<br>Species Magnitude of wild type HTT<br>change Phenotype<br>Human Loss of one normal HTT<br>allele ~50% No detectable abnormal phenotype<br>Adult Nonhuman Primates ~50% No alterations in motor function; No<br>abnormal histopathologic findings<br>Adult Rodents ~50% No alterations in motor performance<br>or activity<br>Leavitt et. al. JAMA Neurology 2020 doi:10.1001/jamaneurol.2020.0299 |
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| HTT Reduction Correlates with Clinical Benefit<br>33<br>Human data: ~50% reduction in HTT transcriptional activity results in<br>mean delay of age of onset by 9.3 years<br>Mouse data: 30-40% reduction in mHTT expression translates to beneficial effects<br>Becanovic et. al. Nat Neurosci. 2015. doi:10.1038/nn.4014<br>Garriga-Canut et. al. PNAS 2012 doi.org/10.1073/pnas.1206506109<br>HD phenotype |
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| PTC518 Huntington’s Disease Deep Dive Agenda<br>34<br>Preclinical Development of PTC518<br>Anu Bhattacharyya,<br>Exec. Director, Biology<br>PTC518<br>Huntington<br>Deep Dive<br>Splicing Platform and<br>Huntington’s Disease<br>Stuart Peltz, CEO<br>PTC518 Phase 1 Study<br>Matthew Klein, CDO |
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| What are the Characteristics of a Promising HD<br>Therapeutic?<br>.. 35<br>Orally bioavailable and<br>penetrates blood brain barrier<br>Reversible and titratable<br>Reduces HTT mRNA and protein<br>in the CNS and periphery<br>Uniform lowering in key regions<br>of the brain<br>Highly selective<br>Not effluxed |
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| Identification of a Novel Splicing Mechanism that Leads to<br>Degradation of Mutant HTT mRNA<br>36<br>With PTC518<br>Pseudoexon is spliced in;<br>Nonsense mutation leads<br>to mRNA degradation<br>No compound<br>Pseudoexon is not spliced in;<br>full length HTT protein is produced<br>Exon 49 Exon 50 psi Exon<br>5’ss 3’ss<br>Exon 49 Exon 50<br>Exon 49 Exon 50 psiExon<br>Nonsense-mediated HTT mRNA decay<br>STOP |
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| Key Preclinical Proof Points<br>CONFIDENTIAL. NOT FOR PROMOTIONAL USE. 37<br>Do the molecules lower<br>HTT levels in cells?<br>Do the molecules lower<br>both HTT mRNA and<br>protein levels?<br>Cellular Activity<br>Reduce cellular toxicity, mutagenicity, and<br>key off target activity<br>Monitor short and long-term safety in animals<br>Toxicology<br>Reduce metabolism<br>Maximize oral<br>bioavailability and<br>exposure in vivo<br>DMPK<br>Assess protein expression in<br>vivo<br>Establish PK/PD correlation<br>Pharmacology |
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| Animal Models Were Selected to Best Show PK and PD<br>38<br>Model Purpose Pros Cons<br>BACHD mouse PK-PD-distribution/<br>HTT lowering biomarker<br>Human Genomic Locus<br>Full-length HTT/PsiExon target<br>Subtle & late onset phenotype/<br>Increased body weight<br>WT Mouse PK-distribution Availability; commonly used; quick PK NO PsiExon target<br>WT NHP PK-distribution Large brain; study efflux (CSF PK) NO PsiExon target |
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| PTC518 is Orally Bioavailable and Crosses the Blood Brain<br>Barrier<br>After swallowing, it<br>makes its way to the<br>stomach<br>Broken down in the<br>stomach, small intestine,<br>and liver<br>Circulates through the<br>bloodstream<br>Crosses blood brain barrier<br>to access neurons<br>Distributed through the<br>body<br>39 |
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| What are the Characteristics of PTC518?<br>40<br>Orally bioavailable and<br>penetrates blood brain barrier<br>Reversible and titratable<br>Reduces HTT mRNA and protein<br>in the CNS and periphery<br>Uniform lowering in key regions<br>of the brain<br>Highly selective<br>Not effluxed |
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| Dose Dependent HTT Lowering in the Brain of BACHD<br>Mice<br>41<br>120<br>100<br>80<br>60<br>40<br>20<br>0<br>Vehicle 1 3 7 21 63<br>HTT Protein Levels in Brain<br>% of baseline<br>H<br>TT protein<br>Dose (mg/kg) |
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| What are the Characteristics of PTC518?<br>42<br>Orally bioavailable and<br>penetrates blood brain barrier<br>Reversible and titratable<br>Reduces HTT mRNA and protein<br>in the CNS and periphery<br>Uniform lowering in key regions<br>of the brain<br>Highly selective<br>Not effluxed |
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| PTC518 is Highly Potent in Promoting Splicing of HTT Pre-<br>mRNA and Lowering HTT Protein Levels in Human Cells<br>43<br>HTT protein lowering HTT pre-mRNA splicing<br>RNA<br>0.001 0.01 0.1 1<br>0<br>20<br>40<br>60<br>80<br>100<br>Cpd, (M)<br>%<br><br>o<br>f<br><br>b<br>a<br>s<br>e<br>l<br>i<br>n<br>e<br><br>H<br>T<br>T<br><br>R<br>N<br>A<br>Protein<br>0.001 0.01 0.1 1<br>0<br>20<br>40<br>60<br>80<br>100<br>Cpd, (M)<br>%<br><br>o<br>f<br><br>b<br>a<br>s<br>e<br>l<br>i<br>n<br>e<br><br>H<br>T<br>T<br><br>p<br>r<br>o<br>t<br>e<br>i<br>n<br>Data on file, human cells expressing endogenous HTT. |
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| 44<br>PTC518 Promotes Splicing of HTT Pre-mRNA in BACHD<br>Mouse Whole Blood<br>0 6 12 18 24<br>10<br>20<br>30<br>40<br>PK Profile (Plasma_PTC518))<br>Time (hours)<br>P<br>l<br>a<br>s<br>m<br>a<br><br>f<br>r<br>e<br>e<br><br>c<br>o<br>n<br>c<br>..<br><br>(<br>n<br>g<br>/<br>m<br>L<br>)<br>HTT IC50<br>0 1 2 4 8 16 24<br>0<br>20<br>40<br>60<br>80<br>100<br>120<br>HTT RNA Levels in Blood<br>Time (hrs)<br>%<br><br>o<br>f<br><br>b<br>a<br>s<br>e<br>l<br>i<br>n<br>e<br><br>H<br>T<br>T<br><br>R<br>N<br>A<br>Data on file |
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| 45<br>PTC518 Showed a Strong Correlation Between HTT mRNA<br>Splicing and Protein Lowering in Blood of BACHD Mice<br>➢ HTT protein lowering in BACHD white blood cells<br>➢ Time – 21 days; multiple doses; PD evaluated 2h post<br>last dose<br>Vehicle PTC518<br>0<br>20<br>40<br>60<br>80<br>100<br>120<br>HTT Protein Levels in Blood<br>%<br><br>o<br>f<br><br>b<br>a<br>s<br>e<br>l<br>i<br>n<br>e<br><br>H<br>T<br>T<br><br>p<br>r<br>o<br>t<br>e<br>i<br>n<br>Data on file |
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| Vehicle PTC518<br>0<br>20<br>40<br>60<br>80<br>100<br>120<br>HTT Protein Levels in Brain<br>%<br><br>o<br>f<br><br>b<br>a<br>s<br>e<br>l<br>i<br>n<br>e<br><br>H<br>T<br>T<br><br>p<br>r<br>o<br>t<br>e<br>i<br>n<br>PTC518 Uniformly Lowers HTT Protein Levels in BACHD<br>Mouse Brain and White Blood Cells<br>46 Data on file<br>Vehicle PTC518<br>0<br>20<br>40<br>60<br>80<br>100<br>120<br>HTT Protein Levels in Blood<br>%<br><br>o<br>f<br><br>b<br>a<br>s<br>e<br>l<br>i<br>n<br>e<br><br>H<br>T<br>T<br><br>p<br>r<br>o<br>t<br>e<br>i<br>n |
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| What are the Characteristics of PTC518?<br>47<br>Orally bioavailable and<br>penetrates blood brain barrier<br>Reversible and titratable<br>Reduces HTT mRNA and protein<br>in the CNS and periphery<br>Uniform lowering in key regions<br>of the brain<br>Highly selective<br>Not effluxed |
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| HD Splicing Small Molecules Demonstrate Robust HTT<br>Reduction in BACHD Mouse Brain<br>48 Data on file from multiple studies<br>Brain and blood HTT lowering<br>Measurements demonstrate uniform HTT lowering across brain regions with ~1:1 brain and blood lowering effect<br>120<br>100<br>80<br>60<br>40<br>20<br>0<br>Vehicle 7 mg/kg<br>120<br>100<br>80<br>60<br>40<br>20<br>0<br>Vehicle 7 mg/kg<br>120<br>100<br>80<br>60<br>40<br>20<br>0<br>Vehicle 7 mg/kg<br>Striatum Cortex Cerebellum<br>% of baseline<br>H<br>TT protein<br>% of baseline<br>H<br>TT protein<br>% of baseline<br>H<br>TT protein<br>Treated<br>Vehicle Brain WBC<br>0<br>20<br>40<br>60<br>80<br>100<br>120<br>%<br><br>o<br>f<br><br>b<br>a<br>s<br>e<br>l<br>i<br>n<br>e<br><br>H<br>T<br>T<br><br>p<br>r<br>o<br>t<br>e<br>i<br>n |
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| PTC518 Crosses the Blood Brain Barrier in Non-Human<br>Primates<br>49 Data on file<br>0 5 10 15 20 25<br>0<br>5<br>10<br>15<br>20<br>25<br>Monkey plasma CSF correlation<br>Calculated plasma free (ng/mL)<br>C<br>S<br>F<br><br>(<br>n<br>g<br>/<br>g<br>)<br> R squared 0.779<br> P value <0.0001 |
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| What are the Characteristics of PTC518?<br>50<br>Orally bioavailable and<br>penetrates blood brain barrier<br>Reversible and titratable<br>Reduces HTT mRNA and protein<br>in the CNS and periphery<br>Uniform lowering in key regions<br>of the brain<br>Highly selective<br>Not effluxed |
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| What are the Characteristics of PTC518?<br>.. 51<br>Orally bioavailable and<br>penetrates blood brain barrier<br>Reversible and titratable<br>Reduces HTT mRNA and protein<br>in the CNS and periphery<br>Uniform lowering in key regions<br>of the brain<br>Highly selective<br>Not effluxed |
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| Why is it Important to Reduce Efflux?<br>52<br>• Reducing efflux has several advantages:<br>− Balancing the extent of peripheral vs brain lowering is critical<br>− Increases the therapeutic window versus non target-related splicing in the periphery<br>− Stronger correlation between blood (peripheral) and brain lowering |
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| PTC518 is Not Effluxed Resulting In ~1:1 Brain and Blood<br>Lowering Effect In BACHD Mice<br>53 Data on file<br>PTC518 Effluxed Molecule<br>Peripheral ≈ Brain Peripheral >> Brain<br>Vehicle Brain WBC<br>0<br>20<br>40<br>60<br>80<br>100<br>120<br>Effluxed molecule<br>%<br><br>o<br>f<br><br>b<br>a<br>s<br>e<br>l<br>i<br>n<br>e<br><br>H<br>T<br>T<br><br>p<br>r<br>o<br>t<br>e<br>i<br>n<br>Vehicle Brain WBC<br>0<br>20<br>40<br>60<br>80<br>100<br>120<br>PTC518<br>%<br><br>o<br>f<br><br>b<br>a<br>s<br>e<br>l<br>i<br>n<br>e<br><br>H<br>T<br>T<br><br>p<br>r<br>o<br>t<br>e<br>i<br>n<br>Vehicle Brain WBC<br>0<br>20<br>40<br>60<br>80<br>100<br>120<br>Effluxed molecule (simulation)<br>%<br><br>o<br>f<br><br>b<br>a<br>s<br>e<br>l<br>i<br>n<br>e<br><br>H<br>T<br>T<br><br>p<br>r<br>o<br>t<br>e<br>i<br>n |
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| What are the Characteristics of PTC518?<br>54<br>Orally bioavailable and<br>penetrates blood brain barrier<br>Reversible and titratable<br>Reduces HTT mRNA and protein<br>in the CNS and periphery<br>Uniform lowering in key regions<br>of the brain<br>Highly selective<br>Not effluxed |
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| PTC518 Huntington’s Disease Deep Dive Agenda<br>55<br>Preclinical Development of PTC518<br>Anu Bhattacharyya,<br>Exec. Director, Biology<br>PTC518<br>Huntington<br>Deep Dive<br>Splicing Platform and<br>Huntington’s Disease<br>Stuart Peltz, CEO<br>PTC518 Phase 1 Study<br>Matthew Klein, CDO |
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| The Phase 1 Trial is a 4-Part Study<br>56<br>Phase 1 trial<br>in healthy<br>volunteers is<br>ongoing<br>Multiple ascending dose<br>• Up to 5 cohorts of 8 healthy volunteers (6 active and 2 placebo)<br>• Evaluate safety & tolerability; HTT mRNA splicing & protein<br>lowering<br>Food effect<br>• Crossover design<br>• Evaluate the effects of food on PTC518 pharmacokinetics<br>CSF sampling<br>• Evaluate pharmacokinetics of PTC518 in the CSF<br>• Compare drug levels in CSF with plasma compartment<br>Single ascending dose<br>• Five cohorts of 8 healthy volunteers (6 active and 2 placebo)<br>• Evaluate safety & tolerability; HTT mRNA splicing |
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| Phase 1 Objective: Establish Dose Dependent HTT<br>Lowering Similar to the BACHD Mouse<br>Data on file 57<br>120<br>100<br>80<br>60<br>40<br>20<br>0<br>Vehicle 1 3 7 21 63<br>HTT Protein Levels in Brain<br>% of baseline<br>H<br>TT protein<br>Dose (mg/kg) |
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| 58<br>SAD Study: Proof of Mechanism of PTC518 Demonstrated<br>By Dose-Dependent HTT Splicing<br>Placebo<br>PTC518_45 m<br>g<br>PTC518_90 m<br>g<br>PTC518_135 m<br>g<br>0<br>20<br>40<br>60<br>80<br>100<br>120<br>%<br><br>o<br>f<br><br>b<br>a<br>s<br>e<br>l<br>i<br>n<br>e<br><br>H<br>T<br>T<br><br>R<br>N<br>A<br>➢ Whole blood HTT splicing in humans<br>➢ Doses evaluated = 45 mg, 90 mg, and 135 mg<br>➢ Time – one day; single dose; splicing evaluated 24h post dose<br>Data on file PTC518 -CNS- 001- HD |
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| SAD PK Demonstrates Dose Predictable Drug Exposure<br>Data on file PTC518 -CNS- 001- HD 59<br>mg<br>135<br>90<br>45<br>15<br>5<br>PTC518 concentration (ng/mL)<br>Time (hr) |
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| Phase 1 SAD Interim Results Summary<br>60<br>Target splicing reduction achieved with single dose<br>Well-tolerated with no safety-related findings<br>Predictable pharmacology<br>Dose-dependent splicing of HTT mRNA |
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| 61<br>MAD Study: Proof of Mechanism of PTC518 Confirmed By<br>Dose-Dependent HTT Splicing<br>➢ Whole blood HTT splicing in humans<br>➢ Doses evaluated = 15 mg and 30 mg<br>➢ Time – Day 14; multiple doses; splicing evaluated 6h post dose on day 14<br>Placebo<br>PTC518_15 m<br>g<br>PTC518_30 m<br>g<br>0<br>20<br>40<br>60<br>80<br>100<br>120<br>%<br><br>o<br>f<br><br>b<br>a<br>s<br>e<br>l<br>i<br>n<br>e<br><br>H<br>T<br>T<br><br>R<br>N<br>A<br>Data on file PTC518 -CNS- 001- HD |
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| Durability of Response: Splicing Activity Persists 72 hrs<br>Post Cessation<br>62<br>0 12 24 36 48 60 72<br>0<br>20<br>40<br>60<br>80<br>100<br>120<br>140<br>Time (hours following final dose)<br>%<br><br>o<br>f<br><br>b<br>a<br>s<br>e<br>l<br>i<br>n<br>e<br><br>H<br>T<br>T<br><br>R<br>N<br>A<br>Placebo<br>PTC518_15 mg_QD14<br>PTC518_30 mg_QD14<br>HTT splicing monitored after the final dose at day 14 (calculated % HTT remaining from baseline (pre-dose_Day0))<br>Data on file PTC518 -CNS- 001- HD |
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| Phase 1 MAD Interim Results Summary<br>63<br>Two cohorts completed; two to three additional planned<br>Well-tolerated with no safety-related findings<br>Dose dependent splicing of HTT mRNA<br>Long-half life with maintenance of splicing up to 72 hours following last dose |
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| Phase 1 Trial Next Steps<br>.. 64<br>1 Complete Additional MAD Cohorts<br>2 Complete CSF Cohort<br>3 Complete Food Effect Cohort<br>4 Finalize Clinical Development Plan |
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| Defining Clinical Next Steps<br>65<br>Natural History<br>1<br>Endpoints<br>2<br>Patient<br>Population<br>3 |
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| Summary |
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| Preclinical Studies Show PTC518 Has all the Characteristics Of a<br>Promising HD Therapeutic<br>.. 67<br>Orally bioavailable and<br>penetrates blood brain barrier<br>Reversible and titratable<br>Reduces HTT mRNA and protein<br>in the CNS and periphery<br>Uniform lowering in key regions<br>of the brain<br>Highly selective<br>Not effluxed |
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| PTC518 Drug Development Objectives<br>68<br>What is the<br>Dose?<br>01<br>What is the<br>Exposure?<br>02<br>What is the<br>Level of HTT<br>Reduction?<br>03<br>How to<br>Demonstrate<br>Clinical<br>Benefit?<br>04 |
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| Risdiplam PTC518 PTC-XXX<br>69<br>Molecules are designed to match a unique pre-mRNA/U1 interface<br>and serve as molecular glue to help initiate splicing events<br>Canonical duplex SMN2 HTT And the next one….<br>The Splicing Platform Has Proven to be a Robust Engine<br>to Identify Development Candidates |
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| Questions?<br>70 |
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