8-K

 

 

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): December 17, 2019

 

 

Proteostasis Therapeutics, Inc.

(Exact name of registrant as specified in its charter)

 

 

 

Delaware   001-37695   20-8436652

(State or other jurisdiction

of incorporation)

 

(Commission

File Number)

 

(I.R.S. Employer

Identification No.)

 

80 Guest Street, Suite 500

Boston, MA

  02135
(Address of principal executive offices)   (Zip Code)

Registrant’s telephone number, including area code (617) 225-0096

(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:

 

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, par value $0.001 per share   PTI   The Nasdaq Global 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.

On December 17, 2019, the Company issued the press release attached hereto as Exhibit 99.1.

The furnishing of the attached press release is not an admission as to the materiality of any information therein. The information contained in the press release is summary information that is intended to be considered in the context of more complete information included in the Company’s filings with the U.S. Securities and Exchange Commission, or the SEC, and other public announcements that the Company has made and may make from time to time by press release or otherwise. The Company undertakes no duty or obligation to update or revise the information contained in this report, although it may do so from time to time as its management believes is appropriate. Any such updating may be made through the filing of other reports or documents with the SEC, through press releases or through other public disclosures. For important information about forward looking statements, see the “Safe Harbor” section of the press release in Exhibit 99.1 attached hereto.

The information in this Item 7.01 of this Current Report on Form 8-K and Exhibit 99.1 attached hereto shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, or otherwise subject to the liabilities of that section or Sections 11 and 12(a)(2) of the Securities Act of 1933, as amended. The information contained in this Item 7.01 and in the press release attached as Exhibit 99.1 to this Current Report shall not be incorporated by reference into any filing with the SEC made by the Company, whether made before or after the date hereof, regardless of any general incorporation language in such filing, except as expressly set forth by specific reference in such filing.

 

Item 8.01

Other Events.

Spokespersons of the Company plan to present the information in the presentation slides attached hereto as Exhibit 99.2.

On December 17, 2019 the Company announced the following information:

Proteostasis Therapeutics, Inc. today announced positive topline results from the Company’s global, multicenter, randomized, placebo-controlled, 28-day, Phase 2 study evaluating its proprietary cystic fibrosis transmembrane conductance regulator (CFTR) modulator combinations in F508del homozygous and heterozygous CF subjects 18 years of age and older.

The trial is designed to assess the efficacy, safety and tolerability of PTI’s once-daily proprietary combinations, 300 mg of dirocaftor (PTI-808) and 600 mg of posenacaftor (PTI-801), with or without 10 mg of nesolicaftor (PTI-428), or placebo, over a four week treatment period. A total of 28 F508del homozygous and 40 F508del heterozygous subjects were enrolled into the doublet, triplet or placebo arms. The compounds were generally well tolerated and the majority of reported adverse events were mild to moderate in severity. Most subjects enrolled in the Phase 2 study carried a high disease burden, with over 80 percent of subjects trying and failing to enroll into trials of currently approved modulators due to ineligibility.

Homozygous subjects receiving the triple combination experienced a mean absolute improvement in ppFEV1 of 8 percentage points over pooled placebo at day 28 (p £ 0.01, 95% CI 3, 12; n=11). Improvements in lung function were the highest in high disease burden subgroups, predefined as subjects with ppFEV1 <70 at baseline (+10 ppFEV1, n=9), subjects with at least 2 pulmonary exacerbations within 12 months prior to study (+12 ppFEV1, n=5) and poor responders to prior CFTR modulators (+12 ppFEV1, n=7). Sweat chloride concentration in homozygous subjects receiving dirocaftor, posenacaftor and nesolicaftor demonstrated a mean improvement of -29 mmol/L at day 28 (p < 0.0005, 95% CI -42, -16; n=11) compared to pooled placebo.

In the homozygous population, the magnitude of the improvements in the ppFEV1 and sweat chloride concentration at day 28 with the dirocaftor, posenacaftor and nesolicaftor were higher than those observed in subjects receiving the double combination of dirocaftor and posenacaftor. These observations highlight the contribution of nesolicaftor to the overall efficacy of the triple combination.

In PTI’s first clinical study with F508del heterozygous population, 40 subjects with at least 26 different genotypes were enrolled. As expected, given the mechanism of action of CFTR modulators, a broad range of ppFEV1 and sweat chloride responses were observed in these subjects. For those on active treatment, ppFEV1 responses ranged from -13 to +20 and sweat chloride concentration responses ranged from +12 mmol/L to -79 mmol/L. Changes in sweat chloride concentration were statistically significant (p<0.01). Responder rate, defined as ppFEV1 improvement of 5 percentage points or more, was three times as high in subjects who received active vs. placebo. Mean changes in ppFEV1 were not statistically significant in the heterozygous population.

Based on these results, the Company is planning to launch a global, Phase 3, randomized, placebo-controlled, MORE trial (Modulator Options to RestorE CFTR study) in CF subjects with the common F508del homozygous mutation, beginning in 2020. The MORE trial complements the CHOICES trial (Crossover trial based on Human Organoid Individual response in CF - Efficacy Study), which is designed to evaluate the translation of organoid ex-vivo response to potential clinical benefit in patients with rare mutations. CHOICES, which is also expected to initiate in 2020, will be the first ever personalized medicine-based study in CF.


Safe Harbor

To the extent that statements in this release are not historical facts, they are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Words such as “aim,” “may,” “will,” “expect,” “anticipate,” “estimate,” “intend,” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. Examples of forward-looking statements made in this release include, without limitation, statements regarding the potential of our proprietary combination therapies for the treatment of CF, the potential benefit to patients of our proprietary combination therapies, expected timing of patient enrollment in, data from, the completion of, our clinical studies and cohorts for our clinical programs, including our planned Phase 3 program and initiation of a registrational or pivotal study. Forward-looking statements made in this release involve substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by the forward-looking statements, and we, therefore cannot assure you that our plans, intentions, expectations or strategies will be attained or achieved. Such risks and uncertainties include, without limitation, the possibility final or future results from our drug candidate trials (including, without limitation, longer duration studies) do not achieve positive results or are materially and negatively different from or not indicative of the preliminary results reported by the Company (noting that these results are based on a small number of patients and small data set), uncertainties inherent in the execution and completion of clinical trials (including, without limitation, the possibility that FDA or other regulatory agency comments delay, change or do not permit trial commencement, or intended label, or the FDA or other regulatory agency requires us to run cohorts sequentially or conduct additional cohorts or pre-clinical or clinical studies), in the enrollment of CF patients in our clinical trials in a competitive clinical environment, in the timing of availability of trial data, in the results of the clinical trials, in possible adverse events from our trials, in the actions of regulatory agencies, in the endorsement, if any, by therapeutic development arms of CF patient advocacy groups (and the maintenance thereof), and those set forth in our Annual Report on Form 10-K for the year ended December 31, 2018, our Quarterly Report on Form 10-Q for the quarter ended September 30, 2019 and our other SEC filings. We assume no obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.

The above information is not an admission as to the materiality of any information therein. The Company undertakes no duty or obligation to update or revise the information contained in this report, although it may do so from time to time as its management believes is appropriate. Any such updating may be made through the filing of other reports or documents with the SEC, through press releases or through other public disclosures.

 

Item 9.01

Financial Statements and Exhibits.

(d) Exhibits.

 

Exhibit
No.

  

Description

99.1    Press release, furnished herewith.
99.2    Presentation slides, filed herewith.


EXHIBIT INDEX

 

Exhibit
No.

  

Exhibit Name

99.1    Press release, furnished herewith.
99.2    Presentation slides, filed herewith.


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.

 

Date: December 17, 2019     PROTEOSTASIS THERAPEUTICS, INC.
    By:  

/s/ Meenu Chhabra

      Meenu Chhabra
      President and Chief Executive Officer
EX-99.1

Exhibit 99.1

 

LOGO

Proteostasis Therapeutics Announces Positive Phase 2 Topline Results from Proprietary CFTR

Modulator Combinations in F508del Homozygous Cystic Fibrosis Patients

PTI Triple Combination which Includes First-in-Class Amplifier Outperformed

PTI Double Combination of a Proprietary Corrector and Potentiator

Launching Two Registrational Studies in 2020 - the MORE Trial in the Common Genotype and the

CHOICES Trial in Rare Genotypes

Company to Host Conference Call and Webcast Today at 8:30 AM ET

BOSTON, Mass. – December 17, 2019 – Proteostasis Therapeutics, Inc. (NASDAQ:PTI), a clinical stage biopharmaceutical company dedicated to the discovery and development of groundbreaking therapies to treat cystic fibrosis (CF), today announced positive topline results from the Company’s global, multicenter, randomized, placebo-controlled, 28-day, Phase 2 study evaluating its proprietary cystic fibrosis transmembrane conductance regulator (CFTR) modulator combinations in F508del homozygous and heterozygous CF subjects 18 years of age and older.

The trial is designed to assess the efficacy, safety and tolerability of PTI’s once-daily proprietary combinations, 300 mg of dirocaftor (PTI-808) and 600 mg of posenacaftor (PTI-801), with or without 10 mg of nesolicaftor (PTI-428), or placebo, over a four week treatment period. A total of 28 F508del homozygous and 40 F508del heterozygous subjects were enrolled into the doublet, triplet or placebo arms. The compounds were generally well tolerated and the majority of reported adverse events were mild to moderate in severity. Most subjects enrolled in the Phase 2 study carried a high disease burden, with over 80 percent of subjects trying and failing to enroll into trials of currently approved modulators due to ineligibility.

Homozygous subjects receiving the triple combination experienced a mean absolute improvement in ppFEV1 of 8 percentage points over pooled placebo at day 28 (p £ 0.01, 95% CI 3, 12; n=11). Improvements in lung function were the highest in high disease burden subgroups, predefined as subjects with ppFEV1 <70 at baseline (+10 ppFEV1, n=9), subjects with at least 2 pulmonary exacerbations within 12 months prior to study (+12 ppFEV1, n=5) and poor responders to prior CFTR modulators (+12 ppFEV1, n=7). Sweat chloride concentration in homozygous subjects receiving dirocaftor, posenacaftor and nesolicaftor demonstrated a mean improvement of -29 mmol/L at day 28 (p < 0.0005, 95% CI -42, -16; n=11) compared to pooled placebo.

In the homozygous population, the magnitude of the improvements in the ppFEV1 and sweat chloride concentration at day 28 with the dirocaftor, posenacaftor and nesolicaftor were higher than those observed in subjects receiving the double combination of dirocaftor and posenacaftor. These observations highlight the contribution of nesolicaftor to the overall efficacy of the triple combination.

In PTI’s first clinical study with F508del heterozygous population, 40 subjects with at least 26 different genotypes were enrolled. As expected, given the mechanism of action of CFTR modulators, a broad range of ppFEV1 and sweat chloride responses were observed in these subjects. For those on active treatment, ppFEV1 responses ranged from -13 to +20 and sweat chloride concentration responses ranged from +12 mmol/L to -79 mmol/L. Changes in sweat chloride concentration were statistically significant (p<0.01).


LOGO

 

Responder rate, defined as ppFEV1 improvement of 5 percentage points or more, was three times as high in subjects who received active vs. placebo. Mean changes in ppFEV1 were not statistically significant in the heterozygous population.

“Evidenced by the variability of subject response and tolerability to currently approved CFTR modulators, it remains clear that the CF community is in need of additional CFTR modulator options. The latest data from the dirocaftor, posenacaftor and nesolicaftor combination suggests that, even in a population with high disease burden and including subjects who were not eligible for studies of currently approved CFTR modulators, this triple combination demonstrated remarkable outcomes across key study endpoints and performed well in the most challenging disease settings, including those subjects with at least two pulmonary exacerbations within 12 months prior to study entry.” said Jennifer Taylor-Cousar, M.D., M.S.C.S., Professor of Medicine and Pediatrics, and Co-Director and CF Therapeutics Development Network Center Director of the Adult CF Program at National Jewish Health. “I look forward to the upcoming MORE and CHOICES pivotal studies, and to seeing people with CF potentially benefit from a broader treatment armamentarium.”

Based on these results, the Company is planning to launch a global, Phase 3, randomized, placebo-controlled, MORE trial (Modulator Options to RestorE CFTR study) in CF subjects with the common F508del homozygous mutation, beginning in 2020. The MORE trial complements the CHOICES trial (Crossover trial based on Human Organoid Individual response in CF - Efficacy Study), which is designed to evaluate the translation of organoid ex-vivo response to potential clinical benefit in patients with rare mutations. CHOICES, which is also expected to initiate in 2020, will be the first ever personalized medicine-based study in CF.

“We look forward to advancing our triple combination into a pivotal study next year, while simultaneously pursuing a personalized medicine clinical and regulatory pathway together with the HIT-CF funded through the European Commission Horizon 2020 program. We are very grateful to the patients, their families and healthcare providers who have supported PTI in our pursuit of delivering more choices to people with CF and to providing the benefit of CFTR modulators to all, regardless of mutation status,” said Geoffrey Gilmartin, M.D., M.M.Sc., Chief Medical Officer of Proteostasis.

Conference Call and Webcast

Proteostasis will hold a conference call and accompanying webcast today, December 17, at 8:30 a.m. ET to discuss the data announced today. The conference call can be accessed by dialing (844) 534-7315 from the United States or (574) 990-3007 from outside the United States and referring to conference ID 4291402. A live webcast and accompanying slide presentation will be available on the Investor Events page in the Investors & Media section of the company’s website, www.proteostasis.com. A replay of the webcast will be available on the company’s website shortly after the conclusion of the conference call.

About Dirocaftor (PTI-808), Posenacaftor (PTI-801) and Nesolicaftor (PTI-428)

Nesolicaftor (PTI-428) is an investigational CFTR amplifier in development for the treatment of CF in patients with at least one F508del mutation in the CFTR gene, as part of PTI’s proprietary triple combination regimen that includes dirocaftor (PTI-808), a novel potentiator, and posencaftor (PTI-801), a third-generation CFTR corrector. Posencaftor received Fast Track Designation from the U.S. Food and Drug Administration (FDA). In May 2019, nesolicaftor received Orphan Drug Designation (ODD) from the European Commission (EC). In addition to ODD from the EC, nesolicaftor has ODD, Breakthrough Therapy Designation and Fast Track Designation from the FDA.


LOGO

 

About Proteostasis Therapeutics, Inc.

Proteostasis Therapeutics, Inc. is a clinical stage biopharmaceutical company developing small molecule therapeutics to treat cystic fibrosis and other diseases caused by dysfunctional protein processing. Headquartered in Boston, MA, the Proteostasis Therapeutics team focuses on identifying therapies that restore protein function. For more information, visit www.proteostasis.com.

Safe Harbor

To the extent that statements in this release are not historical facts, they are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Words such as “aim,” “may,” “will,” “expect,” “anticipate,” “estimate,” “intend,” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. Examples of forward-looking statements made in this release include, without limitation, statements regarding the potential of our proprietary combination therapies for the treatment of CF, the potential benefit to patients of our proprietary combination therapies, expected timing of patient enrollment in, data from, the completion of, our clinical studies and cohorts for our clinical programs, including our planned Phase 3 program and initiation of a registrational or pivotal study. Forward-looking statements made in this release involve substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by the forward-looking statements, and we, therefore cannot assure you that our plans, intentions, expectations or strategies will be attained or achieved. Such risks and uncertainties include, without limitation, the possibility final or future results from our drug candidate trials (including, without limitation, longer duration studies) do not achieve positive results or are materially and negatively different from or not indicative of the preliminary results reported by the Company (noting that these results are based on a small number of patients and small data set), uncertainties inherent in the execution and completion of clinical trials (including, without limitation, the possibility that FDA or other regulatory agency comments delay, change or do not permit trial commencement, or intended label, or the FDA or other regulatory agency requires us to run cohorts sequentially or conduct additional cohorts or pre-clinical or clinical studies), in the enrollment of CF patients in our clinical trials in a competitive clinical environment, in the timing of availability of trial data, in the results of the clinical trials, in possible adverse events from our trials, in the actions of regulatory agencies, in the endorsement, if any, by therapeutic development arms of CF patient advocacy groups (and the maintenance thereof), and those set forth in our Annual Report on Form 10-K for the year ended December 31, 2018, our Quarterly Report on Form 10-Q for the quarter ended September 30, 2019 and our other SEC filings. We assume no obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.

CONTACTS:

Investors:

David Pitts / Claudia Styslinger

Argot Partners

212.600.1902

david@argotpartners.com / claudia@argotpartners.com


LOGO

 

Media:

David Rosen

Argot Partners

212.600.1902

david.rosen@argotpartners.com

EX-99.2

Slide 1

MORE CHOICES IN CYSTIC FIBROSIS TREATMENT: NOVEL CFTR MODULATOR COMBINATIONS #CForward Corporate Presentation December 2019 Exhibit 99.2


Slide 2

Safe Harbor and Disclaimer To the extent that statements in this presentation are not historical facts, they are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Words such as “aim,” “may,” “will,” “expect,” “anticipate,” “estimate,” “intend,” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements.  Examples of forward-looking statements made in this presentation include, without limitation, statements regarding the potential of our proprietary combination therapies for the treatment of CF, the potential benefit to patients, including those with extremely rare genotypes, of our proprietary combination therapies, the expected timing of the initiation of, patient enrollment in, data from, and our completion of, our clinical studies and cohorts for nesolicaftor (PTI-428), posenacaftor (PTI-801), dirocaftor (PTI-808) and our combination therapy candidates, cash guidance, and HIT CF consortium subject recruitment, and in vitro testing and conduct of clinical trials with our drug candidates.  Forward-looking statements made in this presentation involve substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by the forward-looking statements, and we therefore cannot assure you that our plans, intentions, expectations or strategies will be attained or achieved. Such risks and uncertainties include, without limitation, the possibility that final or future results from our drug candidate trials (including, without limitation, longer duration studies) do not achieve positive results or are materially and negatively different from or not indicative of the preliminary results reported in this presentation (noting that these results are on a small number of patients and small data set), uncertainties inherent in the execution and completion of clinical trials (including, without limitation, the possibility FDA requires us to run cohorts sequentially or conduct additional cohorts or pre-clinical or clinical studies), in the enrollment of CF patients in our clinical trials, in the timing of availability of trial data, in the results of the clinical trials, in possible adverse events from our trials, in the actions of regulatory agencies, in endorsement, if any, by CF patient advocacy groups, the potential activity of our drug candidates in organoids and in personalized clinical trials in extremely rare genetic mutations may not be realized, and those set forth in our Annual Report on Form 10-K for the year ended December 31, 2018, our Quarterly Report on Form 10-Q for the period ended September 30, 2019, and our other SEC filings. We assume no obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.   This presentation also contains estimates and other statistical data made by independent parties and by us relating to, among other items, disease incidence, market size and other data about our industry.  This data involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. Projections, assumptions and estimates of our future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of risk and uncertainty.  New risks emerge from time to time, and neither we nor any other person makes any representation as to the accuracy or completeness of such data or undertakes any obligation to update such data after the date of this presentation. By attending, viewing, or receiving this presentation you acknowledge you are solely responsible for your own assessment of the market and our market position and that you will conduct your own analysis and are solely responsible for forming your own view of the potential future performance of our business. The trademarks included in this presentation are the property of the owners thereof and are used for reference purposes only.  Such use should not be construed as an endorsement of the Company or its securities.


Slide 3

Highlights 2019 3 3 novel CFTR modulators ready for registrational studies in 2020 Proof-of-concept established across 14 clinical studies spanning 9 countries with over 300 subjects dosed Proprietary potentiator/corrector/amplifier combination of DIR/POS/NESa delivers competitive ppFEV1 improvement to the recently approved standard of care triple combination ELX/TEZ/IVAa for F508del homozygotes $77.8M at the end of Q3; sufficient to fund operations and Phase 3 programs into 2021 Financially solid Phase 3 Planning Underway (MORE Trial, CHOICES Trial) Based on Positive Phase 2 Data On track to initiate registrational studies in CF subjects with both common (MORE) and rare genotypes (CHOICES) 28 day clinical phase 2 data is consistent with predicted benefit based on independent in vitro testing performed by the Cystic Fibrosis Foundation in HBE cells from individuals with CF Phase 2 dose range finding complete aDIR – dirocaftor; POS – posenacaftor; NES – nesolicaftor; ELX – elexacaftor; TEZ – tezacaftor; IVA – ivacaftor


Slide 4

4 AUG 2012 FIRST HIGH THROUGHPUT SCREEN JUN 2016 FIRST HEALTHY VOLUNTEER DOSED JUL 2016 FIRST PERSON WITH CF DOSED APR 2017 SECOND IND (CORRECTOR POSENACAFTOR) JUL 2017 THIRD IND (POTENTIATOR DIROCAFTOR) JUN 2018 START OF TRIPLE COMBO PHASE 1 JAN 2018 START OF DOUBLE COMBO PHASE 1 JUL 2019 START OF DOUBLE AND TRIPLE COMBO PHASE 2 JAN 2016 FIRST IND (AMPLIFIER NESOLICAFTOR) OVER 300 PEOPLE WITH CF DOSED 14 DIFFERENT CLINICAL STUDIES 9 DIFFERENT COUNTRIES Proteostasis Therapeutics Clinical Development Journey


Slide 5

Amplifier NESOLICAFTOR { { Corrector POSENACAFTOR Potentiator DIROCAFTOR { More Choices for Restoration of CFTR Activity Dirocaftor (PTI-808 or DIR) Fast Track (FDA) Posenacaftor (PTI-801 or POS) Fast Track (FDA) Nesolicaftor (PTI-428 or NES) Breakthrough Therapy (FDA) Orphan Drug (EMA) Fast Track (FDA) 5 Proteostasis Therapeutics (PTI) drug candidates have received designations from US and EU regulatory agencies:


Slide 6

6 Cystic Fibrosis (CF) is a life limiting genetic disease with approximately 48,000 patients in Europe and ~ 30,000 in the US - Only 1 in 3 of the ~48,000 people with CF in Europe have access to any CFTR modulators In Phase 3 study, ELX/TEZ/IVA delivered a wide range of lung function response (-2.5 to +20 ppFEV1); 1 in 2 subjects fall below 5 ppFEV1 improvement; 2 out of 3 subjects fall below 10 ppFEV1a aHeijerman et al, Lancet, 2019 New Options for CFTR Modulators are Needed to Reach All Patients Adapted from Heijerman et al. Lancet, 2019


Slide 7

PTI’s Global Phase 2 Study Recruited 68 Subjects in the US, Canada, Western Europe and New Zealand 7 Competitive enrollment dynamic in ELX/TEZ/IVA studies biases investigators to only enroll subjects with the highest probability of successful screening in order to preserve site’s participation in the study 80% of PTI subjects failed to enroll in trials for currently approved modulators


Slide 8

Phase 2 Study Design Not currently taking CFTR modulator therapies Safety and tolerability of dose combinations of DIR/POS/NES Change in ppFEV1 CF subjects homozygous or heterozygous for the F508del mutation ≥18 years of age Lung function ≥40 to ≤90 (ppFEV1) Excluded subjects: colonized with organisms associated with a more rapid decline in pulmonary status with respiratory instability within 28 days of first dose Study Eligibility Primary Study Objectives Secondary Study Objectives PK profiles of dose combinations of DIR/POS/NES Change in sweat chloride concentration Follow-Up Screening Period 300 mg DIR / 600 mg POS 300 mg DIR / 600 mg POS / 10 mg NES placebo 28 days 4 weeks 14 days Randomization (2:2:1) Treatment Period 8 Sweat chloride concentration above 60 mmol/L ClinicalTrials.gov identifier: NCT03251092


Slide 9

F508del Homozygous F508del Heterozygous Pooled Placebo DIR/POS n=11 DIR/POS/NES n=11 DIR/POS n=16 DIR/POS/NES n=16 - n=14 Age; years (mean, SD) 30.8 (9.2) 30.1 (6.3) 26.7 (7.0) 27.6 (6.4) 35.6 (13.9) Male sex (n, %) 10 (91) 3 (27) 7 (44) 9 (56) 8 (57) Percentage of predicted FEV1 (mean, SD) 52.5 (13.7) 57.6 (11.0) 66.5 (13.6) 56.0 (12.8) 57.2 (12.7) Sweat chloride concentration; mmol/L (mean, SD) 97.6 (5.4) 100.1 (8.7) 97.8 (8.8) 100.2 (7.4) 99.5 (10.3) BMI; kg/m2 (mean, SD) 22.6 (3.8) 22.6 (2.7) 21.9 (2.9) 22.8 (2.6) 22.0 (1.9) Weight; kg (mean, SD) 67.4 (12.0) 63.1 (8.8) 60.3 (9.7) 64.7 (12.0) 62.8 (7.9) Baseline Demographics and Clinical Characteristics of F508del Homozygous and Heterozygous Study Cohorts 9


Slide 10

F508del Homozygous F508del Heterozygous Pooled Placebo DIR/POS n=11 DIR/POS/NES n=11 DIR/POS n=16 DIR/POS/NES n=16 - n=14 Any adverse event (AE) (n, %) 9 (81.8) 9 (81.8) 13 (81.3) 12 (75.0) 13 (92.9) Respiratory-related AEs (occuring in >2 subjects total) Cough (n, %) Sputum increased (n, %) Oropharyngeal pain (n, %) 1 (9.1) 1 (9.1) 1 (9.1) 2 (18.2) 1 (9.1) 1 (9.1) 2 (12.5) 1 (6.3) 1 (6.3) 1 (6.3) 3 (18.8) 0 (0.0) 3 (21.4) 1 ( 7.1) 1 (7.1) Most common AEs Pulmonary exacerbation (n, %) Headache (n, %) 1 (9.1) 0 (0.0) 2 (18.2) 0 (0.0) 3 (18.8) 2 (12.5) 3 (18.8) 1 (6.3) 3 (21.4) 6 (42.9) Drug Combinations in F508del Homozygous and Heterozygous Study Subjects were Generally Well Tolerated 10 No clinically important trends in chemistry, hematology, vital signs or ECG were observed


Slide 11

11 Targeted Exposures of DIR/POS/NES Achieved PK parameters of each study drug were as expected based on the data from the previously reported studies in subjects with CF Mean Cmin concentrations at steady state for DIR/POS exceeded their corresponding in vitro EC90 values PK parameters for DIR/POS were consistent across subjects receiving DIR/POS/NES and subjects receiving DIR/POS in each cohort, indicating DIR/POS PK is not affected by coadministration with NES PK parameters for each study drug were consistent in F508del homozygous and heterozygous subjects, suggesting CFTR genotype does not have an impact on PK of any of the study drugs Mean Cmin concentration at steady state for NES achieved its targeted in vitro EC10 value


Slide 12

Absolute Improvement in ppFEV1 Achieved with DIR/POS/NES in F508del Homozygous Subjects 12 ppFEV1 Lung Function Pooled placebo (n=14) DIR/POS/NES (n=11) aTRIKAFTA Phase 3 Trial; Heijerman et al, Lancet, 2019, not part of a head-to-head study; change with TEZ/IVA alone not reported bTotal ITT population; number of subjects with non-missing measurements at week 4; PBO – placebo; PE – pulmonary exacerbation; n/a – not available LS Mean Treatment Difference in ppFEV1 (Mean Percentage Points, 95% CI, p-value) PTI Ph 2 Trial Treatment Effect by Age, Baseline ppFEV1 PE Burden and Prior Modulator Use DIR/POS/NES vs. PBO n=11b Subjects 18 years and above +8 (3, 12) p ≤ 0.01 (n=11) Subjects with <70 ppFEV1 at baseline +10 (5, 14) p ≤ 0.001 (n=9) Subjects with at least 2 PEs within 12 months prior to study +12 (4, 19) p ≤ 0.01 (n=5) Subjects with prior CFTR modulator use +12 (6, 18) p ≤ 0.001 (n=7) AURORA Ph 3 Trial Heijerman et al. ELX/TEZ/IVA vs. TEZ/IVAa n=53 +8 (6, 11) (n=38) +11 (8, 14) (n=35) n/a +8 (5, 11) (n=31)


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Absolute Improvement in Sweat Chloride Achieved with DIR/POS/NES in F508del Homozygous Subjects 13 Sweat Chloride Sweat chloride is reduced by -29 mmol/L (95% CI; -42, -16) (p < 0.0005) compared to pooled placebo pooled placebo (n=13) DIR/POS/NES (n=11) Number of subjects with non-missing measurements Absolute Change from Baseline in Sweat Chloride Concentration Through Week 4 (mmol/L)


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Absolute Improvement in ppFEV1 with DIR/POS/NES is Greater than DIR/POS in F508del Homozygous Subjects 14 CFTR Modulator Combinations by Age, PE Burden and Prior Modulator Use DIR/POS n=11 DIR/POS/NES n=11 Subjects 18 years and above +3 (-2, 7) ns (n=10)a +8 (3, 12) p ≤ 0.01 (n=11) Subjects with <70 ppFEV1 at baseline +4 (-1, 9) ns (n=9) +10 (5, 14) p ≤ 0.001 (n=9) Subjects with at least 2 PEs within 12 months prior to study +7 (-1, 15) ns (n=6) +12 (4, 19) p ≤ 0.01 (n=5) Subjects with prior CFTR modulator use (TEZ/IVA and/or LUM/IVA poor responders)b +5 (-1, 10) ns (n=5) +12 (6, 18) p ≤ 0.001 (n=7) ppFEV1 Lung Function pooled placebo (n=14) DIR/POS (n=11) aTotal ITT population; number of subjects with non-missing measurements at week 4 b DIR/POS +6 ppFEV1 vs. baseline at week 4 with no prior CFTR modulator use; ns – not significant; PE – pulmonary exacerbation; n/a – not available LS Mean Treatment Difference in ppFEV1 (Mean Percentage Points, 95% CI, p-value)


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Absolute Improvement in Sweat Chloride Achieved with DIR/POS in F508del Homozygous Subjects pooled placebo (n=13) DIR/POS (n=11) 15 Sweat chloride is reduced by -15 mmol/L (95% CI; -24, -6) (p < 0.01) compared to pooled placebo Sweat Chloride Absolute Change from Baseline in Sweat Chloride Concentration Through Week 4 (mmol/L) Number of subjects with non-missing measurements


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Initial Evidence that DIR/POS/NES Has Biological Activity Beyond F508del Homozygous Genotype Responder rate (> ppFEV1 improvement of 5 percentage points or more) was 3x as high in subjects who received active (23%) vs. placebo (7%). Mean changes in ppFEV1 were not statistically significant Absolute Change from Baseline in Sweat Chloride Concentration Through Week 4 (mmol/L) in F508del heterozygous population Changes in sweat chloride concentration were statistically significant (p<0.01, p<0.0001) 16 First clinical study in F508del heterozygous population Subjects on active treatment experienced a range of responses from -13 to +20 in ppFEV1 and from +12 mmol/L to -79 mmol/L in sweat chloride concentration Broad range of responses observed is consistent with CFTR modulators mechanism of action 40 subjects with at least 26 different genotypes enrolled into F508del heterozygous cohort


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17 www.hitcf.org PTI and HIT-CF Partnered to Develop DIR/POS/NES Initially Targeting up to 2,300 Adult Patients in Europe Ex vivo organoid testing Magnitude of organoid swelling will inform responders vs. non-responders Responders and non-responder will be invited to a clinical trial CTN centers collect rectal biopsies RESPONDER NON RESPONDER ~300 patients recruited by Dec 2019 Total target 500 patients by H1 2020 ~Ongoing Ex Vivo study in Patient Derived Organoids to Identify Responders to PTI Combinations ~H1 2020 Patient Recruitment into CHOICES Study ~Mid 2020 Initiation of CHOICES study in CTN centers (58 sites in 17 countries by 2020)


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THANK YOU #CForward “Proteostasis is striving to shake up the CF community in ways better than the vest ever could.” Brad Dell, a person with CF