predisposed to rapid pulmonary decline (subjects who would be ineligible for other CFTR modulators combination studies), the 600 mgPTI-801 cohort saw an improvement in ppFEV1 of +6 (p<0.005) versus baseline, and +8 (p<0.05) versus baseline compared to placebo.
In the Company’s doublet study, enrollment remains ongoing in the cohort of 400 mgPTI-801 and 300 mgPTI-808, with 7 subjects recruited to date. As support for the Company’sPK-PD model, a group unblinding of the sweat chloride endpoint was performed, and demonstrated a mean improvement of-20 mM versus baseline (p<0.0005). Factoring in a broad new dataset that includes all double and triple combination14-day studies, the Company’sPK-PD model shows a strong positive relationship between sweat chloride, ppFEV1improvements and dose levels. This points to a potential best in class doublet combination backbone of 600 mg ofPTI-801 and 300 mg ofPTI-808, which will be further studied and could be used with or withoutPTI-428.
Phase 2 Trials Planned
Based on the totality of data, the Company will be launching three new Phase 2,28-day studies in CF subjects with at least oneF508del mutation. The studies will employ entry criteria comparable to those used in other CFTR modulator combination studies. They will include a placebo controlled, triple and double combination trial in up to 30 patients exploringPTI-801 (600 mg) andPTI-808 (300 mg) with or withoutPTI-428 over a28-day treatment period. PTI’s CFTR modulators will also be evaluated in a homogeneous population over a longer duration. These studies will provide insight on the magnitude ofPTI-428 contribution to efficacy and include:
| | • | | PTI-801/808/42828-day study in CF subjects (F508del homozygotes) |
| | • | | PTI-801/80828-day study in CF subjects (F508del homozygotes) |
| | • | | PTI-801/808/42828-day study in CF subjects (F508del heterozygotes) |
These studies will position the Company to complete Phase 2 enrollment in 2019 and initiate Phase 3 studies inmid-2020, as previously guided.
Add-On Study Results in Detail
For PTI’s two separateadd-on studies, a total of 56 CF subjects who were on background tezacaftor/ivacaftor were randomized and treated with eitherPTI-801 (400 mg) or placebo for 14 days (n=18), orPTI-428 (10 mg or 30 mg) or placebo for 28 days (n=38).
Similar to the Company’s proprietary combination cohorts, these studies were designed with broad entry criteria, endorsed by the CF Foundation as a way to enable recruitment due to limited patient availability. Review of patient medical history records revealed that they experienced an average decline in ppFEV1 of 3 points despite initiating tezacaftor/ivacaftor therapy; approximately a third of the population had 3 or more pulmonary exacerbations in the 12 months prior to screening, and almost half had previously discontinued lumacaftor/ivacaftor for reasons that included intolerability and lack of benefit. These factors all suggest a strong recruitment bias towards CFTR modulatornon-responders for these studies.
Subjects receivingPTI-801 experienced an average sweat chloride improvement of-20 mM (p<0.05) compared to baseline, with individual improvements approaching or exceeding-40 mM during the treatment period. These subjects did not, however, demonstrate a statistically significant improvement in ppFEV1 at the end of 14 days of treatment.
Consistent withPTI-428’s mechanism of action, patients at both the 10 mg and 30 mg doses achieved the targeted increase of CFTR protein expression of approximately 50% (p<0.05) through 28 days compared to baseline. These results were obtained via a proprietary CFTR protein ELISA that analyzes samples from the nasal mucosa of study subjects and is an established biomarker for CFTR amplifiers. Similar to thePTI-801 add on study,PTI-428 subjects did not demonstrate a statistically significant improvement in ppFEV1 at the end of 28 days of treatment.
Safe Harbor
To the extent that statements in this report 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 report 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 presentations and expected timing of the initiation of, patient enrollment in, data from, and the completion of, our clinical studies and cohorts for our clinical programs. 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
