Ann: Polycystic Kidney Disease Program Investor Presentation, page-19

I wanted to do some more investigation into some aspects of PYC's ADPKD program.   Results are below, for anyone interested.


The Patient Population

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease.

Estimations of ADPKD prevalence vary widely. Because the disease progresses over decades, with symptoms often not being evident until the third or fourth decade of life, a significant number of ADPKD cases go undetected.

Far more women than men are diagnosed at an earlier stage of the disease, in part because it is picked up during pregnancy ultrasound testing and also because women appear to be more impacted by pain from the condition and are therefore more likely to consult with a doctor.

Though a commonly published estimate of the US ADPKD population is ~ 600,000, the currently diagnosed population, based on health records, is ~160,000, with an estimated 6,000 new patients diagnosed each year. (1)

ADPKD is caused by mutations in one copy of either PKD1 or PKD2 DNA. An estimated 75 - 85% of ADPKD patients have PKD1 mutation, leading to insufficient expression of the PC1 protein. PYC-003 is aimed at this PKD1 patient population as it works by increasing PC1 protein levels. Thus, my calculation is that the addressable US population for PYC-003 is probably ~120 -130,000. That said, there is obviously potential for increased numbers through higher/earlier rates of diagnosis.

PKD1 type patients have a more severe form of the disease. They present with symptoms earlier in life, have more kidney related complications and progress more rapidly to kidney failure. Typically, dialysis/kidney transplant is required at an earlier age than in the PKD2 population (55 v 75 years).

The mean age for diagnosis of ADPKD caused by PKD1 mutation is 27 years; however, approximately 2-5% of cases present before 15 years of age.


Current Approved Treatments

There is just one approved therapy – tolvaptan  - which was approved in the US in 2018. Tolvaptan only slows the rate of disease progression (increase in TKV p.a of 2.8% v. 5.5% for placebo). In contrast, it is hoped that PYC-003 can not only arrest disease progression, but potentially reverse the disease in patients with less advanced disease progression.

Tolvaptan is unsuitable for a large proportion of the ADPKD population and comes with a black box warning because of risk of potentially fatal liver injury. It is used by approximately 5% of the patient population. Cost of tolvaptan in the US is ~ US$70,000 p.a.


Leading Clinical Competitor

Regulus Therapeutics is developing RGLS-8429 for the treatment of ADPKD. Regulus has completed Phase 1 enrolment and plans to have an End-of-Phase 1 meeting with the FDA before the end of this year.

RGLS-8429 is an oligonucleotide therapy with a different mechanism of action to PYC-003. The miR-17 family of miRNAs is upregulated in ADPKD, in turn decreasing levels of PC1 and PC2. RGLS-8429 works by inhibiting miR-17, thereby increasing PC1 and PC2 levels, and is therefore aimed at treatment of both types of ADPKD.

One risk of the miR-17 inhibition approach is that miR-17 is also involved in the control of the proliferation and neuronal differentiation of neural stem/progenitor cells in both developmental and adult brains. The previous asset Regulus was developing for ADPKD, RGLS-4326, was shelved after off-target CNS toxicities were seen. (2)

The Regulus clinical trial has limited enrolment to Class C-E Mayo Classification ADPKD patients aged 18-70 years. Class C, D and E ADPKD covers patients ranging in severity from intermediate through to fastest disease progression.

In its next phase trial, Regulus is likely to use a 300mg fixed dose, the highest dose used in its Phase 1 MAD trial. RGLS-8429 is administered subcutaneously every 2 weeks.

In comparison, PYC anticipates testing 0.8 – 3.0 mg/kg PYC-003 in its Phase 1 clinical trial, dosed intravenously every 2 months. Another difference is that PYC-003 has higher delivery to the liver, in addition to the kidney. This has been suggested to be desirable as 90% of ADPKD patients also develop liver cysts, although <20% experience negative impact.


PPMOs

There are few other companies developing the PPMO class of drugs being developed by PYC and no PPMO drugs are yet approved by the FDA.

The leading PPMO program in clinical development has been Sarepta’s SRP-5051 for the treatment of a subtype of DMD.

However, despite encouraging efficacy results in Phase 2, Sarepta announced earlier this month that it was discontinuing further development of SRP-5051 and its PPMO program due to safety concerns. The specific concerns were prolonged hypomagnesemia both during the study and following treatment discontinuation, and decline in eGFR, a test that measures kidney function.  Sarepta said that it believed that these concerns were related to the specific cell penetrating peptide used in SRP-5051.

SRP-5051 was being dosed monthly at up to 40mg/kg, 13 times the highest dose proposed for PYC-003.

Another company that is using a PPMO approach to the treatment of DMD is PepGen. PepGen’s lead program, PGN-EDO51, is currently in Phase 2 trials. Dosage is up to 15mg/kg, administered intravenously monthly.

As risk of adverse events increases with increased dosage, PYC’s lower dosage than not only Regulus, but also Sarepta and PepGen, is reassuring.

The longer interval between dosing is also attractive as it increases the likelihood of patient compliance.


(1) https://karger.com/kdd/article/5/2/107/188037/Analysis-of-Nationwide-Data-to-Determine-the

(2) https://www.biospace.com/regulus-th...-autosomal-dominant-polycystic-kidney-disease