Capricor’s Interim Data Could Offer Hope For Older DMD Patients
Executive Summary
Although only interim data from six treated patients, Capricor’s Phase II DMD study shows improvements in upper limb performance, grip strength and respiration. Cardiac performance shows positive trend, but not yet statistical significance.
In a disease with limited therapies for patient subgroups and a landscape littered with clinical setbacks, Capricor Therapeutics Inc.’s interim Phase II data indicate that its intravenous cell therapy can yield statistically significant improvements in upper limb strength and function, grip strength and respiratory function in older Duchenne muscular dystrophy (DMD) patients who lack treatment options.
Before the markets opened on 15 July, the Los Angeles-based firm revealed that CAP-1002 showed statistical significance in the Phase II HOPE-2 study on the primary endpoint and multiple secondary endpoints in six treated patients after six months. The placebo-controlled trial also showed positive trends on respiratory measures of inhalation and expiration, although Capricor CEO Linda Marban cautioned a same-day investor call that these findings are too early to draw conclusions from.
In May, during Capricor’s first quarter 2019 earnings call, Marban said the company was hopeful about the planned interim look from HOPE-2, but said it would use the data to determine whether to continue enrolling the study or change its focus to its preclinical exosome pipeline. With the interim look offering reason for optimism, Marban said on 15 July that Capricor now intends to talk with the US Food and Drug Administration about potential design of a pivotal Phase III program for CAP-1002.
Sarepta Therapeutics Inc. obtained the first US approval for a DMD therapy in 2016 with Exondys (eteplirsen), which addresses a genetic mutation in some DMD patients. (Also see "DMD Pipeline: After Sarepta’s First-Ever Approval, Are Combinations Next?" - Scrip, 25 Sep, 2016.) The approval caused controversy as some wondered if the drug had demonstrated enough benefit in clinical trials; companies ranging from Pfizer Inc. to Eli Lilly & Co. to BioMarin Pharmaceutical Inc. since have suspended development of DMD candidates due to disappointing efficacy data and/or safety issues. (Also see "Sarepta Shares Bounce As Pfizer’s DMD Gene Therapy Sparks Safety Concerns" - Scrip, 1 Jul, 2019.)
Since the Exondys approval, Sarepta has advanced two more late-stage exon-skipping DMD candidates – including golodirsen, under review at the FDA with an approval decision expected in August, and Phase III casimersen.
All three drugs have been tested in younger patients that still are ambulatory, leaving older patients, like those treated with the investigational Capricor drug, with no therapy that's approved for symptoms that come with more advanced DMD, such as lack of pulmonary function.
Sarepta also has the gene therapy AAVrh74.MHCK7.micro-Dystrophin in Phase I/II, part of its GalNac glycosyltransferase 2 (Galgt2) program in accelerated development for DMD. (Also see "Sarepta Commits To Rapid, Thorough Pivotal Study For DMD Gene Therapy Based On Functional Improvements" - Scrip, 4 Oct, 2018.) The company has been relying on partnerships to help it execute on a broader gene therapy strategy beyond DMD. (Also see "Juggling Gene Therapies: Sarepta's Focus Grows, With Many Balls In The Air" - Scrip, 24 Jan, 2019.)
Like other companies developing DMD candidates, Capricor has faced safety issues. In December, it placed development of CAP-1002 on hold after a serious adverse event in which a patient treated with the cell therapy had a strong immune reaction. The company revised the HOPE-2 dosing protocol with a pre-treatment regimen of intravenous steroids and antihistamines and resumed the study. It said on 15 July that only one of 30 patients dosed with CAP-1002 since the revised protocol was implemented has had a serious adverse event, which required overnight observation of the patient.
Candidate Has RMAT, Rare Pediatric Disease Designations
CAP-1002 was one of the first therapeutic candidates to obtain regenerative medicine advanced technology (RMAT) designation from the FDA, although the company stressed that the product is neither a stem cell therapy nor a regenerative medicine. (Also see "Capricor Eyes RMAT Designation Based On Interim Phase II Data" - Pink Sheet, 25 Apr, 2017.)
Unlike a stem cell therapy, CAP-1002 is an allogeneic progenitor cell product that does not engraft into the host’s body, but works by suppressing inflammation and initiating an immunomodulatory effect that stimulates endogenous immune repair functions, Marban told the call.
CAP-1002 also has rare pediatric disease designation in the US and Capricor says it will apply for a priority review voucher if the candidate obtains US approval.
The company's interim look at the Phase II data examined results from 17 patients enrolled in HOPE-2, including 12 who completed six months of treatment (two doses of 150m cells per infusion at three-month intervals), evenly split between treatment and placebo arms.
Among the six treated patients, CAP-1002 showed statistical significance for the primary endpoint Performance of the Upper Limb (PUL) 2.0 at six months (p=0.0389) and showed a positive trend at three months (p=0.0591). At an RMAT meeting with the FDA in late 2018, the agency recommended PUL 2.0 as a validated measure of muscle function in non-ambulatory patients that could deliver registrational data for the candidate, Marban noted.
The therapy also showed statistical significance at six months for grip strength and tip-to-tip pinch strength. Marban said these findings might demonstrate improvements in skeletal muscle function that the FDA said it would look for.
On pulmonary performance, patients on the drug showed statistically significant improvement on inspiratory flow reserve (IFR; absolute) at three months (p=0.0473). However, the measure of inhalation capability that reflects diaphragmatic strength was not statistically significant at six months.
“This is potentially game-changing data, because if these trends continue, we may be one step closer to potentially receiving approval for a product for later-stage DMD patients,” Marban said of the three-month data.
A positive three-month trend was seen for exhalation on the peak expiratory flow (PEF; % predicted) measure. PEF is another endpoint suggested by the FDA as key for potential approval, the CEO pointed out.
It is too soon to set expectations based on these early respiratory data, Marban added, but “the improvements shown here in inspiration as measured by IFR and on expiration as measured by PEF suggests strengthening of the diaphragm, which is highly desirable in DMD.”
Magnetic resonance imaging of the six treated patients for six months also showed positive trends for cardiac muscle function, such as thickening of the systolic wall, the exec said. These data validate findings from the previous Phase I/II HOPE-DUCHENNE study of CAP-1002, from which results were reported in 2016. (Also see "Outcomes Claim May Help Amgen Make Case For PCSK9 Inhibitor Repatha" - Scrip, 1 Dec, 2017.)
Capricor had been partnered with Johnson & Johnson on CAP-1002, but the pharma exited the collaboration in 2017; Marban said the joint work nonetheless had accelerated development of the cell therapy and given her firm manufacturing know-how that it would take forward. (Also see "Without J&J, Capricor Plans To Advance Progenitor Cell Therapy In DMD" - Scrip, 11 Jul, 2017.)
Small Sample Size Warrants Restrained Optimism
Datamonitor Healthcare analyst Karolina Kujawa cautioned against interpreting too much promise from a small sample size in the interim look, but told Scrip that “the study is well designed with endpoints reflecting the multifaceted approach needed for DMD.”
“The long-term benefits of CAP-1002 are ambiguous at this time, as from the interim results it looks like CAP-1002 offers improvement on some of the endpoints at three months, but not all of it was sustained at six months,” the analyst said. “Still, two of the endpoints showed statistically significant improvement compared to the placebo arm, including those required by the FDA for potential registration.”
“With only six months of follow-up (equal to two infusions per patient) there is still uncertainty regarding the safety of CAP-1002,” Kujawa continued, pointing to the earlier safety issues and saying only limited information has been given about the impact of the revised pre-treatment protocol.
In a same-day note, H.C. Wainwright & Co. analyst Joseph Pantginis reiterated a “buy” rating for Capricor’s shares and more than tripled his target price for the stock from $3.50 per share to $12.40. He called the interim data “promising” and said the positive trends on cardiac function suggest “a desirable multi-level efficacy profile” for CAP-1002.
Capricor’s stock finished the trading day on 15 July up by 93% at $6.23 per share.
“These data cannot provide grounds for accelerated approval, but should represent strong Phase II data in designing a Phase III program, which we project should be in the range of 60 patients,” Pantginis wrote. “We believe this interim analysis to be encouraging and to place CAP-1002 in a favorable light in the eyes of both KOLs and regulators, and we expect investors’ interest should be significantly invigorated on the basis of CAP-1002’s unique profile and unmet need in later-stage DMD.”