FDA Expected to Complete its Review of Mycapssa by April 15, 2016:
Chiasma, Inc. (NASDAQ: CHMA) focuses on developing and commercializing oral delivery alternatives for orphan diseases that already have available treatments, but require drug administration through injection with a needle and syringe. Chiasma developed an oral delivery platform trademarked as Transient Permeability Enhancer ((TPE)), which is a technology that protects the drug from the harsh gastrointestinal environment and allows for enhanced permeability in the intestinal wall. Chiasma's success relies heavily on the effectiveness of TPE, as the company hopes to build its product pipeline on this oral delivery technology platform. TPE will endure its first true test in treating disease as the delivery mechanism for Chiasma's flagship drug candidate, Mycapssa.
Mycapssa is an oral capsule containing octreotide, a drug used to treat the orphan disease acromegaly. If approved, Mycapssa will be the first oral drug to treat acromegaly. All other acromegaly drug treatments are currently administered through needle/syringe injection, which cause on-site symptoms specific to the needle delivery, such as pain, scarring, hardening, swelling, and needlestick injuries. Chiasma's oral delivery alternative, Mycapssa, eliminates on-site injection side effects and has the potential to be a serious game-changer for both acromegaly and general oral drug delivery. Oral drug delivery of octreotide has been studied since octreotide's approval in the late 1980s. Further, oral delivery is the "most sought after route of administration" for most drugs. An FDA approval for Mycapssa will validate the effectiveness of TPE, thereby generating greater confidence in the oral delivery platform as well as Chiasma's drug pipeline.
Chiasma submitted a New Drug Application (NDA) for Mycapssa in June 2015, which the FDA accepted in August 2105. The Prescription Drug User Fee Act (PDUFA) date is currently set for April 15th, 2016.
Acromegaly Characterized by Elevated and Sustained Levels of GH and IGF1:
Acromegaly is a rare chronic disorder that presents as disproportionate skeletal, tissue, and organ growth. With an annual incidence of 5 cases per 1 million individuals worldwide, the afflicted have their life expectancy reduced by ~10 years, and their mortality rate doubled due to cardiovascular, cerebrovascular, metabolic, and respiratory comorbidities (J. Clin. Invest. 119:3189-3202 (2009). doi:10.1172/JCI39375.). The hallmarks of acromegaly diagnosis are elevated and sustained levels of growth hormone (GH) and insulin-like growth factor 1 (IGF1), typically resulting from a destabilized tumorous pituitary.
Since acromegaly is often caused by a pituitary adenoma, the first line of therapy is surgery. Depending on adenoma size and metastasis, surgical intervention has a 50-70% success rate in long-term control. In cases where surgery either fails or is unwarranted, the next line of therapy is pharmacological treatment. Irrespective of treatment option, returning GH and IGF1 levels to normal is used to assess treatment success.
Post-treatment GH concentration is used as the best predictive indicator of acromegaly treatment success. Reducing GH values back to normal limits (<2.5 ng/ml) has been shown to return mortality rates back to normal. While successful treatments also reduced IGF1 values back to normal limits (<1.3 x upper limit normal adjusted for sex and age), a strong relationship between post-treatment IGF1 levels and reduced mortality has not been demonstrated. Thus, both GH and IGF1 levels are used as predictors of treatment success, but GH levels appear to be a better indicator.
Current Drug Treatments Restore GH and IGF1 Levels, via Needle Injections:
The most commonly prescribed medical treatments for acromegaly are somatostatin receptor ligands (SRLs). Somatostatin is a natural hormone that exerts control over many physiological functions, including the inhibition of GH release. However, natural somatostatin degrades after 2-3 minutes. Artificial somatostatin analogs are capable of inhibiting GH release, while remaining active up to 2 hours.
First generation SRLs approved by the FDA for acromegaly are octreotide (Sandostatin) and lanreotide (Somatuline). Clinically, both octreotide and lanreotide are similarly efficacious (both with a 50-60% response rate as determined through two studies involving 189 and 115 patients), but octreotide may have greater name recognition as it was the first to be marketed. SRLs such as octreotide and lanreotide do not come without considerable adverse effects ((NYSE:AES)), including abdominal discomfort, flatulence, cramps, diarrhea, gallstones, as well as increased glucose intolerance.
Other medical options available for octreotide/lanreotide non-responders include dopamine agonists and a 2014 FDA-approved SRL called pasireotide (Signifor LAR). Using GH and IGF1 measurements to assess efficacy, a 198-patient study demonstrated that 15% of octreotide/lanreotide non-responders could respond to a 40mg dosage of pasireotide (10 out of 67, p<0.0006). Further, 20% could respond to a 60mg dosage of pasireotide (13 out of 65, p<0.0001). However, pasireotide treated patients were more likely to develop hyperglycemia (~30%) as well as new-onset diabetes mellitus (~20%), therefore warranting careful glucose monitoring.
All acromegaly drug treatments (including approved SRLs) are currently administered by subcutaneous or intramuscular injection. This delivery mechanism, in turn, is responsible for nonspecific AEs of SRLs, such as pain, swelling, hardening, or general needlestick injuries at the injection site. The oral delivery of Mycapssa has previously been shown to reduce GH levels in healthy volunteers (Tuvia, S. et al. J Clin Endocrinol Metab 97(7):2362-2369 (2012)). The question is whether oral delivery of octreotide through Mycapssa is capable of maintaining post-treatment levels of both GH and IGF1 in acromegaly patients who are responsive to injectable SRLs.
Mycapssa Phase III Clinical Trial:
The goal of the Mycapssa Phase III clinical trial was to determine whether TPE oral delivery of octreotide is capable of maintaining post-treatment levels of both GH and IGF1 in acromegaly patients who are responsive to injectable SRLs octreotide (Sandostatin) and lanreotide (Somatuline). Eligible acromegaly patients had to demonstrate responsiveness to injectable SRLs, through measurements of GH (<2.5 ng/ml) and IGF1 (<1.3 x upper limit normal adjusted for sex and age), and had to be on injectable SRLs for at least 3 months prior to enrollment. The study enrolled 155 patients from different countries and switched eligible patients off injectable SRLs for Mycapssa with possible dose escalation before receiving a fixed dosage (starting with twice daily doses of 20mg/capsule, with escalation to 40mg + 20mg or the upper limit of 40mg + 40mg). The patients were treated with Mycapssa for 7 months and then offered a voluntary extension period on Mycapssa for an additional 6 months. During the study, the patients had their GH and IGF1 levels measured. Maintenance of both GH and IGF1 levels indicate successful responders.
One hundred and fifty-one patients underwent at least one measurement for GH or IGF1. Of these, 64.9% (n=98) maintained response throughout the 7-month core treatment while 61.6% (n=93) maintained response for 13 months. Thus, 94.9% (93 out of the 98) of the patients at the end of the 7-month core treatment chose to continue Mycapssa treatment. From the starting 155 sample group, 16.8% (n=26) terminated early due to treatment failure, while another 14.8% (n=23) terminated early due to AEs.
Chiasma says that Pituitary Experts Pre-Specified a Primary Endpoint of a Population Response ≥50%:
Evaluating whether Mycapssa is likely to receive FDA approval is not straightforward. The problem is that we do not know what the FDA considers a reasonable efficacy point. The published study for Mycapssa Phase III clinical trial states, "The primary efficacy endpoint was descriptive and was defined as the proportion of responders at the end of the core treatment [7 months], with an exact 95% confidence interval ((NYSE:CI)) in the modified intent-to-treat ((NYSE:MITT)) population (i.e. all subjects who had at least one post-first-dose efficacy assessment)." This translates to: results will be reported in terms of 95% CI to summarize a sample population at the end of the 7-month treatment. The primary endpoint qualifying an efficacious drug was not explicitly stated. It is worth noting, however, that during investor presentations Chiasma has declared, "Pituitary experts pre-specified a population response ≥50% for a successful product." (Printed in its January 2016 investor presentation, which is no longer accessible online)
Despite not knowing the primary endpoint set out by the FDA, we can reasonably predict the likelihood of FDA approval for Mycapssa. First, we need to consider whether the FDA would deem a population response of ≥50% a reasonable primary endpoint, which we can determine by reviewing the study designs and outcomes of approved acromegaly drugs. This will also allow us to evaluate the safety profile of Mycapssa relative to current acromegaly drugs. Second, we need to consider whether the study design and outcome of Mycapssa Phase III is consistent with the standards previously used by the FDA for granting acromegaly drug approval.
Since the FDA accepted the Mycapssa NDA, the media has covered the outcome of the Phase III clinical trial, with heightened attention as the PDUFA date draws closer. Both CHMA)+Announces+Initiation+of+Second+Octreotide+Caps+Phase+3+for+Acromegaly/11415834.html" rel="nofollow">StreetInsider and Seeking Alpha have released articles on Mycapssa, with the PDUFA date less than a month away. The Seeking Alpha article aimed to evaluate whether Mycapssa will get FDA approval, referencing a PR Newswire article for the description of the Phase III trial. However, conclusions were drawn from an incomplete understanding of the Phase III trial. Neither article noted the study design requirements: 1) all eligible patients must demonstrate responsiveness to SRLs, and 2) maintenance of post-treatment levels of GH and IGF1 in eligible patients. Superiority to SRL injections cannot be determined because all the starting patients were already responsive to SRL injections.
Here, I evaluate whether Mycapssa is likely to receive FDA approval by first evaluating whether a pre-specified population response ≥50% is indeed reasonable, using the information we know about previous studies (reviewed above). Then, I will evaluate whether Mycapssa has met its goal through an appropriately designed study. Both of these assumptions will be used for my basis of whether Mycapssa is likely to receive FDA approval.
Study Design for Mycapssa Phase III Trial is Appropriately Designed to Address Its Goals:
Given the current efficacies of the SRLs for acromegaly treatment and the studies used to assess these drugs, a pre-specified population response ≥50% does indeed seem reasonable for a successful acromegaly drug using a sample size of at least 100 patients. A primary endpoint of, say, 100% would not be realistic due to the diverse genetic nature of the acromegaly (not covered in this article), such as the existence of five different somatostatin receptor subtypes; different SRLs have different binding affinities to different receptors; and different mutations in the receptors make older generation SRLs ineffective in certain patients - non-responders of older generation SRLs who are responsive to pasireotide share a mutation in the same gene. Mycapssa has to deal with its own set of variables. Perhaps the most important is oral absorption, which is affected by differences in the composition of one's gut microbiota, the composition of one's current diet, as well as one's age.
Using a response rate as a readout is also appropriate for measuring efficacy, as long as the response rate is determined by post-treatment levels of GH (<2.5 ng/ml) as well as IGF1 (<1.3 x upper limit normal adjusted for sex and age).
Comparing the study design of Mycapssa Phase III clinical trial with the designs used for the previous studies to assess these drugs, the study design of Mycapssa is appropriate for evaluating efficacy. Further, the study design of Mycapssa is also appropriately controlled to assess its goal of maintaining post-treatment levels of both GH and IGF1 in acromegaly patients who are responsive to injectable SRLs octreotide (Sandostatin) and lanreotide (Somatuline).
There's one more caveat: the 50% cutoff was based on studies used to approve new SRLs. Whether it will be used to decide efficacy of an existing SRL that is repackaged is perhaps another concern. However, it is worth noting that previous attempts at oral delivery of octreotide from other groups show that <1% of the drug will be available. Also, Mycapssa does reduce elevated GH in healthy volunteers, affirming TPE oral delivery of octreotide. It seems that Mycapssa does work, so I think the greater concern may rely on showing how reproducible Mycapssa works in patients rather than deciding on whether the FDA decides to use 50% as a pre-specified efficacy point. Statistically, this is done by describing the range and spread of the data set, based on the experimentally determined mean. In other words, what is the range of possible Mycapssa response rates?
Mycapssa Meets Reasonable Primary Endpoint:
For its sample size, having a response rate of 64.9% at the end of the 7-month core treatment corresponds to a reported range of 58.4%-74.2% that captures the 95% CI. This means that Chiasma is 95% confident that the true response rate for Mycapssa lies between the range of 58.4% and 74.2%. The lower end of this 95% CI range is above a reasonable primary endpoint for determining efficacy for SRLs for treating acromegaly. Given that Mycapssa has met a reasonable primary endpoint that is also consistent with well-established standards, it is likely for the FDA to conclude that Mycapssa is efficacious.
Mycapssa Has a Safe Profile:
Majority of the AEs reported in the Mycapssa Phase III trial are consistent with known AEs related to either SRL treatment or acromegaly.
With the exception of 2 patients, all the reported AEs from the Mycapssa clinical study were related to known AEs of SRLs or the disease. The 2 patients experienced elevated hepatic transaminases and jaundice, possibly related to Mycapssa, but did not die. These 2 patients either had a suspected bile duct obstruction or severe dehydration. Whether the transaminases or jaundice resulted from off-target toxicity of octreotide or the delivery method is unclear, but could be explained with the evidence of dehydration or obstruction. The authors state that it is probably not related to off-target toxicity related to the delivery method. Mycapssa has previously been shown to be safe in healthy volunteers. Two deaths were reported during the study, but neither of which was considered related to Mycapssa. The authors reported:
One was a 37-year-old male with a 10-year history of multiple surgeries for extracellular pituitary macroadenoma. Six months after [Mycapssa] initiation he had a suspected biliary obstruction, and subsequently also developed sepsis and multiple organ failure. At autopsy, no evidence for biliary obstruction was observed. The second was a 60-year-old male with cardiovascular risk factors, diagnosed with pancreatic cancer after six months into the study, and suffered a fatal myocardial infarction.
Given that the safety profile of Mycapssa is consistent with SRL injections and acromegaly, Mycapssa should not raise any safety concerns.
Chiasma Likely to Receive an Approval From the FDA for Mycapssa:
I think that Chiasma is likely to receive an approval from the FDA for Mycapssa for acromegaly treatment. This conclusion is based on the three following points. The study design and endpoint used to assess the efficacy of Mycapssa is consistent with well-established study designs and endpoints for current SRL treatments for acromegaly. Mycapssa has met this primary endpoint. Mycapssa has a safety profile similar with current SRL treatments for acromegaly.
Disclosure: I am/we are long CHMA.
I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it. I have no business relationship with any company whose stock is mentioned in this article.
Additional disclosure: Beacon VP Investments is a team of analysts. This article was written by Minh Vong.This article contains forward-looking statements and information, including statements regarding the safety, efficacy and potential clinical benefits of oral octreotide, and statements regarding the timing of the FDA's review of Chiasma's NDA. Acceptance of the NDA filing does not determine the final evaluation of the adequacy of the data submitted in the NDA and is not a guarantee of approval.