Hitches for Horizon Pharma plc seem unlikely in the upcoming FDA advisory panel to mull the BLA for teprotumumab in thyroid eye disease (TED), though regulators did take issue with the clinical activity score (CAS) as calculated by the company.

“The CAS score is a composite with equal weighting of a number of factors,” the FDA conceded, but the agency’s clinical team “does not consider these factors to be of equal clinical weight either to the patients or to physicians treating these patients.”

Specifically, Dublin-based Horizon used the seven-item European Group on Graves’ Ophthalmopathy amended CAS. But this was a secondary endpoint in the pivotal study called Optic. In that experiment, 82.9% of teprotumumab patients compared to 9.5% of placebo patients achieved a two millimeter reduction or more (p<0.001) in proptosis, or bulging of the eye – the primary endpoint. These data were reported in the first quarter of this year and the co-principal investigator described them as “amazing.”

TED, also known as Graves’ orbitopathy or ophthalmopathy, is a condition in which the eye muscles, eyelids, tear glands and fatty tissues behind the eye become inflamed, which can cause the eyes and eyelids to become red, swollen and uncomfortable. The eyes may be pushed forward for the effect of “staring” or “bulging” eyes. In some cases there is swelling and stiffness of the muscles that move the eyes so that they no longer move in line with each other; this can cause double vision, according to the British Thyroid Foundation. “Rarely, TED can cause reduced vision from pressure on the nerve at the back of the eye or ulcers forming on the front of the eyes, if the eyelids cannot close completely.”

Secondary endpoints in the teprotumumab study included the effect of drug vs. placebo on the overall responder rate at week 24 (the primary endpoint in the phase II study): percent of participants with ≥2 point reduction in the disputed CAS and ≥2 mm reduction in proptosis from baseline, provided there is no corresponding deterioration (≥2-point/mm increase) in CAS or proptosis in the fellow eye. Other secondary endpoints were: percent of participants with a CAS value of 0 or 1 at week 24 in the study eye; percent of patients with a change from baseline of at least one grade in diplopia (double vision); mean change in proptosis measurement from baseline to week 24 in the study eye; and mean change in the Graves' Ophthalmopathy Quality of Life measure from baseline to week 24.

The Dermatologic and Ophthalmic Drugs Advisory Committee also will take up the matter of hyperglycemia, not a surprising effect given that the compound works as an inhibitor of the insulin-like growth factor-1 receptor. Twenty-two placebo subjects and 21 teprotumumab subjects had fasting glucose values available at baseline and at other time points during the treatment period. All of the subjects in the placebo group and 17 (81%) of the 21 subjects in the teprotumumab group had normal fasting glucose values at baseline, with no shifts from the normal range noted during treatment. Three teprotumumab subjects with normal fasting glucose values at baseline turned up elevated fasting glucose values for at least 1 visit during the treatment period. None had a history of diabetes mellitus, but two of the three had somewhat elevated HbA1c values to start. “Glucose monitoring may be warranted after initiation of teprotumumab dosing,” the documents noted.

Genmab potential winner, too

Piper Jaffray analyst David Amsellem called the FDA language about hyperglycemia “instructive.” Other adverse events (AEs) cited include muscle spasms, hearing impairment (at least five patients reported hypoacusis/loss of hearing), gastrointestinal complaints, and infection. “What is important to note here is that in the ‘draft topics for consideration’ section of the documents, there was language suggesting that labeling language can address each of these AEs,” he wrote in a report. “The language strongly suggests to us that these are not issues of approvability, particularly in the context of highly successful studies from an efficacy perspective in a clinical setting for which there are no approved therapies.

Cowen’s Ken Cacciatore agreed with Amsellem, saying that it “appears that the FDA is seeking input from the committee on how each issue (such as duration of use) or safety concern should be resolved via [the drug’s] labeling. We were encouraged by the tenor of the documents, that appear to be seeking collaborative input as opposed to raising approvability concerns in this difficult patient population. We believe this indicates a supportive agency,” he wrote in a report.

Earlier this month at the Piper Jaffray Healthcare Conference, Horizon’s chief operating officer Vikram Karnani said officials at the company “believe that the request [for an adcom] is more driven by procedure” and part of the way new molecular entities are evaluated “as opposed to any specific issue or any specific topic that may be a red flag or anything like that. When you think about safety and the safety profile of the medicine, it's very clean. When you think about all of the AEs or any issues that were seen in the data, all of those patients were managed, and no discontinuations occurred as a result of any adverse events like hearing or hypoglycemia or anything of that nature,” he pointed out, adding that “we’re getting ready as if they will want to dive deep into any one and all of those areas.”

Wainwright analyst Raghuram Selvaraju was optimistic about teprotumumab and forecast peak global sales of $800 million for teprotumumab, with Denmark, Copenhagen-based Genmab A/S collecting a 7% royalty on sales generated by its licensee Horizon, he noted.

Horizon shares (NASDAQ:HZNP) closed at $32.84, up 59 cents.

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