Shares of Entera Bio Ltd. (NASDAQ:ENTX), a lightly traded Israeli drug delivery specialist, fell 27% on May 21 after the company said an ongoing phase II trial of its oral parathyroid hormone (PTH) candidate in osteoporosis patients found the two lowest doses tested demonstrated "suboptimal increases" in P1NP, an important biomarker of bone formation. The doses "likely do not warrant further clinical advancement" after the completion of the trial, the company said. The third dose tested, 1.5 mg, fared better in the interim analysis, though the maximum efficacious dose has not yet been achieved, the company said.

"We continue to be strong believers in this program, given the totality of the data we have generated to date, particularly with the highest 1.5-[mg] dose and the significant unmet market need for an oral therapy that rebuilds bone," said Adam Gridley, CEO of the Jerusalem-based company.

Entera appointed Gridley to lead the company in August 2019, after successfully negotiating a deal to merge Histogenics Corp., where he was president and CEO, with Ocugen Inc. The company established a U.S. office in Boston in November 2019.

PTH has been approved in the U.S. in injectable form for more than a decade. Eli Lilly and Co.'s daily subcutaneous (sc) injectable, Forteo (teriparatide), was the first FDA-approved anabolic agent for the treatment of osteoporosis and continues to lead sales in the category, with $1.4 billion in 2019 global revenue. Radius Health Inc.'s Tymlos (abaloparatide), another once-daily sc injectable PTH analogue, which won FDA approval in mid-2017, logged full-year 2019 net sales of $173.3 million. But despite successes, the products face challenges, especially from payers who have tended to restrict their use to later lines of therapy over cost and a 24-month lifetime limit on use.

With its oral formulation of PTH, EB-613, Entera is looking for advantage in delivering an orally available alternative that reduces treatment and cost burdens vs. injectable forms of PTH. It will face challenges on that path from competitors developing biosimilar PTH analogues, which could help on the cost front, and patch-based formulations, which could address convenience. Interim data from the phase II study could help the company move closer to realizing those goals.

In the interim data drawn from half the trial's participants, Entera said that relative to a placebo, investigators saw EB-613 deliver statistically significant effects on P1NP after one month of treatment (p<0.001) and meaningful increases at months two and three of treatment.

Of the 80 patients enrolled in the study so far, results from 72 patients that had completed their three-month treatment visits were available, the company said. Two months into the study, participating women with osteoporosis who received a 1.5-mg dose of EB-613 saw a 18.6% change from baseline in P1NP, as compared to a 5.4% change from the 1-mg dose, a 3.4% change on the 0.5-mg dose and a 0.2% change in the placebo arm. At three months, only the 1.5-mg dose appeared to differentiate itself, with a 13.2% mean change from baseline.

Now, a planned analysis of six-month bone mineral density data lies just ahead in the third quarter, an important milestone for the company in light of management's belief that the FDA may allow it to use that measure as the primary efficacy endpoint for a phase III trial instead of a fracture endpoint. Those data, if positive, will inform how it moves ahead with clinical development of EB-613, including the design of a planned phase III study, which it has targeted for 2021 or 2022, Gridley said.

At March 31, Entera had cash and cash equivalents of $13.3 million, compared to $15.2 million at the end of 2019. It said it's now evaluating changes to its operating plan based on the new EB-613 data and expects an operating loss of about $10 million for 2020, subject to the impact of COVID-19 and the further evaluation of the phase II results. Its current cash position will be sufficient to fund company operations into the second quarter of 2021, it said.

The company is also working on EB-612, an oral PTH candidate that it said could be used to support the initiation of a phase IIb or phase III trial in patients with hypoparathyroidism in 2021. In that indication, Entera's team has identified its key competitor as Takeda Pharmaceutical Co. Ltd.'s Natpara, an injectable bioengineered recombinant form of PTH (1-84), which was approved by the FDA in January 2015 and conditionally approved by the EMA in April 2017.

Because Natpara has been granted orphan drug status for hypoparathyroidism by the FDA and, as the first approved product for the indication, secured market U.S. exclusivity through January 2022 and later in the EU, Entera would only be able to obtain regulatory approval for EB-612 prior to then if its team demonstrated the oral medicine’s clinical superiority over Natpara or that it otherwise makes a major contribution to patient care. In 2019, Natpara was recalled in the U.S. due to product format issues. In January, Takeda told patients that "additional testing and potential device modifications will likely cause more than a year’s delay" in making the product available to them again.

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