Shares of Paratek Pharmaceuticals Inc. (NASDAQ:PRTK) spiked to a two-year high of $25 after the company reported that its lead candidate, omadacycline, met FDA primary and secondary endpoints and EMA co-primary endpoints in the phase III OPTIC (Omadacycline for Pneumonia Treatment in the Community) trial in patients with community-acquired bacterial pneumonia (CABP). The pivotal study represented the second phase III win for omadacycline, following a positive evaluation of the broad-spectrum antibiotic in patients with acute bacterial skin and skin structure infections (ABSSSIs). The Boston-based company said it plans to file a new drug application (NDA) with the FDA as early as the first quarter of 2018, followed by a filing with the EMA later next year.
After nearly 9 million shares changed hands – more than 23 times the company's three-month moving average – the stock closed Tuesday at $22.85 for a gain of $4.25, or 22.9 percent.
OPTIC was designed to evaluate the safety and efficacy of once-daily, I.V.-to-oral omadacycline in comparison to I.V.-to-oral moxifloxacin in adults with CABP. Omadacycline is the first in a class of tetracyclines known as aminomethylcyclines, which offer broad-spectrum activity against gram-positive, gram-negative and atypical bacteria.
The double-blind, global, multicenter study enrolled 774 adults with moderate to moderately severe CABP who were randomized 1-to-1 to the study drug or comparator. By pneumonia severity index, subjects included approximately 14 percent in PORT class II, 57 percent in PORT class III and 28 percent PORT class IV.
"As you can appreciate, with less than 15 percent of subjects enrolled in the PORT II classification, this population tended towards more serious disease, with more than 85 percent of patients classified as either PORT III or PORT IV," Evan Loh, Paratek's president, chief operating officer and chief medical officer, explained on a conference call with analysts. "This percentage of PORT III and PORT IV subjects is higher than other recently completed pivotal phase III CABP studies."
Patients initially received I.V. administration of either 100 mg of omadacycline or 400 mg of moxifloxacin. Study investigators were permitted to switch patients to oral dosing of their assigned drug (300 mg once daily omadacycline or 400 mg once daily moxifloxacin) for a total of seven to 14 days based on assessment of clinical stability. On average, patients in the omadacycline arm received five days of treatment on both I.V. and oral therapy, according to Loh.
Omadacycline met the FDA-specified primary endpoint of statistical noninferiority (NI) in the intent-to-treat (ITT) population (10 percent NI margin, 95 percent confidence interval [CI]) compared to moxifloxacin at the early clinical response (ECR) 72 to 120 hours following initiation of treatment, with ECR rates of 81.1 percent and 82.7 percent for the omadacycline and moxifloxacin arms, respectively.
FDA-specified secondary endpoints evaluated omadacycline at the post-treatment evaluation (PTE) visit five to 10 days following completion of therapy in both the ITT (87.6 percent for omadacycline vs. 85.1 percent for moxifloxacin) population and clinically evaluable (CE) population (92.9 percent for omadacycline vs. 90.4 percent for moxifloxacin), as determined by investigators. Those endpoints also achieved statistical noninferiority.
"The early clinical response was associated with a higher observed clinical efficacy post-treatment evaluation rate compared to moxifloxacin," Loh pointed out. "This pattern of higher post-treatment evaluation efficacy is consistent with what was observed in our successful phase III study in ABSSSI," which compared omadacycline I.V. to once-daily oral vs. I.V. to twice-daily oral linezolid (Zyvox, Pfizer Inc.). (See BioWorld Today, June 20, 2016.)
Co-primary endpoints for the EMA were noninferiority in the ITT and CE CABP populations in patients with PORT III and IV at the PTE time point. Omadacycline met statistical noninferiority to moxifloxacin for both populations using a prespecified 97.5 percent CI, with response rates of 88.4 percent for omadacycline vs. 85.2 percent for moxifloxacin and 92.5 percent for omadacycline vs. 90.5 percent for moxifloxacin for the ITT and CE populations, respectively.
"These data clearly show that omadacycline met the noninferiority criteria vs. moxifloxacin on both the FDA and EMA efficacy endpoints," Loh told BioWorld Today. "It's particularly impressive that on the EMA endpoints, omadacycline achieved noninferiority at the 97.5 percent confidence interval – a first for antibiotics."
'A SIGNIFICANT COMMERCIAL OPPORTUNITY'
OPTIC also produced stellar safety findings. The most common treatment emergent adverse events (TEAEs) (> 3 percent) were ALT increase (3.7 percent with omadacycline vs. 4.6 percent with moxifloxacin) and hypertension (3.4 percent with omadacycline vs. 2.8 percent with moxifloxacin). Gastrointestinal AEs of interest for omadacycline vs. moxifloxacin included vomiting (2.6 percent vs. 1.5 percent), nausea (2.4 percent vs. 5.4 percent) and diarrhea (1 percent vs. 8 percent). No cases of clostridium difficile colitis or infection occurred in patients treated with omadacycline compared with seven cases (1.8 percent) in those treated with moxifloxacin.
Overall, rates of TEAEs were 41.1 percent for omadacycline vs. 48.5 percent for moxifloxacin while drug-related TEAEs were 10.2 percent for omadacycline vs. 17.8 percent for moxifloxacin. Discontinuation for TEAEs was uncommon, especially for omadacycline (5.5 percent) compared to moxifloxacin (7 percent). Serious TEAEs occurred in 6 percent of omadacycline patients and 6.7 percent of moxifloxacin patients. Four of those were deemed related to study drug – two each for omadacycline and moxifloxacin.
The mortality rate was 2.1 percent with omadacycline and 1 percent with moxifloxacin.
"We have now treated more than 1,500 subjects with omadacycline in our ongoing safety database," Loh pointed out. "The safety and tolerability profile observed in these studies is consistent with the significant body of prior preclinical and clinical data that we have generated to date."
Moreover, omadacycline achieved clinical success against the bad actors in all three categories of pathogens at rates comparable to those of moxifloxacin.
"It's difficult to draw comparisons beyond the immediate comparator," Loh acknowledged, "but there is a significant need for well-tolerated, new broad-spectrum, once-daily, oral and I.V. antibiotics for the treatment of community-acquired pneumonia. Specifically, we believe that the treatment community is looking for an alternative to the quinolone class. Given the strength of these omadacycline data, we believe that all three classes of pathogens will be represented in our label."
Paratek plans to report additional details later this month during an oral presentation and abstracts at the European Congress of Clinical Microbiology and Infectious Diseases in Vienna.
Still, officials regarded the findings as more than sufficient for regulatory filings. The study design was approved under a special protocol assessment with the FDA that also endorsed the company's so-called 1+1 strategy: approvability in both the skin and pneumonia indications for both formulations on the basis of a single successful phase III trial in each indication. Both trials used the expected commercial I.V. and oral formulations of omadacycline.
Meanwhile, the company has a third phase III study underway examining an oral-only dosing regimen of omadacycline in skin infections that is expected to yield top-line data as early as the end of June. The trial was designed to satisfy FDA and EMA registration requirements and to enable dosing recommendations for oral-only use – a strategic consideration to adopting omadacycline in the community setting. Paratek plans to include data from the study in its NDA submission.
"Where generic options are available, we believe that treating physicians should try available generic antibiotics as the first choice," Loh said. "But there are a significant number of patients for whom generics will not be effective either due to resistance of the pathogen – thus, the patient will have failed the initial generic antibiotic therapy – or intolerance to the generic, such as penicillin allergy, or where physicians want to use a once-daily broad-spectrum antibiotic with a favorable safety and tolerability profile and a once-daily oral formulation that allows patients to go home from the hospital or, potentially, to stay home. In such cases, omadacycline may be an attractive choice. We believe, based on our evaluation of the marketplace, that this presents a significant commercial opportunity."
The company is exploring the potential of omadacycline to treat urinary tract infections (UTIs) as a third indication, with a phase Ib study in the indication already complete. A phase II proof-of-concept study could begin as early as December in patients with acute pyelonephritis, the most common subset of complicated UTIs.
As of Dec. 31, 2016, Paratek had cash, equivalents and marketable securities of $128 million, which company officials said would enable the completion of development and pre-commercialization activities through the second half of next year.
Based on the OPTIC data, Leerink Partners LLC analyst Paul Matteis raised the odds of omadacycline's approval to 90 percent in both CABP and ABSSSI and increased the stock's price target to $39 from $32.
Regarding the slight imbalance in mortality rates in OPTIC, "the overall death rate was consistent with management expectations for the CABP trial and observational studies," Matteis wrote in a research note. "Moreover, the 2.1 percent mortality rate seen on omadacycline – while lower than 1 percent on moxi in OPTIC – looks similar to that seen for moxi or levofloxacin, [Cempra Inc.'s] recent phase III I.V.-to-oral CABP trial (1.6 percent) and a prior phase III of Tygacil [tigecycline, Pfizer Inc.] in CABP, where the levofloxacin arm mortality rate was 2.6 percent."
Observed Lifesci Capital analyst David Sherman, "When treating most CABP patients, a physician must select an empiric antibiotic regimen that covers the most likely pathogens based on the patient's history and health care exposure as well as the local epidemiology. This process amounts to a high-stakes guessing game, whereby a physician must guess which antibiotic is best to prescribe, typically without identifying the underlying pathogen and not knowing to which, if any, antibiotics it is resistant."
He added, "Omadacycline was designed to specifically overcome the two known mechanisms of clinically significant bacterial resistance to tetracyclines and is effective against S. pneumonia, including resistant strains, MRSA and many of the atypical pathogens. This broad coverage profile suggests that, based on the current microbial environment, omadacycline may be an ideal monotherapy option when resistance is a concern."
Paratek's second, narrow-spectrum tetracycline-derived antibiotic, sarecycline, is in late-stage development with partner Allergan plc, of Dublin. The companies reported last week that two phase III trials of sarecycline to treat moderate to severe acne met their 12-week primary efficacy endpoints. Allergan, which holds U.S. rights to the drug, plans to file an NDA in the second half of the year.