Startup Axovant Sciences Ltd. is trying to make a case for its oral Alzheimer’s drug RVT-101, finessing an answer to the tricky question of why the drug previously was dumped by GlaxoSmithKline PLC. But the field is inherently risky and the company may need more irons in the fire to keep investors happy.

Axovant is relying on the relatability of the mechanism of action for RVT-101 (SB742457, GSK742457), which is being positioned as an add-on drug to Eisai Co. Ltd./Pfizer Inc.’s mainstay Aricept (donepezil), likely in a fixed-dose combination. Aricept, like other drugs approved for Alzheimer’s disease, inhibits cholinesterase, preventing the release of acetylcholine and other neurotransmitters in order to improve cognition. Axovant explains that RVT-101 blocks the 5-HT6 receptor, promoting the release of acetylcholine and other neurotransmitters, so the mechanism is highly complementary with drugs already established on the market.

Axovant CEO: RVT-101 is only a “single confirmatory study away from approval” in mild-to-moderate Alzheimer’s.

After presenting Phase II data for the drug as an add-on to Aricept at the Alzheimer’s Association International Conference on July 22, the company outlined plans for a Phase III confirmatory study for the combination during a same-day investor briefing.

“While these data show very modest effects on cognition, even mild improvement on top of stable donepezil treatment would fill a large unmet need,” BioMedTracker analyst Edny Inui said.

Execs said that based on feedback from two meetings with FDA, Axovant is planning to start a Phase III trial in the fourth quarter that is similar to the completed Phase II study to secure approval in mild-to-moderate Alzheimer’s. This study also will support a filing in Europe, according to the company.

Unlike other Alzheimer’s candidates, RVT-101 is only “one confirmatory study away” from approval, CEO Vivek Ramaswamy told the call.

Replication of the Phase II trial “could very well lead to approval,” Inui concluded.

Reviving RVT-101

Axovant’s Roivant Sciences Ltd. acquired global rights to the candidate for just $5 million up front, plus milestones and royalties, from GSK in late 2014 [See Deal]. Axovant launched a $300 million-plus initial public offering in June and doubled its stock price on the first day of trading ([A#2015900130]). This achievement drew scrutiny as observers questioned why GSK would have abandoned the drug if it had so much potential, and whether the IPO’s success represented a dangerous sign of a biotech bubble.

However, many data points in the Phase II AZ3110866 study presented at the AAIC meeting were reassuring Also see "Alzheimer’s Drugs Take Baby Steps Toward Brighter Future" - Pink Sheet, 27 July, 2015.). The trial tested two doses of RVT-101 on top of Aricept in 684 patients with mild-to-moderate Alzheimer’s disease. Axovant acknowledges that RVT-101 is not effective alone, based on monotherapy trial results, although it did prove to be well tolerated in single-agent studies.

The co-primary endpoints in the study were the Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-cog) and the Clinical Dementia Rating – Sum of Boxes (CDR-SB). Secondary endpoints included the Alzheimer’s Disease Cooperative Study – Activities of Daily Living scale (ADCS-ADL), which measures function. Axovant reported statistically significant benefits for a 35 mg dose on the ADAS-Cog and ADCS-ADL endpoints through 48 weeks, but when it came to CDR-SB, which assesses cognition and function, effect for the combination arm was only statistically significant at the 12-week mark (see box).

Design: 48-week Phase IIb placebo-controlled trial of RVT-101 once daily in 684 patients with mild-to-moderate Alzheimer’s, 35 mg or 15 mg daily on top of Aricept vs. Aricept alone. After 24 weeks, completers go on to another optional 24 week study phase.

Endpoints: Co-primary endpoints were ADAS-cog (cognition) and CDR-SB (cognition and function). Secondary endpoints included ADCS-ADL, which captures activities of daily living such as feeding and bathing.

Key efficacy findings: In completer analysis, those on 35 mg dose had statistically significant improvement on ADAS-Cog and ADCS-ADL compared to Aricept alone at 12, 24, 36 and 48 weeks of treatment. For CDR-SB, statistically significant improvement at 12 weeks only. Responses were dose-dependent.

Key safety findings: No drug-related serious adverse events observed in the RVT-101 treatment groups at 24 or 48 weeks. No statistically significant difference in withdrawals and adverse events between the treatment groups and control group. Fewer falls reported for placebo patients.

Next steps: Phase III, double-blind confirmatory study to start in Q4 of RVT-101 as an add-on therapy to Aricept, using 35 mg doseand ADAS-cog and ADCS-ADL as co-primary endpoints, with response measured after 24 weeks. Trial will enroll 500 patients per arm.

Source: Axovant July 22 investor call; ClinicalTrials.gov

For the Phase III study, the company plans to use ADAS-cog and ADCS-ADL as co-primary endpoints as these are the endpoints used for marketed drugs in mild-to-moderate Alzheimer’s disease. Execs told the call that CDR-SB is an endpoint more appropriate for earlier-stage disease. It is included in FDA’s guidance on early Alzheimer’s disease.

GSK selected CDR-SB as an endpoint because researchers wanted to see how the drug worked at earlier stages, according to Axovant director Atul Pande, who oversaw the candidate’s development while working as senior VP of neurosciences at the pharma.

GSK “went to great lengths to balance the proportion of patients” who went into the trials at different severity levels because it didn’t want to miss an effect in the mild-to-moderate range, Pande told the call.

Compared to CDR-SB, other instruments are less sensitive in the early stage of disease, he said.

Pande also fielded questions about why GSK sold rights to the asset. The exec said that this was not a reflection of lack of value, but rather due to GSK’s move away from neuroscience R&D as part of a broader restructuring in 2010 Also see "GSK Argues Its Strategy Is Delivering As It Makes More Cuts, Including In R&D" - Pink Sheet, 8 February, 2010..

Pande described the Alzheimer’s candidate as a “jewel in the crown” of the company’s neuroscience portfolio. “I’ve always been a champion for this program, and I remain a champion…” said Pande, who was with GSK up until 2014.

“I think RVT-101 has tremendous promise to mitigate at least some part of the disease burden of Alzheimer’s disease, both on the individual and a family level, but also possibly on the societal level by virtue of the economic benefits that may be possible,” Pande said.

As to the low $5 million upfront price for global rights, Pande said he did not know why GSK let the asset go for that amount but added that the deal included sales royalties (12.5%) and urged analysts to put this question to the big pharma directly.

“When we make a strategic decision not to pursue an asset, we will always look to maximize value to shareholders by partnering, out-licensing or creating companies where appropriate,” a GSK spokesperson told “The Pink Sheet.”

But the data presented at AAIC may not have been enough to allay investor concerns.

Axovant stock price was trading down by 20% on July 24 after the briefing, closing at $15.46 compared to $19.41 on July 21, before the AAIC data presented. The stock did not rebound in the week of July 27, trading at around $15 and closing at $14.01 on July 31.

BioMedTracker’s Inui attributed the reaction to awareness that considering the modest benefits, Phase III is still a risky proposition. Also, Axovant is heavily reliant on RVT-101 as its sole drug.

“It’s a shot on goal, but they’re going to need more in their pipeline to diversify the risk,” Inui said in an interview.

The Commercial Proposition

RVT-101 also faces competition from a drug that is further ahead in the same class.

Lundbeck Inc./Eli Lilly & Co./Otsuka Pharmaceutical Co. Ltd.’s competing 5-HT6 antagonist idalopirdine (Lu AE58054) is already in late-stage development. Three Phase III studies are enrolling and top-line results are expected in 2016. The development program is large, with a total of about 2,500 patients slated to enroll the three studies and another 1,770 in a long-term safety study.

Inui noted that the effect on ADAS-Cog for RVT-101 was smaller than what was seen for Lu AE58054. But the result for the functional measure ADCS-ADL was statistically significant for RVT-101, whereas only a trend has been demonstrated for idalopirdine. The Phase III idalopirdine studies focus on cognition as the primary endpoint, with ADCS-ADL in secondary position.

Axovant stresses the importance of function, for example, the ability to dress, in Alzheimer’s disease.

Gary Small, president of the American Association for Geriatric Psychiatry, noted in the company’s investor call that problems with function are what drive people into nursing homes. “Function trumps cognition,” Small said.

The UCLA physician also thought RVT-101’s oral delivery would be an advantage, as doctors would prefer oral medications that can be taken once daily, offer immediate and sustained improvement and do not require complex monitoring. Primary care doctors as well as caregivers will prefer drugs that do not require sending patients for intravenous infusions or require assessment with PET scans, Small added.

Late-stage Alzheimer’s development has focused on monoclonal antibodies to target beta-amyloid, fragments of proteins in nerve cells that stick together and form damaging plaques in the brain, though there have been many failures over the years for this approach ([A#14150422007]). Anti-beta amyloid antibodies like Lilly’s solanezumab, BiogenInc.’s aducanumab (BIIB037) and Roche’s gantenerumab had a high profile at the 2015 AAIC meeting.

Small said that he and his colleagues have been disappointed with the consistent and high failure rate of drugs that target the beta amyloid pathway, in contrast with the multiple trial successes of cholinergic drugs that increase acetylcholine, like Aricept, Novartis AG’s Exelon (rivastigmine) and Janssen Inc.’s Razadyne (galantamine).

Considering the late-stage molecule landscape, Small said that RVT-101’s profile looks “exciting.”

“If RVT1-1 exhibits the same profile in Phase III, I predict nearly every patient who is on a cholinesterase inhibitor will be on this compound,” he said.

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